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Psychometric Cognitive Decline Precedes the Advent of Subjective Cognitive Decline in the Evolution of Alzheimer's Disease

Reisberg, Barry; Shao, Yongzhao; Moosavi, Mesum; Kenowsky, Sunnie; Vedvyas, Alok; Marsh, Karyn; Bao, Jia; Buj, Maja; Torossian, Carol; Kluger, Alan; Vedvyas, Gaurav; Oo, Thet; Malik, Fawad; Arain, Fauzia; Masurkar, Arjun V; Wisniewski, Thomas
BACKGROUND:We have described the clinical stages of the brain aging and Alzheimer's disease (AD) continuum. In terms of the pre-dementia stages of AD, we introduced the terminology "mild cognitive impairment" (MCI) for the first pre-dementia stage and "subjective cognitive decline" (SCD) for the pre-MCI stage. We now report the characteristics of a pre-SCD condition eventuating in likely AD. OBJECTIVE:The aim of this study was to characterize a pre-SCD condition eventuating in AD. METHOD/METHODS:Sixty healthy persons with "no cognitive decline" (NCD) were recruited and 47 were followed (mean baseline age, 64.1 ± 8.9 years; mean follow-up time, 6.7 ± 3.1 years). Outcome was determined at the final assessment prior to 2002 as "decliner," if SCD or worse, or "nondecliner" if NCD. RESULTS:After controlling for age, gender, years of education, and follow-up time, there was a between-group difference in the decline rate (p < 0.001). Also, after controlling for demographic variables and follow-up time, the combinatorial psychometric score was lower at baseline in the future decliners (p = 0.035). Of the 9 psychometric variables, after controlling for demographic variables and follow-up time, 3 were significantly lower at baseline in future decliners. Since AD is known to be age related and all subjects in this study were otherwise healthy, we also did an analysis without controlling for age. The combinatorial psychometric score was highly significantly better at baseline in the future nondecliners than in the future decliners (p = 0.008). CONCLUSION/CONCLUSIONS:This is ostensibly the first study to link psychometric cognitive decline to the subsequent SCD stage of eventual AD.
PMID: 32388509
ISSN: 1421-9824
CID: 4428002

Two Year Outcomes, Cognitive and Behavioral Markers of Decline in Healthy, Cognitively Normal Older Persons with Global Deterioration Scale Stage 2 (Subjective Cognitive Decline with Impairment)

Reisberg, Barry; Torossian, Carol; Shulman, Melanie B; Monteiro, Isabel; Boksay, Istvan; Golomb, James; Guillo Benarous, Francoise; Ulysse, Anaztasia; Oo, Thet; Vedvyas, Alok; Rao, Julia A; Marsh, Karyn; Kluger, Alan; Sangha, Jaspreet; Hassan, Mudasar; Alshalabi, Munther; Arain, Fauzia; Shaikh, Naveed; Buj, Maja; Kenowsky, Sunnie; Masurkar, Arjun V; Rabin, Laura; Noroozian, Maryam; Sánchez-Saudinós, Mar A Belén; Blesa, Rafael; Auer, Stefanie; Zhang, Yian; de Leon, Mony; Sadowski, Martin; Wisniewski, Thomas; Gauthier, Serge; Shao, Yongzhao
BACKGROUND:Little is known with respect to behavioral markers of subjective cognitive decline (SCD), a condition initially described in association with Global Deterioration Scale (GDS) stage 2. OBJECTIVE:Two-year interval behavioral markers were investigated herein. METHODS:Subjects from a published 7-year outcome study of GDS stage 2 subjects were selected. This study had demonstrated a hazard ratio of 4.5 for progression of GDS stage 2, in comparison with GDS stage 1 (no subjective or objective cognitive decline) subjects, after controlling for demographic and temporal variables. Because GDS 2 subjects have previously demonstrated impairment in comparison with healthy persons free of complaints, we herein suggest the terminology "SCD(I)" for these persons. 98 SCD(I) persons, 63 women and 35 men, mean baseline age, 67.12±8.75 years, with a mean educational background of 15.55±2.60 years, and mean baseline MMSE scores of 28.9±1.24 were followed for 2.13±0.30 years. RESULTS:Observed annual decline on the GDS was 6.701% per annum, very close to a 1986 published estimate. At follow up, the MMSE, and 7 of 8 psychometric tests did not decline significantly. Of 21 Hamilton Depression Scale items, 2 improved and the remainder were unchanged. Anxieties declined from multiple perspectives. The Brief Cognitive Rating Scale (BCRS) declined significantly (p < 0.001), with component declines in Remote memory (p < 0.01), and Functioning/self-care (p = 0.01). CONCLUSION/CONCLUSIONS:SCD(I) persons decline at an annual rate of approximately 6.7% /year from several recent studies. The BCRS assessments and the Digit Symbol Substitution Test can be sensitive measures for future studies of progression mitigation.
PMID: 30689585
ISSN: 1875-8908
CID: 3626022

Neuropsychological and Neuropsychiatric Prediction of Global Cognitive Status Among Older Spanish-Speaking Hispanics and English-Speaking Whites

Guerrero-Berroa, Elizabeth; Kluger, Alan; Schmeidler, James; Sailor, Kevin; Lizardi, Humberto; Golomb, James; Ferris, Steven; Reisberg, Barry
BACKGROUND: Neuropsychological and depression measures have been found to predict cognitive functioning. We compared these associations among whites and Spanish-speaking Hispanics. METHODS: Fifty-two pairs of whites and Hispanics were matched demographically and clinically in a cross-sectional study. Hierarchical regression analyses predicted Global Deterioration Scale (GDS) rating by baseline neuropsychological tests and depression symptoms. RESULTS: Neuropsychological tests predicted GDS better in whites; depression symptoms-specifically retardation-predicted well in Hispanics but not whites. Immediate recall of the New York University (NYU)-Paragraph Test and the Retardation item of the Hamilton Depression Rating Scale were associated with GDS in Hispanics and delayed recall of the NYU-Paragraph Test and Wechsler Adult Intelligence Scale-Digit Symbol in whites. Neuropsychological tests and depression symptoms predicted GDS differently in Hispanics and whites. DISCUSSION: These results suggest that other measures should be considered to increase the predictive accuracy of neuropsychological tests when assessing cognitive status in Spanish-speaking Hispanics. Additional studies of specific ethnic/racial and sociodemographic subgroups are warranted.
PMID: 24759088
ISSN: 0891-9887
CID: 948142

Neural substrates of verbal memory impairments in adults with type 2 diabetes mellitus

Yau, Po Lai; Kluger, Alan; Borod, Joan C; Convit, Antonio
Background: Verbal memory impairment is well documented in type 2 diabetes mellitus (T2DM) but, to date, the neural substrates remain unclear. The present study evaluated verbal memory and ascertained the degree of frontal and temporal lobe involvement in the anticipated verbal memory impairment among adults with T2DM. Method: Forty-six late-middle-aged and elderly adults with T2DM and 50 age-, sex-, and education-matched adults without T2DM underwent medical evaluation, verbal memory assessment, and brain magnetic resonance imaging (MRI) evaluations. Results: As anticipated, participants with T2DM had clear verbal memory impairments. Consistent with prior reports, we found volume reductions restricted to the hippocampus. Our diffusion tensor imaging analysis revealed that participants with T2DM had extensive cerebral gray and white matter microstructural abnormalities predominantly in the left hemisphere, with a larger concentration present in the temporal lobe. In contrast, we uncovered mostly nonspecific microstructural abnormalities in the absence of tissue loss in the frontal lobe. Of great importance, we present the first evidence among participants with T2DM linking verbal memory impairment and compromised microstructural integrity of the left parahippocampal gyrus, a key memory-relevant structure. Conclusions: Our results suggest that the hippocampus and parahippocampal gyrus may be particularly vulnerable to the deleterious effects of T2DM. The parahippocampal gyrus in particular may play a crucial role in the verbal memory impairments frequently reported in T2DM. Future studies should employ methods such as resting state functional magnetic resonance imaging and diffusion tensor imaging tractography to better characterize network connectivity, which may help further characterize the verbal memory impairment frequently reported in T2DM.
PMID: 24417611
ISSN: 1380-3395
CID: 759842

Learning and generalization tasks predict short-term cognitive outcome in nondemented elderly

Myers, Catherine E; Kluger, Alan; Golomb, James; Gluck, Mark A; Ferris, Steven
This study examines whether behavioral measures obtained in nondemented elderly can predict cognitive status at 2-year follow-up. Prior studies have established that delayed paragraph recall can help predict short-term risk for decline to mild cognitive impairment and Alzheimer disease. It was examined whether prediction accuracy can be improved by adding a discrimination-and-generalization task that has previously been shown to be disrupted in nondemented elderly with hippocampal atrophy, a risk factor for Alzheimer disease. Fifty nondemented, medically healthy elderly patients received baseline clinical diagnosis and cognitive testing; 2 years later, patients received a follow-up clinical diagnosis of normal, mild cognitive impairment, or probable Alzheimer disease. In all, 2 baseline variables, delayed paragraph recall and generalization performance, were predictive of follow-up outcome with sensitivity of 81% and specificity of 91%-better than the classification accuracy based on either of these measures alone. These preliminary results suggest that these behavioral tasks may be useful tools in predicting short-term cognitive outcome in nondemented elderly
PMID: 18474718
ISSN: 0891-9887
CID: 79409

Clinical features of MCI: motor changes

Kluger, Alan; Gianutsos, John G; Golomb, James; Wagner, Alvin Jr; Wagner, Danielle; Scheurich, Samantha
Mild cognitive impairment (MCI) is a classification reserved for nondemented elderly individuals at increased risk for future decline to dementia, compared to those with normal cognition. Cognitive tests, particularly those assessing verbal recall, have been found to be useful in the identification of elderly people with MCI. We argue that a variety of motor/psychomotor evaluations are also sensitive to MCI. Motor assessments described as complex correctly categorize normal versus MCI elderly with comparable accuracies to those obtained by cognitive tests. Unlike performance on verbally based cognitive measures, motor-test scores appear to be relatively independent of educational attainment, indicating that the use of certain motor tests may be particularly valuable in the identification of MCI among elderly with widely varying educational backgrounds
PMID: 18072982
ISSN: 1041-6102
CID: 76844

Mild cognitive impairment (MCI): a historical perspective

Reisberg, Barry; Ferris, Steven H; Kluger, Alan; Franssen, Emile; Wegiel, Jerzy; de Leon, Mony J
Descriptions of dementia can be traced to antiquity. Prichard (1837) described four dementia stages and Kral (1962) described a 'benign senescent forgetfulness' condition. The American Psychiatric Association's DSM-III (1980) identified an early dementia stage.In 1982, the Clinical Dementia Rating (CDR) and the Global Deterioration Scale (GDS) were published, which identified dementia antecedents. The CDR 0.5 'questionable dementia' stage encompasses both mild dementia and earlier antecedents. GDS stage 3 described a predementia condition termed 'mild cognitive decline' or, alternatively, beginning in 1988, 'mild cognitive impairment' (MCI). This GDS stage 3 MCI condition is differentiated from both a preceding GDS stage 2, 'subjective cognitive impairment' (SCI) stage and a subsequent GDS 4 stage of mild dementia.GDS stage 3 MCI has been well characterized. For example, specific clinical concomitants, mental status and psychological assessment score ranges, behavioral and emotional changes, neuroimaging concomitants, neurological reflex changes, electrophysiological changes, motor and coordination changes, and changes in activities, accompanying GDS stage 3 MCI have been described.Petersen and associates proposed a definition of MCI in 2001 which has been widely used (hereafter referred to as 'Petersen's MCI'). Important differences between GDS stage 3 MCI and Petersen's MCI are that, because of denial, GDS stage 3 MCI does not require memory complaints. Also, GDS stage 3 MCI recognizes the occurrence of executive level functional deficits, which Petersen's MCI did not. Nevertheless, longitudinal and other studies indicate essential compatibility between GDS stage 3 MCI and Petersen's MCI duration and outcomes
PMID: 18031593
ISSN: 1041-6102
CID: 78351

Mild cognitive impairment: historical development and summary of research

Golomb, James; Kluger, Alan; Ferris, Steven H
This review article broadly traces the historical development, diagnostic criteria, clinical and neuropathological characteristics, and treatment strategies related to mild cognitive impairment (MCI), The concept of MCI is considered in the context of other terms that have been developed to characterize the elderly with varying degrees of cognitive impairment Criteria based on clinical global scale ratings, cognitive test performance, and performance on other domains of functioning are discussed. Approaches employing clinical, neuropsychological, neuroimaging, biological, and molecular genetic methodology used in the validation of MCI are considered, including results from cross-sectional, longitudinal, and postmortem investigations. Results of recent drug treatment studies of MCI and related methodological issues are also addressed
PMID: 22034453
ISSN: 1294-8322
CID: 139908

Efficacy of donepezil in mild cognitive impairment: a randomized placebo-controlled trial

Salloway, S; Ferris, S; Kluger, A; Goldman, R; Griesing, T; Kumar, D; Richardson, S
OBJECTIVE: To evaluate the efficacy and safety of the acetylcholinesterase inhibitor donepezil in a placebo-controlled trial in patients with mild cognitive impairment (MCI). METHODS: A total of 270 patients with MCI were enrolled in a 24-week, multicenter, randomized, double-blind, placebo-controlled study. Patients were randomized to receive donepezil (n = 133; 5 mg/day for 42 days, followed by forced dose escalation to 10 mg/day) or placebo (n = 137). Primary efficacy measures were the New York University (NYU) Paragraph Delayed Recall test and the Alzheimer disease (AD) Cooperative Study Clinician's Global Impression of Change for MCI (ADCS CGIC-MCI). Secondary efficacy measures included the modified AD Assessment Scale-cognitive subscale (ADAS-cog), the Patient Global Assessment (PGA), and additional neuropsychologic measures. Efficacy analyses were performed on intent-to-treat (ITT) and fully evaluable (FE) populations. RESULTS: Primary efficacy measures of the NYU Paragraph Recall test and the ADCS CGIC-MCI did not show significant treatment effects in the ITT population. Some secondary measures showed effects favoring donepezil. More donepezil-treated patients showed improvements in ADAS-cog total scores, in tests of attention and psychomotor speed, and in PGA scores. More donepezil-treated than placebo-treated patients experienced adverse events, most of which were mild to moderate and transient. CONCLUSION: Although significant treatment effects were not seen in the primary efficacy measures, outcomes on secondary measures suggest promising directions for further evaluation of donepezil treatment in patients with MCI.
PMID: 15326237
ISSN: 0028-3878
CID: 158736

The effects of Alzheimer's disease on item output in verbal fluency tasks

Sailor, Kevin; Antoine, Miriam; Diaz, Michael; Kuslansky, Gail; Kluger, Alan
We collected category fluency data from several moderate-to-large samples of participants at three different sites: the New York University Aging and Dementia Center, the Oregon Health Services Aging and Dementia Research Center, and the Einstein Aging Study at the Albert Einstein College of Medicine. These data were analyzed by calculating the average relative frequency (e.g., typicality) of the category members generated by each participant. Alzheimer's disease (AD) patients recalled fewer atypical members of common taxonomic categories than did the elderly control group. In addition, the probability of producing an item declined at a greater rate for AD patients than for the elderly control group over the duration of the task. According to sequential sampling models, this latter result implies that the rate at which AD patients search memory must be slower than the search rate of the elderly controls
PMID: 15099153
ISSN: 0894-4105
CID: 95726