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1.  Neuropathological and biochemical assessments of an Alzheimer’s disease patient treated with the γ-secretase inhibitor semagacestat 
Amyloid deposition has been implicated as the key determinant of Alzheimer’s disease (AD) pathogenesis. Interventions to antagonize amyloid accumulation and mitigate dementia are now under active investigation. We conducted a combined clinical, biochemical and neuropathological assessment of a participant in a clinical trial of the γ-secretase inhibitor, semagacestat. This patient received a daily oral dose of 140 mg of semagacestat for approximately 76 weeks. Levels of brain amyloid-β (Aβ) peptides were quantified using enzyme-linked immunosorbent assays (ELISA). Western blot/scanning densitometry was performed to reveal BACE1, presenilin1, amyloid precursor protein (APP) and its proteolysis-produced C-terminal peptides APP-CT99 and APP-CT83 as well as several γ-secretase substrates. To serve as a frame of reference, the ELISA and Western analyses were performed in parallel on samples from neuropathologically confirmed non-demented control (NDC) and AD subjects who did not receive semagacestat. Neuropathology findings confirmed a diagnosis of AD with frequent amyloid deposits and neurofibrillary tangles in most areas of the cortex and subcortical nuclei as well as cerebellar amyloid plaques. Mean levels of Tris-soluble Aβ40 and glass-distilled formic acid (GDFA)/guanidine hydrochloride (GHCl)-extractable Aβ40 in the frontal lobe and GDFA/GHCl-soluble Aβ40 in the temporal lobe were increased 4.2, 9.5 and 7.7-fold, respectively, in the semagacestat-treated subject compared to those observed in the non-treated AD group. In addition, GDFA/GHCl-extracted Aβ42 was increased 2-fold in the temporal lobe relative to non-treated AD cases. No major changes in APP, β- and γ-secretase and CT99/CT83 were observed between the semagacestat-treated subject compared to either NDC or AD cases. Furthermore, the levels of γ-secretase substrates in the semagacestat-treated subject and the reference groups were also similar. Interestingly, there were significant alterations in the levels of several γ-secretase substrates between the NDC and non-treated AD subjects. This is the first reported case study of an individual enrolled in the semagacestat clinical trial. The subject of this study remained alive for ~7 months after treatment termination, therefore it is difficult to conclude whether the outcomes observed represent a consequence of semagacestat therapy. Additional evaluations of trial participants, including several who expired during the course of treatment, may provide vital clarification regarding the impacts and aftermath of γ-secretase inhibition.
PMCID: PMC4299724  PMID: 25628963
Alzheimer’s disease; semagacestat immunotherapy; Alzheimer’s clinical trial; γ-secretase; γ-secretase inhibitors; γ-secretase substrates; amyloid-β
2.  Type 2 diabetes is associated with increased Alzheimer’s disease neuropathology in ApoE ε4 Carriers 
Current Alzheimer research  2013;10(6):654-659.
Past studies of Alzheimer’s disease (AD) pathology association with diabetes mellitus type 2 (DM2) have provided conflicting results. While several studies indicate that subjects with comorbid AD and DM2 have less AD pathology, others have found no significant differences in AD pathology between the two groups. Other studies have indicated that individuals with AD and DM2 have significantly greater neuropathology than AD individuals who do not have DM2. Additional research has demonstrated that ApoE ε4 carriers with AD and DM2 have significantly greater pathology than ApoE ε4 non-carriers.
Data on clinically and pathologically diagnosed Alzheimer’s disease (NINDS-ADRDA clinically and NIA Reagan intermediate or high pathologically) with DM2 (n= 40) and those without DM2 (n= 322) from the Banner Sun Health Research Institute Brain and Body Donation Program were obtained for this study. Plaque and tangle scores from the frontal, parietal, temporal, entorhinal and hippocampal regions were compared between the DM2+ and DM2 − groups. In addition, total plaque count, total tangle count, and Braak scores were also compared between groups. Similar analyses were carried out to discern differences between ApoE ε4 carriers and non-carriers with AD and DM2.
There were no significant differences in plaque and tangle pathology between DM2+ and DM2 − groups. Logistic regression analyses, which accounted for the effects of ApoE ε4 carrier status and age at death, found no association between total plaque [OR 1.05 (0.87, 1.27), p = .60] or total tangle [OR 0.97 (0.89, 1.07) p = .58] counts and DM2 status. Chi-square analysis found no significant association between ApoE ε4 carrier status and DM2 status [χ2 = 0.30 (df = 1), p = .58]. Within the DM2+ group, ApoE ε4 carriers had significantly greater plaque and tangle pathology when compared to DM2+ ApoE ε4 non-carriers.
Overall, the presence of DM2 does not affect plaque and tangle burden in a sample of clinically and pathologically confirmed AD cases. Among AD individuals with DM2, those who are ApoE ε4 carriers had significantly greater neuropathology than ApoE ε4 non-carriers. The presence of ApoE ε4 appears to exacerbate AD neuropathology in the presence of DM2.
PMCID: PMC4105218  PMID: 23627755
3.  Comparative Analysis of the Alzheimer’s Questionnaire (AQ) with the CDR Sum of Boxes, MoCA, and MMSE 
Alzheimer disease and associated disorders  2012;10.1097/WAD.0b013e3182769731.
The Alzheimer’s Questionnaire (AQ) has been established as a valid and accurate informant-based screening questionnaire for Alzheimer’s disease (AD) and amnestic mild cognitive impairment (aMCI). Although the AQ’s validity and diagnostic accuracy has been established, its performance in comparison to other instruments has not. 39 amnestic mild cognitive impairment (aMCI) cases and 34 Alzheimer’s disease (AD) cases were matched on age, education, and gender to 73 cognitively normal individuals. The sample had a mean age of 82.54±7.77 and a mean education level of 14.61±2.61 years. The diagnostic accuracy of the CDR Sum of Boxes, Mini Mental State Exam (MMSE), Montreal Cognitive Assessment (MoCA), were compared to the AQ. The AQ correlated strongly with the CDR Sum of Boxes (r = .79) and demonstrated similar diagnostic accuracy with the MoCA and MMSE. These results suggest that the AQ is comparable to other established informant-based and patient-based measures.
PMCID: PMC3584226  PMID: 23138174
cognitive screening; mild cognitive impairment; neuropsychological tests; dementia screening
4.  Can platelet BACE1 levels be used as a biomarker for Alzheimer’s disease? Proof-of-concept study 
Platelets  2012;24(3):235-238.
To date there is no validated peripheral biomarker to assist with the clinical diagnosis of Alzheimer’s disease (AD). Platelet proteins have been studied as AD biomarkers with relative success. In the present study we investigated whether platelet BACE1 levels differ between AD and cognitively normal (CN) control patients. Using a newly developed ELISA method, we found that BACE1 levels were significantly lower in AD compare to CN subjects. These data were supported by the observation that several BACE1 isoforms, identified by Western blotting, were also lower in AD platelets. This proof-of-concept study provides evidence for testing platelet BACE1 levels as a peripheral AD biomarker using a novel, sensitive and inexpensive method.
PMCID: PMC4000702  PMID: 22775589
Alzheimer’s disease; BACE1; Biomarker; Peripheral; Platelets
6.  Validation and diagnostic accuracy of the Alzheimer's questionnaire 
Age and Ageing  2012;41(3):396-399.
Background: accurately identifying individuals with cognitive impairment is difficult. Given the time constraints that many clinicians face, assessment of cognitive status is often not undertaken. The intent of this study is to determine the diagnostic accuracy of the Alzheimer's questionnaire (AQ) in identifying individuals with mild cognitive impairment (MCI) and AD.
Methods: utilising a case–control design, 300 [100 AD, 100 MCI, 100 cognitively normal (CN)] older adults between the ages of 53 and 93 from a neurology practice and a brain donation programme had the AQ administered to an informant. Diagnostic accuracy was assessed through receiver-operating characteristic analysis, which yielded sensitivity, specificity and area under the curve (AUC).
Results: the AQ demonstrated high sensitivity and specificity for detecting MCI [89.00 (81.20–94.40)]; [91.00 (83.60–65.80)] and AD [99.00 (94.60–100.00)]; [96.00 (90.10–98.90)]. AUC values also indicated high diagnostic accuracy for both MCI [0.95 (0.91–0.97)] and AD [0.99 (0.96–1.00)]. Internal consistency of the AQ was also high (Cronbach's alpha = 0.89).
Conclusion: the AQ is a valid informant-based instrument for identifying cognitive impairment, which could be easily implemented in a clinician's practice. It has high sensitivity and specificity in detecting both MCI and AD and allows clinicians to quickly and accurately assess individuals with reported cognitive problems.
PMCID: PMC3335371  PMID: 22367356
mild cognitive impairment; Alzheimer's disease; cognitive screening; informant-based assessment
7.  Bapineuzumab Alters Aβ Composition: Implications for the Amyloid Cascade Hypothesis and Anti-Amyloid Immunotherapy 
PLoS ONE  2013;8(3):e59735.
The characteristic neuropathological changes associated with Alzheimer’s disease (AD) and other lines of evidence support the amyloid cascade hypothesis. Viewing amyloid deposits as the prime instigator of dementia has now led to clinical trials of multiple strategies to remove or prevent their formation. We performed neuropathological and biochemical assessments of 3 subjects treated with bapineuzumab infusions. Histological analyses were conducted to quantify amyloid plaque densities, Braak stages and the extent of cerebral amyloid angiopathy (CAA). Amyloid-β (Aβ) species in frontal and temporal lobe samples were quantified by ELISA. Western blots of amyloid-β precursor protein (AβPP) and its C-terminal (CT) fragments as well as tau species were performed. Bapineuzumab-treated (Bapi-AD) subjects were compared to non-immunized age-matched subjects with AD (NI-AD) and non-demented control (NDC) cases. Our study revealed that Bapi-AD subjects exhibited overall amyloid plaque densities similar to those of NI-AD cases. In addition, CAA was moderate to severe in NI-AD and Bapi-AD patients. Although histologically-demonstrable leptomeningeal, cerebrovascular and neuroparenchymal-amyloid densities all appeared unaffected by treatment, Aβ peptide profiles were significantly altered in Bapi-AD subjects. There was a trend for reduction in total Aβ42 levels as well as an increase in Aβ40 which led to a corresponding significant decrease in Aβ42:Aβ40 ratio in comparison to NI-AD subjects. There were no differences in the levels of AβPP, CT99 and CT83 or tau species between Bapi-AD and NI-AD subjects. The remarkable alteration in Aβ profiles reveals a dynamic amyloid production in which removal and depositional processes were apparently perturbed by bapineuzumab therapy. Despite the alteration in biochemical composition, all 3 immunized subjects exhibited continued cognitive decline.
PMCID: PMC3605408  PMID: 23555764
8.  Positron Emission Tomography and Neuropathologic Estimates of Fibrillar Amyloid-β in a Patient With Down Syndrome and Alzheimer Disease 
Archives of Neurology  2011;68(11):1461-1466.
Down syndrome appears to be associated with a virtually certain risk of fibrillar amyloid-β (Aβ) pathology by the age of 40 and a very high risk of dementia at older ages. The positron emission tomography (PET) ligand florbetapir F18 has been shown to characterize fibrillar Aβ in the living human brain and to provide a close correlation with subsequent Aβ neuropathology in individuals proximate to and after the end of life. The extent to which the most frequently used PET ligands can be used to detect fibrillar Aβ in patients with Down syndrome remains to be determined.
To characterize PET estimates of fibrillar Aβ burden in a Down syndrome patient very close to the end of life and to compare them with neuropathologic assessment made after his death.
With the family’s informed consent, florbetapir PET was used to study a 55-year-old Down syndrome patient with Alzheimer disease near the end of life; his brain was donated for neuropathologic assessment when he died 14 days later. Visual ratings of cerebral florbetapir uptake were performed by trained readers who were masked to the patient’s diagnosis as part of a larger study, and an automated algorithm was used to characterize regional-to-cerebellar standard uptake value ratios in 6 cerebral regions of interest. Neuropathologic assessments were performed masked to the patient’s diagnosis or PET measurements.
Visual ratings and automated analyses of the PET image revealed a heavy fibrillar Aβ burden in cortical, striatal, and thalamic regions, similar to that reported for patients with late-onset Alzheimer disease. This matched neuropathologic findings of frequent neuritic and diffuse plaques, as well as frequent amyloid angiopathy, except for neuropathologically demonstrated frequent cerebellar diffuse plaques and amyloid angiopathy that were not detected by the PET scan.
Florbetapir PET can be used to detect increased cerebral-to-cerebellar fibrillar Aβ burden in a Down syndrome patient with Alzheimer disease, even in the presence of frequent amyloid angiopathy and diffuse plaques in the cerebellum. Additional studies are needed to determine the extent to which PET could be used to detect and to track fibrillar Aβ and to evaluate investigational Aβ-modifying treatments in the presymptomatic and symptomatic stages of Alzheimer disease.
PMCID: PMC3346179  PMID: 22084131
9.  Cerebral blood flow in Alzheimer’s disease 
Alzheimer’s disease (AD) dementia is a consequence of heterogeneous and complex interactions of age-related neurodegeneration and vascular-associated pathologies. Evidence has accumulated that there is increased atherosclerosis/arteriosclerosis of the intracranial arteries in AD and that this may be additive or synergistic with respect to the generation of hypoxia/ischemia and cognitive dysfunction. The effectiveness of pharmacologic therapies and lifestyle modification in reducing cardiovascular disease has prompted a reconsideration of the roles that cardiovascular disease and cerebrovascular function play in the pathogenesis of dementia.
Using two-dimensional phase-contrast magnetic resonance imaging, we quantified cerebral blood flow within the internal carotid, basilar, and middle cerebral arteries in a group of individuals with mild to moderate AD (n = 8) and compared the results with those from a group of age-matched nondemented control (NDC) subjects (n = 9). Clinical and psychometric testing was performed on all individuals, as well as obtaining their magnetic resonance imaging-based hippocampal volumes.
Our experiments reveal that total cerebral blood flow was 20% lower in the AD group than in the NDC group, and that these values were directly correlated with pulse pressure and cognitive measures. The AD group had a significantly lower pulse pressure (mean AD 48, mean NDC 71; P = 0.0004). A significant group difference was also observed in their hippocampal volumes. Composite z-scores for clinical, psychometric, hippocampal volume, and hemodynamic data differed between the AD and NDC subjects, with values in the former being significantly lower (t = 12.00, df = 1, P = 0.001) than in the latter.
These results indicate an association between brain hypoperfusion and the dementia of AD. Cardiovascular disease combined with brain hypoperfusion may participate in the pathogenesis/pathophysiology of neurodegenerative diseases. Future longitudinal and larger-scale confirmatory investigations measuring multidomain parameters are warranted.
PMCID: PMC3481957  PMID: 23109807
Alzheimer’s disease; cerebral blood flow; brain hypoperfusion; two-dimensional phase-contrast magnetic resonance imaging; brain morphometric analyses; atherosclerosis; arteriosclerosis; cognitive impairment
10.  Morphological and Pathological Evolution of the Brain Microcirculation in Aging and Alzheimer’s Disease 
PLoS ONE  2012;7(5):e36893.
Key pathological hallmarks of Alzheimer’s disease (AD), including amyloid plaques, cerebral amyloid angiopathy (CAA) and neurofibrillary tangles do not completely account for cognitive impairment, therefore other factors such as cardiovascular and cerebrovascular pathologies, may contribute to AD. In order to elucidate the microvascular changes that contribute to aging and disease, direct neuropathological staining and immunohistochemistry, were used to quantify the structural integrity of the microvasculature and its innervation in three oldest-old cohorts: 1) nonagenarians with AD and a high amyloid plaque load; 2) nonagenarians with no dementia and a high amyloid plaque load; 3) nonagenarians without dementia or amyloid plaques. In addition, a non-demented (ND) group (average age 71 years) with no amyloid plaques was included for comparison. While gray matter thickness and overall brain mass were reduced in AD compared to ND control groups, overall capillary density was not different. However, degenerated string capillaries were elevated in AD, potentially suggesting greater microvascular “dysfunction” compared to ND groups. Intriguingly, apolipoprotein ε4 carriers had significantly higher string vessel counts relative to non-ε4 carriers. Taken together, these data suggest a concomitant loss of functional capillaries and brain volume in AD subjects. We also demonstrated a trend of decreasing vesicular acetylcholine transporter staining, a marker of cortical cholinergic afferents that contribute to arteriolar vasoregulation, in AD compared to ND control groups, suggesting impaired control of vasodilation in AD subjects. In addition, tyrosine hydroxylase, a marker of noradrenergic vascular innervation, was reduced which may also contribute to a loss of control of vasoconstriction. The data highlight the importance of the brain microcirculation in the pathogenesis and evolution of AD.
PMCID: PMC3353981  PMID: 22615835
11.  Informant-reported cognitive symptoms that predict amnestic mild cognitive impairment 
BMC Geriatrics  2012;12:3.
Differentiating amnestic mild cognitive impairment (aMCI) from normal cognition is difficult in clinical settings. Self-reported and informant-reported memory complaints occur often in both clinical groups, which then necessitates the use of a comprehensive neuropsychological examination to make a differential diagnosis. However, the ability to identify cognitive symptoms that are predictive of aMCI through informant-based information may provide some clinical utility in accurately identifying individuals who are at risk for developing Alzheimer's disease (AD).
The current study utilized a case-control design using data from an ongoing validation study of the Alzheimer's Questionnaire (AQ), an informant-based dementia assessment. Data from 51 cognitively normal (CN) individuals participating in a brain donation program and 47 aMCI individuals seen in a neurology practice at the same institute were analyzed to determine which AQ items differentiated aMCI from CN individuals.
Forward stepwise multiple logistic regression analysis which controlled for age and education showed that 4 AQ items were strong indicators of aMCI which included: repetition of statements and/or questions [OR 13.20 (3.02, 57.66)]; trouble knowing the day, date, month, year, and time [OR 17.97 (2.63, 122.77)]; difficulty managing finances [OR 11.60 (2.10, 63.99)]; and decreased sense of direction [OR 5.84 (1.09, 31.30)].
Overall, these data indicate that certain informant-reported cognitive symptoms may help clinicians differentiate individuals with aMCI from those with normal cognition. Items pertaining to repetition of statements, orientation, ability to manage finances, and visuospatial disorientation had high discriminatory power.
PMCID: PMC3306194  PMID: 22304759
12.  Probable Early-Onset Alzheimer's Disease in an Apolipoprotein E2 Homozygote 
To describe a case of early-onset Alzheimer's disease (AD) in an apolipoprotein (Apo) ∊2/∊2 homozygote.
Apo ∊2/∊2 is the rarest of the ApoE genotypes, representing only 1.4% of the population. Cognitive decline in ApoE ∊2 homozygotes has rarely been reported. Case Report/Methods: We report a 58-year-old Apo ∊2/∊2 female who meets clinical criteria for probable AD as confirmed by neuropsychological testing, positron emission/computed tomography scan, CSF analysis and genetic screening for known mutations.
The clinical course is typical of AD, with progressive cognitive and functional decline.
Clinically confirmed early-onset AD is atypical in ApoE2 homozygotes but can occur.
PMCID: PMC2992638  PMID: 20975270
Alzheimer's disease; Apolipoprotein E2; Homozygote; Positron emission tomography scan; Neuropsychological assessment; Cerebrospinal fluid analysis
13.  The Alzheimer’s Questionnaire: A Proof of Concept Study for a New Informant-Based Dementia Assessment 
Journal of Alzheimer's disease : JAD  2010;22(3):1015-1021.
The aim of this pilot study is to determine the feasibility and clinical utility of a brief, informant-based screening questionnaire for Alzheimer’s disease (AD) that can be administered in a primary care setting. The Alzheimer’s Questionnaire (AQ) was administered to the informants of 188 patients in 3 dementia clinics (50 cognitively normal, 69 mild cognitive impairment (MCI), 69 AD). Total score for the AQ is based upon the sum of clinical symptom items in which the informant responds as being present. Clinical symptoms which are known to be highly predictive of the clinical AD diagnosis are given greater weight in the total AQ score. The mean time of administration of the AQ was 2.6 ± 0.6 minutes. Sensitivity and specificity were found to be high for detecting both AD (98.55, 96.00) and MCI (86.96, 94.00) with ROC curves yielding AUC values of 0.99 and 0.95, respectively. This pilot study indicates that the AQ is a brief, sensitive measure for detecting both MCI and AD and could be easily implemented in a primary care setting.
PMCID: PMC3207359  PMID: 20930293
Alzheimer’s disease; instrument; questionnaire; primary care
14.  Possible Alzheimer’s Disease in an Apolipoprotein E2 Homozygote 
The objective of this study was to describe a case of Alzheimer’s disease in an ApoE ε2/ε2 homozygote. ApoE ε2/ε2 is the rarest of the apolipoprotein E genotypes, representing only 1.4% of the population. There is only one case reported in the literature of a nonagenarian with minimal cognitive changes whose brain showed AD pathology on postmortem study. Here we report an 87-year-old ApoE ε2/ε2 female who meets clinical criteria for Alzheimer’s disease, with confirmation from neuropsychological testing and PET scan. Clinical course is typical for Alzheimer’s disease with decline on the Mini-Mental Status Examination from a score of 25 to 19 over 3.5 years. The patient is currently treated with donepezil and memantine. In conclusion, a clinically confirmed case of Alzheimer’s disease is rare in Apo E2 homozygotes but can occur.
PMCID: PMC2954753  PMID: 19158419
Alzheimer’s disease; apolipoprotein E2; homozygote; PET scan

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