Phase I Feasibility Study of Low Dose Whole Brain Irradiation in the Treatment of Alzheimer's Disease
Phase: NA
Conditions: Alzheimer's Disease
Sponsor: Corewell Health East

TITLE:  
Study of Low Dose Whole Brain Irradiation in the Treatment of 
Alzheimer’s Disease 
 
NCT02359864 
Protocol Approval date: 03/21/2022 
 
Study Protocol with appendices and Statistical Analysis Plan 

Low Dose Radiation for Alzheimer’s Disease
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Title:
PHASE I FEASIBILITY STUDY OF LOW DOSE 
WHOLE BRAIN IRRADIATION IN THE
TREATMENT OF ALZHEIMER’S DISEASE
Version:
2.2
Date:
03/10/2022
IDE Sponsor-Investigator: James Fontanesi, M.D. 
Coordinating Center:
Beaumont Coordinating Center 
Participating Sites:
Beaumont Royal Oak:
Principal Investigator:
Prakash Chinnaiyan, M.D.
Beaumont Farmington:
Principal Investigator:
James Fontanesi, M.D.
Co-Investigators:
Radiation Oncology
Craig Stevens, M.D., Ph.D. 
Alvaro A. Martinez, M.D.
Radiobiology
George D. Wilson, Ph.D.
Geriatric Medicine 
Michael E. Maddens, M.D.
Neurosurgery
Daniel B. Michael, M.D., Ph.D. 
Study Managers/Coordinators:
Farmington:Kirsten Gage, RN, MBA, CCRP
Royal Oak:Mary Martin, RN, BS
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Table of Contents
Title and Authors
1
Table of Contents
2
Schema
4
Abbreviations
6
1.0 Background and Rationale
7
1.1 Current and Future Incidence of Alzheimer’s Disease
7
1.2 Pathophysiology  of Alzheimer’s Disease
7
1.3 Current Treatments for Alzheimer’s Disease
8
1.4 Background and Rationale for Radiation Treatment of AD
8
1.5 Preclinical Data Utilizing Radiation Treatment for Alzheimer’s Disease
9
1.5.1
Effect of Radiation on Amyloid β Plaque Burden
9
1.5.2
Effect of Radiation on Cognitive Performance
10
2.0 Objectives and Endpoints
11
2.1 Primary Objectives
11
2.2 Secondary Objectives
11
2.3 Primary Endpoints
12
2.4 Secondary Endpoints
12
3.0 Methodology
12
3.1 Dose Levels and Sample Size Calculation
12
3.2 Study Design
14
3.3 Patient Selection
14
3.3.1 Recruitment to the Study
14
3.3.2 Eligibility Criteria
14
3.4 Pretreatment Evaluation and Management
15
3.5 Pretreatment Evaluation  of Cognitive Status
15
3.6 Pretreatment Amyvid PET/CT Scan
16
3.7 Radiation Simulation
16
3.8 Low Dose Fractionated Whole Brain Radiotherapy
17
3.8.1 Equipment
17
3.8.2 Target Volume
17
3.8.3 Localization
17
3.8.4 Dose Prescription and Delivery
17
3.8.5 Treatment Technique
17
3.9 Radiation On-Treatment Monitoring  and Adverse Events
17
3.10 Cognitive Testing and Quality of Life Assessment During Treatment
18
3.11 Post-treatment Amyvid PET/Scan
19
3.12 Stopping Rules
19
4.0 Risks and Benefits
20
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5.0 Data Safety Monitoring Plan
20
6.0 Study Calendar
21
7.0 References
22
Appendix I: Eligibility Checklist 
Appendix II: NINCDS-ADRDA Score 
Appendix III: CTCAE Version 5
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Schema
For Patients with Probable Alzheimer’s Disease based on NINCDS-ADRDA Criteria and 
having MMSE scores of between 10 - 20
Number of Patients 30
Randomization
N/A
Screening/Baseline
Testing
The following tests/evaluation will be completed prior to initiation of
treatment
1) MMSE
2) ADAS-Cog
3) History and Physical
4) Amyvid PET Scan
5) Toxicity Evaluation using CTC version 5.0/RTOG for following 
sites Skin, Eye, Ear and CNS
6) QOL-AD and QUALID assessment
Imaging
Requirements
An Amyvid PET Scan will be required prior to treatment and at 4 
months following completion of therapy.  These scans will be read by 
the study designated board certified nuclear radiologist.
Treatment
Procedure
Patients will receive whole brain irradiation using standard external 
beam techniques. The initial 15 patients will be treated at Dose Level 
1 (5 x 200 cGy). If after the last patient in the first treatment group has 
been followed for 12 months and there have been no events that 
cause stoppage of the trial, the second group of patients will be 
enrolled at Dose Level 2 (10 x 200 cGy). All patients will receive 1 
treatment per day  on consecutive days excluding weekends
Trial Visits and
Follow-Up
All patients will be followed as per Study calendar. Scheduled post 
treatment visits are at 6 weeks 3, 4, 6, and 12 months
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Stopping Rules
This Study will be stopped for any of the following reasons
1) Any patient death attributed to treatment
2) Any patient who develops a Grade IV adverse event
3) More than 3 of 15 patients who develop a Grade 3 adverse 
event as per CTCAE v.5.0 in either group
4) 50% or more of patients in either group have no change or 
increase in amyloid based on Amyvid PET Scan
5) 5 patients that show greater than 4 point deterioration  in MMSE 
in two consecutive cognition evaluations
6) 5 patients that show mean increases greater than 7 on ADAS-
Cog scale.
Data Safety
Monitoring Board 
(DSMB)
This trial will utilize a DSMB consisting of three physicians and one 
biostatistician who are not directly involved in the trial but who have 
expertise in radiation, Alzheimer’s management, or both.
They will meet monthly to review all new data that has been collected 
on any patient under treatment or in follow up and report quarterly to 
the IRB.
Treatment Groups
There will be two dose levels:
1)  5 x 200 cGy 
2) 10 x 200 cGy
Trial Duration
12 month follow up following completion of therapy for each 
individual.
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Abbreviations
AD
Alzheimer’ Disease
Aβ
amyloid-beta
FDA
Food and Drug Administration
AβPP
amyloid-β precursor protein
BBB
blood–brain barrier
RT
radiation therapy
Gy
Gray
PCI
Prophylactic cranial irradiation
H&E
hematoxylin and eosin
BED
biological effective dose
SD
standard deviation
LET
linear energy transfer
NINCDS-ADRDA
National Institute of Neurological and Communicative Disorders and 
Stroke and the Alzheimer's Disease and Related Disorders Association
PET
positron emission tomography
CTCAE v. 4.0
Common Toxicity Criteria for Adverse Events
RTOG/EORTC
Radiation Therapy Oncology Group/European Organization for Research 
and Treatment of Cancer
MMSE
Mini Mental State Examination
ADAS-Cog
Alzheimer's Disease Assessment Scale-cognitive subscale 
QOL-AD
Quality of Life- Alzheimer’s Disease
QUALID
Quality of Life in Late Stage Dementia
SCLC
small cell lung cancer
IRB
Institutional Review Board
DSM-IV
Diagnostic and Statistical Manual of Mental Disorder, Fourth edition 
CBCT
cone beam computed tomography
HVL
half-value layer
DSMB
Data Safety Monitoring Board
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1.0 Background and Rationale
1.1 Current and Future Incidence of Alzheimer’s Disease 
Alzheimer’s disease (AD) is the most common form of dementia among the elderly and affects 
over five million individuals in the  United  States  [1].  Approximately  200,000  people  younger 
than 65 years with AD comprise the younger onset AD population; 5 million are age 65 years or 
older. By mid-century, fueled in large part by the baby boom generation, the number of people 
living with AD in the United States is projected to grow by about 9 million  [2]. In  2010, official 
death certificates recorded 83,494 deaths from AD, making AD the sixth leading cause of death  
in the United States and the fifth leading cause of death in Americans aged 65 years or older. 
Between 2000 and 2010, the proportion of deaths resulting from heart disease, stroke, and 
prostate cancer decreased 16%, 23%, and 8%, respectively, whereas the proportion resulting 
from AD increased 68%. The actual number of deaths to which AD contributes (or deaths with 
AD) is likely much larger than the number of deaths from AD recorded on death certificates. In 
2014, an estimated 700,000 older Americans will die with AD, and many of them will die from 
complications caused by AD [2].
Data from the Framingham Study were used to estimate lifetime risks of AD and any dementia 
[3]. The study found that 65-year-old women without dementia had a 20% chance of developing 
dementia during the remainder of their lives compared with a 17% chance for men. For AD 
specifically, the estimated lifetime risk at the age of 65 years was nearly one in six (17.2%) for 
women compared with nearly 1 in 11 (9.1%) for men. There is a clear relationship between 
increasing age and AD. The number of Americans surviving into their 80s, 90s, and beyond is 
expected to grow dramatically because of advances  in medicine and  medical technology,  as 
well as social and environmental conditions. By 2030, the segment of  the  US  population  aged 
65 years and older is expected to grow dramatically, and the estimated 72  million older 
Americans will make up approximately 20% of the total population.
1.2 Pathophysiology of Alzheimer’s Disease
The pathophysiology of AD  develops  over  many years. The major pathological  hallmarks  are 
the accumulation of senile amyloid-beta (Aβ) plaques [4,5] and the development of insoluble 
neurofibrillary tangles of tau protein [6]. Aβ is produced by the proteolytic  cleavage  of Aβ 
precursor protein (AβPP) by β- and -secretases [7,8]. The abnormal processing and 
accumulation of Aβ initiates a cascade of events that culminates in neuronal damage and 
dementia [9-12]. In late-onset AD, the amount of Aβ that accumulates can be ~100–200-fold 
higher than normal [13]. The most recognized hypothesis [14] proposes that  AD  can be 
attributed to an imbalance between the production and clearance of Aβ, although Aβ clearing is 
not necessarily accompanied by cognitive improvement [15,16]. Aβ folding [17] and neuro- 
inflammation [18] may also be important in AD progression. The AD inflammatory response is 
associated with both neurodegeneration and neuronal survival with tissue repair [18-21].
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1.3  Current Treatments for Alzheimer’s Disease
The U.S. Food and Drug Administration (FDA) has approved five medications to treat the 
symptoms of Alzheimer's disease. donepezil, rivastigmine, galantamine, memantine and the 
combination of donepezil and memantine. The first three are acetylcholinesterase inhibitors that 
enhance the neurotransmission of acetylcholine in the brain, which is thought to be essential for 
cognition. There are many other strategies that have been studied for AD treatment including 
immunologic, nutraceutical, mitochondrial, phosphodiesterase, 5-HT6  receptor agonists  and 
stem cell-based treatments [22]. The results from large-scale randomized clinical trials of 
pharmacological agents have  been  modest and it  is clear that  AD has multiple risk factors and 
is likely to have multiple pathogenic pathways. AD is not a one-gene, one-protein disease and 
should be attributed to a network of interactions between genes, proteins, organelles, cells, 
neurotransmitters, and the environment. Those disease-modifying agents currently being 
developed typically target one hypothesis and one protein. Thus, it is clear that a single drug for 
the successful treatment of AD is not yet available.
1.4 Background and Rationale for Radiation Treatment of AD
Eliminating amyloid-β has been advocated as a beneficial treatment strategy for AD patients, 
and anti-amyloid therapies remain a rational approach for preventing or delaying AD [23].
Amyloid-β is produced by the proteolytic cleavage of amyloid-β precursor protein (AβPP) by  - 
and -secretases and many novel pharmaceuticals are being developed to prevent the initial 
cleavage of AβPP [24,25]. The blood–brain barrier (BBB) has limited or thwarted the success of 
many of these agents either by preventing the drugs from initially crossing into the brain, or by 
ensuring the rapid removal of those drugs that can cross the BBB [26]. Delivery of an  anti- 
amyloid therapy that is independent of the blood–brain barrier would be  a promising new 
approach. One strategy not investigated previously for the treatment or elimination of amyloid-β 
plaques associated with AD is ionizing radiation therapy (RT). Radiation  therapy  has  been 
shown previously to reduce amyloid-like deposits in extra-cranial disease sites [27-29].
Ionizing RT has not been considered previously for AD patients because of the potential to 
exacerbate cognitive impairment. The potential for side effects from brain RT are dependent on  
the total radiation dose given. Total doses of 3060 Gy given in 2 Gy fractions can produce 
macroscopic tissue destruction [30] and impair cognition [31-35]. However,  only  minimal 
cognitive effects are produced (minor compared with the normal cognitive decline associated 
with AD) if the total dose remains low and  critical brain structures are spared using image- 
guided RT. The severity of cognitive impairment depends upon the dose delivered to the medial 
temporal lobes, the site of the hippocampus [36]. Changes are  evident  using single  doses of 5 
Gy or higher [32-34], although 2 Gy produced no cognitive deficit [34]. Prophylactic cranial 
irradiation (PCI) [37], to a total dose of 1220 Gy in 2 Gy fractions given daily, has become the 
standard-of-care for selected groups of  adult  patients  with small cell lung  cancer and in 
pediatric leukemia patients to decrease CNS relapse[38], with no [39,40],  mild [41,42]  or 
moderate [43] cognitive impairment. Moreover, whole brain RT can lead to the recruitment of 
protective glial cells that would be beneficial in an AD patient [33], and the use of recognized 
protectors or mitigators of RT damage would provide additional clinical safeguards [33,44-48].
Therefore, RT is a potential novel treatment option for AD that could be rapidly and
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inexpensively implemented, especially when compared to the time needed and costs 
associated with developing new pharmaceuticals that are often only partially effective.
1.5 Preclinical Data Utilizing Radiation Treatment for Alzheimer’s Disease 
1.5.1 Effect of Radiation on Amyloid β Plaque Burden
The preclinical studies described in section 1.5.1 and 1.5.2 have been accepted for publication 
[49]. We used an established double transgenic model of AD namely, male B6.Cg-Tg 
(APPswe,PSEN1dE9)85Dbo/J mice. These mice express a chimeric mouse/human amyloid 
precursor protein (Mo/HuAPP695swe) and a mutant human presenilin  1 (PS1-dE9), both 
directed to CNS neurons. Both mutations are associated with early-onset Alzheimer’s  disease. 
In initial proof-of-principle experiments, 30 6-month–old mice were randomized into groups (n=3-
6 per group) and the right half of the brain X-irradiated at room temperature with either a single 
dose of 5Gy, 10Gy or 15Gy and sacrificed either 2, 4 and 8 weeks later. In subsequent studies, 
animals were treated with three different low-dose schedules 1Gyx10, 2Gyx5  or 2Gyx10. To 
assess the effects of treatments, coronal tissue sections (5µm) were cut from the harvested, 
formalin-fixed brains and mounted for antibody-specific immunohistochemistry of amyloid-β (Aβ), 
standard hematoxylin and eosin (H&E) for morphology and Nissl staining to assess neuronal cell 
density. Three
stained coronal slices per mouse were 
analyzed to compare the number and 
size of beta-amyloid plaques in the 
irradiated versus untreated sides of the 
brain. Aβ plaques were counted and 
analyzed using an image analysis 
approach. By using a hemi-brain 
irradiation approach, we were able to 
overcome the inherent variability in Aβ 
plaques between animals as each 
animal served as its own control by 
comparing the irradiated side of the 
brain to the unirradiated side of the 
same brain (Figure 1). The percent 
change in plaque number between the
irradiated and unirradiated side of the 
brain after Hemi-Brain Radiotherapy 
(HBRT) therefore indicated the true 
effect of the radiation treatment
irrespective of the initial number of plaques that were present.  The largest percent decrease in 
Aβ plaques was seen with the 5x2 Gy dose regimen (Table 1). Moreover, the size of the 
remaining Aβ plaques was smaller in the irradiated sides of the brain. At 4 weeks, the average 
decrease in Aβ plaque size was 13.8% (p=0.045), 17.2% (p= 0.021), 27.6% (p=0.011), 29.3% 
(p=0.005) and 28.7% (p=0.049) for animals given 5 Gy, 10 Gy and 15 Gy, 10x1 Gy and 5x2 Gy 
hemi-brain irradiation respectively. Single dose treatments and fractionated treatments can be 
mathematically
Figure 1: The right side in this coronal image was 
irradiated [RT]. The left side was not exposed [no-RT]. 
Fewer plaques are present on the RT side of the brain. 
5x2 Gy was given and assessed at 4 weeks post RT.
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5Gy
10Gy
15Gy
1Gyx10
2Gyx5
2Gyx10
Time
Mean
SD
Mean
SD
Mean
SD
Mean
SD
Mean
SD
Mean
SD
2 weeks
26.2
23.9
32.8
12.5
41.2
17.6
4 weeks
29.3
13.1
45.7
33.6
56.9
33.2
50.6
3.2
71.8
23.4
78.5
14.5
8 weeks
21.5
14.2
54.2
19.3
68.2
14.3
Table 1: Mean percent decrease in the number of Aβ plaques in the whole brain (cortex and hippocampus regions 
combined) for each hemi-brain RT regimen and assessment time. The size of the reduction in Aβ is dependent on the 
RT dose and assessment time. The percent decrease was calculated for each animal individually by comparing the 
plaque count between the irradiated and unirradiated sides of the brain, and then the mean and standard deviation (SD) 
percent reductions were calculated for each treatment group consisting of 3 animals. This analysis method is
independent of the initial number of Aβ plaques present.
compared using the biological effective dose (BED) [50]. A larger percentage reduction  is 
evident after the low-dose fractionated regimes compared with the single dose treatments. For 
example, a 29.3% (SD±13.1) reduction in Aβ plaques was seen after a 5Gy single dose 
(BED=17.5Gy) compared with 50.6% (SD±3.2) and 70% (SD±23.4)  reductions  after  the 
1Gyx10 (BED=15Gy) and 2Gyx5 (BED=20Gy) respectively. The most effective schedule was 
2Gy x 10 (BED=30Gy) where the plaque reduction was 78.5%. This BED comparison clearly 
demonstrates a more pronounced reduction in Aβ plaque number with fractionation compared 
with larger single dose treatments.
All radiation treatments were well-tolerated and no post-radiation behavioral changes were 
observed, suggesting negligible or limited radiation-induced effects on normal brain tissues 
over the time course of the experiment. In addition,
histological examination of the H&E stained tissue 
sections indicated no evidence of a significant 
decrease in cell density and no  compelling evidence 
of significant cellular necrosis. No signs of 
devitalization, malacia or spongiosus or classic acute 
or chronic inflammatory features were seen in the 
tissue sections, confirming that the radiation doses 
were insufficient to produce notable cellular effects on 
normal tissues. A comparison of neuronal cell density 
from Nissl stained brain tissue sections indicated little 
difference in number of neuronal cells between the 
irradiated right-side and unirradiated left side of the 
brain, irrespective of dose or time post-treatment.
1.5.2 Effect of Radiation on Cognitive Performance
The histology data suggested that there were no 
microscopic effects of low dose radiation on the brain; 
this was taken further in the next phase of  the 
research by studying cognitive function after low dose 
radiation treatment. These experiments were
Figure 2: 64-week-old whole-brain 
irradiated animals had significantly 
lower numbers of Aβ plaques at 8- 
9 weeks after irradiation with 5 x 2 
Gy than sham-treated animals.
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performed in collaboration with an independent group of Psychology scientists in a strict 
blinded-fashion and treatment groups were unknown to the individuals conducting the cognitive 
testing. 64-week old male mice were given whole-brain irradiation (n=19) or sham-treated
exposures (n=14) and evaluated 8 weeks later. Figure 2 shows the plaque burden of these 
animals. The average number of plaques in the  unirradiated  cortex of  the brain  at 73  weeks 
was 3787 (SD ±1552; n=14), with a numerical range of 1777-6554 and median of 3560. The 
average number of plaques  in the  cortex of an irradiated  brain was  2642 (SD ±1379;  n=19), 
with a numerical range of 512-4695 and median of 2677. Daily irradiated with 2 Gy for five 
consecutive days with reduced the mean number of plaques (p=0.036). Average  plaque  size 
also decreased following irradiation from 42.95μM (SD ±12.8) to 14.52 μM (SD ±11.6). Spatial 
learning and memory were assessed in a Morris maze protocol over two 5-day periods, once 
before treatment (5 days prior to RT) and once after treatment (8 weeks  after RT). The mice 
were trained to locate a platform submerged in a pool  of opaque  water (22°C±1°C) in  3 
trials/day with a 30-min inter-trial interval over 5 consecutive days. Latency to find the platform 
was measured. Eight weeks following RT mice were retested.  Prior to whole-brain  irradiation, 
the group of animals to be treated with 2Gyx5 (Mean (M) = 48.67 secs, SD = 15.63  secs) and 
the untreated group (M = 58.07, SD = 23.34) did not differ significantly in latency to find the 
platform across trials on the final testing day (day 5), p =0.399. Following irradiation, the treated 
mice showed no deficits in spatial learning and memory relative to the control group prior to 
treatment, again suggesting negligible or limited radiation-induced effects on normal brain 
functioning. Conversely, the treated group displayed significantly reduced latencies  (M = 30.96, 
SD = 17.64) compared to the untreated group (M = 53.93, SD = 14.92) across trials on day 5, 
t(11) = 2.41, p = 0.03.  This difference was not due  to difference in swimming velocity (p=0.545) 
or baseline ambulatory velocity (p=0.165).
In summary, we have demonstrated that external beam low-LET X-irradiation produces a 
significant reduction in amyloid-β plaques, pathologies causatively linked with AD. From our 
data we cannot determine if the radiation treatment is directly or indirectly eliminating the 
plaques or alternatively preventing the production and deposition of new amyloid-β plaques. 
However, these data provide preliminary evidence that these radiation treatments do not 
negatively affect cognitive function and may even improve some aspects of cognition.
2.0  Objectives and Endpoints
2.1 Primary Objectives
In this proposed study we will assess the safety and toxicity/adverse events associated with the 
use of low dose fractionated whole brain irradiation in patients who have been diagnosed with 
probable Alzheimer’s disease according to NINCDS-ADRDA criteria.
2.2 Secondary Objectives
1)
Investigate whether or not the intervention with low dose whole brain irradiation 
changes the recognized progression of Alzheimer’s disease through cognitive 
testing.
2)
To monitor quality of life parameters.
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3)
Collect information from AMYViD ® PET Scans before and after treatment to 
investigate if there is any correlation between neurocognitive/quality of life 
scores and changes in amyloid plaque size, number and location.
2.3 Primary Endpoints
The primary endpoint will be evaluation of toxicity, adverse events and reportable serious 
adverse events, i.e. grade 3 or higher, as defined by the NCI Common Toxicity Criteria for 
Adverse Events (CTCAE v. 5.0). RTOG/EORTC Radiation Toxicity Grading is standard of 
care at Beaumont Hospital for all radiation patients and CTCAE is the standard for reporting 
& publications. These criteria comprise of various parameters, including performance status, 
motor function, sensory function, general mental status, nausea/vomiting, hearing loss, 
xerostomia, and skin toxicity [51]. The CTCAE are cancer-specific and will be supplemented 
by information from neurocognitive testing using MMSE and ADAS-Cog. The tests will be 
administered by an appointed, trained site professional at baseline and at 6 weeks, 3 months, 
6 months, and 12 months during follow-up. In the context of radiation oncology, the optimal 
time period for assessing cognitive impairment is within >6 months to 1 year [52,53].
2.4 Secondary Endpoints
1) Neurocognitive testing will be used to assess changes in cognitive function using the MMSE 
and ADAS-Cog. The tests will be administered by an appointed, trained site professional at 
baseline and at 6 weeks, 3 months, 6 months, and 12 months during follow-up.
2) Quality of life will be monitored via questionnaires completed by the patient prior to the start  
of irradiation and at 6 weeks, 3 months, 6 months, and 12 months during follow-up. Specific 
questionnaires include the QOL-AD and QUALID, which have been established as sensitive 
measures of various parameters of quality of life.
3) A pretreatment and post treatment (4 months) Amyvid PET/CT scan will be carried out to 
determine if there are any correlations between neurocognitive /QOL test results and amyloid 
number, size and location and changes after treatment.
3.0 Methodology
3.1 Dose Levels and Sample Size Calculation
In the context of this pilot study, traditional levels of α (the Type I error rate) and β (the Type II 
error rate) are inappropriate since the objective of the research is not to provide definitive 
support for one treatment over another. In trials of safety such as this the objective is to show 
that the tested intervention produces a safety profile equal to a known standard therapy.
The nearest well-documented clinical situation to this novel study is the use of prophylactic 
cranial irradiation (PCI) in patients with limited disease small cell lung cancer (SCLC). 
Between September1999 and December, 2005, 720 patients with limited-stage SCLC in 
complete remission after chemotherapy and thoracic radiotherapy from 157 centers in 22 
countries were randomly assigned to a standard (n=360, 25 Gy in 10 daily fractions of 2.5 Gy)  
or higher  PCI total dose (n=360, 36 Gy) delivered using either conventional (18 daily fractions 
of 2 Gy) or accelerated hyperfractionated (24 fractions in 16 days with two daily  sessions of 
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1.5 Gy separated by a minimum interval of 6 hours) radiotherapy [54,55]. In this study 52% of 
patients experienced acute toxicity during PCI: headache in 85 patients in the 25 Gy  group 
(24%) and 99 patients in the 36 Gy group (28%), respectively, fatigue in 106 (30%) and 121 
(34%)
patients, insomnia in 14 
(4%) and 13 (4%)
patients, and nausea or
vomiting in 80 (23%) and
101 patients (28%), with 
no significant differences 
between the two groups. 
Only two patients in the 
higher-dose group 
interrupted PCI because 
of acute toxicity: one 
because of grade 2 
nausea or vomiting, and 
one because of scalp 
dermatitis. There were 
five serious adverse 
events, all of which 
occurred in the 25 Gy
group: one death (2 months after PCI) with undocumented neurological deterioration, one 
generalized seizure (12 months after PCI) treated with no sequelae, one transient ischemic 
attack (6 months after PCI), one bilateral cataract (29 months after PCI), and one death due to 
generalized seizure in a patient treated for epilepsy (29 days after PCI).
However, at the doses of radiation initially being used in this study (10 Gy) we are unlikely to 
evoke the common toxicity criteria seen at higher doses. Therefore,  we have  used the 
approach of Carter and Woolson [56] whose simple expression has utility for the generation of 
confidence intervals when zero events are observed.  Fig. 2 illustrates,  for relatively  small 
sample sizes, there is a large amount of uncertainty. It  is critical to convey  this  uncertainty  in 
the findings and to guard against inferring a potential treatment is harmless when no adverse 
effects of interest are observed with limited data. Based on this relationship we have chosen an 
initial cohort of 15 patients to be enrolled in the first treatment scheme (2 Gy x 5 fractions). The 
first cohort of patients will be followed for 12 months after completion of treatment to assess 
safety and any toxicity/adverse events associated with treatment. Using this approach, Dr.
Coffey (biostatistician) has calculated the upper confidence limits for the event rate when there 
are 0 events in a group of fifteen  distinct patients.  The method is consistent with what appears 
in the classical statistical literature for one-sided confidence limits. Supposing  that no events 
are observed in the results from 15 distinct patients, then the following  statements can be 
made:

With 99% confidence, the true underlying  adverse event  rate π does not  exceed  26.4%.

With 95% confidence, the true underlying  adverse event  rate π does not  exceed  18.1%.

With 90% confidence, the true underlying  adverse event  rate π does not  exceed  14.2%.
Fig. 2 Upper limit of the 100 × (1 - α)% one-sided confidence interval 
for the true underlying adverse event rate, π, for increasing sample 
sizes when zero events of interests are observed
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The second treatment arm will not be used until the last patient in the first dose arm has 
completed all follow up. At that point a second cohort of 15 patients will be enrolled in the
second dose arm (2 Gy x 10 fractions). The second cohort will undergo a similar stand-alone 
post-treatment assessment. The starting dose group was chosen as the regimen most 
commonly used in our pre-clinical studies of AD whilst, the 2 Gy x 10 fractions was chosen as it 
represents the most commonly used protocol to treat systemic amyloidosis and was the most 
effective schedule in our preclinical studies of plaque reduction (Table 1) .
As this is a pilot study comprising of two groups of 15 patients, the statistical assessment of 
endpoints will be descriptive and not inferential. This is a pilot study which is  a requisite initial 
step in exploring an innovative application of radiation treatment and  as  such its goal  is  to 
inform feasibility and identify modifications needed in the design of a larger ensuing hypothesis 
testing study. In this study we are not testing hypotheses due to the limited state of knowledge 
about radiation treatment in this population of patients and the FDA-mandated sample size.
3.2 Study Design
This pilot study is a prospective, dose-escalating phase I study that will investigate the safety of 
low dose external beam radiation  of  patients  with probable  moderate stage Alzheimer’s 
Disease. Patients who meet all eligibility requirements and consent to participate in this trial will 
receive either 10 or 20 Gy delivered in daily 2 Gy fractions using standard whole brain 
radiotherapy.
3.3 Patient Selection
3.3.1 Recruitment to the study
Patients will be referred from clinicians in the S.E. Michigan area to 2 institutions, Beaumont- 
Royal Oak and Beaumont-Farmington Hills. If accrual to the study is unsatisfactory, 
advertisements will be placed after approval of the IRB.
3.3.2 Eligibility Criteria
Patients must meet all eligibility criteria to be included in the study:
1.
Must be 55 years of age or older
2.
Patient must meet NINCDS-ADRDA criteria for Alzheimer’s Disease
3.
Patient must be able to complete Mini-Mental Examination and ADAS-Cog Score Sheets
4.
Patient has a Rosin Modified Hachinski Ischemic Score of less than or equal to 4
5.
Patient has a MMSE score of between 10-20
6.
Patient has estimated survival of greater than 12 months
7.
Patient or legally authorized representative must be able to give consent
Patients will be excluded from the study if they meet any of the following criteria:
1.
The patient has a history of cancer except non-melanoma skin cancer
2.
Patient is taking anti-epileptic medication.
3.
Dermatological skin disease (lice, ringworm, eczema, or psoriasis) of the scalp.
4.
Patient taking Alzheimer medication within the last 3 months, i.e. Exelon, Aricept, 
Namenda, Reminyl or Epixa.
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5.
Current presence of a clinically significant major psychiatric disorder (e.g. major depressive 
disorder, bipolar illness, schizophrenia, etc., according to DSM-IV
6.
Patient currently participating in another Clinical Trial.
7.
Patient and legally authorized representative unable to give informed consent
8.
Patient has history of focal neurological deficits (with the exception of vibratory peripheral 
neuropathy)
9.
Non-Alzheimer dementia
10. Patient has previous history of CNS radiation
11. Patient has evidence of substance abuse (alcohol / or other drugs of dependence) during 
previous 12 months
12. Patient has history of subdural hygroma / subdural hematoma
13. Patient has history of cerebral infection / hemorrhage
14. Patient has history of being immunocompromised
15. Patient  has history of seizure activity
16. Patient  has  history of hydrocephalus
3.4 Pre-treatment Evaluation and Management
The following tests/evaluations will be completed prior to initiation of treatment:
1) Informed consent: If determined that patient has cognitive impairment which includes 
decision making capability,  a LAR will be used as appropriate  for  this   potentially 
vulnerable population.
2) Consultation with Co-Investigators(Geriatrics/Neuro Specialists) to assess suitability.
3) The mini-mental state examination (MMSE)
4) The Alzheimer's Disease Assessment Scale2r-Cognitive Subscale (ADAS-Cog)
5) Baseline Quality of life questionnaires (QOL-AD; QUALID)
6) Pre-treatment Amyvid PET/CT Scan
7) Consultation with Radiation Oncologist Investigator prior to enrollment
8) History and Physical
3.5 Pretreatment Evaluation of Cognitive Status
Candidate patients for the study will undergo assessment of general and neurologic history, 
physical and neurologic examinations and administration of the following psychometric or 
behavioral tests: the Alzheimer's Disease Assessment Scale2r-Cognitive Subscale (ADAS- 
Cog) and the mini–mental state examination (MMSE).
The mini–mental state examination (MMSE) and the Alzheimer’s Disease Assessment Scale 
Cognitive scales (ADAS-Cog) have been the most widely used in clinical trials of AD 
treatments. The MMSE is a sensitive, valid and reliable 30-point questionnaire that is used 
extensively in clinical and research settings to measure cognitive impairment. It is commonly 
used to screen for dementia. It is also used to estimate the severity and progression of 
cognitive impairment and to follow the course of cognitive changes in an individual over time; 
thus making it an effective way to document an individual's response to treatment.
Administration of the test takes between 5–10 minutes and examines functions including 
registration, attention and calculation, recall, language, ability to follow simple commands and 
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orientation. The ADAS-Cog test is more thorough than the Mini Mental State Exam, and it 
primarily measures language and memory. The ADAS-Cog consists of 11 parts and takes 
approximately 30 minutes to administer. It is suggested that a change of 4 or greater in  the 
MMSE is needed before results can be considered different from random events whilst results 
changes greater than 7 in the ADAS-Cog have been proposed to represent clinically significant 
changes.
3.6 Pretreatment Amyvid PET/CT Scan
Amyvid (Florbetapir-F18) is a radiopharmaceutical compound approved by the FDA as a 
diagnostic tool in AD. Amyvid binds to amyloid-β with a half-life of 110 minutes. The tracer 
significantly accumulates more in brains of patients with AD particularly in the regions known to 
be associated with amyloid-β deposits [57]. A negative Amyvid scan indicates sparse to no 
amyloid-β neuritic plaques and is inconsistent with a neuropathological diagnosis of AD  at the 
time of image acquisition. A positive Amyvid scan indicates  moderate to frequent  amyloid 
neuritic plaques; neuropathological examination has shown this  amount of  amyloid neuritic 
plaque is present in patients with AD, but may also be present in patients with other types of 
neurologic conditions as well as older  people  with normal cognition.  Amyvid  will  be 
administered at a dose of 370 MBq (10 mCi) administered as a single intravenous bolus  in  a 
total volume of 10 mL or less. Following the injection, an intravenous  flush of 0.9%  sterile 
sodium chloride will be administered. A 10-minute PET image will be acquired starting 30 to 50 
minutes after Amyvid intravenous injection.  The patient  will be supine  and the head positioned 
to center the brain, including the cerebellum, in the PET scanner field of view. Reducing head 
movement with tape or other flexible head restraints may be employed.  Image  reconstruction 
will include attenuation correction with resulting transaxial pixel sizes between 2 and 3 mm.
Amyvid images will be interpreted only by the study designated board certified  nuclear 
radiologist. The current guidelines for display and interpretation  of Amyvid  images will be 
followed (Appendix VII). Briefly, images will be displayed  in  the transaxial  orientation  with 
access as needed to the sagittal and coronal planes. In reviewing the images, all  transaxial 
slices of the brain will be included using a black-white scale with the maximum intensity of the 
scale set to the maximum intensity of all the brain pixels. The brain slice with the highest levels  
of image contrast (highest radioactivity signals for Amyvid uptake) will be located and the 
contrast adjusted appropriately. Image interpretation will be initiated by displaying slices 
sequentially from the bottom of the brain to the top. Image interpretation is based upon the 
distribution of radioactive signal within the brain; clinical information is not a component of the 
image assessment. Images are designated as positive or negative  by comparing the 
radioactivity in cortical gray matter with activity in the adjacent white matter.
3.7 Radiation Simulation
Simulation will occur following pretreatment assessments. The patient will be simulated in the supine 
position, with the shoulders down and the head in neutral position. Non-contrast treatment planning CT 
will be acquired with the patient in the treatment position. Serial axial images with 2 mm slice thickness 
will be taken and span the entire head, from at least 5 cm beyond the cranial extent of the skull to the 
caudal aspect of the seventh  cervical vertebral body.
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3.8.
Low Dose Fractionated Whole Brain Radiation Therapy
3.8.1.
Equipment
Treatment will be delivered via a linear accelerator.
3.8.2.
Target Volume
The target volume consists of the entire  brain  and meninges, including  the  frontal lobe 
as well as the posterior halves of the globes of the eyes, with the optic disk and nerve, 
superior to the vertex and posterior to the occiput. The caudal border shall be below the 
skull base at the top of the C2 vertebral level
3.8.3.
Localization
The planning target volume shall be defined by means of a simulator
3.8.4.
Dose Prescription and Delivery
The prescription point  in the cranial volume is at or near the center.  NOTE:  regardless  
of the location of the central axis, the dose should be prescribed at the center on the 
cranial volume (midway between the maximum separations). The total dose to the 
prescription point will be 10 Gy for the initial 15 patients then 20 Gy for  patients 16-30. 
This dose will be delivered in 5 fractions or 10 fractions of 2 Gy. All radiation  fields shall 
be treated once each day. The treatment shall be given 5 days a week. No  corrections 
for bone attenuation shall be made. The dose variations in the target volume shall be 
within +7% (- 5% of the prescription-point dose). No corrections shall be made for 
treatment interruptions less than 3 days. For interruptions greater  than seven  days, 
please contact the site PI.
3.8.5.
Treatment Technique
It is recommended that the patient be treated supine.  The  use of Aquaplast 
immobilization mask is encouraged but not mandatory.  The cranial  volume is  treated 
with two lateral, equally weighted photon beams. The fields shall extend at least 1 cm 
beyond the periphery of the  scalp.  “Compensating beams” that block  hot spots (these 
hot spots are typically present along the midline due to less tissue present in these 
regions compared to mid-brain) are allowed to achieve better dose homogeneity.Field 
shaping shall be done with blocks that are at least 5 half-value layers (HVL) thick. Multi- 
leaf collimation is allowed.
3.9.
Radiation On-Treatment Monitoring and Adverse Events
Radiotherapy will be continued without interruption if at all possible as prescribed. If the sum of 
total radiotherapy interruptions  exceeds  seven normally  scheduled treatment days, the 
treatment will be considered an unacceptable deviation from the protocol. This patient should
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be reported to the principal investigator, and the patient will not be considered for final data 
analysis. Patients who do not complete a complete, total course of study radiotherapy will be 
replaced in the study in order to have 15 evaluable patients in each arm.
Patients will be monitored weekly by the treating radiation oncologist for the duration of 
radiotherapy and at regular intervals following  radiotherapy.  Scheduled post treatment visits  are 
at 6 weeks 3, 6 and 12 months. At each visit, the patient will undergo an interval history and 
physical exam and completion of Common Terminology Toxicity Criteria (Version  5.0),  and 
RTOG toxicity scoring to assess any toxicity associated with this  study. The RTOG toxicity 
scoring is done as radiation/oncology standard of care at Beaumont. This  will include  not only 
the effects on the CNS but any general adverse effects which may or may not be related to the 
treatment delivered. Each patient will be assigned a baseline  score for skin, eye,  ear and CNS 
and this will be monitored and evaluated during and after treatment for both acute and late 
toxicity. All adverse events will be recorded on an Adverse Event Reporting Form. The known 
risks associated with whole brain irradiation at the dose levels  described may include,  but are 
not limited to 1) hair loss, 2) decreased hearing, 3) nausea, 4) vomiting and  5) visual  changes 
and 6) skin reactions. The grade or severity of adverse event that is common with the planned 
radiation dose for this trial based on the RTOG Common Toxicity Criteria are  skin (Grade 1), 
CNS (Grade 1), ocular (Grade 0) and brain (Grade 1). All related/possibly related Grade > 3 
Toxicities will be reported as unexpected in severity to the IRB and monthly to the DSMB.
If at any time during the study there is an increase of 2 or more points, an evaluation by the 
DSMB will take place within the week to determine if it is therapy related or due to other non- 
study related events. Should this happen during the course of the treatment, therapy will be 
immediately stopped and all medical attempts will be made to correct the cause of the noted 
decline. The records and information related to the event will be reported to the IRB and the 
FDA using standard reporting mechanism. If it is determined that the toxicity was not study 
related accrual will resume once cleared by IRB.
Supportive management of symptoms (e.g., the use of oral or intravenous steroids for brain 
edema and the use of antiemetics) is permitted at the discretion of the treating radiation 
oncologist, neurologist or neurosurgeon.
3.10.
Cognitive Assessment and Quality of Life Assessment During Treatment
The Mini Mental Exam and ADAS-Cog are the two most commonly used tests of cognition in 
Alzheimer’s Disease [58]. After treatment these tests will be administered by study designated, 
trained professional at 6 (+1) weeks, 3 (+1) months, 6 (+1) months and 12 months. Given that 
the ADAS-Cog is not used routinely in clinical practice (but rather a research assessment) and 
that the personnel involved may not necessarily be doing other studies requiring  ADAS-Cog,  it 
will not be possible to blind the professional doing the testing. The ADAS-Cog yields a single 
score that reflects the arbitrary weighting of performance in several cognitive domains including 
learning, language and spatial cognition  but does not  address executive  function. A normal 
score for someone who does not have Alzheimer's or another type of dementia is 5; the greater 
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the dysfunction, the greater the score [59]. The properties of the ADAS-Cog are well understood; 
there is a curvilinear relationship between disease severity  and rate of change on the ADAS-Cog. 
In a large clinical trial the baseline score for placebo-treated patients in the ADAS-Cog range of 13 
to 26 was 24.2 ± 9.4 and this increased to 29.9 ± 13.7 representing a decline of 5.7 ± 8.2 points 
over 1 year  [60]. In  this trial, a significant benefit  in the active group was considered to be a 50% 
reduction in cognitive decline as  indicated by change in  ADAS- Cog score compared with the 
placebo group. In this study, patients who have an increase of no more than 50% (~3 points) on 
the ADAS-Cog at the end of treatment will be considered responders. This is equivalent to a delay 
in decline of about  6-8 months. Longitudinal  analysis will be carried out for each individual  
patient  using a  fixed  quadratic  effect of time, dependent on the baseline level of ADAS-Cog, i.e., 
an interaction of baseline ADAS-Cog and the quadratic component of time.
The MMSE is a commonly used 30-point scale for assessing cognitive function  in the  domains 
of orientation, registration, attention  and  calculation, recall, language,  and praxis.  A MMSE 
score of 10 to 20 suggests moderate dementia. On average, the MMSE score of a person with 
moderate dementia declines about three to four points  in a 12-month period.  A similar analysis 
to that described above for the ADAS-Cog test will be carried out taking into account time and 
baseline MMSE score.
Completion of Quality of Life indices (Quality of Life-AD and QUALID Scale) analysis will be 
completed by PI designated research staffat the same visit for cognitive testing.
3.11 Post-treatment Amyvid PET/CT Scan
A second Amyvid (Florbetapir-F18) PET scan will be done at 4 months after completion of 
treatment. Amyvid will be administered at a dose of 370 MBq (10 mCi) administered as a single 
intravenous bolus in a total  volume of 10  mL or less. Following the injection,  an intravenous 
flush of 0.9% sterile sodium chloride will be administered. A 10-minute PET image will be 
acquired starting 30 to 50 minutes after Amyvid intravenous injection. The patient will be supine 
and the head positioned to center the brain,  including  the  cerebellum, in the  PET scanner field 
of view. Reducing head movement with tape or other flexible head restraints may be employed. 
Image reconstruction will include attenuation correction with resulting transaxial pixel sizes 
between 2 and 3 mm. Amyvid images will be interpreted only by the study designated nuclear 
radiologist. Analysis will be carried out as previously  described.Pre- and  post-radiation  scans 
will be presented in random order, with the nuclear radiologist  blinded  to the  order of 
presentation and patient identity or clinical details
3.12 Stopping Rules
This study will be stopped for any of the following reasons
1) Any patient death attributed to treatment
2) Any patient who develops a Grade IV adverse event
3) More than 3 of 15 patients who develop a Grade 3 adverse event as per CTCAE v.5.0 in 
either group
4) 50% or more patients in either group have no change or increase in amyloid based on
Amyvid PET Scan
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5) 5 patients that show greater than 4 point deterioration in MMSE in two consecutive 
cognition evaluations
6) 5 patients that show increases greater than 7 on ADAS-Cog scale.
4.0 Risks and Benefits
Patients will be advised that the use of radiation to treat Alzheimer’s disease has not been 
reported and such treatment should be considered investigational. There is the possibility that 
treatment-related adverse events may be  observed. Close monitoring with frequent 
assessment of toxicity and signs of progression will be performed and reported. There is the 
possibility that radiation treatment may improve cognitive decline resulting in benefit for the 
patient.
5.0 Data Safety Monitoring Plan
The appointed  Data Safety  and  Monitoring  Board (DSMB)  will  act in  an advisory  capacity  to 
the IDE Sponsor/Investigator and the Beaumont Research Institute  to monitor  participant  safety, 
data quality and evaluate the progress of the study.
The DSMB will consist of four members (three voting, one  non-voting) who  are not  directly 
involved in the trial and have expertise in the fields of radiation and/or Alzheimer’s disease 
management, clinical trial methodology, and/or biostatistics.  Prior  to implementation  of the 
protocol, the DSMB will meet to review the protocol and informed consent documents, approve 
templates for study summary reports, and to adopt the charter.
The DSMB will review cumulative study data to evaluate safety, study conduct, and scientific 
validity and integrity of the trial. Meetings of the DSMB may occur as frequently  as monthly 
during the enrollment and treatment phase of the trial. Monthly meetings will be scheduled, 
however, prior to each meeting, the DSMB Chair will review the agenda. If there are no new 
enrollments, additional study data, or updates from the IDE Sponsor/Investigator, the DSMB 
Chair may cancel the meeting.
After enrollment has stopped, the DSMB will meet quarterly.  The  DSMB will  discharge  itself 
from its duties when the last participant completes the study.
The DSMB Chair will provide a written report after each meeting containing DSMB 
recommendations as to whether the study should continue without change, be modified, or 
terminated. The DSMB Chair will  provide  the  written  report to the  IDE  Sponsor/Investigator 
and the Beaumont Research  Institute.  The IDE Sponsor/Investigator  will  submit  the  report to  
the Site Investigator(s) and the FDA. The Site Investigator(s) will submit the reports to their 
respective IRBs.
Along with meeting at regular intervals during the conduct of the trial,  the DSMB will  meet  
within one week of any adverse event that increases by 2 or more points according to the
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Common Terminology Toxicity Criteria and RTOG toxicity scoring. The DSMB will meet to 
determine if the adverse event is related to therapy or due to other non-study related events.
Following the meeting, the DSMB Chair will provide  the  DSMB determination  in  writing  to the 
IDE Sponsor/Investigator and  the  Beaumont  Research  Institute.  The  IDE Sponsor/Investigator 
will submit the determination to the FDA, if required, and the Site Investigator(s). The Site 
Investigator(s) will submit the DSMB determination to their respective IRBs.
The DSMB will consist of the following individuals:

Paul Chuba, MD, Medical Director of Radiation Oncology, St. John Hospital and 
Medical Center, Detroit, MI

Martin Hauer-Jensen, MD, PhD, Director of Radiation Biology Research, University of 
Arkansas for Medical Science, Little Rock, AR

H. Michael Yu, MD, Professor of Radiation Oncology, CNS Service Chief, H. Lee 
Moffitt Cancer Center and Research Institute, Tampa, FL

Robert Podolsky, PhD, Director of Informatics and Biostatistics, Beaumont Research 
Institute, Royal Oak, MI (non-voting member)
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6.0 Study Calendar
Post Treatment 
(Months)
Pre 
Treatment
Daily 
Radiation 
Treatment
6 Weeks 
Post 
Treatment
+/- 1 week
3
+/- 2
weeks
4
+/- 2
weeks
6
+/- 2
weeks
12
+/- 2
weeks
ADAS-Cog
X
X
X
X
X
MMSE
X
X
X
X
X
History & 
Physical
X
X
X
X
X
AMYViD
PET scan
X
X
Toxicity 
Evaluation
X
X
X
X
X
X
QOL-AD and 
QUALID
X
X
X
X
X
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31. Huang Z, Jiang J, Belikova NA, Stoyanovsky DA, Kagan VE, Mintz AH. Protection of 
normal brain cells from gamma-irradiation- induced apoptosis by a mitochondria- 
targeted triphenyl-phosphonium-nitroxide: A possible utility in glioblastoma therapy. 
Journal of neuro-oncology 2010;100:1-8.
32. Raber J, Rola R, LeFevour A, Morhardt D, Curley J, Mizumatsu S, VandenBerg  SR, Fike  
JR. Radiation- induced cognitive impairments  are associated  with  changes  in  indicators 
of hippocampal neurogenesis. Radiat Res 2004;162:39-47.
33. Ramanan S, Kooshki M, Zhao W, Hsu FC, Riddle DR, Robbins ME.  The  pparalpha 
agonist fenofibrate preserves hippocampal neurogenesis and  inhibits  microglial 
activation after whole-brain irradiation. International journal of radiation oncology, 
biology, physics 2009;75:870-877.
34. Rola R, Raber J, Rizk A, Otsuka S, VandenBerg SR, Morhardt DR, Fike JR. Radiation- 
induced impairment  of hippocampal  neurogenesis  is  associated  with  cognitive  deficits 
in young mice. Exp Neurol 2004;188:316-330.
35. Rowe CC, Villemagne VL. Brain amyloid imaging. J Nucl Med 2011;52:1733-1740.
36. Abayomi OK. Pathogenesis of irradiation- induced cognitive dysfunction. Acta oncologica 
(Stockholm, Sweden) 1996;35:659-663.
37. Marsh JC, Gielda BT, Herskovic AM, Abrams RA. Cognitive sparing during the 
administration of whole brain radiotherapy and prophylactic cranial irradiation: 
Current concepts and approaches. Journal of oncology 2010;2010:198208.
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38. Pui CH, Cheng C, Leung W, Rai SN, Rivera GK, Sandlund JT, Ribeiro RC, Relling MV, 
Kun LE, Evans WE, Hudson MM. Extended follow-up of long-term survivors of 
childhood acute lymphoblastic leukemia. The New England journal of medicine 
2003;349:640-649.
39. Waber DP, Turek J, Catania L, Stevenson K, Robaey P, Romero I, Adams H, Alyman C, 
Jandet-Brunet C, Neuberg DS, Sallan  SE,  Silverman  LB.  Neuropsychological 
outcomes  from  a randomized  trial  of triple  intrathecal chemotherapy compared  with 
18 gy cranial  radiation  as cns  treatment  in  acute  lymphoblastic  leukemia:  Findings 
from dana-farber cancer institute all consortium protocol 95-01. J Clin Oncol 
2007;25:4914-4921.
40. Komaki R, Meyers CA, Shin DM, Garden AS, Byrne  K, Nickens  JA, Cox JD. Evaluation 
of cognitive  function  in  patients  with  limited  small  cell  lung  cancer prior  to  and 
shortly following prophylactic cranial irradiation. International journal of radiation 
oncology, biology, physics 1995;33:179-182.
41. Edelstein K, D'Agostino N, Bernstein LJ, Nathan  PC, Greenberg  ML,  Hodgson  DC, 
Millar BA, Laperriere N, Spiegler BJ. Long-term neurocognitive outcomes in young 
adult survivors of childhood acute lymphoblastic leukemia. Journal of pediatric 
hematology/oncology 2011;33:450-458.
42. Slotman BJ, Mauer ME, Bottomley A, Faivre-Finn C, Kramer GW, Rankin EM, Snee M, 
Hatton M, Postmus  PE,  Collette  L,  Senan  S. Prophylactic cranial irradiation in 
extensive disease small-cell lung cancer: Short-term health-related  quality  of life  and 
patient reported symptoms: Results  of an international  phase iii  randomized  controlled 
trial by the eortc radiation oncology and lung cancer groups. J Clin Oncol  2009;27:78-  
84.
43. Spiegler BJ, Kennedy K, Maze R, Greenberg ML, Weitzman S, Hitzler JK, Nathan PC. 
Comparison of long-term neurocognitive outcomes in young children with acute 
lymphoblastic leukemia treated with cranial radiation or high-dose or very high-dose 
intravenous methotrexate. J Clin Oncol 2006;24:3858-3864.
44. Conner KR, Forbes ME, Lee WH, Lee YW, Riddle DR. At1 receptor antagonism does not 
influence  early  radiation-induced  changes  in  microglial  activation  or neurogenesis   in 
the normal rat brain. Radiation research 2011;176:71-83.
45. Conner KR, Payne VS, Forbes ME, Robbins ME, Riddle DR. Effects of the at1 receptor 
antagonist l-158,809 on microglia and neurogenesis after fractionated whole-brain 
irradiation. Radiation research 2010;173:49-61.
46. Motomura K, Ogura M, Natsume A, Yokoyama H,  Wakabayashi  T.  A free-radical 
scavenger protects the neural progenitor cells in the dentate subgranular zone of the 
hippocampus from cell death after x-irradiation. Neuroscience letters 2010;485:65-70.
47. Gauthier S, Aisen  PS, Ferris  SH, Saumier  D, Duong  A, Haine  D, Garceau D, Suhy  J, Oh 
J, Lau W, Sampalis J. Effect of tramiprosate in patients with  mild-to-moderate 
alzheimer's disease: Exploratory analyses of the  mri  sub-group  of the  alphase  study. 
The journal of nutrition, health & aging 2009;13:550-557.
48. Zhao W, Payne V, Tommasi E, Diz DI, Hsu FC, Robbins ME. Administration of the 
peroxisomal proliferator-activated receptor gamma agonist pioglitazone during 
fractionated brain irradiation prevents radiation- induced cognitive impairment. 
International journal of radiation oncology, biology, physics 2007;67:6-9.
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49. Marples B, Wilson, G.D. McGee,  M., Callan,  B.S., Bowen,  S.E. Thibodeau,  B.J. 
Michael, D.B. Fontanesi, J and Martinez, A.A. . Low dose cranial irradiation 
significantly reduces beta amyloid plaques in the brain and improves cognition in a 
murine model of alzheimer’s disease (ad). Radiotherapy & Oncology 2015.
50. Fowler JF. 21 years of biologically effective dose. Br J Radiol 2010;83:554-568.
51. McDuff SG, Taich ZJ, Lawson JD, Sanghvi P, Wong ET, Barker FG, 2nd, Hochberg FH, 
Loeffler JS, Warnke PC, Murphy KT, Mundt AJ, Carter BS, McDonald CR, Chen CC. 
Neurocognitive  assessment  following  whole  brain  radiation  therapy  and  radiosurgery 
for patients with cerebral metastases. Journal of neurology, neurosurgery, and 
psychiatry 2013;84:1384-1391.
52. Gondi V, Pugh SL, Tome WA, Caine C, Corn B, Kanner A, Rowley H,  Kundapur  V, 
DeNittis A, Greenspoon JN, Konski AA, Bauman GS, Shah S, Shi W, Wendland M, 
Kachnic L, Mehta MP. Preservation of memory with conformal avoidance of the 
hippocampal neural stem-cell compartment during whole-brain radiotherapy for brain 
metastases (rtog 0933): A phase ii multi- institutional trial. J Clin Oncol 2014;32:3810- 
3816.
53. Li J, Bentzen SM, Renschler M, Mehta MP. Regression after whole-brain radiation 
therapy for brain metastases correlates with survival and improved neurocognitive 
function. J Clin Oncol 2007;25:1260-1266.
54. Le Pechoux C, Laplanche A, Faivre-Finn C, Ciuleanu T, Wanders R, Lerouge D, Keus R, 
Hatton M, Videtic GM, Senan S, Wolfson A, Jones  R,  Arriagada  R, Quoix  E,  Dunant 
A,  Prophylactic  Cranial  Irradiation  Collaborative G.  Clinical   neurological   outcome 
and quality of life among patients  with  limited  small-cell  cancer treated  with  two 
different doses of prophylactic cranial irradiation in the intergroup  phase  iii  trial (pci99-
01, eortc 22003-08004, rtog 0212 and ifct 99-01). Ann Oncol 2011;22:1154- 1163.
55. Le Pechoux C, Dunant A, Senan S, Wolfson A, Quoix E, Faivre-Finn C, Ciuleanu T, 
Arriagada R, Jones R, Wanders R, Lerouge D, Laplanche A, Prophylactic Cranial 
Irradiation Collaborative G. Standard-dose versus higher-dose prophylactic cranial 
irradiation (pci) in patients with limited-stage small-cell lung cancer in complete 
remission after chemotherapy and thoracic radiotherapy (pci 99-01, eortc 22003- 
08004, rtog 0212, and ifct 99-01): A randomised clinical trial. Lancet Oncol 
2009;10:467-474.
56. Carter RE, Woolson RF. Statistical design considerations for pilot studies transitioning 
therapies from the bench to the bedside. J Transl Med 2004;2:37.
57. Wong DF, Rosenberg PB, Zhou Y, Kumar A, Raymont  V, Ravert  HT, Dannals  RF, Nandi  
A, Brasic JR, Ye W, Hilton J, Lyketsos C, Kung HF, Joshi AD, Skovronsky DM, 
Pontecorvo MJ. In vivo imaging of amyloid deposition in alzheimer disease using the 
radioligand 18f-av-45 (florbetapir [corrected] f 18). J Nucl Med 2010;51:913-920.
58. Behl P, Stefurak TL, Black SE. Progress in clinical neurosciences: Cognitive markers of 
progression in alzheimer's disease. Can J Neurol Sci 2005;32:140-151.
59. Knopman DS. Clinical trial design issues in  mild to moderate alzheimer disease. 
Cognitive and behavioral neurology : official journal of the Society for Behavioral 
and Cognitive Neurology 2008;21:197-201.
60. Aisen PS, Schafer KA, Grundman M, Pfeiffer E, Sano M, Davis KL, Farlow MR, Jin S, 
Thomas RG, Thal LJ, Alzheimer's Disease Cooperative S. Effects of rofecoxib or
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naproxen vs placebo on alzheimer disease progression: A randomized controlled trial.
Jama 2003;289:2819-2826.
IRB NUMBER: 2017-471
IRB APPROVAL DATE: 03/21/2022

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28
Appendix I: Eligibility Checklist
Patient No: 
Patient Name: 
Inclusion Criteria for Eligibility (All responses must be Yes) 
Yes
No
 
   
  1. Patient is 55 years of age or older
 
   
  2. Patient meets NINCDS-ADRDA criteria for Alzheimer’s Disease
 
   
  3. Patient must be able to complete Mini-Mental Examination and ADAS-Cog
Score Sheets
 
   
  4.
Patient has a Rosin Modified Hachinski Ischemic Score of less than or
equal to 4
 
   
  5. Patient has a MMSE score of between 10-20
 
   
  6. Patients has estimated survival of greater than 12 months
 
   
  7. Patient or legally authorized representative is able to give consent
Investigator Signature
Date
IRB NUMBER: 2017-471
IRB APPROVAL DATE: 03/21/2022

Low Dose Radiation for Alzheimer’s Disease
29
Exclusion Criteria for Eligibility (All responses must be No) 
Yes
No
 
   
  1. Patient has a history of cancer except non-melanoma skin cancer
 
   
  2. Patient is taking anti-epileptic medication.
 
   
  3. Patient has dermatological skin disease (lice, ringworm, eczema, or
psoriasis) of the scalp
 
   
  4. Patient is taking Alzheimer medication within the last 3 months, i.e.
Exelon, Aricept, Namenda, Reminyl or Epixa.
 
   
  5. Patient has current presence of a clinically significant major psychiatric
disorder (e.g. major depressive disorder, bipolar illness, schizophrenia, etc., according to 
DSM-IV)
 
   
  6. Patient is currently participating in another Clinical Trial.
 
   
  7. Patient and legally authorized representative are unable to give informed
consent
 
   
  8. Patient has history of focal neurological deficits (with the exception of
vibratory peripheral neuropathy)
 
   
  9. Patient has non-Alzheimer dementia
 
   
 10. Patient has previous history of CNS radiation
 
   
 11. Patient has evidence of substance abuse (alcohol / or other drugs of
dependence) during the previous 12 months
 
   
  12. Patient has history of subdural hygroma / subdural hematoma
 
   
  13. Patient has history of cerebral infection / hemorrhage
 
   
  14. Patient has history of being immunocompromised
 
   
  15.  Patient  has history of seizure activity
 
   
  16.  Patient  has  history of hydrocephalus
Investigator Signature
Date
IRB NUMBER: 2017-471
IRB APPROVAL DATE: 03/21/2022

Low Dose Radiation for Alzheimer’s Disease
30
Appendix II: NINCDS-ADRDA Score
https://www.alzheimersanddementia.com/article/S1552-5260(11)00101- 
4/fulltext
IRB NUMBER: 2017-471
IRB APPROVAL DATE: 03/21/2022

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31
Appendix III: CTCAE V.5.0 criteria for assessment of anticipated toxicity
ALZHEIMER DISEASE RT STUDY TOXICITY WORKSHEET
Date______________
ID#_______________ _ _ Name________ _ _ _ _ _ _ _ _ _ _ __MD_________ _ _ _
Physician Signature:______________   _   _   _   _   _   _   _   _   _   _   _   _ Date/Time: __________ ___  
Skin Toxicity:
Radiation recall reaction (dermatologic)
Grade 0, None
Grade 1, Faint erythema or dry desquamation
Grade 2, Moderate to brisk erythema; patchy moist desquamation mostly confined to skin folds and creases; 
moderate edema
Grade 3, Moist desquamation in areas other than skin folds and creases; bleeding induced by minor trauma or 
abrasions
Grade 4, Life threatening consequences; skin necrosis or ulceration of full thickness dermis; spontaneous
bleeding from involved site; skin graft indicated
Alopecia
Grade 0, None
Grade 1, Hair loss <50% normal for that individual; not obvious from distance but only on close inspection 
Grade 2, Hair loss >50%; wig/hair piece need if patient desires to completely camouflage hair loss associated
with psychosocial impact
Xerostomia
Grade 0, None
Grade 1, Symptomatic (dry or thick saliva) without significant dietary alteration, unstimulated saliva 
flow > 0.2 ml/minute
Grade 2, Moderate symptoms, oral intake alteration (copious water, other lubricants, diet limited to purees 
and/or soft, moist foods); unstimulated saliva elow 0.1-0.2 ml/minute
Grade 3, Inability to adequately aliment orally (IV fluids, tube feedings, or TPN 
indicated), unstimulated saliva flow < 0.1 ml/minute
Other skin toxicity not listed above_______________________ _ __
Eye Toxicity:
Blurred Vision
Grade 0, None
Grade 1, Intervention not indicated
Grade 2, Symptomatic; limiting instrumental ADL 
Grade 3, Limiting self care ADL
Cataract
Grade 0, None
Grade 1, Asymptomatic; intervention not indicated
Grade 2, Symptomatic; moderate decrease in visual acuity (20/40 or better)
Grade 3, Symptomatic with marked decrease in visual acuity-operative intervention indicated 
Grade 4, Blindness (20/200 or worse) in affected eye
Other eye toxicity not listed above_______________________ _ __
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Low Dose Radiation for Alzheimer’s Disease
32
Ear Toxicity:
Ear Pain (Definition: a disorder characterized by a sensation of marked discomfort inside the ear)
Grade 0, None 
Grade 1, Mild pain
Grade 2, Moderate pain; limiting instrumental ADL 
Grade 3, Severe pain; limiting self care ADL
Hearing Loss
Grade 0, None
Grade 1, Subjective change in hearing in the absence of documented hearing loss
Grade 2, Hearing loss but hearing aid or intervention not indicated; limiting instrumental ADL. 
Grade 3, Hearing loss with hearing aid or intervention indicated
Grade 4, Decrease in hearing to profound bilateral loss; non-servicable hearing.
Additional   hearing loss since treatment
No
Yes
Other ear toxicity not listed above______________________________
CNS Toxicity:
Fatigue
Grade 0, None
Grade 1, Fatigue relieved by rest
Grade 2, Fatigue not relieved by rest; limiting instrumental ADL 
Grade 3, Fatigue not relieved by rest, limiting self care ADL
Neuropathy (Motor)
Grade  0, None
Grade 1, Asymptomatic, clinical or diagnostic observations only; intervention not indicated 
Grade 2, Moderate symptoms; limiting instrumental ADL
Grade 3, Severe symptoms; limiting self care ADL; assistive device indicated 
Grade 4, Life threatening consequences; urgent intervention indicated
Neuropathy (Sensory)
Grade 0, None
Grade 1, Asymptomatic, loss of deep tendon reflexes or paresthesia 
Grade 2, Moderate symptoms; limiting instrumental ADL
Grade 3, Severe symptoms; limiting self care ADL
Grade 4, Life threatening consequences; urgent intervention indicated
Nausea
Grade 0, None
Grade 1, Loss of appetite without alteration in eating habits
Grade 2, Oral intake decreased without significant weight loss, dehydration or malnutrition 
Grade 3, Inadequate oral caloric or fluid intake; tube feeding, TPN or hospitalization indicated
Vomiting
Grade 0, None
Grade 1, 1-2 episodes, separated by 5 minutes, in 24 hours 
Grade 2, 3-5 episodes, separated by 5 minutes, in 24 hours
Grade 3, > 6 episodes, separated by 5 minutes, in 24 hrs; tube feeding, TPN or hospitalization indicated 
Grade 4, Life threatening consequences; urgent intervention indicated
Other CNS toxicity not listed above_______________________ _ __
IRB NUMBER: 2017-471
IRB APPROVAL DATE: 03/21/2022

Beaumont Health 
Beaumont Geriatric Center
Name:
Date
Mental Status (Folstein Scale)
Item
Score
1-5     
What is today’s date?
1.
Date
2.
Year
3.
Month
4.
Day
5.
Season
Orientation
6-10
Can you tell me the name of the place where we are today?
What floor are we on?  What town are we in?  What County are we in? 
What State are we in?
6.
Institution
7.
Floor
8.
Town
9.
County
10. State
Registration
11-13
Ask if you may test memory.  Use 3 objects: ball, flag, & tree.
State them slowly and clearly.  Ask for them to be repeated. The first 
repetition determines the score (0-3), but continue until repeated 
correctly (maximum 6 tries)
11. Ball
12. Flag
13. Tree
Attention 
and 
Calculation
14-18
Begin with 100 and count backwards by 7.  Stop after 5 subtractions 
(65).  Score the total number of correct answers.  If the subject cannot 
perform this, ask him/her to spell “world” backwards, scoring the 
number of letters in correct order. 
14. 93
15. 86
16. 79
17. 72
18. 65 or
dlrow
Recall
19-21
“Now recall the 3 words I asked you to remember”
19. Ball
20. Flag
21. Tree
22-23
Naming: Show and ask the names of wristwatch, pencil
22. Watch
23. Pencil
24
Repetition: no ifs, ands or buts”
       24.   Repetition
25-27
3-stage command: Give the subject a blank sheet of paper and say  
“take the paper in your right hand, fold it in half and place on the 
floor”.
25. Takes
26. Folds
27. Places
28
Reading: Print “close your eyes” in large letters and instruct subject to 
“Do what this says”.
       28.  Reading
29
Spontaneous writing: Ask the subject to write a sentence on a sheet of 
paper.  It should be a sensible sentence with a subject and verb
        29.  Sentence
Language
30.
Coping: Draw this figure – all 10 angles must be present with 2 
intersects to score one point.
30. Draws 
         pentagons
TOTAL
SCORE:
IRB NUMBER: 2017-471
IRB APPROVAL DATE: 01/09/2020

IRB NUMBER: 2017-471
IRB APPROVAL DATE: 11/09/2018
IRB NUMBER: 2016-088
IRB APPROVAL DATE: 10/12/2018
IRB NUMBER: 2017-471
IRB APPROVAL DATE: 11/09/2018

IRB NUMBER: 2017-471
IRB APPROVAL DATE: 11/09/2018
IRB NUMBER: 2016-088
IRB APPROVAL DATE: 10/12/2018
IRB NUMBER: 2017-471
IRB APPROVAL DATE: 11/09/2018

IRB NUMBER: 2017-471
IRB APPROVAL DATE: 11/09/2018
IRB NUMBER: 2016-088
IRB APPROVAL DATE: 10/12/2018
IRB NUMBER: 2017-471
IRB APPROVAL DATE: 11/09/2018

IRB NUMBER: 2017-471
IRB APPROVAL DATE: 11/09/2018
IRB NUMBER: 2016-088
IRB APPROVAL DATE: 10/12/2018
IRB NUMBER: 2017-471
IRB APPROVAL DATE: 11/09/2018

IRB NUMBER: 2017-471
IRB APPROVAL DATE: 11/09/2018
IRB NUMBER: 2016-088
IRB APPROVAL DATE: 10/12/2018
IRB NUMBER: 2017-471
IRB APPROVAL DATE: 11/09/2018

IRB NUMBER: 2017-471
IRB APPROVAL DATE: 11/09/2018
IRB NUMBER: 2016-088
IRB APPROVAL DATE: 10/12/2018
IRB NUMBER: 2017-471
IRB APPROVAL DATE: 11/09/2018

IRB NUMBER: 2017-471
IRB APPROVAL DATE: 11/09/2018
IRB NUMBER: 2016-088
IRB APPROVAL DATE: 10/12/2018
IRB NUMBER: 2017-471
IRB APPROVAL DATE: 11/09/2018

IRB NUMBER: 2017-471
IRB APPROVAL DATE: 11/09/2018
IRB NUMBER: 2016-088
IRB APPROVAL DATE: 10/12/2018
IRB NUMBER: 2017-471
IRB APPROVAL DATE: 11/09/2018

IRB NUMBER: 2017-471
IRB APPROVAL DATE: 11/09/2018
IRB NUMBER: 2016-088
IRB APPROVAL DATE: 10/12/2018
IRB NUMBER: 2017-471
IRB APPROVAL DATE: 11/09/2018

IRB NUMBER: 2017-471
IRB APPROVAL DATE: 11/09/2018
IRB NUMBER: 2016-088
IRB APPROVAL DATE: 10/12/2018
IRB NUMBER: 2017-471
IRB APPROVAL DATE: 11/09/2018

IRB NUMBER: 2017-471
IRB APPROVAL DATE: 11/09/2018
IRB NUMBER: 2016-088
IRB APPROVAL DATE: 10/12/2018
IRB NUMBER: 2017-471
IRB APPROVAL DATE: 11/09/2018

IRB NUMBER: 2017-471
IRB APPROVAL DATE: 11/09/2018
IRB NUMBER: 2016-088
IRB APPROVAL DATE: 10/12/2018
IRB NUMBER: 2017-471
IRB APPROVAL DATE: 11/09/2018

IRB NUMBER: 2017-471
IRB APPROVAL DATE: 11/09/2018
IRB NUMBER: 2016-088
IRB APPROVAL DATE: 10/12/2018
IRB NUMBER: 2017-471
IRB APPROVAL DATE: 11/09/2018

IRB NUMBER: 2017-471
IRB APPROVAL DATE: 11/09/2018
IRB NUMBER: 2016-088
IRB APPROVAL DATE: 10/12/2018
IRB NUMBER: 2017-471
IRB APPROVAL DATE: 11/09/2018

IRB NUMBER: 2017-471
IRB APPROVAL DATE: 11/09/2018
IRB NUMBER: 2016-088
IRB APPROVAL DATE: 10/12/2018
IRB NUMBER: 2017-471
IRB APPROVAL DATE: 11/09/2018

IRB NUMBER: 2017-471
IRB APPROVAL DATE: 11/09/2018
IRB NUMBER: 2016-088
IRB APPROVAL DATE: 10/12/2018
IRB NUMBER: 2017-471
IRB APPROVAL DATE: 11/09/2018

I R B N U M B E R: 2 0 1 7- 4 7 1
I R B A P P R O V A L D A T E: 1 1/ 0 9/ 2 0 1 8
W
HI T E -  A D C S CO P Y                         YE L L O W -  IN V E S TI G A T O R 'S  CO P Y                         PI N K- CLI NI C A L  MO NI T O R 'S  CO P Y
    C e nt er N a m e               P ati e nt N u m b er              P ati e nt I niti al s   E x a mi n er I niti al s       E x a mi n ati o n D at e
M o nt h      D a y        Y e ar
 P   R
   2.  N A MI N G O B J E C T S A N D FI N G E R S: C h e c k e a c h o bj e ct/fi n g er
  n a m e d c orr e ctl y  or c h e c k " N O N E.”
             N O N E
           Fl o w er 
                R attl e                            W all et
           B e d 
                M a s k 
                   H ar m o ni c a
           W hi stl e 
                S ci s s or s 
                   St et h o s c o p e
           P e n cil 
                C o m b                            T o n g s
N o n e.
V er y Mil d : 1 or 2 i n st a n c e s, n ot cli ni c all y si g nifi c a nt.
Mil d : n oti c e a bl e cir c u ml o c uti o n or s y n o n y m s u b stit uti o n.
M o d er at e : l o s s of w or d s wit h o ut c o m p e n s ati o n o n
   o c c a si o n.
M o d er at el y S e v er e : fr e q u e nt l o s s of w or d s wit h o ut
   c o m p e n s ati o n.
S e v er e : n e arl y t ot al l o s s of c o nt e nt w or d s; s p e e c h
   s o u n d s e m pt y; 1 – t o 2- w or d utt er a n c e s.
N o n e .
V er y Mil d : f or g et s o n c e.
Mil d : m u st b e r e mi n d e d 2 ti m e s.
M o d er at e : m u st b e r e mi n d e d 3 – 4 ti m e s.
M o d er at el y S e v er e : m u st b e r e mi n d e d 5 – 6 ti m e s
S e v er e : m u st b e r e mi n d e d 7 or m or e ti m e s.
   1 1.  R E M E M B E RI N G T E S T I N S T R U C TI O N S: C h e c k l e v el of
       i m p air m e nt.
F ull n a m e
D a y
M o nt h
S e a s o n
D at e
Pl a c e
Y e ar
Ti m e of d a y
   5.   I D E A Tl O N A L P R A XI S: C h e c k e a c h st e p c o m pl et e d
       c orr e ctl y or c h e c k “ N O N E”
             N O N E
N o n e: att e m pt e d b ut dr e w n o f or m s c orr e ctl y.
P ati e nt dr e w n o f or m s; s cri b bl e d; wr ot e w or d s.
Cir cl e
T w o o v erl a p pi n g r e ct a n gl e s
R h o m b u s
C u b e
M a k e a fi st.
P oi nt t o t h e c eili n q, t h e n t o t h e fl o or.
P ut t h e p e n cil o n t o p of t h e c ar d, t h e n p ut it b a c k.
P ut t h e w at c h o n t h e ot h er si d e of t h e p e n cil a n d t ur n o v er
   t h e c ar d.
T a p e a c h s h o ul d er t wi c e wit h t w o fi n g er s k e e pi n g y o ur e y e s
   s h ut.
N o n e : p ati e nt u n d er st a n d s.
V er y Mil d :  o n e i n st a n c e of mi s u n d er st a n di n g.
Mil d : 3 – 5 i n st a n c e s of mi s u n d er st a n di n g.
M o d er at e : r e q uir e s s e v er al r e p etiti o n s a n d r e p hr a si n g.
M o d er at el y S e v er e : p ati e nt o nl y o c c a si o n all y r e s p o n d s
   c orr e ctl y; i. e., y e s – n o q u e sti o n s.
S e v er e : p ati e nt r ar el y r e s p o n d s t o q u e sti o n s
   a p pr o pri at el y; n ot d u e t o p o v ert y of s p e e c h.
   1.  W O R D R E C A L L T A S K: I n di c at e t h e t ot al n u m b er of
c orr e ct  r e s p o n s e s f or e a c h tri al
     7.  W O R D R E C O G NI TI O N T A S K : S c ori n g will b e d o n e b y t h e
  A. D. C. S. D at a C o or di n ati n g C e nt er.
Tri al 1 
Tri al 2 
Tri al 3
Tri al 1 
Tri al 2 
Tri al 3
   8.  L A N G U A G E: C h e c k l e v el of i m p air m e nt.
N o n e : p ati e nt s p e a k s cl e arl y a n d/ or i s u n d er st a n d a bl e.
V er y Mil d : o n e i n st a n c e of l a c k of u n d er st a n d a bilit y.
Mil d : p ati e nt h a s diffi c ult y < 2 5 % of t h e ti m e.
M o d er at e : p ati e nt h a s diffi c ult y 2 5 – 5 0 % of t h e ti m e.
M o d er at el y S e v er e : p ati e nt h a s diffi c ult y m or e t h a n
   5 0 % of t h e ti m e.
S e v er e : o n e- or t w o- w or d utt er a n c e s; fl u e nt, b ut e m pt y
   s p e e c h; m ut e.
   9.  C O M P R E H E N SI O N O F S P O K E N L A N G U A G E: C h e c k l e v el
     of  i m p air m e nt
   3.  C O M M A N D S: C h e c k e a c h c o m m a n d p erf or m e d
     c orr e ctl y or c h e c k “ N O N E.”
             N O N E
   4.   C O N S T R U C TI O N A L P R A XI S:  C h e c k e a c h fi g ur e
  dr a w n c orr e ctl y .
   1 0. W O R D FI N DI N G DI F FI C U L T Y: C h e c k o n e r e s p o n s e.
F ol d a l ett er.
P ut l ett er i n e n v el o p e.
S e al e n v el o p e.
A d dr e s s e n v el o p e.
I n di c at e w h er e st a m p g o e s.
   6.   O RI E N T A TI O N:  C h e c k e a c h it e m a n s w er e d
      c orr e ctl y or c h e c k “ N O N E.”
             N O N E
   T h u m b
        I n d e x 
           Ri n g
   Pi n k y
        Mi d dl e
Al z h ei m er's Dis e as e C o o p er ati v e St u d y
A D A S – C o g niti v e B e h a vi or
S A M P L E F O R M – P a g e 1 of 4

I R B N U M B E R: 2 0 1 7- 4 7 1
I R B A P P R O V A L D A T E: 1 1/ 0 9/ 2 0 1 8
W
HI T E -  A D C S CO P Y                         YE L L O W -  IN V E S TI G A T O R 'S  CO P Y                         PI N K- CLI NI C A L  MO NI T O R 'S  CO P Y
    C e nt er N a m e               P ati e nt N u m b er              P ati e nt I niti al s   E x a mi n er I niti al s       E x a mi n ati o n D at e
M o nt h      D a y        Y e ar
 P   R
C h e c k E A C H w or d c orr e ctl y r e c all e d.
I n di c at e t ot al n u m b er of w or d s c orr e ctl y r e c all e d f or E A C H tri al o n t h e A D A S C o g niti v e B e h a vi or F or m.
Pr e s e nt W or d Li st # 2.
    B O T T L E
    P O T A T O
    GI R L
    T E M P L E
    S T A R
    A NI M A L
    F O R E S T
    L A K E
    C L O C K
    O F FI C E
T RI A L 1
F O R E S T
T E M P L E
B O T T L E
S T A R
P O T A T O
GI R L
C L O C K
A NI M A L
L A K E
O F FI C E
T RI A L 2
GI R L
T E M P L E
P O T A T O
A NI M A L
F O R E S T
L A K E
O F FI C E
C L O C K
B O T T L E
S T A R
T RI A L 3
T O T A L                                       T O T A L                                      T O T A L
Al z h ei m er's Dis e as e C o o p er ati v e St u d y
A D A S – W or d R e c all
S A M P L E F O R M – P a g e 2 of 4
1 2.  E x e c uti v e F u n cti o n ( M a z e):
a. 
n u m b er of err or s
b. 
ti m e at c o m pl eti o n or s e c o n d err or
(t ot al s e c o n d s)
1 3.  N u m b er C a n c ell ati o n:
a. 
n u m b er of t ar g et s hit
( R a n g e: 0 - 4 0)
b. 
n u m b er of err or s
c. 
n u m b er of ti m e s t o r e mi n d of t a s k
If a n y it e m( s) 1- 1 3 ar e i n c o m pl et e or n ot
d o n e, pl e a s e s p e cif y r e a s o n:
S u bj e ct t o o c o g niti v el y i m p air e d t o
c o m pl et e
S u bj e ct w a s u n a bl e t o c o m pl et e f or
p h y si c al r e a s o n s
S u bj e ct r ef u s e d
N ot D o n e, f or r e a s o n ot h er t h a n
a b o v e e x pl ai n: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

I R B N U M B E R: 2 0 1 7- 4 7 1
I R B A P P R O V A L D A T E: 1 1/ 0 9/ 2 0 1 8
W
HI T E -  A D C S CO P Y                         YE L L O W -  IN V E S TI G A T O R 'S  CO P Y                         PI N K- CLI NI C A L  MO NI T O R 'S  CO P Y
    C e nt er N a m e               P ati e nt N u m b er              P ati e nt I niti al s   E x a mi n er I niti al s       E x a mi n ati o n D at e
M o nt h      D a y        Y e ar
 P   R
    B O T T L E
    P O T A T O
    GI R L
    T E M P L E
    S T A R
    A NI M A L
    F O R E S T
    L A K E
    C L O C K
    O F FI C E
T O T A L
c h e c k E A C H w or d c orr e ctl y r e c all e d.
I n str u cti o n s:  S a y t o t h e p ati e nt, “ N O W I W A N T Y O U T O T R Y T O R E M E M B E R T H E
W O R D S T H A T I S H O W E D Y O U E A R LI E R O N P RI N T E D C A R D S.  C A N Y O U T E L L M E
A N Y O F T H O S E W O R D S ? ”
All o w a m a xi m u m of t w o mi n ut e s f or r e c all.
Al z h ei m er's Dis e as e C o o p er ati v e St u d y
A D A S – D el a y e d R e c all
S A M P L E F O R M – P a g e 3 of 4

I R B N U M B E R: 2 0 1 7- 4 7 1
I R B A P P R O V A L D A T E: 1 1/ 0 9/ 2 0 1 8
C O S T
N A TI O N
C HI M N E Y
S P A R R O W
D A M A G E S
T R A F FI C
S A N D WI C H
S E R VI C E
S H E L L
S O L U TI O N
Y A R D
T U B E
B O D Y
G R O U N D
S TI C K
E N GI N E
RI C H E S
G R A VI T Y
S U M M E R
WI S D O M
M A N
M E A L
P A S S E N G E R
A CI D
    C e nt er N a m e               P ati e nt N u m b er              P ati e nt I niti al s   E x a mi n er I niti al s       E x a mi n ati o n D at e
Al z h ei m er's Dis e as e C o o p er ati v e St u d y
W
HI T E -  A D C S CO P Y                         YE L L O W -  IN V E S TI G A T O R 'S  CO P Y                         PI N K- CLI NI C A L  MO NI T O R 'S  CO P Y
A D A S – W or d R e c o g niti o n
S A M P L E F O R M – P a g e 4 of 4
M o nt h      D a y        Y e ar
 P   R
* s e e pr o c e d ur e s m a n u al f or f urt h er cl arifi c ati o n
C h e c k s u bj e ct' s r e s p o n s e f or e a c h w or d.  S u bj e ct s h o ul d r e s p o n d " y e s " t o ori gi n al w or d s
w hi c h ar e b ol d e d.  I N C O R R E C T r e s p o n s e s ar e s h a d e d.  T hr e e tri al s of r e a di n g a n d
r e c o g niti o n ar e gi v e n.
Pr e s e nt W or d Li st # 2.
B A T T L E
M U C H
T U B E
T E A M
C O P Y
E N GI N E
G R A VI T Y
C O S T
J A R
DI S T A N C E
T RI U M P H
T E M P E R
S E N T E N C E
F O X
P A S S E N G E R
S A N D WI C H
S O L U TI O N
W HI S T L E
C HI M N E Y
U NI O N
A CI D
M E A L
D A M A G E S
RI C H E S
VI SI T O R
A CI D
S P E A K
S O L U TI O N
N A M E
M E A L
LI N E
BI L L
C HI M N E Y
E N GI N E
W E A L T H
T U B E
I M A G E
C O S T
S A N D WI C H
D A M A G E S
E L E P H A N T
RI C H E S
G R A VI T Y
F U T U R E
P A S S E N G E R
S T RI N G
B A N N E R
B E R R Y
Y e s  
N o
Y e s  
N o
Y e s  
N o

I R B N U M B E R: 2 0 1 7- 4 7 1
I R B A P P R O V A L D A T E: 1 1/ 0 9/ 2 0 1 8

I R B N U M B E R: 2 0 1 7- 4 7 1
I R B A P P R O V A L D A T E: 1 1/ 0 9/ 2 0 1 8

I R B N U M B E R: 2 0 1 7- 4 7 1
I R B A P P R O V A L D A T E: 1 1/ 0 9/ 2 0 1 8

I R B N U M B E R: 2 0 1 7- 4 7 1
I R B A P P R O V A L D A T E: 1 1/ 0 9/ 2 0 1 8

I R B N U M B E R: 2 0 1 7- 4 7 1
I R B A P P R O V A L D A T E: 1 1/ 0 9/ 2 0 1 8
E x a m pl e

IRB NUMBER: 2017-471
IRB APPROVAL DATE: 11/09/2018

I R B N U M B E R: 2 0 1 7- 4 7 1
I R B A P P R O V A L D A T E: 1 1/ 0 9/ 2 0 1 8
1
2
2
4
5
9
5
6
6
9
1
9
6
7
8
3
2
4
3
7
2
1
4
2
2
1
2
6
6
3
" 6 "  a n d  " 1 "
E x a m pl e f or u s e wit h v er si o n s A, B, a n d C

I R B N U M B E R: 2 0 1 7- 4 7 1
I R B A P P R O V A L D A T E: 1 1/ 0 9/ 2 0 1 8
" 2 "  a n d  " 8 "
6
2
6
7
2
3
1
3
8
5
5
5
8
1
7
9
1
7
2
7
4
5
7
6
1
3
9
6
2
1
9
4
6
9
5
7
1
8
9
5
6
5
4
2
7
1
5
2
7
9
1
7
1
1
1
4
2
8
5
8
1
9
7
9
7
1
6
7
8
6
5
5
7
2
9
6
5
9
5
4
7
3
2
4
5
6
1
4
3
4
4
6
8
4
1
4
1
7
2
4
7
1
7
6
7
5
4
9
8
7
5
6
2
1
6
9
3
1
4
8
7
8
6
7
1
7
1
3
4
3
9
8
6
5
1
8
3
4
2
6
9
9
6
1
6
4
3
9
3
4
4
9
3
8
7
2
5
4
4
8
7
6
4
1
4
7
2
6
8
7
5
6
3
2
6
4
4
6
8
4
4
8
3
4
7
5
4
4
7
9
7
3
6
8
6
5
4
7
4
3
4
9
2
5
3
5
4
7
3
5
4
9
3
3
8
1
8
4
2
6
5
6
6
1
7
2
4
2
9
7
9
7
6
1
5
1
4
1
9
8
A

IRB NUMBER: 2017-471
IRB APPROVAL DATE: 11/09/2018
Administration Manual
for the
Alzheimer’s Disease Assessment Scale
ADAS
ADAS
Adapted from the Administration and Scoring Manual for the
Alzheimer’s Disease Assessment Scale,
1994 Revised Edition, Richard C. Mohs, Ph.D.
Copyright © 1994 by
The Mount Sinai School of Medicine
Present manual modified by:
Donald Connor, Ph.D
Kimberly Schafer, MS
(3/98)
A Publication of the
Alzheimer’s Disease          Cooperative Study

IRB NUMBER: 2017-471
IRB APPROVAL DATE: 11/09/2018
ADAS
ADAS
1
INTR
INTR
INTR
INTR
INTRODUCTION
ODUCTION
ODUCTION
ODUCTION
ODUCTION
The test items on the cognitive part of the ADAS should be given in the order indicated.
The WORD RECALL test is given first
and the
WORD RECOGNITION task is given last
with the
other cognitive tests given in-between.
Separating the two word memory tasks in this way minimizes the chance that a subject will confuse
the words from the two tasks.
At the start of a test session, before giving the WORD RECALL test, the tester should have a short
conversation with the subject about neutral topics such as the weather, the subject’s trip to the
clinic, or what the subject had for breakfast. This conversation will help to put the subject at ease
before the testing begins and will give the tester an opportunity to observe how the subject can use
and understand language.
Â There are three clinical ratings of language ability on the cognitive part of the ADAS.
The ADAS is not a timed test and the subject’s score does not depend upon how rapidly the test is
completed. The cognitive items should be given so that the session moves smoothly and quickly, but
not so that the subject feels pressured to respond rapidly.
Feedback to the subject should be neutral and, usually, should not indicate whether or not the
response was correct. Comments such as, “That’s fine” or “You’re doing well” are appropriate
as long as the subject is trying. If the subject specifically asks whether or not they were correct,
feedback can be given.
TABLE OF CONTENTS
PAGE
Word Recall Task.................................................................... 2
Naming Task ......................................................................... 3 - 4
Commands .............................................................................. 5
Constructional Praxis ........................................................ 6 - 7
Ideational Praxis ..................................................................... 8
Orientation ............................................................................. 9
Word Recognition ............................................................10 - 11
Remembering Test Instructions.......................................... 12
Spoken Language Ability ...................................................... 13
Word–Finding Difficulty and Comprehension ................ 14

IRB NUMBER: 2017-471
IRB APPROVAL DATE: 11/09/2018
ADAS
ADAS
2
On this task, the subject is given three trials to learn a list of high-frequency, high-
imagery nouns.  The 10 words are printed in block letters on white cards.
Use the appropriate word list for each visit as indicated on the study worksheet, and record the
subject’s responses on the study worksheet.
INS
INS
INS
INS
INSTR
TR
TR
TR
TRUCTIONS f
UCTIONS f
UCTIONS f
UCTIONS f
UCTIONS for W
or W
or W
or W
or WORD REC
ORD REC
ORD REC
ORD REC
ORD RECALL T
ALL T
ALL T
ALL T
ALL TASK
ASK
ASK
ASK
ASK
At the start of the first trial,
the tester gives instructions
similar to the following:
The examiner can prompt with:
After the presentation, the
tester asks the subject to try
to recall as many of the
words as possible by saying:
For trials 2 and 3, say to the
subject:
“I am going to show you some words printed on these
white cards one at a time. Please read each word out loud
and try to remember it, because later I will ask you to try
to remember all of the words I have shown you. Ready,
read the word and try to remember it.”
“Read it out loud and try to remember it” as necessary.
“Good, now tell me all the words you remember that were
on the list.”
“Now I’m going to show you that same list again. Read
each word out loud and try to remember it.”
If the subject cannot read the word or is slow, the examiner can say the word out loud and have the
subject repeat it. Note this and continue with this procedure at each testing. In some cases, the
examiner may have to say all of the words and have the subject repeat them. Regardless, make sure
the subject looks at each word while repeating it.
Two more learning and recall trials follow.
Encouragement can be given if the subject is nervous or giving up.
SCORING:
The subject’s score is the mean number of words not
recalled on three trials (maximum score = 10)
Enter the subject’s score on the study worksheet

IRB NUMBER: 2017-471
IRB APPROVAL DATE: 11/09/2018
ADAS
ADAS
3
For this task, the subject is asked to name the 12 randomly presented real objects, with
high (Flower, Bed, Whistle, Pencil),
medium (Rattle, Mask, Scissors, Comb), and
low (Wallet, Harmonica, Stethoscope, Tongs) frequency values.
The subject is also asked to name the fingers on his/her dominant hand.
Â Use the study worksheet to record the subject’s responses.
Â Objects should be presented in random order.  Do not allow the subject to touch the objects.
Â If the subject does not respond, the examiner should give the clue for that item provided
below. If the subject still does not respond or makes an error, go on to the next object.
ITEM
CLUES
Flower
grows in a garden
Bed
used for sleeping in
Whistle
makes a sound when you blow on it
Pencil
used for writing
Rattle
a baby’s toy
Mask
hides your face
Scissors
cuts paper
Comb
used on hair
Wallet
holds your money
Harmonica
a musical instrument
Stethoscope
doctor uses it to listen to your heart
Tongs
picks up food
INS
INS
INS
INS
INSTR
TR
TR
TR
TRUCTIONS f
UCTIONS f
UCTIONS f
UCTIONS f
UCTIONS for N
or N
or N
or N
or NAMIN
AMIN
AMIN
AMIN
AMING T
G T
G T
G T
G TASK
ASK
ASK
ASK
ASK
Give the subject instructions
similar to the following:
Continue to present objects
in random order.  The first
question about each object
should be:
If the subject responds with
the object’s function say:
“Now I am going to show you some objects. I want you to
tell me what their names are.  What is this called?”
(present object)
“What is this called?” or “ What is the name of this thing?”
“Yes, that’s what it does, but what is its name?”

IRB NUMBER: 2017-471
IRB APPROVAL DATE: 11/09/2018
ADAS
ADAS
4
INS
INS
INS
INS
INSTR
TR
TR
TR
TRUCTIONS f
UCTIONS f
UCTIONS f
UCTIONS f
UCTIONS for N
or N
or N
or N
or NAMIN
AMIN
AMIN
AMIN
AMING T
G T
G T
G T
G TASK 
ASK 
ASK 
ASK 
ASK (Cont
(Cont
(Cont
(Cont
(Cont’d.)
d.)
d.)
d.)
d.)
Give the subject instructions
similar to the following:
For the 4 fingers, if a query is
necessary, say:
Â The subject is also asked to name the fingers of his/her dominant hand (e.g., thumb, index
[pointer/forefinger], middle, ring finger, and pinky).
“Now I am going to point to a part of your hand and I want
you to tell me what it’s called.  What is this?”
“What is another name for this finger?”
ITEM
Thumb
Index/forefinger/pointer
Middle
Ring
Pinky
The hardest part of scoring the naming task is determination of the range of correct responses
based on the subject’s cultural and geographical background.  A response other than the name given
on the response form should be scored as correct if it is a name that would be used by a non-
demented person with the same cultural background as the subject.
 FOR EXAMPLE: the Mask might be called a “false face” in some parts of the U.S.; the Wallet
might be called a “billfold” or the Harmonica might be called a “mouth organ”.
Â Descriptions of the object, semantic or phonemic paraphasias should not be scored as correct.
 EXAMPLES OF INCORRECT RESPONSES  ARE: “listening thing” for Stethoscope,
“cutter” for Scissors, and
“prongs” for Tongs.
SCORING
0 =
0-2
items (objects and fingers) named incorrectly
1 =
3-5
items (objects and fingers) named incorrectly
2 =
6-8
items (objects and fingers) named incorrectly
3 =
9-11
items (objects and fingers) named incorrectly
4 = 12-14
items (objects and fingers) named incorrectly
5 = 15-17
items (objects and fingers) named incorrectly
Enter the subject’s score on the study worksheet.

IRB NUMBER: 2017-471
IRB APPROVAL DATE: 11/09/2018
ADAS
ADAS
5
Â There should be no other materials near the
pencil, watch and card (pens, paper, etc.)
Â Each underlined element represents a single
step.
Â Each command is scored as a whole (no
partial credit).  All components must be
correct for the response to be scored as
correct.
Â Use the study worksheet to record the
subject’s responses.
Give the subject instructions
similar to the following:
“Now I am going to ask you to do a few things. First, ...
“Make a FIST.” (“Relax it” if needed)
“Point to the CEILING and then to the FLOOR.”
Line up a Pencil, Watch, and
Card on the table. Say:
“Put the PENCIL ON TOP OF THE CARD and then
PUT IT BACK.”
“Put the WATCH on the OTHER SIDE OF  THE PENCIL
and then TURN OVER THE CARD.”
Remove the Pencil, Watch,
and Card from the table. Say:
“TAP EACH SHOULDER TWICE with TWO FINGERS
keeping your EYES SHUT.”
INS
INS
INS
INS
INSTR
TR
TR
TR
TRUCTIONS f
UCTIONS f
UCTIONS f
UCTIONS f
UCTIONS for C
or C
or C
or C
or COMMANDS
OMMANDS
OMMANDS
OMMANDS
OMMANDS
SCORING
0 =
All commands correct
1 =
1 command incorrect, 4 commands correct
2 =
2 commands incorrect, 3 commands correct
3 =
3 commands incorrect, 2 commnads correct
4 =
4 commands incorrect, 1 command correct
5 =
All 5 commands correct
Enter the subject’s score on the study worksheet
This task is designed to assess receptive speech. The subject is asked to carry out
5 separate commands with 1 to 5 steps per command.
Â Each command should be read once. If the
subject does not respond or makes an
error, the tester should give the ENTIRE
command one more time.
Â All commands should be given to every
subject.
Â If the subject demonstrates hearing or
attentional difficulties, orient them by
saying, “Ready?” or “Now I want you
to...” prior to giving the command. Do
NOT give the command more than twice.

IRB NUMBER: 2017-471
IRB APPROVAL DATE: 11/09/2018
ADAS
ADAS
6
INS
INS
INS
INS
INSTR
TR
TR
TR
TRUCTIONS f
UCTIONS f
UCTIONS f
UCTIONS f
UCTIONS for C
or C
or C
or C
or CONS
ONS
ONS
ONS
ONSTR
TR
TR
TR
TRUCTION
UCTION
UCTION
UCTION
UCTIONAL PRAXIS
AL PRAXIS
AL PRAXIS
AL PRAXIS
AL PRAXIS
Â Use the study worksheet to score the subject’s responses.
Â The forms provided should be presented one at a time.
Â The tester should give the subject a lead pencil with an
eraser along with the drawing.
Â The subject should be allowed two attempts for each
shape. Allow a second attempt only if the subject asks or
indicates a problem with their drawing. The subject may
erase if they need to. If the subject draws on top of the
printed design, count this as one attempt and indicate that
they should try on an empty part of the page. If the
subjects says the reproduction is poor, query if the
subject wants another try.  When two attempts are made,
ask the subject to indicate which one is the best, and then
score that attempt.
Â If the subject cannot reproduce the figure in two attempts,
the tester should go on to the next item.
Â A drawing should be scored as correct if the subject has
reproduced all of the essential features of the original.
Changes in size do not count as errors. Small gaps
between lines do not indicate an error, as long as the
shape has been reproduced.
The instructions to the subject
should be similar to the
following:
“On this piece of paper is a shape. Try to draw another one
that looks just like this, somewhere on the page.”
(Examiner may point to shape)
If the subject’s response is
quick or sloppy, prompt with:
“Take your time and try to draw it just like this one.”
This test assesses the subject’s ability to copy 4 geometric forms ranging from a very
simple one (circle) to a fairly difficult one (cube).

IRB NUMBER: 2017-471
IRB APPROVAL DATE: 11/09/2018
ADAS
ADAS
7
The forms should be presented in the following
order:
Circle
Two Overlapping Rectangles
Diamond (Rhombus)
Cube
SCORING GUIDELINES:
Circle: A closed curved figure
Two Overlapping Rectangles: Forms
must be four-sided, and overlap must be
similar to presented form. Changes in
size are not scored.
Diamond (Rhombus): Figure must be four-
sided, oriented so that the points are at the
top and bottom, and the sides are
approximately equal length (e.g., longest
side is not > 1.5 times the length of the
shortest side).
Cube: The form is 3-dimensional, with
front face in the correct orientation,
internal lines drawn correctly
between corners. Opposite sides of
faces should be approximately parallel.
Examples of Correct and Incorrect Drawings:
Overlapping Rectangles
Correct
Incorrect
Diamond
Correct
Incorrect
Cube
Correct
Incorrect
  SCORING
0 = All 4 drawings correct
1 = 1 form drawn incorrectly
2 = 2 forms drawn incorrectly
3 = 3 forms drawn incorrectly
4 = 4 forms drawn incorrectly
5 = No figures drawn, scribbles; parts of
forms; words instead of forms
Enter the subject’s score on the study
worksheet
INS
INS
INS
INS
INSTR
TR
TR
TR
TRUCTIONS f
UCTIONS f
UCTIONS f
UCTIONS f
UCTIONS for C
or C
or C
or C
or CONS
ONS
ONS
ONS
ONSTR
TR
TR
TR
TRUCTION
UCTION
UCTION
UCTION
UCTIONAL PRAXIS 
AL PRAXIS 
AL PRAXIS 
AL PRAXIS 
AL PRAXIS (cont
(cont
(cont
(cont
(cont’d)
d)d)
d)d)

IRB NUMBER: 2017-471
IRB APPROVAL DATE: 11/09/2018
ADAS
ADAS
8
Â Use the study worksheet to record the
subject’s responses.
Â There are 5 components to this task and
each one is underlined in the instruction.
Â If the subject forgets part of the task, or is
having difficulty, the tester should repeat the
instruction for the component of the task
where the subject is having difficulty.
 FOR EXAMPLE:  If the subject stops after
folding the paper and putting it  in  the
envelope, the tester should give one
reminder on the next component:, “Now
seal the envelope.” If the subject cannot
do this part, move on and give one
reminder on the next component:“Now
address the envelope to yourself.”
Â A long envelope, an 8.5” x 11” sheet of
paper and a pencil are placed in front of
the subject.
After the first complete instruction only one
additional reminder should be given for
each component.
Â Impairment on this item should reflect
dysfunction in executing an overlearned
task only and not recall difficulty.
Â Any address which would enable a postal
worker to deliver the envelope is counted
as correct, even though it might not
contain the subject’s current address. The
address should contain: name, street, city,
and state. Zip code is not required.
Â Have the subject indicate where the stamp
goes by placing an “X” on the envelope.
This task is designed to determine whether the subject can perform a familiar but complex
sequence sequence of actions.
SCORING
0 =
All components performed correctly
1 =
Failure to perform 1 component
2 =
Failure to perform 2 components
3 =
Failure to perform 3 components
4 =
Failure to perform 4 components
5 =
Failure to perform 5 components
Enter the subject’s score on the study worksheet
INS
INS
INS
INS
INSTR
TR
TR
TR
TRUCTIONS f
UCTIONS f
UCTIONS f
UCTIONS f
UCTIONS for IDEA
or IDEA
or IDEA
or IDEA
or IDEATION
TION
TION
TION
TIONAL PRAXIS
AL PRAXIS
AL PRAXIS
AL PRAXIS
AL PRAXIS
Give the subject instructions
similar to the following:
“I want you to pretend you have written yourself a letter.
Take this piece of paper, fold it so that it will fit into the
envelope, and then put it into the envelope. Then, seal the
envelope, address the envelope to yourself, and show me
where the stamp goes.”

IRB NUMBER: 2017-471
IRB APPROVAL DATE: 11/09/2018
ADAS
ADAS
9
INS
INS
INS
INS
INSTR
TR
TR
TR
TRUCTIONS f
UCTIONS f
UCTIONS f
UCTIONS f
UCTIONS for ORIENT
or ORIENT
or ORIENT
or ORIENT
or ORIENTATION
TION
TION
TION
TION
This task is designed to determine how well oriented the subject is with regard to time
and place.
Â Use the study worksheet to record the
subject’s responses.
Â The components of orientation are:
Person
Day of the Week
Date, Month, Year
Season
Time of Day
Place
Â The tester should ask the subject for each of
these pieces of information one at a time.
Â Make sure no watches, clocks, calendars, etc.
are visible to the subject.
Â One restatement of question is allowed
(e.g.,if subject confuses day and date).
Â Acceptable range for answers include:
Date:
+ one day
Time:
+ one hour
Place:
Partial name acceptable (e.g., name
of hospital, clinic or professional
building)
Season:
Within one week prior to onset or
within two weeks of termination
Â Month,  Year,  Day of the Week, and the
subject’s first and last name must be
exact.
SCORING: One point is given for each incorrect
response (maximum = 8)
Â Enter the subject’s score on the study
worksheet.

IRB NUMBER: 2017-471
IRB APPROVAL DATE: 11/09/2018
ADAS
ADAS
10
INS
INS
INS
INS
INSTR
TR
TR
TR
TRUCTIONS f
UCTIONS f
UCTIONS f
UCTIONS f
UCTIONS for W
or W
or W
or W
or WORD REC
ORD REC
ORD REC
ORD REC
ORD RECOGNITION
OGNITION
OGNITION
OGNITION
OGNITION
On this task the subject is given one trial to learn a list of 12 words.
Â Use the appropriate word list as indicated
on the study worksheet, and record the
subject’s responses on the study worksheet.
Â The learning part of this trial is similar to
the learning part of the WORD RECALL
TEST since the subject is asked to read each
word aloud and try to remember it.
Â For the one test trial, the 12 studied words
are mixed with 12 new words matched to the
studied words for frequency and imagery and
the subject is asked to decide for each word
whether or not it was one of the studied
words.
At the start of the Learning
Trial, give the subject
instructions similar to the
following:
“I am going to show you some words printed on these
white cards. I want you to read each word out loud and
try to remember it.”
Some of the words on the WORD RECOGNITION TASK may not be familiar to the subject and the
subject may have difficulty reading them. If the subject cannot read a word, the tester should say the
word out loud. However, it is important for the subject to actually look at each word and try to read it.
At the end of the learning
portion of a trial the tester
should say something to the
subject  similar to the following:
“Now I’m going to show you another set of words.  Some of the
words were on the list I just showed you and others are new.
For each word I want you to tell me whether it is one of the
words I just showed you.”
The tester shows the first word
and says either:
“Is this one of the words I showed you before, yes or no?
or:
“Did I show you this word before?’
The same instruction is given
before the second test word. For
the remaining test words the
tester should say:
“How about  this one?”

IRB NUMBER: 2017-471
IRB APPROVAL DATE: 11/09/2018
ADAS
ADAS
11
INS
INS
INS
INS
INSTR
TR
TR
TR
TRUCTIONS f
UCTIONS f
UCTIONS f
UCTIONS f
UCTIONS for W
or W
or W
or W
or WORD REC
ORD REC
ORD REC
ORD REC
ORD RECOGNITION 
OGNITION 
OGNITION 
OGNITION 
OGNITION (cont
(cont
(cont
(cont
(cont’d)
d)d)
d)d)
Â If the subject does not remember the task (e.g., reads the word rather than responding “Yes” or
“No”) then the tester should repeat or rephrase the entire question and make a note in the
appropriate column on the worksheet that the subject had to be reminded of the task instructions.
Likewise, if the subject appears to have fallen into a response set (i.e., saying “Yes” to every
word or saying “No” to every word), then the test instructions should be repeated.

IRB NUMBER: 2017-471
IRB APPROVAL DATE: 11/09/2018
ADAS
ADAS
12
INS
INS
INS
INS
INSTR
TR
TR
TR
TRUCTIONS f
UCTIONS f
UCTIONS f
UCTIONS f
UCTIONS for REMEMBERIN
or REMEMBERIN
or REMEMBERIN
or REMEMBERIN
or REMEMBERING TES
G TES
G TES
G TES
G TEST INS
T INS
T INS
T INS
T INSTR
TR
TR
TR
TRUCTIONS
UCTIONS
UCTIONS
UCTIONS
UCTIONS
This item evaluates the subject’s ability to remember the requirements of the WORD
RECOGNITION TASK.
On each recognition trial,
the subject is asked prior to
presentation of the first two
words:
“Did I show you this word before, or is this a new word?”
For the third word, the
subject is asked:
“How about this one?”
Â If the subject responds accurately,  i.e., “Yes” or “No”, then memory for the instructions is accurate.
Â If the subject fails to respond, this signifies that the instructions have been forgotten and the
instruction is repeated.
Â The procedure used for the third word is repeated for words 4-24. Each instance of memory
failure for the test instructions is noted.
SCORING
0 =
Subject never needs extra reminders of instructions
1 =
Very mild – forgets once
2 =
Mild – must be reminded 2 times
3 =
Moderate – must be reminded 3 or 4 times
4 =
Moderately severe – must be reminded 5 or 6 times
5 =
Severe – must be reminded 7 or more times
Enter the subject’s score on the study worksheet

IRB NUMBER: 2017-471
IRB APPROVAL DATE: 11/09/2018
ADAS
ADAS
13
This item is a global rating of the quality of speech, i.e., clarity, difficulty in making
oneself understood.
Â In rating this item the tester should consider all of the speech produced by the subject during
the test session.
Â Quantity of speech and word finding difficulty are not rated on this item.
Â It should be noted that the higher scores (4-5) on this item are reserved for subjects whose
expressive language abilities are impaired to such an extent that they seldom communicate
without difficulty.
INS
INS
INS
INS
INSTR
TR
TR
TR
TRUCTIONS f
UCTIONS f
UCTIONS f
UCTIONS f
UCTIONS for SPOKEN L
or SPOKEN L
or SPOKEN L
or SPOKEN L
or SPOKEN LAN
AN
AN
AN
ANGU
GU
GU
GU
GUAGE ABILIT
GE ABILIT
GE ABILIT
GE ABILIT
GE ABILITY
SCORING
0 =
No instances when it is difficult to understand the subject
1 =
Very mild – one instance of lack of understandability
2 =
Mild – subject has difficulty less than 25% of the time
3 =
Moderate – subject has difficulty 25-50% of the time
4 =
Moderately severe – subject has difficulty 50% of the time
5 =
Severe – one or two word utterance; fluent, but empty speech; mute
Enter the subject’s score on the study worksheet

IRB NUMBER: 2017-471
IRB APPROVAL DATE: 11/09/2018
ADAS
ADAS
14
INS
INS
INS
INS
INSTR
TR
TR
TR
TRUCTIONS f
UCTIONS f
UCTIONS f
UCTIONS f
UCTIONS for W
or W
or W
or W
or WORD-FINDIN
ORD-FINDIN
ORD-FINDIN
ORD-FINDIN
ORD-FINDING DIFFICUL
G DIFFICUL
G DIFFICUL
G DIFFICUL
G DIFFICULTY AND C
Y AND C
Y AND C
Y AND C
Y AND COMPREHENSION
OMPREHENSION
OMPREHENSION
OMPREHENSION
OMPREHENSION
Word-Finding Difficulty in Spontaneous Speech
Along with Spoken Language Ability, this item rates impairment in expressive speech, but it rates
only word finding difficulty, whereas Spoken Language Ability is a more global rating of the extent
to which the subject can communicate verbally.
Â To rate this item, the tester must determine whether the subject has difficulty in finding the
desired word in spontaneous speech. The problem may be overcome by circumlocution, i.e.,
giving explanatory phrases or nearly satisfactory synonyms.
Â Do not include finger and object naming in this rating.
SCORING
0 =
No evidence of poor comprehension
1 =
Very mild – 1 or 2 instances of misunderstanding
2 =
Mild –  3-5 instances of misunderstanding
3 =
Moderate –  requires several repetitions and rephrasing
4 =
Moderately severe – subject only occasionally responds correctly, i.e.,
yes/no questions
5 =
Severe – subject rarely responds to questions appropriately, not due
to poverty of speech
Enter the subject’s score on the study worksheet
SCORING
0 =
No evidence of word finding difficulty in spontaneous speech
1 =
Very mild – 1 or 2 instances, not clinically significant
2 =
Mild –  noticeable circumlocution or synonym substitution
3 =
Moderate –  loss of words without comprehension on occasion
4 =
Moderately severe – frequent loss of words without comprehension
5 =
Severe – near total loss of content of words; speech sounds empty;
1 – 2 word utterances
Enter the subject’s score on the study worksheet
Comprehension    This item rates the subject’s ability to understand speech
Â To rate this item, the tester should consider how well the subject was able to understand the
tester’s speech during the opening discussion and during the test session
Â Do not include responses to commands

IRB NUMBER: 2017-471
IRB APPROVAL DATE: 11/09/2018

IRB NUMBER: 2017-471
IRB APPROVAL DATE: 11/09/2018

IRB NUMBER: 2017-471
IRB APPROVAL DATE: 11/09/2018

IRB NUMBER: 2017-471
IRB APPROVAL DATE: 11/09/2018

IRB NUMBER: 2017-471
IRB APPROVAL DATE: 11/09/2018

IRB NUMBER: 2017-471
IRB APPROVAL DATE: 11/09/2018

IRB NUMBER: 2017-471
IRB APPROVAL DATE: 11/09/2018

IRB NUMBER: 2017-471
IRB APPROVAL DATE: 11/09/2018

IRB NUMBER: 2017-471
IRB APPROVAL DATE: 11/09/2018

Hachinski Ischemic Scale 
 
Study ID ___ ___ ___ ___ ___ ___ ___ 
Rater __________________  
Date ___/___/___ 
 
This form to be completed by the clinician. 
Circle only one number per characteristic 
 
HACHINSKI ISCHEMIC SCORE1 
Please complete the following scale using information obtained from 
history/physical/neurological exam and/or medical records. Indicate if a 
characteristic is present or characteristic of the patient by circling the 
appropriate value 
 
 
Present 
Absent 
1. Abrupt onset (re: cognitive status) 
2 
0 
2. Stepwise deterioration (re: cognitive status) 
1 
0 
3. Somatic complaints 
1 
0 
4. Emotional incontinence 
1 
0 
5. History of presence of hypertension 
1 
0 
6. History of stroke 
2 
0 
7. Focal neurological symptoms 
2 
0 
8. Focal neurological signs 
2 
0 
 
9. Sum all circled answers for a Total Score:  ____ 
 
 
IRB NUMBER: 2017-471
IRB APPROVAL DATE: 01/10/2020

1 Rosen Modification of Hachinski Ischemic Score (An Neurol 7:486-488. 1980). 
Copyright © John Wiley & Sons, Inc. Reproduced by permission. 
 
(Version 1.2, March 2006) 
IRB NUMBER: 2017-471
IRB APPROVAL DATE: 01/10/2020