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1.  Everyday Cognition scale items that best discriminate between and predict progression from clinically normal to mild cognitive impairment 
Current Alzheimer research  2014;11(9):853-861.
Background
Impairment in instrumental activities of daily living (IADL) starts as individuals with amnestic mild cognitive impairment (MCI) transition to Alzheimer’s disease (AD) dementia. However, most IADL scales have not shown IADL alterations in clinically normal (CN) elderly. The objective of this study was to determine which of the IADL-related Everyday Cognition (ECog) scale items are most sensitive for detection of early functional changes.
Methods
We assessed 290 CN and 495 MCI participants from the Alzheimer’s Disease Neuroimaging Initiative. We performed logistic regression analyses predicting the probability of CN vs. MCI diagnosis using only the 17 participant-based and 17 informant-based ECog items related to IADL. We then performed Cox regression analyses to predict progression from CN to MCI. All analyses were adjusted for demographic characteristics.
Results
We found that worse performance on “remembering a few shopping items” (participant and informant-based p<0.0001), “remembering appointments” (participant and informant-based p<0.0001), “developing a schedule in advance of anticipated events” (participant-based p=0.007), “balancing checkbook” (participant-based p=0.02), and “keeping mail and papers organized” (informant-based p=0.002) best discriminated MCI from CN. We found that worse performance on “keeping mail and papers organized” (participant-based Hazard Ratio (HR)=2.27, p=0.07) marginally predicted greater hazard of progressing from CN to MCI.
Conclusions
Our results indicate that a few simple questions targeting early functional changes, addressed either to the individual or informant, can effectively distinguish between CN elderly and individuals with MCI. Additionally, one of the above questions related to organization suggested which CN individuals are likely to progress to MCI.
PMCID: PMC4247808  PMID: 25274110
Activities of daily living; Alzheimer’s disease; clinical assessment; daily functioning; clinically normal elderly; mild cognitive impairment
2.  Unrecognized vitamin D3 deficiency is common in Parkinson disease 
Neurology  2013;81(17):1531-1537.
Objective:
To conclusively test for a specific association between the biological marker 25-hydroxy-vitamin D3, a transcriptionally active hormone produced in human skin and liver, and the prevalence and severity of Parkinson disease (PD).
Methods:
We used liquid chromatography/tandem mass spectrometry to establish an association specifically between deficiency of 25-hydroxy-vitamin D3 and PD in a cross-sectional and longitudinal case-control study of 388 patients (mean Hoehn and Yahr stage of 2.1 ± 0.6) and 283 control subjects free of neurologic disease nested in the Harvard Biomarker Study.
Results:
Plasma levels of 25-hydroxy-vitamin D3 were associated with PD in both univariate and multivariate analyses with p values = 0.0034 and 0.047, respectively. Total 25-hydroxy-vitamin D levels, the traditional composite measure of endogenous and exogenous vitamin D, were deficient in 17.6% of patients with PD compared with 9.3% of controls. Low 25-hydroxy-vitamin D3 as well as total 25-hydroxy-vitamin D levels were correlated with higher total Unified Parkinson’s Disease Rating Scale scores at baseline and during follow-up.
Conclusions:
Our study reveals an association between 25-hydroxy-vitamin D3 and PD and suggests that thousands of patients with PD in North America alone may be vitamin D–deficient. This finding has immediate relevance for individual patients at risk of falls as well as public health, and warrants further investigation into the mechanism underlying this association.
doi:10.1212/WNL.0b013e3182a95818
PMCID: PMC3888173  PMID: 24068787
3.  SIST-M-IR activities of daily living items that best discriminate clinically normal elderly from those with mild cognitive impairment 
Current Alzheimer research  2014;11(8):785-791.
Background
Activities of daily living (ADL) impairment is a hallmark of Alzheimer's disease (AD) dementia, but impairment in instrumental ADL (IADL) has been reported in mild cognitive impairment (MCI). The Structured Interview and Scoring Tool-Massachusetts Alzheimer's Disease Research Center (MADRC)-Informant Report (SIST-M-IR) includes 60 graded items that assist in scoring the Clinical Dementia Rating; it assesses the spectrum of cognitive and ADL changes relevant to early AD. Of the 60 SIST-M-IR items, 41 address IADL; we aimed to determine which of these best discriminate individuals with MCI from clinically normal (CN) elderly.
Methods
We assessed 447 subjects participating in the MADRC longitudinal cohort (289 CN, 158 MCI). We performed logistic regression analyses predicting the probability of CN vs. MCI diagnosis using the SIST-M-IR items. Analyses were adjusted for demographic characteristics.
Results
We found that 4 SIST-M-IR items best discriminated between CN and MCI subjects (MCI performing worse than CN): “participating in games that involve retrieving words” (p=0.0001), “navigating to unfamiliar areas” (p=0.001), “performing mental tasks involved in a former primary job” (p=0.002), and “fixing things or finishing projects” (p=0.002).
Conclusions
Our results point to the earliest functional changes seen in elderly at risk for AD, which could be captured by a few simple questions. Honing the sensitivity of clinical assessment tools will help clinicians differentiate those individuals with normal aging from those who are developing cognitive impairment.
PMCID: PMC4163929  PMID: 25212917
Activities of daily living; Alzheimer's disease; clinical assessment; daily functioning; clinically normal elderly; mild cognitive impairment
4.  Striatal and extrastriatal dopamine transporter levels relate to cognition in Lewy body diseases: an 11C altropane positron emission tomography study 
Introduction
The biological basis of cognitive impairment in parkinsonian diseases is believed to be multifactorial. We investigated the contribution of dopamine deficiency to cognition in Parkinson disease (PD) and dementia with Lewy bodies (DLB) with dopamine transporter (DAT) imaging.
Methods
We acquired 11C altropane PET, magnetic resonance imaging and cognitive testing in 19 nondemented subjects with PD, 10 DLB and 17 healthy control subjects (HCS). We analyzed DAT concentration in putamen, caudate, anterior cingulate (AC), orbitofrontal and prefrontal regions, using the Standardized Uptake Volume Ratio with partial volume correction, and we related DAT concentration and global cortical thickness to neuropsychological performance.
Results
DAT concentration in putamen and in caudate were similar in PD and DLB groups and significantly lower than in HCS. Reduced caudate DAT concentration was associated with worse Clinical Dementia Rating Scale–sum of boxes (CDR-SB) scores and visuospatial skills in DLB but not in PD or HCS groups. Adjusting for putamen DAT concentration, as a measure of severity of motor disease, caudate DAT concentration was lower in DLB than in PD. Higher AC DAT concentration was associated with lower putamen DAT concentration in DLB and with higher putamen DAT concentration in PD. Higher AC DAT concentration in DLB correlated with greater impairment in semantic memory and language.
Conclusions
Caudate and AC dopamine dysfunction contribute in opposing directions to cognitive impairment in DLB.
Electronic supplementary material
The online version of this article (doi:10.1186/s13195-014-0052-7) contains supplementary material, which is available to authorized users.
doi:10.1186/s13195-014-0052-7
PMCID: PMC4245149  PMID: 25429309
5.  Regional fluorodeoxyglucose metabolism and instrumental activities of daily living across the Alzheimer's disease spectrum 
Background
Impairment in instrumental activities of daily living (IADL) begins as individuals with amnestic mild cognitive impairment (MCI) transition to Alzheimer's disease (AD) dementia. IADL impairment in AD dementia has been associated with inferior parietal, inferior temporal, and superior occipital hypometabolism using 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET).
Objective
To investigate the relationship between regional FDG metabolism and IADL in clinically normal (CN) elderly, MCI, and mild AD dementia subjects cross-sectionally and longitudinally.
Methods
One hundred and four CN, 203 MCI, and 95 AD dementia subjects from the Alzheimer's Disease Neuroimaging Initiative underwent clinical assessments every 6 to 12 months for up to three years and baseline FDG PET. The subjective, informant-based Functional Activities Questionnaire was used to assess IADL. General linear models and mixed effects models were used, covarying for demographics, cogniton, and behavior.
Results
The cross-sectional analysis revealed middle frontal and orbitofrontal hypometabolism were significantly associated with greater IADL impairment. Additionally, the interaction of diagnosis with posterior cingulate and with parahippocampal hypometabolism showed a greater decline in IADL performance as metabolism decreased for the AD dementia relative to the MCI group, and the MCI group relative to the CN group. The longitudinal analysis showed that baseline middle frontal and posterior cingulate hypometabolism were significantly associated with greater rate of increase in IADL impairment over time.
Conclusion
These results suggest that regional synaptic dysfunction, including the Alzheimer-typical medial parietal and less typical frontal regions, relates to daily functioning decline at baseline and over time across the early AD spectrum.
doi:10.3233/JAD-131796
PMCID: PMC4133312  PMID: 24898635
18F-fluorodeoxyglucose positron emission tomography; Alzheimer's disease; instrumental activities of daily living; mild cognitive impairment
6.  Regional cortical thinning and cerebrospinal biomarkers predict worsening daily functioning across the Alzheimer disease spectrum 
Background
Impairment in instrumental activities of daily living (IADL) heralds the transition from mild cognitive impairment (MCI) to dementia and is a major source of burden for both the patient and caregiver.
Objective
To investigate the relationship between IADL and regional cortical thinning and cerebrospinal fluid (CSF) Alzheimer disease (AD) biomarkers cross-sectionally and longitudinally in clinically normal (CN) elderly, MCI, and mild AD dementia subjects.
Methods
Two hundred and twenty nine CN, 395 MCI, and 188 AD dementia subjects participating in the Alzheimer's Disease Neuroimaging Initiative underwent baseline magnetic resonance imaging, baseline lumbar puncture, and clinical assessments, including the Functional Activities Questionnaire used to measure IADL, every 6 to 12 months up to 3 years. General linear regression and mixed effects models were employed.
Results
IADL impairment was associated with the interactions between lower inferior temporal cortical thickness and diagnosis (p<0.0001), greater lateral occipital cortical thickness and diagnosis (p<0.0001), and greater amyloid-beta 1-42 (Aβ1-42) and diagnosis (p=0.0002) at baseline (driven by AD dementia). Lower baseline supramarginal (p=0.02) and inferior temporal (p=0.05) cortical thickness, lower Aβ1-42 (p<0.0001), and greater total tau (t-tau) (p=0.02) were associated with greater rate of IADL impairment over time.
Conclusions
Temporal atrophy is associated with IADL impairment in mild AD dementia at baseline, while baseline parietal and temporal atrophy, lower CSF Aβ1-42, and greater t-tau predict worsening IADL impairment over time across the AD spectrum. These results emphasize the importance of assessing IADL at the stage of MCI and even at the transition from CN to MCI.
doi:10.3233/JAD-132768
PMCID: PMC4111766  PMID: 24685624
Alzheimer's disease; cerebrospinal fluid; instrumental activities of daily living; magnetic resonance imaging; mild cognitive impairment
7.  Amyloid is linked to cognitive decline in patients with Parkinson disease without dementia 
Neurology  2013;80(1):85-91.
ABSTRACT
Objective:
To determine whether amyloid burden, as indexed by Pittsburgh compound B (PiB) retention, identifies patients with Parkinson disease with mild cognitive impairment (PD-MCI) compared to those with normal cognition (PD-nl). A related aim is to determine whether amyloid burden predicts cognitive decline in a cohort of subjects with PD without dementia.
Methods:
In this prospective cohort study, we examined 46 subjects with PD without dementia, of whom 35 had normal cognition and 11 met criteria for PD-MCI at study baseline. All subjects underwent standardized neurologic and neuropsychological examinations and PiB PET at baseline, and clinical examinations were conducted annually for up to 5 years.
Results:
At baseline, precuneus PiB retention did not distinguish PD-MCI from PD-nl. Subjects with PD-MCI declined more rapidly than PD-nl subjects on cognitive tests of memory, executive function, and activation retrieval. Of the 35 PD-nl subjects, 8 progressed to PD-MCI and 1 to dementia; of the 11 PD-MCI subjects, 5 converted to dementia. Both higher PiB retention and a diagnosis of PD-MCI predicted a greater hazard of conversion to a more severe diagnosis. Baseline PiB retention predicted worsening in executive function over time. The APOE ε4 allele also related to worsening in executive function, as well as visuospatial function, activation retrieval, and performance on the Mini-Mental State Examination. In contrast to its relation to cognitive decline, PiB retention did not affect progression of motor impairment.
Conclusions:
At baseline measurements, amyloid burden does not distinguish between cognitively impaired and unimpaired subjects with PD without dementia, but our data suggest that amyloid contributes to cognitive, but not motor, decline over time.
doi:10.1212/WNL.0b013e31827b1a07
PMCID: PMC3589197  PMID: 23243071
8.  An Overview of Longitudinal Data Analysis Methods for Neurological Research 
The purpose of this article is to provide a concise, broad and readily accessible overview of longitudinal data analysis methods, aimed to be a practical guide for clinical investigators in neurology. In general, we advise that older, traditional methods, including (1) simple regression of the dependent variable on a time measure, (2) analyzing a single summary subject level number that indexes changes for each subject and (3) a general linear model approach with a fixed-subject effect, should be reserved for quick, simple or preliminary analyses. We advocate the general use of mixed-random and fixed-effect regression models for analyses of most longitudinal clinical studies. Under restrictive situations or to provide validation, we recommend: (1) repeated-measure analysis of covariance (ANCOVA), (2) ANCOVA for two time points, (3) generalized estimating equations and (4) latent growth curve/structural equation models.
doi:10.1159/000330228
PMCID: PMC3243635  PMID: 22203825
Analysis; Longitudinal studies; Methods; Neurology; Statistics
9.  Neuropsychiatric symptoms and global functional impairment along the Alzheimer’s continuum 
Background/Aims
Neuropsychiatric symptoms in Alzheimer’s disease (AD) are highly prevalent. We sought to determine whether neuropsychiatric symptoms were related to global functional impairment at baseline and over a 3 year period in normal older control (NC), mild cognitive impairment (MCI), and mild AD dementia subjects.
Methods
Eight hundred and twelve subjects (229 NC, 395 MCI, 188 AD) from the Alzheimer’s Disease Neuroimaging Initiative study underwent 3 years of cognitive and behavioral assessments.
Results
Greater hallucinations, anxiety, and apathy were associated with greater global functional impairment at baseline, while baseline hallucinations and apathy were associated with greater global functional impairment over time across all subjects. The following neuropsychiatric symptoms were not significantly associated with global functioning: delusions, agitation, depression, euphoria, disinhibition, irritability, aberrant motor behaviors, sleep, and appetite.
Conclusions
These results suggest that increased baseline hallucinations and apathy are associated with current and future disease progression in AD.
doi:10.1159/000342119
PMCID: PMC3549662  PMID: 22922821
Alzheimer’s disease; anxiety; apathy; disease progression; hallucinations; MCI; Neuropsychiatric Symptoms
10.  A Luminex Assay Detects Amyloid β Oligomers in Alzheimer’s Disease Cerebrospinal Fluid 
PLoS ONE  2013;8(7):e67898.
Amyloid beta (aβ) protein assembles into larger protein aggregates during the pathogenesis of Alzheimer’s disease (AD) and there is increasing evidence that soluble aβ oligomers are a critical pathologic species. Diagnostic evaluations rely on the measurement of increased tau and decreased aβ42 in the cerebrospinal fluid (CSF) from AD patients and evidence for oligomeric aβ in patient CSF is conflicting. In this study, we have adapted a monoclonal single antibody sandwich ELISA assay to a Luminex platform and found that this assay can detect oligomerized aβ42 and sAPPα fragments. We evaluated oligomeric aβ reactivity in 20 patients with AD relative to 19 age matched controls and compared these values with a commercially available Alzbio3 kit that detects tau, phosphorylated tau and aβ42 on the same diagnostic platform. We found that CSF samples of patients with AD had elevated aβ oligomers compared to control subjects (p < 0.05) and the ratio of aβ oligomers to aβ42 was also significantly elevated (p < 0.0001). Further research to develop high sensitivity analytical platforms and rigorous methods of developing stable assay standards will be needed before the analysis of oligomeric aβ becomes a routine diagnostic assay for the evaluation of late onset AD patients.
doi:10.1371/journal.pone.0067898
PMCID: PMC3699502  PMID: 23844122
11.  Effects of Simvastatin on Cholesterol Metabolism and Alzheimer Disease Biomarkers 
Preclinical and epidemiologic studies suggest a protective effect of statins on Alzheimer disease (AD). Experimental evidence indicates that some statins can cross the blood-brain barrier, alter brain cholesterol metabolism, and may ultimately decrease the production of amyloid-β (Aβ) peptide. Despite these promising leads, clinical trials have yielded inconsistent results regarding the benefits of statin treatment in AD. Seeking to detect a biological signal of statins effect on AD, we conducted a 12-week open-label trial with simvastatin 40 mg/d and then 80 mg/d in 12 patients with AD or amnestic mild cognitive impairment and hypercholesterolemia. We quantified cholesterol precursors and metabolites and AD biomarkers of Aβ and tau in both plasma and cerebrospinal fluid at baseline and after the 12-week treatment period. We found a modest but significant inhibition of brain cholesterol biosynthesis after simvastatin treatment, as indexed by a decrease of cerebrospinal fluid lathosterol and plasma 24S-hydroxycholesterol. Despite this effect, there were no changes in AD biomarkers. Our findings indicate that simvastatin treatment can affect brain cholesterol metabolism within 12 weeks, but did not alter molecular indices of AD pathology during this short-term treatment.
doi:10.1097/WAD.0b013e3181d61fea
PMCID: PMC3694274  PMID: 20473136
Alzheimer disease; simvastatin; cholesterol; biomarker
12.  Pattern of Depressive Symptoms in Parkinson’s Disease 
Psychosomatics  2009;50(5):448-454.
Background
Depressive symptoms are common in Parkinson’s disease (PD); however, it is unclear whether there are specific depressive symptom patterns in patients with PD and co-morbid depression (dPD).
Objective
The goal of this study is to examine the frequency and correlates of specific depressive symptoms in PD.
Method
A sample of 158 individuals with PD completed the self-rated Harvard Department of Psychiatry/National Depression Screening Day Scale (HANDS). By multiple-regression analysis, the authors examined the association between HANDS total and subscale scores and various demographic variables.
Results
The frequency of depression was 37% (N=58). Patients with a history of depression before PD had significantly more serious depression than those who had no such history. Of those who were more depressed, the most common symptoms of depression endorsed were low energy, difficulty with concentration/making decisions, feeling blue, feeling hopeless, and having poor sleep.
Conclusion
There is a relatively high prevalence of dPD. Items on the HANDS that discriminated best between depressed and nondepressed subjects with PD included feeling blue, feeling hopeless, feeling worthless, lack of interest, and self-blame. It remains to be defined whether dPD should be understood primarily as a psychological reaction to a physical disability or perceived impending one, or as a direct expression of the neuropathology of PD.
doi:10.1176/appi.psy.50.5.448
PMCID: PMC3529169  PMID: 19855029
13.  Plasma Amyloid β-Protein and C-reactive Protein in Relation to the Rate of Progression of Alzheimer Disease 
Archives of neurology  2008;65(6):776-785.
Objective
To examine whether plasma markers of amyloid precursor protein metabolism (amyloid β-protein ending in Val-40 [Aβ40] and Ala-42 [Aβ42]), inflammation (high-sensitivity C-reactive protein), and folic acid metabolism (folic acid, vitamin B12, and total homocysteine levels) are associated with the rate of cognitive and functional decline in persons with Alzheimer disease.
Design
Longitudinal study across a mean (SD) of 4.2 (2.6) years with assessments at approximately 6- to 12- month intervals.
Setting
Out patient care.
Patients
A cohort of 122 patients having a clinical diagnosis of probable Alzheimer disease, each with at least 2 assessments across time.
Main Outcome Measures
Scores on the cognitive Information-Memory-Concentration subscale of the Blessed Dementia Scale and the functional Weintraub Activities of Daily Living Scale.
Results
Low plasma levels of Aβ40, Aβ42, and high-sensitivity C-reactive protein were associated with a significantly more rapid cognitive decline, as indexed using the Blessed Dementia Scale, than were high levels. Low levels of Aβ42 and high-sensitivity C-reactive protein were significantly associated with more rapid functional decline on the Weintraub Activities of Daily Living Scale than were high levels. These plasma markers contributed about 5% to 12% of the variance accounted for on the Blessed Dementia Scale and the Activities of Daily Living Scale by fixed-effects predictors. Measures of folic acid metabolism were not associated with changes on either the Blessed Dementia Scale or the Activities of Daily Living Scale.
Conclusions
Plasma markers of amyloid precursor protein metabolism and C-reactive protein may be associated with the rate of cognitive and functional decline in patients with Alzheimer disease.
doi:10.1001/archneur.65.6.776
PMCID: PMC2662621  PMID: 18541797
14.  Statistical adjustments for brain size in volumetric neuroimaging studies: Some practical implications in methods 
Psychiatry research  2011;193(2):113-122.
Volumetric magnetic resonance imaging (MRI) brain data provide a valuable tool for detecting structural differences associated with various neurological and psychiatric disorders. Analysis of such data, however, is not always straightforward, and complications can arise when trying to determine which brain structures are “smaller” or “larger” in light of the high degree of individual variability across the population. Several statistical methods for adjusting for individual differences in overall cranial or brain size have been used in the literature, but critical differences exist between them. Using agreement among those methods as an indication of stronger support of a hypothesis is dangerous given that each requires a different set of assumptions be met. Here we examine the theoretical underpinnings of three of these adjustment methods (proportion, residual, and analysis of covariance) and apply them to a volumetric MRI data set. These three methods used for adjusting for brain size are specific cases of a generalized approach which we propose as a recommended modeling strategy. We assess the level of agreement among methods and provide graphical tools to assist researchers in determining how they differ in the types of relationships they can unmask, and provide a useful method by which researchers may tease out important relationships in volumetric MRI data. We conclude with the recommended procedure involving the use of graphical analyses to help uncover potential relationships the ROI volumes may have with head size and give a generalized modeling strategy by which researchers can make such adjustments that include as special cases the three commonly employed methods mentioned above.
doi:10.1016/j.pscychresns.2011.01.007
PMCID: PMC3510982  PMID: 21684724
MRI; Statistics; Regression models; Morphometry
15.  Executive function and instrumental activities of daily living in MCI and AD 
Background
Impairment in instrumental activities of daily living (IADL) leads to early loss in productivity and adds significant burden to caregivers. Executive dysfunction is thought to be an important contributor to functional impairment. The objective of this study was to investigate the relationship between executive function and IADL in a large cohort of well characterized normal older controls (NC), mild cognitive impairment (MCI) and mild Alzheimer’s disease (AD) patients, separately as well as across the entire sample, while accounting for demographic, cognitive, and behavioral factors.
Methods
Subjects with baseline clinical datasets (n=793) from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) study (228 NC, 387 MCI, 178 AD) were included in the analyses. A multiple regression model was used to assess the relationship between executive function and IADL.
Results
A multiple regression model, including diagnosis, global cognitive impairment, memory performance, and other covariates demonstrated a significant relationship between executive dysfunction and IADL impairment across all subjects (R2=0.60, p<0.0001 for model; Digit Symbol, partial β=−0.044, p=0.005; Trailmaking Test B – A, quadratic relation, p=0.01). An analysis using MCI subjects only also yielded a significant relationship (R2=0.16, p<0.0001 for model; Digit Symbol, partial β=−0.08, p=0.001).
Conclusions
These results suggest that executive dysfunction is a key contributor to impairment in IADL. This relationship was evident even after accounting for degree of memory deficit across the continuum of cognitive impairment and dementia.
doi:10.1016/j.jalz.2010.04.005
PMCID: PMC3096844  PMID: 21575871
Alzheimer’s disease; executive function; instrumental activities of daily living; memory; mild cognitive impairment
16.  Test-Retest Reliability of Memory Task fMRI in Alzheimer’s Disease Clinical Trials 
Archives of Neurology  2011;68(5):599-606.
Objective
To examine feasibility and test-retest reliability of encoding-task functional MRI (fMRI) in mild Alzheimer’s disease (AD).
Design
Randomized, double-blind, placebo-controlled (RCT) study.
Setting
Memory clinical trials unit.
Participants
Twelve subjects with mild AD (MMSE 24.0±0.7, CDR 1), on >6 months stable donepezil, from the placebo-arm of a larger 24-week (n=24, four scans on weeks 0,6,12,24) study.
Interventions
Placebo and three face-name paired-associate encoding, block-design BOLD-fMRI scans in 12 weeks.
Main Outcomes
Whole-brain t-maps (p<0.001, 5-contiguous voxels) and hippocampal regions-of-interest (ROI) analyses of extent (EXT, %voxels active) and magnitude (MAG, %signal change) for Novel-greater-than-Repeated (N>R) face-name contrasts. Calculation of Intraclass Correlations (ICC) and power estimates for hippocampal ROIs.
Results
Task-tolerability and data yield were high (95 of 96 scans yield good quality data). Whole-brain maps were stable. Right and left hippocampal ROI ICCs were 0.59–0.87 and 0.67–0.74, respectively. To detect 25–50% changes in 0–12 week hippocampal activity using L/R-EXT or R-MAG with 80% power (2-sided-α=0.05) requires 14–51 subjects. Using L-MAG requires >125 subjects due to relatively small signals to variance ratios.
Conclusions
Encoding-task fMRI was successfully implemented in a single-site, 24-week, AD RCT. Week 0–12 whole-brain t-maps were stable and test-retest reliability of hippocampal fMRI measures ranged from moderate to substantial. Right hippocampal-MAG may be the most promising of these candidate measures in a leveraged context. These initial estimates of test-retest reliability and power justify evaluation of encoding-task fMRI as a potential biomarker for “signal-of-effect” in exploratory and proof-of-concept trials in mild AD. Validation of these results with larger sample sizes and assessment in multi-site studies is warranted.
doi:10.1001/archneurol.2011.94
PMCID: PMC3291175  PMID: 21555634
α = alpha; β = Beta
17.  A web-based normative calculator for the uniform data set (UDS) neuropsychological test battery 
Introduction
With the recent publication of new criteria for the diagnosis of preclinical Alzheimer's disease (AD), there is a need for neuropsychological tools that take premorbid functioning into account in order to detect subtle cognitive decline. Using demographic adjustments is one method for increasing the sensitivity of commonly used measures. We sought to provide a useful online z-score calculator that yields estimates of percentile ranges and adjusts individual performance based on sex, age and/or education for each of the neuropsychological tests of the National Alzheimer's Coordinating Center Uniform Data Set (NACC, UDS). In addition, we aimed to provide an easily accessible method of creating norms for other clinical researchers for their own, unique data sets.
Methods
Data from 3,268 clinically cognitively-normal older UDS subjects from a cohort reported by Weintraub and colleagues (2009) were included. For all neuropsychological tests, z-scores were estimated by subtracting the raw score from the predicted mean and then dividing this difference score by the root mean squared error term (RMSE) for a given linear regression model.
Results
For each neuropsychological test, an estimated z-score was calculated for any raw score based on five different models that adjust for the demographic predictors of SEX, AGE and EDUCATION, either concurrently, individually or without covariates. The interactive online calculator allows the entry of a raw score and provides five corresponding estimated z-scores based on predictions from each corresponding linear regression model. The calculator produces percentile ranks and graphical output.
Conclusions
An interactive, regression-based, normative score online calculator was created to serve as an additional resource for UDS clinical researchers, especially in guiding interpretation of individual performances that appear to fall in borderline realms and may be of particular utility for operationalizing subtle cognitive impairment present according to the newly proposed criteria for Stage 3 preclinical Alzheimer's disease.
doi:10.1186/alzrt94
PMCID: PMC3308021  PMID: 22078663
Alzheimer's disease; cognitive aging; MCI; memory; norms
18.  Assessing depression and factors possibly associated with depression during the course of Parkinson’s disease 
BACKGROUND
Although research suggests depression is common among individuals with Parkinson’s disease (PD), it is unclear how to best assess depression in PD (dPD). We wanted to examine the prevalence of dPD using different definitions of depression, as well as examine factors associated with dPD.
METHODS
One hundred fifty-eight individuals (68% male; age 66.8 ± 9.6 SD) with a primary diagnosis of PD were assessed for depression using the Harvard Department of Psychiatry/National Depression Screening Day Scale (HANDS) in an outpatient setting at the Movement Disorders Clinic at Massachusetts General Hospital. We defined depression using 4 thresholds based on the HANDS and whether or not an individual was ever on an antidepressant regimen. We also examined potential predictors of the presence of dPD.
RESULTS
The prevalence of depression among study participants ranged from 11% to 57%, depending on which of the 4 definitions of depression was applied. Younger age and longer duration of PD predicted a relatively higher prevalence of depression. Having a history of depression prior to onset of PD also was predictive of dPD.
CONCLUSIONS
Depression appears to be relatively common among individuals with PD, and history of depression, younger age, and longer PD duration may be factors associated with dPD.
PMCID: PMC3164778  PMID: 21808748
age; depression; Parkinson’s disease; prevalence; rating scales; severity of illness index
19.  PGC-1α, A Potential Therapeutic Target for Early Intervention in Parkinson’s Disease 
Science translational medicine  2010;2(52):52ra73.
Parkinson’s disease affects 5 million people worldwide, but the molecular mechanisms underlying its pathogenesis are still unclear. Here, we report a genome-wide meta-analysis of gene sets (groups of genes that encode the same biological pathway or process) in 410 samples from patients with symptomatic Parkinson’s and subclinical disease and healthy controls. We analyzed 6.8 million raw data points from nine genome-wide expression studies, and 185 laser-captured human dopaminergic neuron and substantia nigra transcriptomes, followed by two-stage replication on three platforms. We found 10 gene sets with previously unknown associations with Parkinson’s disease. These gene sets pinpoint defects in mitochondrial electron transport, glucose utilization, and glucose sensing and reveal that they occur early in disease pathogenesis. Genes controlling cellular bioenergetics that are expressed in response to peroxisome proliferator–activated receptor γ coactivator-1α (PGC-1α) are underexpressed in Parkinson’s disease patients. Activation of PGC-1α results in increased expression of nuclear-encoded subunits of the mitochondrial respiratory chain and blocks the dopaminergic neuron loss induced by mutant α-synuclein or the pesticide rotenone in cellular disease models. Our systems biology analysis of Parkinson’s disease identifies PGC-1α as a potential therapeutic target for early intervention.
doi:10.1126/scitranslmed.3001059
PMCID: PMC3129986  PMID: 20926834
Parkinson’s disease; incidental Lewy body disease; systems biology; microarray; transcriptional profiling; pathway; gene set enrichment analysis; meta-analysis; peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PPARGC1A); α-synuclein; PINK1; parkin; mitochondria; oxidative phosphorylation; glucose utilization; complex I
20.  Cognition, Reserve, and Amyloid Deposition in Normal Aging 
Annals of neurology  2010;67(3):353-364.
Objective
To determine whether amyloid deposition is associated with impaired neuropsychological (NP) performance and whether cognitive reserve (CR) modifies this association.
Methods
In 66 normal elderly controls and 17 patients with Alzheimer disease (AD), we related brain retention of Pittsburgh Compound B (PiB) to NP performance and evaluated the impact of CR using education and American National Adult Reading Test intelligence quotient as proposed proxies.
Results
We found in the combined sample of subjects that PiB retention in the precuneus was inversely related to NP performance, especially in tests of memory function, but also in tests of working memory, semantic processing, language, and visuospatial perception. CR significantly modified the relationship, such that at progressively higher levels of CR, increased amyloid deposition was less or not at all associated with poorer neuropsychological performance. In a subsample of normal controls, both the main effect of amyloid deposition of worse memory performance and the interaction with CR were replicated using a particularly challenging memory test.
Interpretation
Amyloid deposition is associated with lower cognitive performance both in AD patients and in the normal elderly, but the association is modified by CR, suggesting that CR may be protective against amyloid-related cognitive impairment.
doi:10.1002/ana.21904
PMCID: PMC3074985  PMID: 20373347
21.  Preservation of Neuronal Number Despite Age-Related Cortical Brain Atrophy In Elderly Subjects Without Alzheimer Disease 
Cerebral volume loss has long been associated with normal aging but whether this is due to aging itself or to age-related diseases including incipient Alzheimer disease (AD) is uncertain. To understand the changes that occur in the aging brain, we examined the cerebral cortex of 27 normal individuals ranging in age from 56 to 103 years. None fulfilled the criteria for the neuropathological diagnosis of AD or other neurodegenerative disease. Seventeen of the elderly participants had cognitive testing an average of 6.7 months prior to death. We used quantitative approaches to analyze cortical thickness, neuronal number, and density. Frontal and temporal neocortical regions had clear evidence of cortical thinning with age but total neuronal numbers in frontal and temporal neocortical regions remained relatively constant over a 50-year age range. These data suggest that loss of neuronal and dendritic architecture, rather than loss of neurons, underlies neocortical volume loss with increasing age in the absence of AD.
doi:10.1097/NEN.0b013e31818fc72f
PMCID: PMC2734185  PMID: 19018241
Aging; Cerebral cortex; Neurons; Stereology
22.  Long-term Course and Effectiveness of Combination Therapy in Alzheimer’s Disease 
Objective
To compare the real-world clinical effectiveness and long-term clinical trajectory in patients with Alzheimer’s disease (AD) treated with combination (COMBO) therapy consisting of cholinesterase-inhibitor (CI) plus memantine (MEM) versus CI alone versus no treatment with either.
Methods
382 subjects with Probable AD underwent serial clinical evaluations at a memory disorders unit. Cognition was assessed by the Information-Memory-Concentration subscale of the Blessed Dementia Scale (BDS) and function was assessed by the Weintraub Activities of Daily Living Scale (ADL) at six-month intervals. 144 subjects received standard care without CI or MEM (NO-RX), 122 received CI-monotherapy (CI), and 116 received combination therapy (COMBO) with CI plus MEM. Mean follow-up was 30 months (4.1 visits) and mean cumulative medication treatment time was 22.5 months. Rates of declines were analyzed using mixed-effects regression models, and Cohen’s d effect sizes were calculated annually for years 1–4.
Results
Covarying for baseline scores, age, education and duration of illness, the COMBO group had significantly lower mean annualized rates of deterioration in BDS and ADL scores compared to the CI (p<0.001; Cohen’s dBDS=0.10–0.34 and dADL=0.23–0.46 at 1–2 years) and NO-RX groups (p<0.001; Cohen’s dBDS=0.56–0.73 and dADL=0.32–0.48 at 1–2 years). For the COMBO group, Cohen’s d effect sizes increased with treatment duration. Similar comparisons significantly favored the CI over the NO-RX group on the BDS.
Conclusions
Combination therapy slows cognitive and functional decline in AD compared to CI-monotherapy and no treatment. These benefits had small-to-medium effect sizes that increased with time on treatment and were sustained for years.
doi:10.1097/WAD.0b013e31816653bc
PMCID: PMC2718545  PMID: 18580597
treatment efficacy; modeling progression; cholinesterase inhibitor; memantine; memory; cognition and function in dementia
23.  Cognition, Reserve, and Amyloid Deposition in Normal Aging 
Annals of Neurology  2009;67(3):353-364.
Objective
To determine whether amyloid deposition is associated with impaired neuropsychological (NP) performance and whether cognitive reserve (CR) modifies this association.
Methods
In 66 normal elderly controls and 17 patients with Alzheimer disease (AD), we related brain retention of Pittsburgh Compound B (PiB) to NP performance and evaluated the impact of CR using education and American National Adult Reading Test intelligence quotient as proposed proxies.
Results
We found in the combined sample of subjects that PiB retention in the precuneus was inversely related to NP performance, especially in tests of memory function, but also in tests of working memory, semantic processing, language, and visuospatial perception. CR significantly modified the relationship, such that at progressively higher levels of CR, increased amyloid deposition was less or not at all associated with poorer neuropsychological performance. In a subsample of normal controls, both the main effect of amyloid deposition of worse memory performance and the interaction with CR were replicated using a particularly challenging memory test.
Interpretation
Amyloid deposition is associated with lower cognitive performance both in AD patients and in the normal elderly, but the association is modified by CR, suggesting that CR may be protective against amyloid-related cognitive impairment. ANN NEUROL 2010;67:353–364
doi:10.1002/ana.21904
PMCID: PMC3074985  PMID: 20373347

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