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1.  Arteriolosclerosis that affects multiple brain regions is linked to hippocampal sclerosis of ageing 
Brain  2013;137(1):255-267.
Hippocampal sclerosis of ageing is a prevalent brain disease that afflicts older persons and has been linked with cerebrovascular pathology. Arteriolosclerosis is a subtype of cerebrovascular pathology characterized by concentrically thickened arterioles. Here we report data from multiple large autopsy series (University of Kentucky Alzheimer’s Disease Centre, Nun Study, and National Alzheimer’s Coordinating Centre) showing a specific association between hippocampal sclerosis of ageing pathology and arteriolosclerosis. The present analyses incorporate 226 cases of autopsy-proven hippocampal sclerosis of ageing and 1792 controls. Case–control comparisons were performed including digital pathological assessments for detailed analyses of blood vessel morphology. We found no evidence of associations between hippocampal sclerosis of ageing pathology and lacunar infarcts, large infarcts, Circle of Willis atherosclerosis, or cerebral amyloid angiopathy. Individuals with hippocampal sclerosis of ageing pathology did not show increased rates of clinically documented hypertension, diabetes, or other cardiac risk factors. The correlation between arteriolosclerosis and hippocampal sclerosis of ageing pathology was strong in multiple brain regions outside of the hippocampus. For example, the presence of arteriolosclerosis in the frontal cortex (Brodmann area 9) was strongly associated with hippocampal sclerosis of ageing pathology (P < 0.001). This enables informative evaluation of anatomical regions outside of the hippocampus. To assess the morphology of brain microvasculature far more rigorously than what is possible using semi-quantitative pathological scoring, we applied digital pathological (Aperio ScanScope) methods on a subsample of frontal cortex sections from hippocampal sclerosis of ageing (n = 15) and control (n = 42) cases. Following technical studies to optimize immunostaining methods for small blood vessel visualization, our analyses focused on sections immunostained for smooth muscle actin (a marker of arterioles) and CD34 (an endothelial marker), with separate analyses on grey and white matter. A total of 43 834 smooth muscle actin-positive vascular profiles and 603 798 CD34-positive vascular profiles were evaluated. In frontal cortex of cases with hippocampal sclerosis of ageing, smooth muscle actin-immunoreactive arterioles had thicker walls (P < 0.05), larger perimeters (P < 0.03), and larger vessel areas (P < 0.03) than controls. Unlike the arterioles, CD34-immunoreactive capillaries had dimensions that were unchanged in cases with hippocampal sclerosis of ageing versus controls. Arteriolosclerosis appears specific to hippocampal sclerosis of ageing brains, because brains with Alzheimer’s disease pathology did not show the same morphological alterations. We conclude that there may be a pathogenetic change in aged human brain arterioles that impacts multiple brain areas and contributes to hippocampal sclerosis of ageing.
PMCID: PMC3891448  PMID: 24271328
TDP-43; NACC; FTLD; SMA; HS-Ageing
2.  Hippocampal sclerosis of aging is a key Alzheimer's disease mimic: clinical-pathologic correlations and comparisons with both Alzheimer's disease and non-tauopathic frontotemporal lobar degeneration 
Hippocampal sclerosis of aging (HS-Aging) neuropathology was observed in more than 15% of aged individuals in prior studies. However, much remains unknown about the clinical correlates of HS-Aging pathology or the association(s) between HS-Aging, Alzheimer's disease (AD), and frontotemporal lobar degeneration (FTLD) pathology. Clinical and comorbid pathological features linked to HS-Aging pathology were analyzed using National Alzheimer's Coordinating Center (NACC) data. From autopsy data extending back to 1990 (N=9,817 participants), the neuropathologic diagnoses were evaluated from American AD Centers (ADCs). Among participants who died between 2005-2012 (N=1,422), additional analyses identified clinical and pathological features associated with HS-Aging pathology. We also compared cognitive testing and longevity outcomes between HS-Aging cases and a subsample with non-tauopathy FTLD (N=210). Reporting of HS pathology increased dramatically among ADCs in recent years, to nearly 20% of autopsies in 2012. Participants with relatively “pure” HS-Aging pathology were often diagnosed clinically as having probable (68%) or possible (15%) AD. However, the co-occurrence of HS-Aging pathology and AD neuropathology (AD-NP) did not indicate any pattern of correlation between the two pathologies. Compared other pathologies, participants with HS-Aging pathology had higher overall cognitive/functional ability (versus AD-NP) and verbal fluency (versus both AD-NP and FTLD) but similar episodic memory impairment at one clinic visit 2 -5 years prior to death. Patients with HS-Aging live considerably longer than patients with non-tauopathy FTLD. We conclude that the manifestations of HS-Aging, increasingly recognized in recent years, probably indicate a separate disease process of direct relevance to patient care, dementia research, and clinical trials.
PMCID: PMC3946156  PMID: 24270205
TDP-43; oldest-old; hippocampus; human; APOE
3.  Self-reported head injury and risk of late-life impairment and AD pathology in an AD Center cohort 
To evaluate the relationship between self-reported head injury and cognitive impairment, dementia, mortality, and Alzheimer’s (AD)-type pathological changes.
Clinical and neuropathological data from participants enrolled in a longitudinal study of aging and cognition (N=649) were analyzed to assess the chronic effects of self-reported head injury.
The effect of self-reported head injury on clinical state depends on age at assessment: for a 1-year increase in age, the OR^ for transition to clinical MCI at the next visit for participants with a history of head injury is 1.21 and 1.34 for transition from MCI to dementia. Without respect to age, head injury increases the odds of mortality ( OR^=1.54). Head injury increases the odds of a pathological diagnosis of AD for men ( OR^=1.47) but not women ( OR^=1.18). Men with head injury have higher mean amyloid plaque counts in the neocortex and entorhinal cortex than men without.
Conclusions: Self-reported head injury is associated with earlier onset, increased risk of cognitive impairment and dementia, increased risk of mortality, and AD-type pathological changes.
PMCID: PMC4057973  PMID: 24401791
head injury; Alzheimer’s disease; neuropathology; dementia; cognition
4.  Sugihara causality analysis of scalp EEG for detection of early Alzheimer's disease 
NeuroImage : Clinical  2014;7:258-265.
Recently, Sugihara proposed an innovative causality concept, which, in contrast to statistical predictability in Granger sense, characterizes underlying deterministic causation of the system. This work exploits Sugihara causality analysis to develop novel EEG biomarkers for discriminating normal aging from mild cognitive impairment (MCI) and early Alzheimer's disease (AD). The hypothesis of this work is that scalp EEG based causality measurements have different distributions for different cognitive groups and hence the causality measurements can be used to distinguish between NC, MCI, and AD participants. The current results are based on 30-channel resting EEG records from 48 age-matched participants (mean age 75.7 years) — 15 normal controls (NCs), 16 MCI, and 17 early-stage AD. First, a reconstruction model is developed for each EEG channel, which predicts the signal in the current channel using data of the other 29 channels. The reconstruction model of the target channel is trained using NC, MCI, or AD records to generate an NC-, MCI-, or AD-specific model, respectively. To avoid over fitting, the training is based on the leave-one-out principle. Sugihara causality between the channels is described by a quality score based on comparison between the reconstructed signal and the original signal. The quality scores are studied for their potential as biomarkers to distinguish between the different cognitive groups. First, the dimension of the quality scores is reduced to two principal components. Then, a three-way classification based on the principal components is conducted. Accuracies of 95.8%, 95.8%, and 97.9% are achieved for resting eyes open, counting eyes closed, and resting eyes closed protocols, respectively. This work presents a novel application of Sugihara causality analysis to capture characteristic changes in EEG activity due to cognitive deficits. The developed method has excellent potential as individualized biomarkers in the detection of pathophysiological changes in early-stage AD.
•We explore EEG-based biomarkers for early Alzheimer's disease.•We investigate causality connectivity from scalp EEG in Sugihara sense.•Excellent diagnosis accuracies are achieved under three different protocol conditions.•We present the first biomedical application of Sugihara causality analysis.
PMCID: PMC4300018  PMID: 25610788
Early Alzheimer's disease; Mild cognitive impairment; EEG-based diagnosis; Causality analysis
5.  Dopaminergic modulation of memory and affective processing in Parkinson depression 
Psychiatry research  2013;210(1):146-149.
Depression is common in Parkinson’s disease and is associated with cognitive impairment. Dopaminergic medications are effective in treating the motor symptoms of Parkinson’s disease; however, little is known regarding the effects of dopaminergic pharmacotherapy on cognitive function in depressed Parkinson patients. This study examines the neuropsychological effects of dopaminergic pharmacotherapy in Parkinsonian depression. We compared cognitive function in depressed and non-depressed Parkinson patients at two time-points: following overnight withdrawal and after the usual morning regimen of dopaminergic medications. A total of 28 non-demented, right-handed patients with mild to moderate idiopathic Parkinson’s disease participated. Ten of these patients were depressed according to DSM IV criteria. Results revealed a statistically significant interaction between depression and medication status on three measures of verbal memory and a facial affect naming task. In all cases, depressed Parkinson’s patients performed significantly more poorly while on dopaminergic medication than while off. The opposite pattern emerged for the non-depressed Parkinson’s group. The administration of dopaminergic medication to depressed Parkinson patients may carry unintended risks.
PMCID: PMC3805794  PMID: 23838419
Parkinson; mood; cognition; emotion; dopamine
6.  Repeated Retrieval During Working Memory Is Sensitive to Amnestic Mild Cognitive Impairment 
Journal of clinical and experimental neuropsychology  2013;35(9):10.1080/13803395.2013.838942.
Study of repeated learning mechanisms has been limited in amnestic mild cognitive impairment, a preclinical stage of Alzheimer disease modifiable by cognitive rehabilitation. We assessed repeated contextual working memory decline as an indicator of amnestic mild cognitive impairment in a sample of 45 older adults recruited from the tertiary care setting. Results indicated that contextual working memory impairment distinguished adults with preclinical disease from those without impairment despite similar overall cognitive performance, and comparison of the indicator with standard-of-care neuropsychological measures indicated discriminant validity. Contextual working memory impairment may represent a novel predictor of Alzheimer disease conversion risk.
PMCID: PMC3884808  PMID: 24074205
Alzheimer disease; mild cognitive impairment; working memory; repetition priming; neuropsychological tests; cognitive therapy; aging
7.  Alzheimer's Disease in Down Syndrome 
A key challenge to adults with Down syndrome (DS) as they age is an increased risk for cognitive decline, dementia, and Alzheimer disease (AD). In DS persons ranging from 40-49 years of age, 5.7-55% may be clinically demented and between 50-59 years, dementia prevalence ranges from 4-55% (reviewed in [1]). Despite the wide ranges reported for dementia prevalence, a consistent feature of aging in DS is the progressive accumulation of AD brain pathologies. By the age of 40 years, virtually all have sufficient senile plaques and neurofibrillary tangles for a neuropathological diagnosis of AD [2]. Thus, there is dissociation between the age of onset of AD neuropathology (40 years) and increasing signs of clinical dementia. We discuss the hypothesis that frontal impairments are a critical factor affecting cognitive function and are associated with white matter (WM) and AD neuropathology. While these may be an early sign of conversion to dementia, we also review several other clinical comorbidities that may also contribute to dementia onset.
PMCID: PMC4184282  PMID: 25285303
beta-amyloid; dementia; neurofibrillary tangles; oxidative damage; Trisomy 21
8.  Con: are we ready to translate Alzheimer’s disease-modifying therapies to people with down syndrome? 
Adults with Down syndrome develop Alzheimer’s disease neuropathology in an age-dependent manner. This unique feature provides an opportunity to test interventions targeted for prevention of Alzheimer’s disease neuropathology and dementia in Down syndrome.
In considering clinical trial designs, however, there are several challenges that we believe will be critical to examine further. These include: accuracy in dementia, mild cognitive impairment and preclinical Alzheimer’s disease diagnoses in Down syndrome; clinical trial outcome measures appropriate for individuals with Down syndrome; in vivo imaging outcome measures (and practical considerations); and contributions of medical co-morbidities to disease progression. Also, when studies are designed, the molecular target may appear to be obvious (for example, targeting beta-amyloid pathology), but chromosome 21 has over 200 additional genes that could influence both positive and negative clinical trial outcomes.
Observational longitudinal studies of aging in Down syndrome will be critically important as there is a need to establish sensitive clinical outcome measures and understand the consequences of gene overexpression in relation to specific interventions.
PMCID: PMC4255531  PMID: 25478026
9.  APOE associations with severe CAA-associated vasculopathic changes – collaborative meta-analysis 
Cerebral amyloid angiopathy (CAA) is associated with lobar intracerebral haemorrhage (ICH). While only the ε4 allele of the apolipoprotein E gene (APOE) is associated with the presence of CAA, both APOE-ε4 and ε2 are associated with lobar ICH. The generally accepted explanation is that APOE-ε4 promotes vascular amyloid deposition, while APOE-ε2 promotes progression to severe CAA with associated vasculopathic changes that cause vessel rupture and ICH. We assessed the evidence for these allele-specific effects.
We systematically identified published studies with data on APOE genotype and histopathological assessment of post-mortem brains for CAA severity. We obtained unpublished data from these for meta-analyses of the effects of ε4-containing (ε4+) and ε2-containing (ε2+) genotypes on progression to severe CAA.
Of six eligible studies (543 eligible participants), data were available from five (497 participants, 353 with CAA). Meta-analyses showed a possible association of ε4+ genotypes with severe CAA (ε4+ versus ε4-: severe versus mild/moderate CAA, odds ratio [OR] 2.5, 95% confidence interval [CI] 1.4 to 4.5, p=0.002; severe versus moderate CAA, OR 1.7, 95%CI 0.9 to 3.1, p=0.11). For ε2+ versus ε2-genotypes, there was no significant association, but the very small number of participants with ε2+ genotypes (22) precluded reliable estimates.
We found a possible association of severe CAA with APOE-ε4 but not APOE-ε2. However, our findings do not exclude a biologically meaningful association between APOE-ε2 and severe CAA. Further work is needed to elucidate fully the allele-specific associations of APOE with CAA and their mechanisms.
PMCID: PMC4018226  PMID: 24163429
Cerebral Amyloid Angiopathy; Apolipoproteins E; Cerebral Hemorrhage; Systematic Review
10.  Hippocampal sclerosis of aging, a prevalent and high-morbidity brain disease 
Acta neuropathologica  2013;126(2):161-177.
Hippocampal sclerosis of aging (HS-Aging) is a causative factor in a large proportion of elderly dementia cases. The current definition of HS-Aging rests on pathologic criteria: neuronal loss and gliosis in the hippocampal formation that is out of proportion to AD-type pathology. HS-Aging is also strongly associated with TDP-43 pathology. HS-Aging pathology appears to be most prevalent in the oldest-old: autopsy series indicate that 5–30 % of nonagenarians have HS-Aging pathology. Among prior studies, differences in study design have contributed to the study-to-study variability in reported disease prevalence. The presence of HS-Aging pathology correlates with significant cognitive impairment which is often misdiagnosed as AD clinically. The antemortem diagnosis is further confounded by other diseases linked to hippocampal atrophy including frontotemporal lobar degeneration and cerebrovascular pathologies. Recent advances characterizing the neurocognitive profile of HS-Aging patients have begun to provide clues that may help identify living individuals with HS-Aging pathology. Structural brain imaging studies of research subjects followed to autopsy reveal hippocampal atrophy that is substantially greater in people with eventual HS-Aging pathology, compared to those with AD pathology alone. Data are presented from individuals who were followed with neurocognitive and neuroradiologic measurements, followed by neuropathologic evaluation at the University of Kentucky. Finally, we discuss factors that are hypothesized to cause or modify the disease. We conclude that the published literature on HS-Aging provides strong evidence of an important and under-appreciated brain disease of aging. Unfortunately, there is no therapy or preventive strategy currently available.
PMCID: PMC3889169  PMID: 23864344
TDP43; TDP-43; TARDBP; Dementia; Aging; Neuropathology; FTLD; Epidemiology; Genetics; Cognition; Neuroradiology; MRI; Hippocampus; Pathology; Arteriolosclerosis; Cerebrovascular; Oldest-old
11.  Improving dementia care: The role of screening and detection of cognitive impairment 
The value of screening for cognitive impairment, including dementia and Alzheimer's disease, has been debated for decades. Recent research on causes of and treatments for cognitive impairment has converged to challenge previous thinking about screening for cognitive impairment. Consequently, changes have occurred in health care policies and priorities, including the establishment of the annual wellness visit, which requires detection of any cognitive impairment for Medicare enrollees. In response to these changes, the Alzheimer's Foundation of America and the Alzheimer's Drug Discovery Foundation convened a workgroup to review evidence for screening implementation and to evaluate the implications of routine dementia detection for health care redesign. The primary domains reviewed were consideration of the benefits, harms, and impact of cognitive screening on health care quality. In conference, the workgroup developed 10 recommendations for realizing the national policy goals of early detection as the first step in improving clinical care and ensuring proactive, patient-centered management of dementia.
PMCID: PMC4049530  PMID: 23375564
Alzheimer; Dementia; Screening; Detection; Health care; Policy; Priority; Quality; Medicare; Annual wellness visit; Cognitive impairment; Cost-benefit analysis; Management; Patient-centered
12.  Quality of Education and Memory Test Performance in Older Men: The New York University Paragraph Recall Test Normative Data 
Current Alzheimer research  2013;10(7):776-783.
Memory evaluation is a key component in the accurate diagnosis of cognitive disorders. One memory procedure that has shown promise in discriminating disease-related cognitive decline from normal cognitive aging is the New York University Paragraph Recall Test; however, the effects of education have been unexamined as they pertain to one’s literacy level. The current study provides normative data stratified by estimated quality of education as indexed by irregular word reading skill.
Conventional norms were derived from a sample (N = 385) of cognitively intact elderly men who were initially recruited for participation in the PREADViSE clinical trial. A series of multiple linear regression models were constructed to assess the influence of demographic variables on mean NYU Paragraph Immediate and Delayed Recall scores.
Test version, assessment site, and estimated quality of education were significant predictors of performance on the NYU Paragraph Recall Test. Findings indicate that estimated quality of education is a better predictor of memory performance than ethnicity and years of total education. Normative data stratified according to estimated quality of education are presented.
The current study provides evidence and support for normative data stratified by quality of education as opposed to years of education.
PMCID: PMC4030724  PMID: 23906000
aging; literacy; memory; New York University (NYU) paragraph recall; normative data; norms; paragraph recall
13.  Vitamin E and all-cause mortality: A meta-analysis 
Current aging science  2011;4(2):158-170.
The current analysis reexamines the relationship between supplemental vitamin E and all-cause mortality. All randomized, controlled trials testing the treatment effect of vitamin E supplementation in adults for at least one year were sought. MEDLINE, the Cochrane Library, and Biological Abstracts databases were searched using the terms “vitamin E,” “alpha-tocopherol,” “antioxidants,” “clinical trial,” and “controlled trial” for studies published through April 2010; results were limited to English, German, or Spanish language articles. Studies were also obtained through reference mining. All randomized controlled trials using vitamin E, with a supplementation period of at least one year, to prevent or treat disease in adults were identified and abstracted independently by two raters. Mortality data from trials with a supplementation period of at least one year were pooled. The selected trials (n = 57) were published between 1988 and 2009. Sample sizes ranged from 28 to 39,876 (median = 423), yielding 246,371 subjects and 29,295 all-cause deaths. Duration of supplementation for the 57 trials ranged from one to 10.1 years (median = 2.6 years). A random effects meta-analysis produced an overall risk ratio of 1.00 (95% confidence interval: 0.98, 1.02); additional analyses suggest no relationship between dose and risk of mortality. Based on the present meta-analysis, supplementation with vitamin E appears to have no effect on all-cause mortality at doses up to 5,500 IU/d.
PMCID: PMC4030744  PMID: 21235492
all-cause mortality; α-tocopherol; clinical trials; meta-analysis; oral supplements; Vitamin E
14.  CERAD Practice Effects and Attrition Bias in a Dementia Prevention Trial 
International psychogeriatrics / IPA  2013;25(7):1115-1123.
The Consortium to Establish a Registry for Alzheimer's Disease (CERAD) set of tests is frequently used for tracking cognition longitudinally in both clinical and research settings. Repeated cognitive assessments are an important component in measuring such changes; however, practice effects and attrition bias may obscure significant clinical change over time. The current study sought to examine the presence and magnitude of practice effects and the role of attrition bias in a sample of cognitively normal older men enrolled in a prevention trial.
Participants were grouped according to whether they completed five years of follow-up (n = 182) or less (n = 126). Practice effects were examined in these participants as a whole (n = 308) and by group.
Findings indicate that moderate practice effects exist in both groups on the CERAD T-score and that attrition bias likely does not play a contributing role in improved scores over time.
The current study provides additional evidence and support for previous findings that repeated cognitive assessment results in rising test scores in longitudinally collected data and demonstrates that these findings are unlikely to be due to attrition.
PMCID: PMC4012228  PMID: 23570673
practice effects; CERAD; attrition bias; aging
15.  Using mice to model Alzheimer's dementia: an overview of the clinical disease and the preclinical behavioral changes in 10 mouse models 
The goal of this review is to discuss how behavioral tests in mice relate to the pathological and neuropsychological features seen in human Alzheimer's disease (AD), and present a comprehensive analysis of the temporal progression of behavioral impairments in commonly used AD mouse models that contain mutations in amyloid precursor protein (APP). We begin with a brief overview of the neuropathological changes seen in the AD brain and an outline of some of the clinical neuropsychological assessments used to measure cognitive deficits associated with the disease. This is followed by a critical assessment of behavioral tasks that are used in AD mice to model the cognitive changes seen in the human disease. Behavioral tests discussed include spatial memory tests [Morris water maze (MWM), radial arm water maze (RAWM), Barnes maze], associative learning tasks (passive avoidance, fear conditioning), alternation tasks (Y-Maze/T-Maze), recognition memory tasks (Novel Object Recognition), attentional tasks (3 and 5 choice serial reaction time), set-shifting tasks, and reversal learning tasks. We discuss the strengths and weaknesses of each of these behavioral tasks, and how they may correlate with clinical assessments in humans. Finally, the temporal progression of both cognitive and non-cognitive deficits in 10 AD mouse models (PDAPP, TG2576, APP23, TgCRND8, J20, APP/PS1, TG2576 + PS1 (M146L), APP/PS1 KI, 5×FAD, and 3×Tg-AD) are discussed in detail. Mouse models of AD and the behavioral tasks used in conjunction with those models are immensely important in contributing to our knowledge of disease progression and are a useful tool to study AD pathophysiology and the resulting cognitive deficits. However, investigators need to be aware of the potential weaknesses of the available preclinical models in terms of their ability to model cognitive changes observed in human AD. It is our hope that this review will assist investigators in selecting an appropriate mouse model, and accompanying behavioral paradigms to investigate different aspects of AD pathology and disease progression.
PMCID: PMC4005958  PMID: 24795750
Alzheimer's disease; mouse models; neuropsychological assessment; behavior; cognition; APP mice; APP/PS1 mice; 3×TG-AD mice
16.  Neuroinflammatory phenotype in early Alzheimer’s disease 
Neurobiology of aging  2012;34(4):1051-1059.
Alzheimer’s disease (AD) involves progressive neurodegeneration in the presence of misfolded proteins and poorly-understood inflammatory changes. However, research has shown that AD is genetically, clinically and pathologically heterogeneous.
In frozen brain samples of frontal cortex (diseased) and cerebellum (non-diseased) from the University of Kentucky Alzheimer’s Disease Center autopsy cohort, we performed gene expression analysis for genes categorizing inflammatory states (termed M1 and M2) from early and late stage AD, and age-matched non-demented controls. We performed analysis of the serum samples for a profile of inflammatory proteins and examined the neuropathological data on these samples.
Striking heterogeneity was found in early AD. Specifically, early-stage AD brain samples indicated apparent polarization toward either the M1 or M2 brain inflammatory states when compared to age-matched non-disease control tissue. This polarization was observed in the frontal cortex and not in cerebellar tissue. We were able to detect both differences in AD neuropathology, and changes in serum proteins that distinguished the individuals apparent M1 versus M2 brain inflammatory polarization.
PMCID: PMC3579221  PMID: 23062700
17.  Dependence as a unifying construct in defining Alzheimer’s disease severity 
This article reviews measures of Alzheimer’s disease (AD) progression in relation to patient dependence and offers a unifying conceptual framework for dependence in AD. Clinicians typically characterize AD by symptomatic impairments in three domains: cognition, function, and behavior. From a patient’s perspective, changes in these domains, individually and in concert, ultimately lead to increased dependence and loss of autonomy. Examples of dependence in AD range from a need for reminders (early AD) to requiring safety supervision and assistance with basic functions (late AD). Published literature has focused on the clinical domains as somewhat separate constructs and has given limited attention to the concept of patient dependence as a descriptor of AD progression. This article presents the concept of dependence on others for care needs as a potential method for translating the effect of changes in cognition, function, and behavior into a more holistic, transparent description of AD progression.
PMCID: PMC3884683  PMID: 21044778
Alzheimer’s disease; Dementia; Functional impairment; Dependence; Disease progression
18.  A randomized controlled Alzheimer’s disease prevention trial’s evolution into an exposure trial: the PREADVISE trial 
To summarize the ongoing Prevention of Alzheimer’s Disease (AD) by Vitamin E and Selenium (PREADViSE) trial as a cooperative study to SELECT (a large prostate cancer prevention trial) and to present the blinded results of the first year as an exposure study.
PREADViSE was designed as a double blind randomized controlled trial (RCT).
SELECT terminated after 5.5 years of accrual and follow-up due to a futility analysis. Both trials then converted into an exposure study.
In the randomized component PREADViSE enrolled 7,547 men age 62 or older (60 if African American). Once the trial terminated 4,246 of these men volunteered for the exposure study. Demographics were similar for both groups with exposure volunteers having baseline mean age 67.3 ± 5.2 years, 15.3 ± 2.4 years of education, 9.8% African Americans, and 22% reporting a family history of dementia.
In the RCT men were randomly assigned to either daily doses of 400 IU of vitamin E or placebo and/or 200 μg of selenium or placebo using a 2×2 factorial structure.
In the RCT, participants completed the brief Memory Impairment Screen (MIS) and if they failed, underwent a longer screening (based on an expanded Consortium to Establish a Registry in AD [CERAD] battery). CERAD failure resulted in visits to their clinician for medical examination with records of these examinations forwarded to the PREADViSE center for further review. In the exposure study, men are contacted by telephone and complete the MIS-T screen. If they fail the MIS-T a Modified Telephone Interview of Cognitive Status (TICS-M) exam is given. A failed TICS-M exam also leads to a visit to their clinician for an in depth examination and forwarding of records for a centralized consensus diagnosis by expert clinicians. A subgroup of the men who pass the MIS-T also take the TICS-M exam for validation purposes.
While this ancillary trail was open to all 427 SELECT clinical sites, only 34% chose to participate in PREADViSE. Continual staff turnover at the sites presented challenges when training persons unfamiliar with cognitive testing procedures to conduct the memory screens. In the RCT few participants (1.6%) failed the MIS screen and among those who passed this screen a significant practice effect was encountered.
In the exposure study 3,581 men were reached by phone in year 1, 15.7% could not be reached after 5 calls, and of those contacted 6.0% refused the screen even after consenting to the procedures at their clinical site. Most notable is that the failure rate for the MIS-T increased fourfold to 7.2%. Of the 257 men who took the TICS-M, 84% failed and were asked to contact their physicians for a more detailed memory assessment and approximately half of these had some form of dementia or cognitive impairment. Several of these dementia cases are not AD.
Partnering with SELECT led to an AD prevention trial conducted at a very reasonable cost by taking advantage of the experience and efficient clinical trial management found in a cancer cooperative group (SWOG). Once unblinded, the RCT and exposure study data have the potential to yield new information on long term exposure to antioxidant supplements under controlled conditions.
PMCID: PMC3636980  PMID: 23299383
Alzheimer’s disease; prevention; telephone screening; cognitive assessments; case ascertainment
19.  Digital Pathology and Image Analysis for Robust High-Throughput Quantitative Assessment of Alzheimer Disease Neuropathologic Changes 
Quantitative neuropathologic methods provide information that is important for both research and clinical applications. The technological advancement of digital pathology and image analysis offers new solutions to enable valid quantification of pathological severity that is reproducible between raters regardless of experience. Using an Aperio ScanScope XT and its accompanying image analysis software, we designed algorithms for quantitation of amyloid and tau pathologies on 65 β-amyloid (6F/3D antibody) and 48 phospho-tau (PHF-1)-immunostained sections of human temporal neocortex. Quantitative digital pathologic data were compared with manual pathology counts. There were excellent correlations between manually counted and digitally analyzed neuropathologic parameters (R2 values 0.56-0.72). Data were highly reproducible among 3 participants with varying degrees of expertise in neuropathology (Intra-class correlation coefficient values >0.910). Digital quantification also provided additional parameters, including average plaque area, which show statistically significant differences when samples are stratified according to APOE allele status (average plaque area 380.9 μm2 in ApoE ε4 carriers vs. 274.4 μm2 for non-carriers, p < 0.001). Thus, digital pathology offers a rigorous and reproducible method for quantifying AD neuropathologic changes and may provide additional insight into morphologic characteristics that were previously more challenging to assess due to technical limitations.
PMCID: PMC3511606  PMID: 23147505
Alzheimer disease; Autopsy; Digital pathology; Image analysis; Neuropathology
20.  Comparing Clinical Profiles in Alzheimer's Disease and Parkinson's Disease Dementia 
Greater understanding of differences in baseline impairment and disease progression in patients with Alzheimer's disease (AD) and Parkinson's disease dementia (PDD) may improve the interpretation of drug effects and the design of future studies.
This was a retrospective analysis of three randomized, double-blind rivastigmine databases (one in PDD, two in AD). Impairment on the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog), Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) scale, 10-item Neuropsychiatric Inventory (NPI-10) and the ADCS-Clinical Global Impression of Change (CGIC) was compared [standardized difference (Cohen's d), similar if <0.1].
Patients with AD or PDD had similar levels of impairment on the ADAS-cog and NPI-10. Scores on the ADCS-ADL scale (standardized difference = 0.47) and the ADAS-cog memory domain (total, 0.33; items, 0.10-0.58) were higher in AD; PDD patients were more impaired in the language (0.23) and praxis (0.34) domains. AD patients receiving placebo showed greater deterioration on the ADAS-cog (0.14) and improvement on the NPI-10 (0.11) compared with patients with PDD.
Differing patterns of impairment occur in AD and PDD.
PMCID: PMC3808221  PMID: 24174923
Alzheimer's disease; Parkinson's disease dementia; Rivastigmine; Alzheimer's Disease Assessment Scale–cognitive subscale; Alzheimer's Disease Cooperative Study–Activities of Daily Living scale; 10-item Neuropsychiatric Inventory; Alzheimer's Disease Cooperative Study–Clinical Global Impression of Change

21.  Age-expanded normative data for the Ruff 2&7 Selective Attention Test: Evaluating cognition in older male 
The Clinical neuropsychologist  2012;26(5):751-768.
The Ruff 2&7 Selective Attention Test’s (RSAT) current scoring data are relatively limited for older adults because persons over the age of 70 years were not included in the normative sample. Prior evidence suggests that changes in attention skills, such as those evaluated by the RSAT, may distinguish normal cognitive aging from pathologic cognitive decline. Thus, normative data for older individuals on this measure increases its utility in diagnosing Mild Cognitive Impairment (MCI) and dementia, and enhance its potential use in clinical and research settings. Data from 415 male volunteers (mean age = 69.5 ± 5.7 years) in the PREADViSE clinical trial were used in the current investigation. Analysis of covariance (ANCOVA) shows statistically significant effects of age, race, and education on RSAT Speed measures. Results indicate that age-expanded norms will provide a more accurate reflection of the typical performance of older individuals on the RSAT.
PMCID: PMC3734957  PMID: 22651854
22.  Adjusting for mortality when identifying risk factors for transitions to MCI and dementia 
Risk factors for mild cognitive impairment (MCI) and dementia are often investigated without accounting for the competing risk of mortality, which can bias results and lead to spurious conclusions, particularly regarding protective factors. Here, we apply a semi-Markov modeling approach to 531 participants in the University of Kentucky Biologically Resilient Adults in Neurological Studies (BRAiNS) longitudinal cohort, over one-third of whom died without transitioning to a cognitively impaired clinical state. A semi-Markov approach enables a statistical study of clinical state transitions while accounting for the competing risk of death and facilitates insights into both the odds that a risk factor will affect clinical transitions as well as the age at which the transition to MCI or dementia will occur. Risk factors assessed in the current study were identified by matching those reported in the literature with the data elements collected on participants. The presence of Type II diabetes at baseline shortens the time it takes cognitively intact individuals to transition to MCI by seven years on average while use of estrogen replacement therapy at enrollment (baseline) decreases the time required to convert from MCI to dementia by 1.5 years. Finally, smoking and being overweight do not promote transitions to impaired states but instead hasten death without a dementia. In contrast, conventional statistical analyses based on Cox proportional hazards models fail to recognize diabetes as a risk and show that being overweight increases the risk of clinical MCI while high blood pressure at baseline increases the risk of a dementia.
PMCID: PMC3703851  PMID: 23507772
MCI; dementia; multi-state models; semi-Markov; risk factors; competing events
23.  Association between frontal cortex oxidative damage and beta-amyloid as a function of age in Down syndrome 
Biochimica et Biophysica Acta  2011;1822(2):130-138.
Down syndrome (DS) is the most common genetic cause of intellectual disability in children, and the number of adults with DS reaching old age is increasing. By the age of 40 years, virtually all people with DS have sufficient neuropathology for a postmortem diagnosis of Alzheimer disease (AD). Trisomy 21 in DS leads to an overexpression of many proteins, of which at least two are involved in oxidative stress and AD: superoxide dismutase 1 (SOD1) and amyloid precursor protein (APP). In this study, we tested the hypothesis that DS brains with neuropathological hallmarks of AD have more oxidative and nitrosative stress than those with DS but without significant AD pathology, as compared with similarly aged-matched non-DS controls. The frontal cortex was examined in 70 autopsy cases (n=29 control and n=41 DS). By ELISA, we quantified soluble and insoluble Aβ40 and Aβ42, as well as oligomers. Oxidative and nitrosative stress levels (protein carbonyls, HNE-bound proteins, and 3-nitrotyrosine) were measured by slot-blot. We found that soluble and insoluble Aβ and oligomers increase as a function of age in DS frontal cortex. Of the oxidative stress markers, HNE-bound proteins were increased overall in DS. Protein carbonyls were correlated with Aβ40 levels. These results suggest that oxidative damage, but not nitrosative stress, may contribute to the onset and progression of AD pathogenesis in DS. Conceivably, treatment with antioxidants may provide a point of intervention to slow pathological alterations in DS.
PMCID: PMC3260028  PMID: 22009041
Alzheimer disease; 4-hydroxy-2-nonenal; 3-nitrotyrosine; oligomers; protein carbonyl; trisomy 21
24.  Practice effects in a longitudinal, multi-center Alzheimer’s disease prevention clinical trial 
Trials  2012;13:217.
Practice effects are a known threat to reliability and validity in clinical trials. Few studies have investigated the potential influence of practice on repeated screening measures in longitudinal clinical trials with a focus on dementia prevention. The current study investigates whether practice effects exist on a screening measure commonly used in aging research, the Memory Impairment Screen (MIS).
The PREADViSE trial is a clinical intervention study evaluating the efficacy of vitamin E and selenium for Alzheimer’s disease prevention. Participants are screened annually for incident dementia with the MIS. Participants with baseline and three consecutive follow-ups who made less than a perfect score at one or more assessments were included in the current analyses (N=1,803). An additional subset of participants with four consecutive assessments but who received the same version of the MIS at baseline and first follow-up (N=301) was also assessed to determine the effects of alternate forms on mitigating practice. We hypothesized that despite efforts to mitigate practice effects with alternate versions, MIS scores would improve with repeated screening. Linear mixed models were used to estimate mean MIS scores over time.
Among men with four visits and alternating MIS versions, although there is little evidence of a significant practice effect at the first follow-up, mean scores clearly improve at the second and third follow-ups for all but the oldest participants. Unlike those who received alternate versions, men given the same version at first follow-up show significant practice effects.
While increases in the overall means were small, they represent a significant number of men whose scores improved with repeated testing. Such improvements could bias case ascertainment if not taken into account.
PMCID: PMC3543284  PMID: 23171483
Practice effects; Clinical trials; Alzheimer’s disease; Neuropsychological assessment
25.  University of Kentucky Sanders-Brown Healthy Brain Aging Volunteers: Donor Characteristics, Procedures and Neuropathology 
Current Alzheimer research  2012;9(6):724-733.
Cognitively intact elderly research volunteers at the University of Kentucky have been recruited, followed longitudinally, and autopsied with extensive neuropathological evaluations since 1989. To date, the cohort has recruited 1,030 individuals with 552 participants being actively followed, 363 deceased, and 273 autopsied. An extensive database has been constructed with continuous updates that include textured clinical, neuropsychological, neuroimaging, and pathological information. The history, demographics, clinical observations, and pathological features of this research cohort are described. We also explain some of the evolving methodologies and the academic contributions that have been made due to this motivated group of older Kentuckians.
PMCID: PMC3409295  PMID: 22471862
Aging; Alzheimer’s; autopsy; brain; dementia; Lewy bodies; longitudinal; neuropathology; neurocognition; neuritic plaques; neurofibrillary tangles

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