Phase IIa Trial of Low Dose Radiation THerapy to Reduce Cerebral Amyloidosis in Early Alzheimer's Dementia
Phase: NA
Conditions: Alzheimer's Disease
Sponsor: Virginia Commonwealth University

 
 
Title: Low Dose RT to Reduce Cerebral Amyloidosis in Early Alzheimer's 
 
NCT #: NCT02769000 
 
Document date: 9/23/19 
 
Document Type: Protocol and SAP 
 
 
 

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Table of Contents 
Study Design / Schema 
Page 3 
Protocol Synopsis 
Page 4 
Eligibility Criteria Worksheet 
Page 8 
1. Introduction 
Page 9 
2. Study Purpose 
Page 14 
3. Study Design and Duration 
Page 14 
4. Study Objectives 
Page 15 
5. Subject Selection: Inclusion and Exclusion Criteria 
Page 15 
6. Low Dose Fractionated Whole Brain Radiation Therapy Guidelines 
Page 16 
7. Amyvid (Florbetapir) Neuritic Plaque Guidelines 
Page 18 
8. FDG (18F-fluorodeoxyglucose) PET-CT Metabolic Imaging Guidelines 
Page 20 
9. Isolation of Neuronal Specific Exosomes 
Page 20 
10. Study Procedures 
Page 21 
11. LAR/Caregiver Participation 
Page 24 
12. Study Calendar 
Page 24 
13. Adverse Events 
Page 25 
14. Study Stopping Rules 
Page 27 
15. Data Safety Monitoring Board (DSMB) 
Page 27 
16. Endpoints 
Page 28 
17. Statistical Plan 
Page 29 
18. Plan for Loss to Follow-up 
Page 29 
Appendix 1: CTCAE Adverse Event Evaluation Form 
Page 31 
Bibliography 
Page 33 
 
 
 
 
 
 
 

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Study Design 
Schema 
For Patients with Early Alzheimer’s Dementia based on NINCDS-ADRDA Criteria 
Prior to treatment  
Treatment: Radiation therapy 
Follow-up 
• 
Signed Consent 
• 
History and Physical 
• 
Neurocognitive Function 
Assessments 
• 
Psychological Function 
Assessments 
• 
Quality of Life Assessments 
• 
 FDG- PET Scan 
• 
Amyvid PET Scan 
• 
Baseline Toxicity scores 
• 
Ocular Exam (pts with at 
least 1 natural lens only) 
Whole brain radiation therapy  
• 
Cohort 1:  
Subjects # 1 – 15 
10 Gy in 5 daily fractions 
 
• 
Cohort 2:  
Subjects # 16 – 30 
     20 Gy in 10 daily fractions 
• 
6wks, 3mo, 9mo, 12 mo: 
Neurocognitive function 
Assessments 
Psychological Function 
Assessments 
Quality of Life Assessments 
Physical Exam and Toxicity 
Assessments 
• 
6mo: 
FDG-PET scan 
Amyvid PET Scan 
• 
9mo: 
Ocular exam (pts w/ at least 1 
natural lens only) 
 
Subject Population:  See Section 5 for Subject Eligibility 
 
 
 
 
 
 
 
 
 

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Protocol Synopsis 
Protocol Number 
HM20004955 
Protocol Short Title 
Low Dose RT to Reduce Cerebral Amyloidosis in early Alzheimer’s 
Protocol Title 
Phase IIa Trial of Low Dose Radiation Therapy (RT) to Reduce Cerebral 
Amyloidosis in Early Alzheimer’s Dementia (AD) 
Device 
Commercially and widely available linear accelerator 
Standard-of-Care 
Treatment 
At the present time there is no “active” treatment for AD. The standard options 
available are solely for symptomatic relief. This study is designed to directly treat 
the cerebral amyloid deposits believed to be “triggering” event leading to 
neurofibrillary tangles and neurocognitive decline with AD 
Type of Protocol 
Phase IIa 
Protocol Design 
Single arm, non-randomized trial, employing 2 sequential dose schedules 
Study Objective 
To assess outcomes following low dose whole brain RT in subjects diagnosed 
with AD on the basis of clinical and imaging findings. Study outcomes will include 
cerebral amyloid accumulation, neurocognitive function, safety, and adverse 
events with each of the 2 sequential RT dosing schedules. 
Primary Endpoint 
Evaluate safety and toxicity/adverse events associated with delivery of low 
dose whole brain irradiation in subjects with Alzheimer’s dementia. Adverse 
events and reportable serious adverse event as defined by NCI Common 
Toxicity Criteria for Adverse Events (CTCAEv.4.0) 
Secondary Endpoints 
To determine whether low dose whole brain RT stabilizes or decreases cerebral 
amyloid deposits. 
To determine if neurocognitive function (NCF), psychological function (PF) ,and 
quality of life (QOL), assessed by accepted testing methods, is stabilized or 
improved by low dose whole brain RT. 
To determine whether there are correlations between NCF, PF, and/or QOL test 
results and PET imaging with respect to amyloid accumulations, including 
number, size and location. 
Trial Population 
Individuals greater than 55 years of age, with probable diagnosis of AD based 
on NINCDS-ADRDA criteria. 
Number of Subjects 
30 (15 in each RT dose schedule cohort) 
Randomization 
N/A 
Number of Institutions 
1 
 
 
 

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Eligibility Criteria 
Subjects must meet all eligibility criteria: 
1. Must be male or female, 55 years of age or older 
2. Must be a native English speaker and have the legally authorized 
representative available for consenting if one has been designated. 
3. Must be able to complete neurocognitive function assessments, psychological 
function assessments, and QOL assessments administered at screening visit 
4. Rosen Modified Hachinski Ischemic Score< 4 
5. Estimated survival of greater than 12 months 
6. Meet the clinical definition of AD diagnosis based on NINCDS-ADRDA criteria, 
with confirmatory PET findings 
7. If on any of the following medications for AD treatment must be a stable dose 
for 60 days or greater: Rivastigmine, Donepezil, Memantine, Glantamine, 
Tacrine 
8. No current or past history of any oncologic disease mitigating low dose whole 
brain RT 
9. No evidence of substance abuse (alcohol/or other drugs or dependence during 
previous 12 months (DSM-V criteria) 
10. No clinically or radiographically significant evidence of stroke 
11. No evidence of subdural hygroma or subdural hematoma 
12. No active or recent (defined as within 3 months of screening) cerebral 
infection or hemorrhage 
13. No current conditions that may lead to the subject being in an immuno-
compromised state 
14. No previous history of cranial radiation. 
15. No history of seizure activity 
16. No history of hydrocephalus 
17. No Evidence of active dermatological skin disease of the scalp (except actinic 
keratosis) 
18. No evidence of clinically significant major depressive disorder identified in a 
psychological diagnostic interview according to the criteria of the Diagnostic 
and Statistical Manual of Mental Disorder, FifthEdition (DSM-V) 
19. No evidence of psychotic disorder or psychotic episode or bipolar affective 
disorder identified in a psychological diagnostic interview according to the 
criteria of the Diagnostic and Statistical Manual of Mental Disorder, Fifth 
Edition (DSM-V) 
20. No evidence of active suicidal or homicidal ideation according to psychological 
diagnostic interview 
21. Not currently receiving other experimental treatments 
22. Not currently requiring full time institutional care. 
23. Not a pregnant, nursing or incarcerated individual. 
Screening Testing 
The following test / evaluation will be completed prior to initiation of treatment 
1. History and Physical 
2. Review of any available prior CT, MRI, or PET brain imaging studies 
3. Psychological Diagnostic Interview completed by a licensed clinical 
psychologist 
4. Neurocognitive function assessments (WTAR, MMSE, HVLT, BVMT-R, WMS-
IV Digit Span and Coding subtests, Trailmaking Tests, California Oral Word 
Association Test and Semantic Fluency Test, Pegboard Test) 
5. Psychological function assessments (PHQ-9, GAD-7) 
6. QOL assessments (QOL-AD, QUALID, and ECog) 

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Baseline Testing 
The following test / evaluation will be completed for all participants who met 
study criteria in the screening visit. The following test / evaluation will be 
completed prior to initiation of treatment: 
1. Neurocognitive function assessments (WTAR, MMSE, HVLT, BVMT-R, WAIS-
IV Digit Span and Coding subtests, Trailmaking Tests, Controlled Oral Word 
Association Test and Semantic Fluency Test, Pegboard Test, BNT, and JLO)  
2. Psychological function assessments (PHQ-9, GAD-7)  
3. QOL assessments (QOL-AD, QUALID, ECog) 
4. Amyvid and FDG PET/ CT Scans 
5. Toxicity Evaluation using CTCAE version 4.0for following sites Skin, Eye, Ear 
and CNS 
6. Blood Draw for Neuronal Specific Exosome Analysis 
Other Variables 
Ocular exams will be performed for each subject who has at least one natural lens 
and are intended to determine if any subject has a supranuclear cataract 
Imaging Requirements 
FDG-PET and Amyvid PET scans will be required prior to treatment and at 6 
months following completion of therapy. These scans will be read by board 
certified diagnostic radiologist / nuclear medicine specialist who has been 
certified to interpret these scans 
 
Treatment Procedure 
Subjects will receive whole brain RT using commonly employed and standard 
external beam techniques. The initial 15 subjects will be in Cohort 1 and receive 
the lower dose regimen (5 x 200 cGy).  If after the last subject in Cohort 1has been 
followed for 9 months, and there have been no events that cause stoppage of the 
trial, Cohort 2 will be enrolled using a higher dose regimen of 10 x 200 cGy.  
Subjects in both Cohorts will be followed for a total of 12 months. 
All subjects will receive 1 treatment per day and will receive treatments on 
consecutive week days (Monday through Friday). 
Trial Visits and  
Follow-Up 
All subjects will be followed as per study calendar.  Scheduled post treatment 
visits are at 6 weeks, 3, 6, 9 and 12 months 
Stopping Rules 
This Study will be stopped for any of the following reasons: 
1. Any subject’s death attributed to the radiation, or any irreversible adverse 
effects caused by the treatment in either group (excluding alopecia) 
2. More than 3 of first 10 subjects develop a Grade 3 adverse event as per CTCAE 
v.4.0 in either Cohort 
3. 50% or more of the subjects in either cohort have increase in amyloid based 
on FDG and/or Amyvid PET Scan 
4. 50% or more of the subjects show greater than a 4-point decrease in MMSE 
5. If any subject selects a response 1-3 on item 1.i. of the PHQ-9 at any time 
during the study, the Suicide Behaviors Questionnaire-Revised (SBQ-R) will be 
administered and if the score on this scale is ≥7, the study will be stopped and 
the subject will be referred for appropriate clinical care.  
6. Any subject develops a Grade IV adverse event in either Cohort 

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Data Safety 
Monitoring Board 
(DSMB) 
This trial will utilize a DSMB consisting of two physicians who have expertise in 
radiation and an arbitrator who has expertise in Alzheimer’s management. 
They will meet bi-annually to review all new data that has been collected on any 
subject under treatment or in follow up. 
Treatment Cohorts 
There will be two dose levels: 
1. 5 x 200 cGy 
2. 10 x 200 cGy 
Trial Duration 
12 months follow up after completion of radiation therapy for each subject. It is 
thought overall time will be 48 months. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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1 Introduction 
Alzheimer’s disease (AD) is currently the 7th leading cause of death in the United States with 
approximately 5.9 million Americans living with the progressive and debilitating condition (1).  AD 
predominantly affects older individuals as 86% of AD cases are in individuals 65 years of age and older 
(2).  Further, approximately $172 billion of health care spending annually can be attributed to costs 
associated with AD care (3) on top of the 11 million caregivers that provide care in unpaid capacities, 
such as family members, friends, etc. 
 
In 1975, a cohort of nearly 2,800 people who were 65 years of age and free of dementia provided a basis 
for an incident study of dementia, as well as for Alzheimer’s disease. This cohort was followed for almost 
29 years and its sentinel findings included a significantly higher lifetime risk for both Alzheimer’s and 
dementia in women compared to men (4).  The estimated lifetime risk was nearly one in five for women 
compared to one in ten for men (5).  In addition to the higher lifetime risk in women, longer life 
expectancies and the aging of the “baby boomers” combined with improved healthcare is expected to 
increase the number of Americans who will reach 85 years of age or more (6).It is very clear that as the 
age increases, so does the incidence of Alzheimer’s and other forms of dementia. 
 
Between 2010 and 2050, it is expected that there will be a 30% increase in the number of individuals 
greater than 85 years of age.  Although the absolute number may not appear to be significant, this 
increase of approximately 17 million people will challenge the healthcare system because of the cost 
associated with dealing various acute and chronic medical conditions including AD. 
 
While other major causes of death continue to experience decline, those from AD continues to rise.  In 
1991, only approximately 14,000 death certificates recorded Alzheimer’s disease as an underlying cause.  
In 2006, it was noted that there was an increase of approximately 46% in which Alzheimer’s disease was 
listed as the direct cause of death. This is significant when compared to the 
present leading cause of death, heart disease, which decreased by 11% in the same time (7). 
 
From a neurophysiological standpoint, what is known about Alzheimer’s disease is that there appears to 
be a progressive process that is associated with the deposition of β Amyloid (8,9). This appears to have a 
triggering mechanism, which causes the phosphorylation of a TAU protein, which then leads to 
development neurofibrillary tangles (NFT), which are believed to be responsible for memory loss, 
especially short-term and other associated problems with Alzheimer’s related dementia (10, 11).  It also 
appears that there may be a selective deposition of the β Amyloid in the hippocampus and the 
prefrontal regions, which are the major short-term memory regions of the brain (12). 
 
Extensive research has been ongoing to try to find various ways in which the excess deposition of 
βAmyloid, the removal of excess β Amyloid, the initiation sequence that it is involved in with 

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phosphorylated TAU and other selective processes can be altered in an effort to mitigate the 
devastating end term results.  To date, there have been several trials, including a vaccine trial performed 
in Europe and in the United States, which seem to show that clearance of the β Amyloid is possible (13).  
However, there was not significant improvement in neurocognitive function (NCF), which led to the 
discontinuation of these trials. 
 
This lack of improvement in NCF was believed to be secondary to the fact that the β Amyloid had 
already resulted in the phosphorylation of the TAU protein and development of NFT.  Thus removal of 
the initiator was accomplished, but only after the end damage had developed. Then why consider 
irradiation? 
 
The use of radiation in the treatment of non-oncologic human populations has enjoyed a long history 
and a more recent renaissance.  It is now commonly used to prevent heterotopic bone formation (14-
15) and re-development of keloids or heterotrophic scars post-operatively (16-17). It has been shown in 
a randomized trial to effectively treat planter fasciitis (18) and has been used in post-operative 
treatment of resected pterygium (19-20).  It has been used in the treatment of Hidradenitis suppurativa, 
Duputryen’s disease and Ledderhose’s disease. (21-22).  These sites routinely are treated with low dose 
fractionated external beam irradiation, commonly in doses that ranging from 7to 24 Gy. 
 
The use of external irradiation has also been reported in the treatment of symptomatic systemic 
amyloidosis.  In published peer reviewed articles treatment sites have include trachea-pulmonary (23-
24) ocular (25-26), laryngeal (27) and for use as a conditioning agent for autologous Bone Marrow 
Transplant in patients with systemic amyloidosis (28).These reports used external beam irradiation that 
ranged from 5.5 – 45Gy and detail durable local control with these doses. 
 
Because of this effect, a series of basic science experiments were initiated with genetically altered mice: 
the B6;  Cg – Tg (Appswe, PSEN1dE9) 85 Dbo/J (005864)over express amyloid and the B6; 129-
Psen1tm1MpmTg (APPswe tauP301L) over express both amyloid and TAU, making them prone to early 
Alzheimer’s disease development.    
 
Both single and fractionated Central Nervous System (CNS) irradiation in a genetically altered mouse 
model were tested, and have shown similar results with reduction in amyloid plaque number, size and 
volume.  Moreover, the fractionated studies we have demonstrated statistically significant improvement 
in the treated mice using the Morris Water Maze Test when compared to control non-treated animals, 
an effect which held up whether the animals were adolescent, mature or aged (up to 18 months old). 
 
The exact mechanism by which radiation therapy confers benefit in the Alzheimer’s disease mouse 
model will be difficult to elucidate as the exact pathobiology of Alzheimer’s disease is not known.  

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Possible mechanisms include the following:  reduction of β amyloid by reducing production or increasing 
clearance; reduction in Tau; induction of beneficial inflammatory mechanisms; induction or inhibition of 
heat shock proteins; altering cerebral microvasculature; and/or reversal of maladaptive neuroplasticity 
in the hippocampus. Investigations of these possible mechanisms are currently underway. 
 
One of the complications related to studying Alzheimer’s disease is the actual diagnosis.  Unlike 
malignancies where a biopsy can be obtained, Alzheimer’s disease is a diagnosis of exclusion or made at 
autopsy.  While the Europeans have recently identified and agreed on cerebral spinal fluid 
(CSF)biomarkers for diagnosis of Alzheimer’s disease, we have not accepted that premise in the United 
States.  At the present time, PET imaging which utilizes various compounds has been utilized to identify 
depositions of amyloid in the CNS.  More recently, there is some suggestive evidence that a specific type 
of cataract may be seen in a high percentage of patients with Alzheimer’s disease related to possible β 
Amyloid deposition in the lens region (29-30). Many rely on the National Institute of Neurological and 
Communicative Disorders and Stroke (NINCDS) and the Alzheimer’s Disease and Related Disorders 
Association (ADRDA)criteria for clinical diagnosis of Alzheimer’s disease. 
 
While it is a diagnosis of exclusion, there are well-accepted neurocognitive tests (NCT) used to monitor 
Alzheimer’s disease progression.  The Mini Mental State Exam (MMSE) is one of the general NCT used to 
help establish the diagnosis of Alzheimer’s dementia. There are other more sensitive neurocognitive 
tests available to track progression of Alzheimer’s dementia, which we will use in this study. Table 1 lists 
the cognitive domains and NCT that will be used to comprehensively evaluate individuals’ 
neurocognitive function (NCF) in this study. Note estimation of premorbid IQ is only completed at the 
screening appointment and administration of the JLO and BNT only occur at the baseline pre-treatment 
visit and the 12-months post-treatment follow up visit to minimize participant fatigue and familiarity 
with the test materials. Administration of the NCT at the screening visit will serve two purposes. Data 
obtained from the screening visit will ensure that subjects who are enrolled in the trial meet criteria for 
early AD based on the more comprehensive battery of tests, as diagnosis of dementia is improved with 
use of quantitative measurement of multiple domains (31). The NCT at this screening visit will also 
expose participants to the NCT and since practice effects are greatest between the first and second 
exposure to NCT (32), practice effects will be minimized using this exposure and repeated measures 
ANOVAs (analysis of variance).  
 
 
 
 
 
 
 

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Table 1. Neurocognitive Functioning Assessment Battery 
Neurocognitive Domain 
Neurocognitive Test 
Estimated Premorbid Intelligence 
Quotient 
Wechsler Test of Adult Reading (33) 
Dementia Screener 
MMSE-2 (33) 
Processing Speed 
Grooved Pegboard Test (33), Trailmaking Part A and B (34), 
Wechsler Adult Intelligence Scale-IV (WAIS-IV) Coding subtest 
(35) 
Attention 
WAIS-IV Digit Span subtest (35) 
Visuospatial Skills 
BVMT-R Copy subtest (36), Judgment of Line Orientation Test 
(JLO)*(33) 
Language Skills 
Boston Naming Test (BNT)* (33) 
Learning and Memory 
Hopkins Verbal Learning Test-R (HVLT-R) (37) and Brief Visual 
Memory Test-R (BVMT-R) (36) 
Executive Functions 
Controlled Oral Word Association Test (COWAT)and Semantic 
Fluency (38), Trailmaking Part B (34) 
*The BNT and JLO tests will only be administered at baseline and 12 month follow up.  
Psychological functioning and quality of life (QOL) will also be evaluated to monitor participants’ 
emotional status throughout the trial. The Patient Health Questionnaire-9 (39) and the Generalized 
Anxiety Disorder-7 (40) questionnaires will be used to assess depression and anxiety, respectively. If any 
participant endorses suicidal ideation on the PHQ-9, the Suicide Behaviors Questionnaire-Revised (SBQ-
R) (41) will be administered to fully evaluate the participant’s suicidal ideation and study stopping rules 
will be implemented as needed to ensure the individual’s safety. QOL will be evaluated by the Quality of 
Life in Alzheimer’s disease (QOL-AD)(42) and Quality of Life in Late-stage Dementia (QUALID)(43) and 
Everyday Cognition (ECog) questionnaires (patient and caregiver forms) (44).  
 
Concern may be raised regarding the use of whole brain irradiation and its potential deleterious effect 
on neurocognitive testing. There have been reports on post-radiation neurocognitive testing in the 
setting of prophylactic cranial irradiation (PCI), which is whole brain fractionated RT commonly 
employed for patients with pulmonary small cell carcinoma(45-47). The standard whole brain PCI dose is 
2.5 Gy x 10, considerably higher than the 2.0 Gy x 5 or 2.0 Gy x 10 schemes planned in the present study. 
Furthermore, patients in the PCI studies also received chemotherapy in addition to whole brain 
irradiation, and chemotherapy itself effects long-term NCF (48).  In these PCI reports (45-48), if any 
neurocognitive decline was identified, it was modest, occurred within a short interval, e.g. 6-9months, 
and improved. We are thus proposing a 9-month follow up period for the 1stsubject cohort (2.0 Gy x 5) 
before proceeding with the 2nd cohort (2.0 Gy x 10), although both cohorts will undergo NCF and QOL 
testing through 12 months. 

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Grosshans and colleagues from M. D. Anderson found that PCI is “unlikely to significantly affect NCF.”  
They evaluated cognitive function in small cell lung cancer patients who received PCI (mean 2.5 Gy x 10). 
After chemotherapy, but before PCI, 47% already had evidence of impaired cognitive function.  On 
multivariate analysis, there were no significant further declines after PCI. On univariate analysis, there 
were unsustained, early decreases in executive and language function, which did not persist with follow-
up (45). A Japanese group applied the Hopkins Verbal Learning Test (revised Japanese version, HVLT-R) 
in 40 whole brain RT patients, at baseline, 4 months, and 8 months. Whole brain fractionation was 
either 2.5 Gy x 4, 3.0 Gy x 10, or 2.5 Gy x 10. The respective probabilities of decline in HVLT-R total recall 
at 4 months were, respectively, 40%, 7%, and 0%, and at 8 months 13%, 14% and 0% (48). 
 
Also applicable is a recent report of whole brain (and whole spine) radiation therapy (RT) for 
medulloblastoma in children, a population believed more vulnerable to cognitive decline from RT. They 
did not receive chemotherapy, rather RT alone, 36 Gy in 36 fractions (1.0 Gy BID) to the entire brain and 
spine, followed by a boost to 68 Gy in 68 fractions to the tumor bed, typically posterior fossa.  Using the 
Wechsler Intelligence Scale for Children to give verbal quotient, performance quotient, and full-scale 
intelligence quotient, cognitive function was preserved for all test domains throughout the study at 3 
months, 1 year, and 2 years, with no decline over time (49).  
 
Low dose whole brain RT has demonstrated safety in many studies, and we will be using even lower 
doses. These lower radiation therapy doses have a history of excellent success for patients with non-
cerebral amyloidosis, and have had durable response combined with the necropsy / neurocognitive 
testing in genetically altered Alzheimer’s disease mouse model, we decided to proceed with a human 
trial, using fractionated whole brain radiation doses of 2.0 Gy x 5, then 2.0 Gy x 10.Subjects will be 
followed with neurocognitive testing at 6 weeks, 3, 9,and 12 months post RT. Additionally, given that 
the development of supranuclear cataract has been reported in a high percent of AD patients, we will 
recommend ocular testing at baseline and at 1 year to assess a potential abscopal effect, collateral 
benefit to the non-targeted lenses from treatment of the primary disease in the brain (29-30). 
 
With respect to the development of cataracts in association with AD, early and accurate diagnosis of 
Alzheimer’s disease (AD) is still a challenge and the confirmatory diagnosis is made by presence of 
features including beta-amyloid plaques postmortem. In 2014, Tian et al suggested that AD may have a 
common pathophysiology with supranuclear deposits of beta-amyloid in the human lens (29). The brain 
and the lens tissue both arise from the ectoderm tissue (neuroectoderm and surface ectoderm 
respectively).  Their conclusions were based on a meta-analysis of studies, which provided mixed data 
regarding the correlation of beta-amyloid in the lens samples of patients with AD, Down syndrome and 
controls. Given the chronicity of the terminally differentiated cell types in the lens that may be affected 
by Alzheimer disease’s pathology, they concluded that there is a possibility than an ocular biomarker for 
early AD may exist in the lens. This would suggest that an early ophthalmic examination may provide a 

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window of hope into early diagnosis of AD.  It may also provide an opportunity for early treatment and 
perhaps monitoring of improvement in supranuclear cataracts with systemic therapy. 
 
A precedent for this is already found in Wilson’s disease. Kayser-Fleischer (K-F) ring seen in Wilson's 
disease (WD) is due to copper deposition in the Descemet's membrane in the sclero-corneal junction in 
the eye. Although believed to be pathognomic of WD, it may be seen in many other hepatic conditions 
and intraocular copper-containing foreign bodies. The K-F ring detected in pre-symptomatic cases of WD 
may lead to speedy diagnosis and early management. Co-relation of K-F ring in WD to the disease 
severity, disappearance with successful treatment, reappearance with non-compliant treatment aids in 
management of WD. K-F ring detection in first-degree relatives of the index case is also important. 
 
With the proposed ocular exams at baseline and at 9-months post treatment, we hope to detect any 
cataracts in the subjects and effects of the proposed radiation treatments. The questions we will have 
are how often we encounter cataracts in early Alzheimer's and whether they improve (an abscopal 
effect) after radiation therapy, even though the lenses will be excluded from the RT treatment fields. 
Exams will only be done for subjects who have at least one natural lens still present. Subjects with 
previous bilateral cataract corrections will not have ocular exams performed. 
 
2 Study Purpose 
The purpose of the study is to evaluate safety and toxicity/adverse events associated with delivery of 
low dose whole brain irradiation in subjects with early Alzheimer’s dementia according to NINCDS-
ADRDA Criteria.   
 
As a secondary goal it will establish whether or not the intervention with low dose whole brain 
irradiation stabilizes or decreases cerebral amyloid deposits and whether these correlate with the 
recognized progression of Alzheimer’s dementia.  We will also collect information from the FDG and 
Amyvid PET Scans to determine if there is any correlation between neurocognitive/quality of life scores 
and changes in amyloid plaque size, number and location.  
 
3 Study Design and Duration 
An initial 15 subjects will be enrolled in the first treatment cohort (2 Gy x 5 fractions) and will be 
followed at 9 months after completion of treatment to assess safety and any toxicity/adverse events 
associated with treatment. The second treatment cohort will not be used until the last subject in the 
first dose cohort has completed 9 months of follow up. At that point, subjects #16-30 will be enrolled in 
the second dose cohort (10 daily fractions of 2 Gy). A total of 30subjects will be enrolled and each will be 
followed for a total of 12months to assess safety and toxicity/adverse events.  

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In Cohort 1 the 15 study participants will be enrolled in total at Virginia Commonwealth University 
Hospital. Once a total combined 15 subjects are entered, this cohort will be closed. In Cohort 2, the 15 
study participants will also be enrolled in total at Virginia Commonwealth University.  Once a total 
combined 15 subjects are entered (30 subjects total), this cohort will be closed, at which point the entire 
study will be close to accrual. 
 
4 Study Objectives 
4.1 Primary Aim  
To evaluate the safety and toxicity/adverse events associated with delivery of low dose 
fractionated whole brain irradiation in subjects with early Alzheimer’s dementia (AD).CTCAE 
Version 4.0will be utilized for toxicity evaluation. 
4.2 Secondary Aims 
4.2.1 To determine whether low dose whole brain RT stabilizes or decreases cerebral amyloid    
deposits 
4.2.2 To determine by use of established neurocognitive function testing (NCT) whether low 
dose fractionated whole brain RT, utilizing the doses described, impact the disease progression 
of subjects with AD 
4.2.3 To determine if psychological function (PF) and quality of life (QOL), using the 
established testing methods, is adversely affected by use of low dose whole brain irradiation. 
4.2.4 To determine if there are correlations between NCF/PF/QOL test results and any 
changes identified by PET scan imaging based on amyloid number, size, and location. 
 
5 Subject Selection: Inclusion and Exclusion Criteria 
5.1   Inclusion Criteria 
• 
Male or female subjects at least 55 years old.  
• 
Must be a native English speaker and have the legally authorized representative 
available for consenting if one has been designated. 
• 
Able to complete neurocognitive function assessments, psychological function 
assessments, and QOL assessments administered at screening visit. 
• 
Has a Rosen Modified Hachinski Ischemic Score <4. 
• 
Has estimated survival of greater than 12 months. 
• 
Meets the clinical definition of Alzheimer’s Disease based on NINCDS –  
                ADRDA criteria and has confirmatory FDG-PET and/or Amyvid-PET scan findings. 
• 
If on any of the following medications, must be on a stable dose for 60 days or greater: 
Rivastigmine, Donepezil, Memantine, Galantamine, Tacrine. 
 

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5.2   Exclusion Criteria 
• 
Current or past history of any oncologic disease, which may mitigate the ability to 
receive low dose whole brain irradiation. 
• 
Evidence of substance abuse: alcohol/or other drugs or dependence during previous 12 
months (DSM-V criteria) 
• 
Clinically or radiographically significant evidence of stroke 
• 
Evidence of subdural hygromas or subdural hematomas 
• 
Active or recent (defined as within 3 months of screening) cerebral infection or 
hemorrhage 
• 
Any current conditions that may lead to the subject being in an immuno-compromised 
state 
• 
Any previous history of cranial radiation. 
• 
History of seizure activity 
• 
History of hydrocephalus 
• 
Evidence of active dermatological skin disease of the scalp (except Actinic Keratosis) 
• 
Evidence of clinically significant major depressive disorder according to the criteria of the 
Diagnostic and Statistical Manual of Mental Disorder, Fifth Edition (DSM-V) 
• 
Evidence of psychotic disorder or psychotic episode or bipolar affective disorder 
according to the criteria of the Diagnostic and Statistical Manual of Mental Disorder, Fifth 
Edition (DSM-V) 
• 
Evidence of active suicidal or homicidal ideation according to psychological diagnostic 
interview 
• 
Currently receiving other experimental treatments 
• 
Currently requiring full-time institutional care 
• 
Is pregnant, nursing, or incarcerated 
 
6 Low Dose Fractionated Whole Brain Radiation Therapy Guidelines 
6.1   Definitions and Schedule 
6.1.1 
Equipment 
Modality:  X-ray beams with a nominal energy between 4 and 6 MV. 
6.1.2 
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. 
6.1.3 
Localization 
 
The planning target volume shall be defined by means of a simulator. 

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6.2  Target Dose 
 
6.2.1 
Prescription Point 
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). 
6.2.2 
Dose Definition 
 
The absorbed dose is specified below in Gy to muscle. 
6.2.3 
Tissue Heterogeneity 
No corrections for bone attenuation shall be made. 
6.2.4 
Prescribed Dose and Fractionation 
The total dose to the prescription point will be 10 Gy for the initial 15 subjects, then 20 
Gy for subjects 16-30. This dose will be delivered in 5 fractions or 10 fractions of 2Gy.  
All radiation fields shall be treated once each day.  The treatment shall be given 5 days a 
week. 
6.2.5 
Dose Uniformity 
The dose variations in the target volume shall be within +7% (- 5% of the prescription-
point dose). 
6.2.6 
Treatment Interruptions 
No corrections shall be made for treatment interruptions less than seven days.  For 
interruptions greater than seven days, please contact 
 
6.3  Treatment Technique 
6.3.1 
Subject Position 
 
It is recommended that the subject be treatment supine. Use of Aquaplast  
 
immobilization mask is encouraged but not mandatory. 
6.3.2 
Beam Configuration 
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. 
6.3.3 
Field Shaping 
Shall be done with blocks that are at least 5 half-value layers (HVL) thick.  Multi-leaf 
collimation is allowed. 
 

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7 Amyvid (Florbetapir) Neuritic Plaque Guidelines 
7.1 
Indication and Usage 
Amyvid is indicated for Positron Emission Tomography (PET) imaging of the brain to 
estimate β-amyloid neuritic plaque density in adult patients with cognitive impairment 
who are being evaluated for Alzheimer’s Disease (AD) and other causes of cognitive 
decline. A negative Amyvid scan indicates sparse to no neuritic plaques and is 
inconsistent with a neuropathological diagnosis of AD at the time of image acquisition; a 
negative scan result reduces the likelihood that a patient’s cognitive impairment is due 
to AD. 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 is an 
adjunct to other diagnostic evaluations. 
7.2 
Limitations of Use 
• 
A positive Amyvid scan does not establish a diagnosis of AD or other cognitive 
disorder. 
• 
Safety and effectiveness of Amyvid have not been established for: 
• 
Predicting development of dementia or other neurologic condition; 
• 
Monitoring responses to therapies. 
7.3 
Dosage and Administration 
The recommended dose for Amyvid is 370 MBq (10 mCi), maximum 50 μg mass dose, 
administered as a single intravenous bolus in a total volume of 10 mL or less. Follow the 
injection with an intravenous flush of 0.9% sterile sodium chloride. 
7.4 
Image Acquisition Guidelines 
A 10-minute PET image should be acquired starting 30 to 50 minutes after Amyvid 
intravenous injection. The patient should 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 should include attenuation correction with resulting transaxial pixel sizes 
between2 and 3 mm. 
7.5 
Image Display and Interpretation 
Amyvid images should be interpreted only by readers who successfully complete a 
special training program. Training is provided by the manufacturer using either an in-
person tutorial or an electronic process. The objective of Amyvid image interpretation is 
to provide an estimate of the brain β-amyloid neuritic plaque density, not to make a 
clinical diagnosis. Image interpretation is performed independently of a patient’s clinical 
features and relies upon the recognition of unique image features. 

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7.6 
Radiation Dosimetry 
The estimated radiation absorbed doses for adults from intravenous injection of Amyvid 
are shown in Table 2. 
 
Table 2:  Estimated Radiation Absorbed Dose, Amyvid (Florbetapir F18 injection) 
Organ/Tissue 
Mean Absorbed Dose Per Unit 
Administered Activity (uGy/MBq) 
Adrenal 
14 
Bone- Osteogenic Cells 
28 
Bone –Red Marrow 
14 
Brain 
10 
Breasts 
6 
Gall Bladder Wall 
143 
GIᵃ - Lower Large Intestine Wall 
28 
GI – Small Intestine 
66 
GI – Stomach Wall 
12 
GI – Upper Large Intestine Wall 
74 
Heart Wall 
13 
Kidneys 
14 
Liver  
64 
Lungs 
9 
Muscle 
9 
Ovaries 
18 
Pancreas 
14 
Skin 
6 
Spleen 
9 
Testes 
7 
Thymus 
7 
Thyroid 
7 
Urinary Bladder Wall 
27 
Uterus 
16 
Total Body 
12 
Effective Dose (uSv/MBq)b 
19 
a Gastrointestinal 
b Assumed radiation weighting factor, wr, (formerly defined as quality factor, Q) of 1 for conversion of absorbed dose 
(Gray or rads) to dose equivalent (Sieverts or rem) for F 18. To obtain radiation absorbed dose in rad/mCi from above 
table, multiply the dose in μGy/MBq by 0.0037, (e.g., 14 μGy/MBq x 0.0037 =0.0518 rad/mCi) 
 
The effective dose resulting from a 370 MBq (10 mCi) dose of Amyvid is 7.0 mSv in an adult, (19 x 370 = 7030 μSv = 
7.030 mSv). The use of a CT scan to calculate attenuation correction for reconstruction of Amyvid images (as done in 
PET/CT imaging) will add radiation exposure. Diagnostic head CT scans using helical scanners administer an average of 
2.2 ± 1.3 mSv effective dose (CRCPD Publication E-07-2, 2007). The actual radiation dose is operator and scanner 
dependent. The total radiation exposure from Amyvid administration and subsequent scan on a PET/CT scanner is 
estimated to be 9 mSv. 

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8 FDG (18F-fluorodeoxyglucose) PET-CT Metabolic Imaging Guidelines 
8.1 
FDG PET-CT Subject Prep and Dosing Guidelines 
FDG PET/CT scans will be obtained on a GE Discovery 690 (General Electric Company, 
Fairfield, CT, USA) after routine subject preparation (NPO for at least 4 hours, no 
nicotine or caffeine for 12 hours, no intravenous glucose for 4 hours).  Subjects will 
receive an intravenous (IV) infusion of 18F-fluorodeoxyglucose (FDG) after resting in a 
dimly lit, quiet room for at least 15 minutes. FDG dose will be determined as follows:  
12-18 mCi (444 MBq-666MBq) <220 lbs.  16-24 mCi (592 MBq-888MBq) >220 lbs.  
Imaging will be conducted 45-60 minutes after IV FDG infusion. 
8.2 
FDG PET-CT Scam Acquisition Parameters 
Helical computed tomography (CT) scans will be obtained at 120 kVp with auto mA    
(150 max, 10 min).  FDG PET scans will be then obtained in 3D mode, with 10 minute 
emission acquisitions.  Standard filtered back projection CT and iterative PET 
reconstructions will be obtained with CT matrix size 512, 4.25 mm interval. 
8.3 
FDG PET-CT Interpretation 
All FDG PET Scans will be read by a board certified radiologist that has been credentialed 
in reading / interpreting these scans. 
 
9 Isolation of Neuronal Specific Exosomes 
Analysis of plasma exosomal protein and miRNA may provide clues to the underlying mechanisms of how 
RT improves cognitive function in AD patients.   
This approach is based on recent studies demonstrating that small membrane vesicles between 40 and 
100 nm in diameter, derived from the endosomal system, are secreted by most cell types.  They are 
isolated not only from the tissues from which they are derived but also in biological fluids such as blood, 
urine, CSF, milk, and saliva. They contain a number of interesting proteins and miRNA.  One proposed role 
for these exosomes is intercellular communication since they can fuse with the plasma membrane 
transferring their contents from one cell to another. Neural-specific exosomes isolated from the plasma 
of patients with AD contain not only elevated levels of Aβ peptides and P-S396-tau, P-T181-tau also the 
α- and β-secretases involved in cleavage of the amyloid precursor protein and the generation of Aβ 
(Seminars Cell and Developmental Biol 40:89, 2015; Alzheimers and Dementia 11:600, 2015).  In contrast 
plasma neural derived exosomes contained lower levels of survival proteins including LRP6, a mediator of 
Wnt signaling and its downstream target REST, both of which are critical for diverse neurodevelopmental 
processes (Ann.Clin. Transl.Neurol 2:769, 2015).  A 16-miRNA signature derived from exosomes from 
patients with AD was prognostic for the diseases as assessed by psychological and neuroimaging 
assessment (Molecular Psychiatry, 2014 page 1).  Many of these miRNA have been implicated in AD 
pathogenesis using mouse and cell models.  For example, hsa-miR-101 targets the 3′ untranslated region 
of APP to significantly reduce APP levels and the accumulation of Aβ.  The miR-15 family regulates Tau 

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phosphorylation through ERK1 leading to neuronal death in Neuro2a cells and primary cortical neurones. 
miR-424- 5p shares the same seed sequence as miR-15, thus belonging to the same miR-15 family.  Hsa-
miR-1306 is predicted to target the 3′ untranslated region of α-secretase responsible for the generation 
of secreted APP.  
9.1 
Sample Processing, Storage, and Analysis 
At pretreatment baseline, at 6 weeks, and at 3, 6, 9, and 12 months post-treatment, 10 
ml blood samples will be obtained by phlebotomy from each patient.  The blood 
samples will be brought to 
 laboratory on the day they are drawn and 
after centrifugation, the serum plasma is frozen in multiple 0.5 cc aliquots and stored in 
a liquid nitrogen vapor freezer for future molecular profiling analyses as described 
below.   
Once the blood samples are collected they are labeled with the protocol number, case 
ID number, collection date and time and they are then brought to 
 
laboratory for centrifugation and processing into serum samples.  These processed 
samples are stored in a locked liquid nitrogen vapor freezer within 
 Lab.  
This lab in Goodwin Research Laboratories has limited ID access control authorized by 
Massey cancer Center.  Specimen logs are maintained by 
 lab.  Personnel 
in 
 laboratory including 
 do not have access to the patient 
PHI or identifiers. 
Serum samples are used for identification of biomarkers for radiation induced toxicity   
These serum samples are also used to obtain exosomes which are released from cells 
and contain specific miRNA that are potential biomarkers for neurodegenerative 
diseases.  The miRNA is isolated from the exosomes and sequenced.  The sequence data 
is provided to 
 for further analysis with patient outcomes. 
 
10 Study Procedures 
After informed consent has been provided, the subjects in this study will have screening and pre-
treatment procedures completed prior to the study treatment. After the study treatment, subject 
will be scheduled for follow up visits and testing at 6 weeks, 3, 6, 9, and 12 months post treatment.  
10.1 
Study procedures: 
10.1.1 Screening: 
• 
The Psychological Diagnostic Interview, the Neurocognitive function tests (WTAR, 
MMSE, HVLT, BVMT-R, WMS-IV Digit Span and Coding subtests, Trailmaking Tests, 
California Verbal Fluency Tests, Pegboard Test, BNT, and JLO), the Psychological 
Function Assessments (PHQ-9 and GAD-7), and the Quality of Life Assessments 
(Quality of Life in Alzheimer’s disease (QOL-AD), Quality of Life in Late-stage 

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Dementia (QUALID), and Everyday Cognition (ECog-patient and caregiver 
questionnaires) will be completed by a neuropsychology specialist. 
• 
The medical history will be reviewed. 
• 
Data obtained from the screening visit will ensure that subjects who are enrolled in 
the trial meet criteria for early AD based on the more comprehensive battery of 
tests, as diagnosis of dementia is improved with use of quantitative measurement of 
multiple domains (31). If the subject does not meet the criteria for early AD, they 
will be withdrawn from the study prior to undergoing the Pre-Treatment 
Assessments including the FDG PET scan and AmyVID PET scan. 
10.1.2 Pre-Treatment: 
• 
The Neurocognitive function tests (not including JLO and BNT), and the Quality of 
Life Assessments will be completed by a neuropsychology specialist after at least 30 
days have elapsed since the Screening Neurocognitive function testing was 
completed. 
• 
The Ocular exam will be completed by an Ophthalmologist for subjects who have at 
least one natural lens. 
• 
A medical history and physical exam will be completed, including baseline CTCAE 
Toxicity assessment scoring. 
• 
A blood sample will be collected. A 10 ml blood samples will be obtained by 
phlebotomy from each patient.  The blood samples will be brought to 
 
 laboratory on the day they are drawn and processed as described in 
Section 9.1.   
• 
The FDG-PET scan and Amyvid PET scans will be completed. The Amyvid PET Scan is 
used to image macroscopic amyloid plaque, giving information on number, size and 
location. 
If the subject does not meet the clinical definition of AD based on NINCDS-ADRDA 
criteria with confirmatory PET findings, they will be withdrawn from the study prior to 
receiving the study radiation treatment. 
10.1.3 Study Treatment: 
• 
Cranial irradiation will be given over 5 consecutive days (M-F x1) for Cohort 1, and 
over 10 days (M-F x 2 consecutive weeks) for Cohort 2 
10.1.4 Follow-up: 
• 
Follow-up assessments will be completed at 6 weeks, 3 months, 6 months, 9 months 
and 12 months after the study treatment: 
 
At 6 weeks post-treatment, the Neurocognitive function tests (not including 
JLO and BNT), Psychological Function Tests, and Quality of Life Assessments 
will be completed by the neuropsychology specialist, medical history and 

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physical exam with concomitant medications review and CTCAE Toxicity 
assessment will be completed by a study investigator, and a blood sample 
will be collected and processed as described in Section 9.1. 
 
At 3 months post-treatment, the Neurocognitive function tests (not 
including JLO and BNT), Psychological Function Tests, and Quality of Life 
Assessments will be completed by the neuropsychology specialist, medical 
history and physical exam with concomitant medications review and CTCAE 
Toxicity assessment will be completed by a study investigator, and a blood 
sample will be collected and processed as described in Section 9.1. 
 
At 6-months post-treatment, the FDG-PET scan and Amyvid PET scan will be 
completed, concomitant medications will be reviewed by study staff, and a 
blood sample will be collected and processed as described in Section 9.1.  
 
At 9 months post-treatment, the Neurocognitive function tests (not 
including JLO and BNT), Psychological Function Tests, Quality of Life 
Assessments will be completed by the neuropsychology specialist, medical 
history and physical exam with concomitant medications review and CTCAE 
Toxicity assessment will be completed by a study investigator, and a blood 
sample will be collected and processed as described in Section 9.1. For 
subjects with at least one natural lens, the Ocular exam will be completed 
by an Ophthalmologist. 
 
At 12 months post-treatment, the Neurocognitive function tests(including 
JLO and BNT), Psychological Function Tests, Quality of Life Assessments 
neuropsychology specialist, medical history and physical exam with 
concomitant medications review, CTCAE Toxicity assessment will be 
completed by a study investigator, and a blood sample will be collected and 
processed as described in Section 9.1 
10.2 
Toxicity Assessments 
Common Terminology Criteria for Adverse Events (CTCAE, Version 4.0) will be used to 
assess any toxicity associated with this study, not only the effects on the CNS, but any 
general adverse effects which may or may not be associated with the treatment. 
Using the CTCAE Adverse Event Evaluation Form (Appendix 1), each subject will be 
assigned score at pre-treatment, and at the 6-week, 3-month, 9-month and 12-month 
follow-up visits in the following categories:   
1. Skin (CTCAE Sections: Alopecia, Dermitis radiation, Hyperpigmentation, 
Hypopigmentation)  
2. Eye (CTCAE Sections: Cataract, Dry Eye Syndrome) 
3. Ear (CTCAE Sections: Hearing Impaired) 
4. CNS (CTCAE Sections: Concentration Impairment, Memory Impairment, Neurology -
other/specify) 
5. Other (CTCAE Sections: Fatigue, Nausea, Vomiting) 

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11 LAR/Caregiver Participation 
The Legally Authorized Representative (LAR) or Caregiver will be asked to complete Everyday Cognition 
(ECog) questionnaires regarding the caregiver’s assessment of the subject’s current ability to perform 
everyday tasks in the present time and compare this to the subject’s ability to perform these same 
everyday tasks ten years previously.  For this reason, LAR/Caregivers will be asked to sign a separate 
informed consent for their participation in the study and will have specified inclusion criteria used.  
These questionnaires will be completed at the same visits (Screening, Pre-treatment, and following 
treatment at 6 weeks, 3 months, 9 months, and 12 months) that the study subject completes 
neurocognitive assessments,  and will be administered by the study neuropsychologist.  The 
LAR/Caregiver will complete the questionnaires in a different room as the study participant to ensure 
privacy and confidentiality.  The LAR/Caregiver will have the ability to decline or withdraw from 
participation in their portion of the study.  If this occurs, the study subject will continue participation as 
outlined in the protocol with no questionnaires being completed by the LAR/Caregiver. 
LAR/Caregiver Inclusion Criteria 
1. Must be the patient’s LAR or primary caregiver 
2. Must be a fluent English speaker 
3. Must be able and willing to provide consent 
4. Must be able to complete questionnaires with the neuropsychologist throughout the trial 
 
12 Study Calendar 
 
 
 
 
Follow-up (Post-Treatment) 
 
Screening 
(up to 120 
days before 
Tx) 
Pre-
Treatment 
(up to 35 days 
before Tx) 
Treat-
ment 
6 wks 
(± 1 wk)    
Post-Tx 
3 mo 
(± 1 wk)     
Post-Tx 
6 mo 
(± 1 wk)     
Post-Tx 
9 mo 
(± 1 wk)    
Post-Tx 
12 mo 
(± 1 wk)    
Post-Tx 
Psychological 
Diagnostic Interview 
X 
 
 
 
 
 
 
 
Neuro-cognitive 
function (NCF) Tests 
(JLO and BNT) 
X 
 
 
 
 
 
 
X 
Neuro-cognitive 
function (NCF) Tests 
(WTAR, MMSE, HVLT, BVMT-
R, WMS-IV, Digit span and 
Coding Subsets, Trailmaking 
Tests, California Oral Word 
Association Test, Semantic 
Fluency Tests, Pegboard 
Test) 
X 
X1 
 
X 
X 
 
X 
X 
Psychological Function 
Assessments(PHQ-9, 
GAD-7, ECog) 
X 
X1 
 
X 
X 
 
X 
X 

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Follow-up (Post-Treatment) 
 
Screening 
(up to 120 
days before 
Tx) 
Pre-
Treatment 
(up to 35 days 
before Tx) 
Treat-
ment 
6 wks 
(± 1 wk)    
Post-Tx 
3 mo 
(± 1 wk)     
Post-Tx 
6 mo 
(± 1 wk)     
Post-Tx 
9 mo 
(± 1 wk)    
Post-Tx 
12 mo 
(± 1 wk)    
Post-Tx 
Quality of Life 
Assessments (QOL-AD 
and QUALID) 
X 
X1 
 
X 
X 
 
X 
X 
Medical History 
X 
X 
 
X 
X 
 
X 
X 
Physical Exam 
 
X 
 
X 
X 
 
X 
X 
Concomitant 
Medications 
X 
X 
 
X 
X 
 
X 
X 
Ocular Exam 
 
X2, 3 
 
 
 
 
X3 
 
FDG-PET Scan 
 
X 
 
 
 
X 
 
 
AmyVID PET Scan 
 
X 
 
 
 
X 
 
 
Study Treatment: 
Cranial Irradiation 
 
 
X4 
 
 
 
 
 
Toxicity Evaluation 
(CTCAE, Version 4.0) 
 
 
X 
X 
X 
 
X 
X 
Blood Collection 
 
X5 
 
X5 
X5 
X5 
X5 
X5 
Adverse Event 
Assessment 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
1 At least 30 days must elapse between completion of NCF testing, PF questionnaires, and QOL-AD/QUALID at Screening Visit and 
same testing done at Pre-treatment Visit 
2 Initial Ocular exam can be performed any time after Subject meets eligibility criteria and up to 2 weeks after Study Treatment 
3 Ocular exams will only be done for subjects who have at least one natural lens. 
4 Cranial irradiation will be given over 5 consecutive days (M-F x1) for Cohort 1, and over 10 days (M-F x 2 consecutive weeks) for 
Cohort 2 
5  Blood draw will be performed to collect 10ml of whole blood and will be used to isolate neuronal specific exosomes for analysis of 
their protein and miRNA cargo. 
 
13 Adverse Events 
13.1 
Adverse Event (AE): 
For the purpose of this study, an Adverse Event is an untoward medical condition 
experience by a study participant during treatment or in follow up or by applicable 
guidance, regulation, or policy.  An AE is any unfavorable or unintended sign (including 
an abnormal laboratory finding), symptom or disease temporally associated with 
participation in the study, regardless of exposure to an agent or procedure, and 
regardless of whether it is considered to be caused by the agent, device, or process 
under investigation. 
Life-Threatening Adverse Event:  A life-threatening AE is any adverse event that places 
the study participant, in the clinical opinion of the investigator, at immediate risk of 
death. 

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13.2 
Serious Adverse Event (SAE): 
An SAE is defined as any untoward medical occurrence that meets any on of the 
following criteria: 
• 
Results in death or is life-threatening at the time of the event 
• 
Requires inpatient hospitalization, or prolongs a hospitalization 
• 
Results in a persistent or significant disability/incapacity 
• 
Is a congenital anomaly/birth defect (in a participant’s offspring) 
• 
Requires intervention to prevent any of the above, per the investigator/sponsor 
13.3 
Acute and Late AE/SAE Assessment 
Each subject will be monitored during the study treatment for toxicity and adverse 
events. 
Each subject will be assessed for toxicity and adverse events at the 6-week, 3-month, 9-
month and 12-month post-treatment follow-up visits. The CTCAE Adverse Event 
Evaluation Form (Appendix 1) will be used to assign a score in each of the five categories 
as listed in section 10.2.  
If at any time during the study there is an increase of 2 or more grades in any category 
section other than Alopecia, an evaluation by the Data Safety Monitoring Board 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 increase in CTCAE section score.  The records and information related to the 
event will be reported to the IRB using standard reporting mechanism. 
In addition, any general adverse effect will also be scored which may or may not be 
related to the treatment delivered. 
All SAEs are to be followed by investigator until resolution, stabilization, scientifically 
and clinically satisfactory explanation as to attribution and etiology, or until subject is 
lost to follow up. 
13.4 
Anticipated Treatment Toxicities (Acute and Late) 
Risk 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.   
5. Visual changes.    
6. Skin reaction. 

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reporting procedures of the IRB, detailing but not limited to data collected, quality of data collected, 
toxicity scoring, any changes in the physical exam, and imaging information.  If there is a disagreement 
between the two DSMB members, a third arbitrator who has extensive knowledge of Neurology and 
Alzheimer’s Disease, will be used to make the final determination.  
We will also monitor MMSE scores periodically during follow up.  Based on literature review the 
following will be noted:  it is expected that the MMSE score will drop about four points / year.  If any 
subject exhibits a greater than four-point drop in the MMSE score they will have review of case 
parameter to determine if this drop should be assigned as treatment related or is a result of other 
causes. Any score change found to be related to therapy will be reported through the DMSB to IRB for 
review and comment.  No new subjects will be allowed on Clinical Trial until study is re-approved or 
accrual by IRB. 
 
16 Endpoints 
16.1 
Primary Endpoint 
To evaluate safety and toxicity/adverse event associated with delivery of low dose 
fractionated whole brain irradiation in subjects with Alzheimer’s dementia (AD). CTCAE 
Version 4.0 will be utilized, for toxicity evaluation while neurocognitive functioning tests 
in Table 1 will be used to evaluate any neurocognitive changes.  
16.1.1 Treatment Toxicities (Acute and Late) 
Risk 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.   
5. Visual changes.    
6. Skin reaction. 
The following are the grades, or severity, of Adverse Event that is common with the 
planned radiation dose for this trial based on the Criteria: 
• 
Skin:  Grade 2 (Alopecia) 
• 
Eye:  Grade 0 
• 
Ear: Grade 1 
• 
CNS:  Grade 1 
• 
Other: Grade 1 

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16.1.2 To determine, using established neurocognitive testing, if low dose fractionated 
whole brain irradiation described may impact the neurocognitive progression of 
subjects with AD.  
16.2 
Secondary Endpoints 
16.2.1 To determine if low dose whole brain radiation therapy (RT) stabilizes or 
decreases cerebral amyloid. 
16.2.2 To determine if neurocognitive function (NCF), psychological function (PF), and 
quality of life (QOL), as assess by accepted testing methods, is stabilized or improved by 
low dose whole brain RT.  
16.2.3 To determine if there are correlations between neurocognitive 
test/psychological functioning/quality of life test results and results of FDG and Amyvid 
PET imaging for amyloid number, size and location. 
 
17 Statistical Plan 
Data will be entered on an ongoing basis and managed using REDCap electronic data capture tools 
hosted at VCU. REDCap (Research Electronic Data Capture) is a secure, web-based application designed 
to support data capture for research studies. REDCap is provided to the VCU community by Award 
Number UL1TR000058 from the National Center for Research Resources (50). 
For the primary endpoint, the toxicity scores based on CTCAE toxicity grading system will be compared 
between each radiation dose group using 2-sample inference procedures to see if low dose radiation 
affects safety and toxicity. For NCT data, the data will consist of descriptive statistics for demographic 
data and means and standard deviations of outcome measures. To control for baseline 
neuropsychological status, repeated measures ANOVA will be used to explore within and between group 
differences on target neuropsychological outcomes. Estimated effect sizes (i.e. Cohen’s d) calculated 
from this RCT will be used in later power analyses to determine necessary sample size for an efficacy 
study of these programs in individuals with AD.  
For the secondary endpoints, paired 2-sample tests would be used to determine 1) whether low dose 
whole brain RT stabilizes or decreases cerebral amyloid deposits between the baseline and the end of 
the study; 2) whether low dose whole brain RT stabilizes or improves NCF, PF, and QOL. 
Pearson’s correlation coefficient or Spearman's rank correlation coefficient would be used to assess the 
relationship about NCF, PF and/or QOL results with PET imaging with respect to amyloid accumulations, 
including but not limiting to number, size and location.   
 

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18 Plan for Loss to Follow-up 
In order to prevent biased results of the clinical trial due to subjects who drop out, a plan has been 
established to reduce or eliminate loss to follow up. The inclusion/exclusion criteria and consent process 
stresses to the clinical trial participants the importance of follow up to participate in the clinical trial.  
Study staff is instructed to communicate to study participants’ the dates and times of their follow up 
appointments, make reminder calls within 1 week before scheduled appointment, contact subject by 
phone and/or letter for missed appointments and obtain secondary phone numbers for emergency 
contacts to assist with maintaining follow up appointments. 
• 
For each subject that does not complete follow up, the sponsor will investigate/find, record and 
list the reasons for loss to follow-up (e.g., subject moved out of state, etc.), and also record the 
time of the missed follow up. 
• 
In case of a subject drop out (e.g., move out-of-state, or subject’s death) before the scheduled 
visit time (e.g., 3 months, 9 months or 12 months), the sponsor may consider a replacement 
with a new subject. 

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Appendix 1: CTCAE Adverse Event Evaluation Form 

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