Alireza Atri

Alterations in Memory Networks in Mild Cognitive Impairment and Alzheimer's Disease: An Independent Component Analysis

Memory function is likely subserved by multiple distributed neural networks, which are disrupted by the pathophysiological process of Alzheimers disease (AD). In this study, we used multivariate analytic techniques to investigate memory-related functional magnetic resonance imaging (fMRI) activity in 52 individuals across the continuum of normal aging, mild cognitive impairment (MCI), and mild AD. Independent component analyses revealed specific memory-related networks that activated or deactivated during an associative memory paradigm. Across all subjects, hippocampal activation and parietal deactivation demonstrated a strong reciprocal relationship. Furthermore, we found evidence of a nonlinear trajectory of fMRI activation across the continuum of impairment. Less impaired MCI subjects showed paradoxical hyperactivation in the hippocampus compared with controls, whereas more impaired MCI subjects demonstrated significant hypoactivation, similar to the levels observed in the mild AD subjects. We found a remarkably parallel curve in the pattern of memory-related deactivation in medial and lateral parietal regions with greater deactivation in less-impaired MCI and loss of deactivation in more impaired MCI and mild AD subjects. Interestingly, the failure of deactivation in these regions was also associated with increased positive activity in a neocortical attentional network in MCI and AD. Our findings suggest that loss of functional integrity of the hippocampal-based memory systems is directly related to alterations of neural activity in parietal regions seen over the course of MCI and AD. These data may also provide functional evidence of the interaction between neocortical and medial temporal lobe pathology in early AD.

A single-pool model for intracellular calcium oscillations and waves in the Xenopus laevis oocyte

We construct a minimal model of cytosolic free Ca2+ oscillations based on Ca2+ release via the inositol 1,4,5-trisphosphate (IP3) receptor/Ca2+ channel (IP3R) of a single intracellular Ca2+ pool. The model relies on experimental evidence that the cytosolic free calcium concentration ([Ca2+]c) modulates the IP3R in a biphasic manner, with Ca2+ release inhibited by low and high [Ca2+]c and facilitated by intermediate [Ca2+]c, and that channel inactivation occurs on a slower time scale than activation. The model produces [Ca2+]c oscillations at constant [IP3] and reproduces a number of crucial experiments. The two-dimensional spatial model with IP3 dynamics, cytosolic diffusion of IP3 (Dp = 300 microns 2 s-1), and cytosolic diffusion of Ca2+ (Dc = 20 microns 2 s-1) produces circular, planar, and spiral waves of Ca2+ with speeds of 7-15 microns.s-1, which annihilate upon collision. Increasing extracellular [Ca2+] influx increases wave speed and baseline [Ca2+]c. A [Ca2+]c-dependent Ca2+ diffusion coefficient does not alter the qualitative behavior of the model. An important model prediction is that channel inactivation must occur on a slower time scale than activation in order for waves to propagate. The model serves to capture the essential macroscopic mechanisms that are involved in the production of intracellular Ca2+ oscillations and traveling waves in the Xenopus laevis oocyte.

Long-term Course and Effectiveness of Combination Therapy in Alzheimer Disease

ObjectiveTo compare the real-world clinical effectiveness and long-term clinical trajectory in patients with Alzheimer disease (AD) treated with combination (COMBO) therapy consisting of cholinesterase-inhibitor (CI) plus memantine (MEM) versus CI alone versus no treatment with either. MethodsThree hundred eighty-two 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 6-month intervals. One hundred forty-four subjects received standard care without CI or MEM (NO-RX), 122 received CI monotherapy, and 116 received COMBO therapy 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 decline were analyzed using mixed-effects regression models, and Cohens d effect sizes were calculated annually for years 1 to 4. ResultsCovarying 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 with the CI (P<0.001; Cohens dBDS=0.10−0.34 and dADL=0.23−0.46 at 1 to 2 y) and NO-RX groups (P<0.001; Cohens dBDS=0.56−0.73 and dADL=0.32−0.48 at 1 to 2 y). For the COMBO group, Cohens d effect sizes increased with treatment duration. Similar comparisons significantly favored the CI over the NO-RX group on the BDS. ConclusionsCOMBO therapy slows cognitive and functional decline in AD compared with CI monotherapy and no treatment. These benefits had small-to-medium effect sizes that increased with time on treatment and were sustained for years.

Scopolamine Reduces Persistent Activity Related to Long-Term Encoding in the Parahippocampal Gyrus during Delayed Matching in Humans

Recent computational modeling and slice physiology studies have suggested that long-term encoding may depend on sustained spiking during brief memory delays in parahippocampal neurons, and that this persistent spiking activity is modulated by effects of acetylcholine at muscarinic receptors. Our recent functional magnetic resonance imaging (fMRI) study has shown that sustained parahippocampal delay period activity during delayed match-to-sample performance in healthy young individuals predicted subsequent memory of visual stimuli on a recognition memory assessment 20 min later (Schon et al., 2004). The current study combined this fMRI paradigm with a pharmacological manipulation to test whether this long-term encoding-related delay activity is reduced in subjects who receive the muscarinic cholinergic antagonist scopolamine before fMRI scanning. Subsequent memory was predicted by sustained activity during brief memory delays bilaterally in the perirhinal/entorhinal cortex, in the right posterior parahippocampal and mid-fusiform gyri, and in the hippocampal body in healthy young individuals without a scopolamine challenge. This activity was reduced in subjects receiving scopolamine. The results are consistent with computational modeling data and behavioral pharmacological studies, suggesting that long-term encoding-related activity may be reduced if cholinergic receptors are blocked by scopolamine.

Blockade of Central Cholinergic Receptors Impairs New Learning and Increases Proactive Interference in a Word Paired-Associate Memory Task

Experimental data and computational models suggest that blockade of muscarinic cholinergic receptors impairs paired-associate learning and increases proactive interference (E. DeRosa & M. E. Hasselmo, 2000; M. E. Hasselmo & J. M. Bower, 1993). The results presented here provide evidence in humans supporting these hypotheses. Young healthy subjects first learned baseline word pairs (A-B) and, after a delay, learned additional overlapping (A-C) and nonoverlapping (D-E) word pairs. As predicted, when compared with subjects who received the active placebo glycopyrrolate (4 microg/kg) and subjects who were not injected, those who received scopolamine (8 microg/kg) showed (a) overall impairment in new word paired-associate learning, but no impairment in cued recall of previously learned associates; and (b) greater impairment in learning overlapping (A-C) compared with nonoverlapping (D-E) paired associates.

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.

Memantine in patients with Alzheimer's disease receiving donepezil: new analyses of efficacy and safety for combination therapy

IntroductionMemantine and cholinesterase inhibitors potentially offer additional benefits in Alzheimers disease (AD) when used together. This study assessed the efficacy and safety of combination treatment with memantine added to stable donepezil in patients with moderate to severe AD, and in a subset with moderate AD.MethodsPost hoc meta-analyses of data combined from two 24-week, randomised, double-blind, placebo-controlled trials of memantine 20 mg/day versus placebo, added to a stable cholinesterase inhibitor, were conducted. Data were included for all patients receiving donepezil 10 mg/day with Mini-Mental State Examination (MMSE) scores < 20 (n = 510). Efficacy was assessed using measures of cognition, function, and global status. Furthermore, marked clinical worsening, defined as concurrent deterioration from baseline in the three main efficacy domains, and safety, measured by treatment-emergent adverse events, were assessed. Analyses were performed for patients with moderate to severe AD (MMSE 5-19; MOD-SEV subgroup), and also for patients with moderate AD (MMSE 10-19; MOD subgroup; n = 367).ResultsAt week 24, in the MOD-SEV subgroup, patients receiving memantine added to donepezil significantly outperformed those receiving placebo added to donepezil in measures of cognition (P < 0.0001), function (P = 0.02), and global status (P = 0.010), with standardised mean differences (SMDs) of 0.36, 0.21, and 0.23, respectively (all last observation carried forward). Similarly, in the MOD subgroup, significant benefits were observed for cognition (P = 0.008), function (P = 0.04) and global status (P = 0.008), with SMDs of 0.28, 0.21, and 0.28, respectively. Significantly fewer patients receiving memantine added to donepezil showed marked clinical worsening than those receiving placebo added to donepezil, in both subgroups (MOD-SEV: 8.7% versus 20.4%, P = 0.0002; MOD: 5.9% versus 15.0%, P = 0.006). The incidence of adverse events was similar between treatment groups.ConclusionsThese results support and extend previous evidence that combination treatment with memantine added to stable donepezil in patients with moderate AD, and in those with moderate to severe AD, is associated with significant benefits in reducing 24-week decline in cognition, function and global status. Combination treatment produces substantially reduced rates of marked clinical worsening, has good safety and tolerability, and generates effect sizes that are both statistically significant and clinically meaningful.

A web-based normative calculator for the uniform data set (UDS) neuropsychological test battery

IntroductionWith the recent publication of new criteria for the diagnosis of preclinical Alzheimers 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 Alzheimers 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.MethodsData 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.ResultsFor 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.ConclusionsAn 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 Alzheimers disease.

Cognitively Stimulating Activities: Effects on Cognition across Four Studies with up to 21 Years of Longitudinal Data

Engagement in cognitively stimulating activities has been considered to maintain or strengthen cognitive skills, thereby minimizing age-related cognitive decline. While the idea that there may be a modifiable behavior that could lower risk for cognitive decline is appealing and potentially empowering for older adults, research findings have not consistently supported the beneficial effects of engaging in cognitively stimulating tasks. Using observational studies of naturalistic cognitive activities, we report a series of mixed effects models that include baseline and change in cognitive activity predicting cognitive outcomes over up to 21 years in four longitudinal studies of aging. Consistent evidence was found for cross-sectional relationships between level of cognitive activity and cognitive test performance. Baseline activity at an earlier age did not, however, predict rate of decline later in life, thus not supporting the concept that engaging in cognitive activity at an earlier point in time increases ones ability to mitigate future age-related cognitive decline. In contrast, change in activity was associated with relative change in cognitive performance. Results therefore suggest that change in cognitive activity from ones previous level has at least a transitory association with cognitive performance measured at the same point in time.

Effectiveness of antidementia drugs in delaying Alzheimer's disease progression

Randomized controlled trials (RCTs) provide safety and efficacy data for regulatory approval of antidementia drugs, but offer limited data regarding real‐world effectiveness. Long‐term observational controlled studies (LTOCs) extend our understanding by providing longitudinal data across multiple stages of Alzheimers disease (AD).