A Reader Study to Assess Accuracy and Reliability of Flortaucipir F 18 PET Scan Interpretation
Phase: PHASE3
Conditions: Alzheimer Disease
Sponsor: Avid Radiopharmaceuticals

18F-AV-1451-FR01 Protocol Amendment 1 
 
A Reader Study to Assess Accuracy and Reliability of Flortaucipir F 18 PET Scan Interpretation 
 
NCT03901092 
Approval date: 21 Mar 2019

Protocol: 18F-AV-1451-FR01 Confidential 
 
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Protocol Number:  
 
18F-AV-1451-FR01 
“A reader study to assess accuracy and reliability of flortaucipir F 18 PET scan interpretation.” 
 
 
Date and Version: 
21MAR2019 
Amendment 1 
Final  
 
Name of Compound: Flortaucipir F 18 (18F-AV-1451) 
 
Sponsor: 
Avid Radiopharmaceuticals, Inc. 
Philadelphia, Pennsylvania USA 
 
 
 
CONFIDENTIAL 
This material is the property of Avid Radiopharmaceuticals, Inc. (Avid).  The information is confidential and 
is to be used only in connection with matters authorized by Avid and no part of it is to be disclosed to others 
without prior written permission from Avid. 

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TABLE OF CONTENTS 
. 
1. 
Rationale/Introduction ......................................................................................................................... 3 
2. 
Study Objectives .................................................................................................................................. 4 
2.1. 
Primary Objectives ......................................................................................................................... 4 
2.2. 
Secondary Objectives ..................................................................................................................... 4 
3. 
Study Design ........................................................................................................................................ 5 
4. 
Procedures and Methods ...................................................................................................................... 6 
4.1. 
Selection and Number of Investigators (Readers) .......................................................................... 6 
4.2. 
Selection/Number of Images .......................................................................................................... 6 
4.3. 
Blinded Read Method ..................................................................................................................... 6 
4.4. 
Data Collection ............................................................................................................................... 7 
4.5. 
Good Clinical Practice and Monitoring .......................................................................................... 7 
5. 
Statistical Methods ............................................................................................................................... 8 
5.1. 
General Statistical Considerations .................................................................................................. 8 
5.2. 
Population for Analysis .................................................................................................................. 8 
5.2.1. 
Analysis Population for Scan Accuracy Assessment ............................................................ 8 
5.2.2. 
Analysis Population for Scan Interpretation Precision Assessment ...................................... 8 
5.3. 
Power Analysis ............................................................................................................................... 8 
5.4. 
Efficacy Analysis. .......................................................................................................................... 9 
5.4.1. 
Primary Analyses .................................................................................................................. 9 
5.4.1.1. 
Assessing the Accuracy of Flortaucipir F 18 PET Scan ................................................. 9 
5.4.1.2. 
Assessing the Precision of Flortaucipir F 18 PET Scan Reads ..................................... 11 
5.4.2. 
Secondary Analyses ............................................................................................................ 11 
5.4.2.1. 
Analyses for Secondary Objective 1 ............................................................................. 12 
5.4.2.2. 
Analysis for Secondary Objective 2.............................................................................. 13 
5.4.2.3. 
Analysis for Secondary Objective 3.............................................................................. 13 
5.4.2.4. 
Analysis for Secondary Objective 4.............................................................................. 13 
6. 
Study Documentation ........................................................................................................................ 14 
6.1. 
Investigators (Readers) ................................................................................................................. 14 
6.2. 
Use of Study Scan Data for Research Purposes ........................................................................... 14 
7. 
References .......................................................................................................................................... 15 
 

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1. Rationale/Introduction 
In prior clinical studies supporting accuracy and reliability of flortaucipir F 18 positron emission 
tomography (PET) scans, interpretation has been shown to have acceptable performance when 
compared to the autopsy truth standard (TS).  
This study is designed to further evaluate the accuracy and reliability of multiple readers’ 
interpretations of flortaucipir F 18 PET scans, not only from those subjects who came to autopsy, 
but also in the intended population for clinical use.  

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2. Study Objectives 
2.1. Primary Objectives  
• Test the relationship between ante-mortem flortaucipir F 18 PET imaging and tau 
neurofibrillary pathology associated with Alzheimer’s disease (AD), as measured at autopsy.  
• Assess inter-reader reliability.  
2.2. Secondary Objectives  
• Test the relationship between ante-mortem flortaucipir F 18 PET imaging of an AD pattern 
with uptake beyond the temporal/occipital regions (i.e., τAD++; see Table 1) and tau 
neurofibrillary pathology associated with AD, as measured at autopsy. 
• Assess inter-reader reliability for scans with an AD pattern that is beyond the 
temporal/occipital regions (i.e., τAD++; see Table 1). 
• Assess agreement among readers of flortaucipir F 18 PET scans in subjects known to be from 
the intended population (interpretation of scans from Avid Study 18F-AV-1451-A05 [A05]). 
• Assess intra-reader reliability for scans read twice by each reader. 

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3. Study Design 
All training and reads will be conducted by an imaging contract research organization (CRO) as 
described in the imaging review charter (IRC).  Five readers will be trained in-person on the 
flortaucipir F 18 PET scan read methodology using the previously developed read method.  The 
training will consist of teaching the readers the steps of interpretation, followed by a practice 
session using a set of demonstration and practice cases. After the training phase is complete, 
readers will then independently read 262 scans; 83 from Study 18F-AV-1451-A16 (A16) and 159 
from Study A05.  
The study population for Study A16 (18F-AV-1451-A16:  A clinico-pathological study of the 
correspondence between 18F-AV-1451 PET imaging and post-mortem assessment of tau 
pathology) consisted of subjects at the end of life, who were imaged with flortaucipir F 18 and 
came to autopsy.  Subjects were enrolled in the study with the intent of capturing a range of tau 
neurofibrillary pathology in AD.  
The study population for Study A05 confirmatory cohort (18F-AV-1451-A05:  An open label, 
multicenter study, evaluating the safety and imaging characteristics of 18F-AV-1451 in 
cognitively healthy volunteers, subjects with mild cognitive impairment, and subjects with 
Alzheimer’s disease) consisted of subjects with cognitive impairment who had mild cognitive 
impairment (MCI) or dementia with a suspected neurodegenerative cause, and a Mini Mental 
State Examination (MMSE) score of 20-27, inclusive. Subjects were imaged with flortaucipir 
F 18 and followed longitudinally for 18 months to assess the subsequent rate of cognitive 
decline.  
 
 

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4. Procedures and Methods 
4.1. Selection and Number of Investigators (Readers)  
Five qualified physicians will perform the blinded reads.  Readers will be selected using the 
following criteria: 
• Board Certified in radiology or nuclear medicine 
• Experience interpreting PET scans 
• Have not received training on the Avid flortaucipir F 18 read methodology   
4.2. Selection/Number of Images  
Two hundred and forty-two unique scans will be read for this study, comprised of the following: 
• All 83 subjects from Study A16 (primary and supplemental) who have a valid scan and 
autopsy 
• All 159 subjects from the Study A05 confirmatory cohort who have a valid scan 
• In addition, a sub-set of 20 randomly selected cases  will be used for intra-reader 
reliability purposes for a total of 262 scan reads  
4.3. Blinded Read Method  
Readers will be blinded to all demographic and clinical data.  All readers will be trained in-
person on the steps of image interpretation, using a set of demonstration and practice cases, prior 
to starting their independent reads.  A copy of the training materials will be provided to each 
reader for reference.  The read methodology is briefly outlined below. 
After scaling images to the cerebellar reference region and selecting an appropriate color scale, 
regions of the neocortex (the posterolateral temporal [PLT], occipital, parietal, and frontal 
regions) are evaluated for increased tracer uptake; and scans are interpreted as either not 
consistent (τAD-), consistent with an AD pattern (τAD+), or consistent with an AD pattern and 
likely to progress (τAD++) using the criteria shown in Table 1.  
 
 
 

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Table 1. 
Clinical Read Method Criteria  
Read Outcome 
Objective Image Features 
Not consistent with AD pattern 
(τAD-) 
No increased neocortical activity, or increased neocortical 
activity  isolated to the mesial temporal, anterolateral temporal, 
and/or frontal regions. 
AD pattern (τAD) 
τAD+ 
In either hemisphere, increased neocortical activity in the 
posterolateral temporal (PLT) or occipital region(s).  
τAD++ 
In either hemisphere, increased neocortical activity in the 
parietal/precuneus region(s), or frontal region(s) with increased 
uptake in the PLT, parietal, or occipital region(s).  
4.4. Data Collection  
Data will be collected using electronic case report forms (eCRFs).   
4.5. Good Clinical Practice and Monitoring  
All clinical studies performed under the direction of Avid/CRO will be conducted in accordance 
with applicable regulatory requirements and International Conference on Harmonization, Good 
Clinical Practice, and Avid/CRO Standard Operating Procedures.  Monitoring of study data will 
be performed by the Imaging CRO and will be performed in accordance with their standard 
operating procedures. 

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5. Statistical Methods 
5.1. General Statistical Considerations  
All statistical analyses will be performed using SAS® version 9.0 or higher.  The specific 
analyses to address the objectives will be described in the Statistical Analysis Plan. 
5.2. Population for Analysis  
Five readers will independently interpret the flortaucipir F 18 PET scans collected from 
2 completed Avid Studies, A16 and A05.  No new subjects will be enrolled for purposes of this 
study.  All 83 autopsy scans were collected from Study A16 (67 from main study and 16 from 
supplementary autopsy cohort (SAC)).  All 159 scans from Study A05 confirmatory cohort will 
be included.  
Valid images will be considered unevaluable only if 3 out of 5 independent readers declare the 
image unevaluable for the same reason.  Subjects with invalid or unevaluable PET data will be 
excluded from analyses.  Criteria for declaring an image invalid or not evaluable will be 
specified in advance in the IRC.  
5.2.1. Analysis Population for Scan Accuracy Assessment  
Flortaucipir F 18 scan accuracy (sensitivity and specificity) will be assessed using all 83 cases 
from Study A16 that had an autopsy diagnosis by pathologist panel, including: 
• 3 front-runners 
• 64 main study autopsy cases 
• 16 autopsy cases collected under SAC 
5.2.2. Analysis Population for Scan Interpretation Precision 
Assessment  
The precision of flortaucipir F 18 PET scan interpretation will be assessed in 2 ways:  inter-
reader (i.e., reader-to-reader) reliability, and intra-reader reliability (i.e., agreement between the 
repeated reads on same scan from same reader).  The inter-reader reliability will be assessed 
using all 242 scans included for this study (83 Study A16 scans and 159 Study A05 scans).  The 
inter-reader reliability will also be assessed separately on the 159 Study A05 scans (i.e., the 
targeted population for clinical usage), and on the 83 Study A16 scans.  Twenty scans will be 
randomly selected and will be read twice by the 5 readers in a randomized sequence, along with 
all the other scans.  The repeated reads on these 20 scans will be used to assess the intra-reader 
reliability.   
5.3. Power Analysis   
Assuming 80% sensitivity and 80% specificity, 14 TS positive or TS negative cases will be 
needed to show the lower bounds of 95% confidence interval (CI; 2-sided) greater than 50%, for 

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either sensitivity or specificity, with a Wilson score method to calculate the 95% CI.  Out of the 
83 Study A16 cases with autopsy results, 47 were neurofibrillary tangle (NFT) stage B3 per 
pathologist’s panel diagnosis (TS positive for primary analysis 1), and 36 were NFT stage B2 or 
lower (TS negative for primary analysis 1); 41 were high AD neuropathologic change (ADNC) 
according to panel diagnosis (TS positive for primary analysis 2), and 42 were low to 
intermediate  ADNC  (TS negative for primary analysis 2).  Therefore, this sample size provides 
adequate power to assess the accuracy of flortaucipir F 18 PET scan in detecting underlying 
pathological changes. 
Fleiss’ Kappa will be used to assess the reader-to-reader consistency in flortaucipir F 18 scan 
visual interpretation.  Five independent qualified physicians will read 242 unique scans 
(83 autopsy scans from Study A16 and 159 scans from Study A05).  Assuming the Fleiss’ Kappa 
is expected to be 0.7, this sample size provides over 90% power in detecting a kappa value 
greater than 0.6, under a two-sided type I error rate of 0.05. 
5.4. Efficacy Analysis. 
5.4.1. Primary Analyses  
The primary objectives for this study are to assess both the accuracy and precision of flortaucipir 
F 18 PET imaging to detect tau neurofibrillary pathology associated with (AD).  
5.4.1.1. Assessing the Accuracy of Flortaucipir F 18 PET Scan  
Analyses for Primary Objective 1: 
For the first primary objective, 2 analyses will be planned to assess the accuracy of flortaucipir 
F 18 PET imaging in detecting tau pathology, as measured at autopsy. 
Primary Analysis 1  
The diagnostic performance (sensitivity/specificity) of 5 independent readers’ interpretations of 
ante-mortem flortaucipir F 18 PET imaging for detection of a pattern of flortaucipir F 18 
neocortical uptake that corresponds to NFT Score of B3 (Hyman et al. 2012; Montine et al. 
2012) at autopsy will be evaluated; and 
Primary Analysis 2  
The diagnostic performance (sensitivity/specificity) of 5 independent readers’ interpretations of 
ante-mortem flortaucipir F 18 PET imaging for detection of a pattern of flortaucipir F 18 
neocortical uptake that corresponds to high levels of AD neuropathologic change as defined by 
National Institute on Aging-Alzheimer's Association (NIA-AA) criteria (Hyman et al. 2012) will 
be evaluated.  For individuals with cognitive impairment, high levels of AD neuropathologic 
change are considered adequate to explain cognitive impairment or dementia symptoms.  
For Primary Analysis 1, the hypothesis to be tested is that for the same 3 out of 5 independent 
readers;  the lower bound of the two-sided 95% CI for both sensitivity and the specificity of 
flortaucipir F 18 PET reading results will be ≥50%.  As detailed in Section 5.4.1, Table 2, NFT 
scores for autopsy cases will be categorized as either B0/B1/B2 or B3 level; and will serve as the 
NFT Score TS for this analysis.  Flortaucipir F 18 PET imaging will be classified by each reader 

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as either neocortical uptake not consistent with AD (τAD-), or neocortical uptake consistent with 
AD (τAD+) or neocortical uptake consistent with AD and likely to progress (τAD++).  
Sensitivity and specificity will be calculated for each reader as the proportions of true positive 
(TP) and true negative (TN) cases correctly identified as such, according to Table 2 below: 
Table 2. 
Primary Objective 1 Analysis 1:  Diagnostic Performance 
Calculations for flortaucipir F 18 PET Scan Reader Interpretation 
vs. Autopsy NFT Score Truth Standard  
 
Autopsy NFT Score TS 
Physician Reader Interpretation 
NFT Score B3 
[Truth Positive] 
NFT Score B0–B2 
[Truth Negative] 
Flortaucipir F 18 neocortical uptake; AD 
pattern (τAD+/τAD++) 
True Positive (TP) 
False Positive (FP) 
Flortaucipir F 18 neocortical uptake not 
consistent with AD (τAD-) 
False Negative (FN) 
True Negative (TN) 
Two-sided 95% CIs for sensitivity and specificity will be calculated using the Wilson score 
method.  The first primary endpoint is considered to be met if for the same 3 out of 5 readers, the 
lower bound of the 95% CIs for both sensitivity and specificity are ≥50% (i.e., statistically 
significant at two-sided significance level of 0.05).  
Like Primary Analysis 1, the hypothesis to be tested for Primary Analysis 2 is that for the same 
3 out of 5 readers, the lower bound of the 95% CIs for both sensitivity and the specificity will be 
≥50%.  For Primary Analysis 2, autopsy cases will be categorized as either not, low, or 
intermediate versus high level of AD neuropathologic change according to NIA-AA criteria, 
considering Braak stage, Thal plaque score, and Consortium to Establish a Registry for 
Alzheimer’s Disease (CERAD) amyloid neuritic plaque score, and this level of AD 
neuropathologic change will be used as the NIA-AA autopsy diagnosis TS as detailed in Section 
5.4.1 Table 3.  Flortaucipir F 18 PET images will be interpreted by visual examination as either 
τAD- or τAD+/τAD++ as for Primary Analysis 1.  Sensitivity and specificity will then be 
calculated for each reader as the proportions of TP and TN cases correctly identified as such, 
according to Table 3 below: 
 
 
 

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Table 3. 
Primary Objective 1 Analysis 2:  Diagnostic Performance 
Calculations for Flortaucipir F 18 PET Scan Reader Interpretation 
vs. NIA-AA Autopsy Diagnosis Truth Standard  
 
NIA-AA Autopsy Diagnosis TS 
Physician Reader Interpretation 
High 
AD Neuropathologic 
Change 
[Truth Positive] 
Not, Low, or Intermediate 
AD Neuropathologic Change 
[Truth Negative] 
Flortaucipir F 18  neocortical uptake; 
AD pattern (τAD+, τAD++) 
True Positive (TP) 
False Positive (FP) 
Flortaucipir F 18  neocortical uptake; 
not consistent with AD pattern (τAD-) 
False Negative (FN) 
True Negative (TN) 
 
Two-sided 95% CIs will be calculated using the Wilson score method.  The second primary 
endpoint is met if for the same 3 out of 5 readers, the lower bounds of the 95% CIs for both 
sensitivity and specificity are ≥50%. 
The pathological diagnosis (for both NFT score TS and NIA-AA autopsy diagnosis TS) for 
Study A16 SAC cases were based on tissue samplings from 1 side of brain.  Therefore, the reads 
from the corresponding hemisphere upon which the pathological diagnosis was based on will be 
used for primary analyses 1 and 2. 
5.4.1.2. Assessing the Precision of Flortaucipir F 18 PET Scan Reads  
The second primary objective will assess inter-reader reliability. 
Primary Objective Analysis 2 
The inter-reader reliability of flortaucipir F 18 PET scan visual interpretation will be assessed 
using kappa statistics. Fleiss’ Kappa and the associated 95% CI will be calculated based on 
5 readers’ visual interpretations on the 242 scans (comprised of 83 scans from Study A16 
autopsy cases, and 159 cases from Study A05).  The p-value will be calculated using normal 
approximation method.  The lower bound of the 95% CI for Fleiss’ Kappa must be greater than 
or equal to 0.6 to meet the inter-reader reliability criterion.  If the scan is selected (by random) to 
be read twice for the intra-reader reliability assessment, the first read will be used for the second 
primary objective analysis; for Study A16 SAC cases; the overall reads (using both hemispheres) 
from each reader will be used for the second primary objective analysis. 
5.4.2. Secondary Analyses  
Four secondary objectives/analyses will further evaluate the precision of flortaucipir PET scan 
results.   

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5.4.2.1. Analyses for Secondary Objective 1 
With the same TS as used in primary analyses 1 and 2, these secondary analyses will assess the 
diagnostic performance (sensitivity/specificity) of a τAD++ pattern found on flortaucipir PET 
scan interpretation as below: 
Table 4. 
Secondary Objective 1 Analysis 1:  Diagnostic Performance 
Calculations for Flortaucipir F 18 PET Scan Reader Interpretation 
vs. Autopsy NFT Score Truth Standard  
 
Autopsy NFT Score TS 
Physician Reader Interpretation 
NFT Score B3 
[Truth Positive] 
NFT Score B0–B2 
[Truth Negative] 
Flortaucipir F 18  neocortical uptake; 
τAD++ pattern 
True Positive (TP) 
False Positive (FP) 
Flortaucipir F 18  neocortical uptake; non-
τAD++ pattern (τAD- or τAD+) 
False Negative (FN) 
True Negative (TN) 
 
Table 5. 
Secondary Objective 1 Analysis 2:  Diagnostic Performance 
Calculations for Flortaucipir F 18 PET Scan Reader Interpretation 
vs. NIA-AA Autopsy Diagnosis Truth Standard 
 
NIA-AA Autopsy Diagnosis TS 
Physician Reader Interpretation 
High 
AD Neuropathologic 
Change 
[Truth Positive] 
Not, Low, or Intermediate 
AD Neuropathologic 
Change 
[Truth Negative] 
Flortaucipir F 18  neocortical uptake; 
τAD++ pattern 
True Positive (TP) 
False Positive (FP) 
Flortaucipir F 18  neocortical uptake; 
non-τAD++ pattern (τAD- or τAD+) 
False Negative (FN) 
True Negative (TN) 
 
Two-sided 95% CIs will be calculated using the Wilson score method.  The second primary 
endpoint is met if for the same 3 out of 5 readers, the lower bounds of the 95% CIs for both 
sensitivity and specificity are ≥50%. 
The pathological diagnosis (for both NFT score TS and NIA-AA autopsy diagnosis TS) for 
Study A16 SAC cases were based on tissue samplings from 1 side of the brain.  Therefore, the 

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reads from the corresponding hemisphere upon which the pathological diagnosis was based on 
will be used for secondary objective 1, analyses 1 and 2. 
For both analyses as listed above, the hypotheses for testing are that for the same 3 out of 
5 readers, the lower bound of the 95% CIs for both sensitivity and the specificity will be ≥50%. 
5.4.2.2. Analysis for Secondary Objective 2 
Like the analysis for primary objective 2, kappa statistics will be used to assess inter-reader 
reliability of flortaucipir F 18 PET scan visual interpretation with a τAD++ pattern.  Fleiss’ 
Kappa and the associated 95% CI will be calculated based on 5 readers’ visual interpretations on 
the 242 scans (comprised of 83 scans from Study A16 autopsy cases, and 159 cases from Study 
A05). The p-value will be calculated using a normal approximation method.  The lower bound of 
the 95% CI for Fleiss’ Kappa must be greater than or equal to 0.6 to meet the inter-reader 
reliability criterion.  If the scan is selected (by random) to be read twice for the intra-reader 
reliability assessment, the first read will be used for this analysis; for Study A16 SAC cases, the 
overall reads (using both hemispheres) from each reader will be used for this analysis. 
5.4.2.3. Analysis for Secondary Objective 3  
For this objective, inter-reader reliability of flortaucipir F 18 PET scan visual interpretation in 
the Study A05 scans, a population similar to the intended population for clinical use will be 
assessed similar to the second primary objective analysis except that the Fleiss’ Kappa will be 
calculated based on 5 readers’ visual interpretations on the 159 scans from Study A05.  If any of 
the scans are selected (by random) to be read twice for the intra-reader reliability assessment, the 
first read will be used for this analysis. As an exploratory analysis, a similar analysis will be 
conducted using Study A16 scans. 
5.4.2.4. Analysis for Secondary Objective 4 
Twenty scans will be randomly selected for this analysis, and the 5 readers will read them in 
random sequence along with other scans.  Cohen’s Kappa will be calculated for each of these 5 
readers, based on these 20 scans read repeatedly to assess the intra-reader reliability of 
flortaucipir F 18 PET scan visual interpretation.  The 95% CI as well as p-values will be 
calculated using normal approximation method.  

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6. Study Documentation  
Avid will be responsible for the submission of the protocol to the Instututional Review 
Board/Independent Ethics Committee for regulatory approval prior to start of the study.  
All data required by the protocol will be recorded in the eCRF.  Completed eCRFs may need to 
be made available for an audit by the United States Food and Drug Administration or other 
international regulatory authorities at any time. The eCRFs and all other records will be filed in 
accordance with applicable laws and regulations.  
6.1. Investigators (Readers)  
Readers must supply Avid with the following documentation prior to performing any tasks 
associated with this protocol: 
• Signed and dated 1572 
• Signed and dated curriculum vitae  
• Medical license  
• Financial disclosure form  
In order to ensure blinding, readers will not be provided a copy of the protocol for review; 
therefore, a Protocol Signature Page will not be collected as part of the trial master file.  
6.2. Use of Study Scan Data for Research Purposes  
Patients who participated in the parent Studies A16 and A05 consented to the use of their data 
(including scans) for future research purposes.  All data (scans) will be anonymized and 
confidential for the purposes of this study.  Additional details around the process for 
anonymizing scans can be found in the IRC.  

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7. References 
Hyman BT, Phelps CH, Beach TG, Bigio EH, Cairns NJ, Carrillo MC, Dickson DW, Duyckaerts 
C, Frosch MP, Masliah E, Mirra SS, Nelson PT, Schneider JA, Thal DR, Thies B, Trojanowski 
JQ, Vinters HV, Montine TJ. National Institute on Aging-Alzheimer's Association guidelines 
for the neuropathologic assessment of alzheimer's disease. Alzheimers Dement. 
2012;8(1):1-13. 
Montine TJ, Phelps CH, Beach TG, Bigio EH, Cairns NJ, Dickson DW, Duyckaerts C, Frosch 
MP, Masliah E, Mirra SS, Nelson PT, Schneider JA, Thal DR, Trojanowski JQ, Vinters HV, 
Hyman BT; National Institute on Aging; Alzheimer’s Association.. National Institute on 
Aging-Alzheimer’s Association guidelines for the neuropathologic assessment of alzheimer’s 
disease: a practical approach. Acta Neuropathol. 2012;123(1):1-11.