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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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

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.