Neuropsychological Test Norms in Cognitively Intact Oldest-Old.

OBJECTIVES: Individuals aged 90 or older (oldest-old), the fastest growing segment of the population, are at increased risk of developing cognitive impairment compared with younger old. Neuropsychological evaluation of the oldest-old is important yet challenging in part because of the scarcity of test norms for this group. We provide neuropsychological test norms for cognitively intact oldest-old. METHODS: Test norms were derived from 403 cognitively intact participants of The 90+ Study, an ongoing study of aging and dementia in the oldest-old. Cognitive status of intact oldest-old was determined at baseline using cross-sectional approach. Individuals with cognitive impairment no dementia or dementia (according to DSM-IV criteria) were excluded. Participants ranged in age from 90 to 102 years (mean=94). The neuropsychological battery included 11 tests (Mini-Mental Status Examination, Modified Mini-Mental State Examination, Boston Naming Test - Short Form, Letter Fluency Test, Animal Fluency Test, California Verbal Learning Test-II Short Form, Trail Making Tests A/B/C, Digit Span Forward and Backwards Test, Clock Drawing Test, CERAD Construction Subtests), and the Geriatric Depression Scale. RESULTS: Data show significantly lower scores with increasing age on most tests. Education level, sex, and symptoms of depression were associated with performance on several tests after accounting for age. CONCLUSIONS: Provided test norms will help to distinguish cognitively intact oldest-old from those with cognitive impairment. (JINS, 2019, 25, 530-545).

Cognitive Profiles on the Severe Impairment Battery Are Similar in Alzheimer Disease and Down Syndrome With Dementia.

Previous research has revealed similarities in the neuropathology, clinical presentation, and risk factors between persons with Alzheimer disease from the general population (GP-AD) and those with Down syndrome (DS-AD). Less is known, however, about the extent of similarities and differences in the cognitive profiles of these 2 populations. Fifty-one moderate to severely demented GP-AD and 59 DS-AD individuals participated in this study which compared the cognitive profiles of these 2 populations on the Severe Impairment Battery (SIB), controlling for sex as well as level of functional ability using a modified version of the Bristol Activities of Daily Living Scale. Overall, the neuropsychological profiles of the higher-functioning individuals within the DS-AD and advanced GP-AD groups, as represented by mean difference scores on the SIB as a whole and across the 9 separate cognitive domains, were very similar to one another after adjusting for sex and functional impairment. To our knowledge, this is the first study to directly compare the cognitive profiles of these 2 populations on the SIB. Findings suggest that the underlying dementia in GP-AD and DS-AD may have corresponding and parallel effects on cognition.

The utility of the Dementia Severity Rating Scale in differentiating mild cognitive impairment and Alzheimer disease from controls.

The current study investigated the utility of the Dementia Severity Rating Scale (DSRS) total score to identify individuals at the earliest stage of impairment (ie, mild cognitive impairment/MCI). In addition, the authors sought to investigate how well the measure correlates with an expanded battery of cognitive tests and other measures of functional abilities. Of the 320 participants included in this study, 85 were normal controls, 96 had single-domain or multiple-domain amnestic MCI, and 139 had possible or probable Alzheimer disease (AD). Each participant underwent a thorough cognitive, neurological, and physical examination. Results from this study indicated that the DSRS total scores differed significantly between the 3 groups (P<0.001) and accurately identified 81% of the control group, 60% of the MCI group, and 78% of the AD group in a post hoc discriminant analysis. When combined with a brief cognitive measure (ie, Consortium to Establish a Registry for Alzheimer's Disease Word List 5 min recall test), the DSRS accurately identified 98% of the control group, 76% of the MCI group, and 82% of the AD group. Implications for clinical practice and proposed areas of future research are discussed.

Cardiovascular fitness is associated with altered cortical glucose metabolism during working memory in ɛ4 carriers.

BACKGROUND: The possibility that ɛ4 may modulate the effects of fitness in the brain remains controversial. The present exploratory FDG-PET study aimed to better understand the relationship among ɛ4, fitness, and cerebral metabolism in 18 healthy aged women (nine carriers, nine noncarriers) during working memory. METHODS: Participants were evaluated using maximal level of oxygen consumption, California Verbal Learning Test, and FDG-PET, which were collected at rest and during completion of the Sternberg working memory task. RESULTS: Resting FDG-PET did not differ between carriers and noncarriers. Significant effects of fitness on FDG-PET during working memory were noted in the ɛ4 carriers only. High fit ɛ4 carriers had greater glucose uptake in the temporal lobe than the low fit ɛ4 carriers, but low fit ɛ4 carriers had greater glucose uptake in the frontal and parietal lobes. CONCLUSIONS: We demonstrate that fitness differentially affects cerebral metabolism in ɛ4 carriers only, consistent with previous findings that the effects of fitness may be more pronounced in populations genetically at risk for cognitive decline.

The common objects memory test (COMT): a simple test with cross-cultural applicability.

The Common Objects Memory Test (COMT) was developed to assess age-related memory impairments in individuals with a range of educational, language and cultural backgrounds. The COMT is a list-learning protocol that uses photographs of common objects to bypass difficulties posed by written words for individuals who are illiterate or have limited education. Preliminary data are presented for 336 healthy adults and 90 patients with dementia. Their age ranged from 54 to 99 years, education ranged from 0 to 22 years, and they were from five culturally and linguistically distinct populations: Caucasian and African-American English speakers, and native Chinese, Spanish, and Vietnamese speakers. Performance on the COMT was influenced by age, but little influenced by education, and un-influenced by gender or ethnic background. Among 11 neuropsychological tests, the recall scores from the COMT best distinguished healthy individuals from patients with dementia, underscoring its clinical utility for ethnically diverse populations.

A fibril-specific, conformation-dependent antibody recognizes a subset of Abeta plaques in Alzheimer disease, Down syndrome and Tg2576 transgenic mouse brain.

Beta-amyloid (Abeta) is thought to be a key contributor to the pathogenesis of Alzheimer disease (AD) in the general population and in adults with Down syndrome (DS). Different assembly states of Abeta have been identified that may be neurotoxic. Abeta oligomers can assemble into soluble prefibrillar oligomers, soluble fibrillar oligomers and insoluble fibrils. Using a novel antibody, OC, recognizing fibrils and soluble fibrillar oligomers, we characterized fibrillar Abeta deposits in AD and DS cases. We further compared human specimens to those obtained from the Tg2576 mouse model of AD. Our results show that accumulation of fibrillar immunoreactivity is significantly increased in AD relative to nondemented aged subjects and those with select cognitive impairments (p < 0.0001). Further, there was a significant correlation between the extent of frontal cortex fibrillar deposit accumulation and dementia severity (MMSE r = -0.72). In DS, we observe an early age of onset and age-dependent accumulation of fibrillar OC immunoreactivity with little pathology in similarly aged non-DS individuals. Tg2576 mice show fibrillar accumulation that can be detected as young as 6 months. Interestingly, fibril-specific immunoreactivity was observed in diffuse, thioflavine S-negative Abeta deposits in addition to more mature neuritic plaques. These results suggest that fibrillar deposits are associated with disease in both AD and in adults with DS and their distribution within early Abeta pathology associated with diffuse plaques and correlation with MMSE suggest that these deposits may not be as benign as previously thought.

Alterations in regional brain volume and individual MRI-guided perfusion in normal control, stable mild cognitive impairment, and MCI-AD converter.

Regional differences in tissue volume and perfusion in brains of individuals with mild cognitive impairment (MCI) versus normal healthy age-matched controls (NC), and the differences between MCI-AD converters and stable MCI patients were investigated. MRI and SPECT scans were performed on 13 MCI (74+6 years) and 12 NC (75+4 years). Of the MCI patients, 10 were followed for up to three years and 4 subsequently converted to Alzheimer's disease (AD). Episodic memory function was assessed using tests of delayed recall for word lists and stories. The volume reductions and hypoperfusion were mainly confined to the medial temporal lobe (MTL) of MCI patients and associated with worse scores on memory tests. Perfusion in the corpus callosum and the gray matter of frontal, lateral temporal, parietal or occipital lobe was not significantly affected in MCI. The 4 MCI-AD converters had relatively low MTL structural volume and perfusion compared to their stable peers.

Diagnosing depression in Alzheimer disease with the national institute of mental health provisional criteria.

OBJECTIVE: To compare the rates of depression in Alzheimer Disease (AD) determined using National Institute of Mental Health (NIMH) provisional criteria for depression in AD (NIMH-dAD) to those determined using other established depression assessment tools. DESIGN: Descriptive longitudinal cohort study. SETTING: The Alzheimer's Disease Research Centers of California. PARTICIPANTS: A cohort of 101 patients meeting NINDS-ADRDA criteria for possible/probable AD, intentionally selected to increase the frequency of depression at baseline. MEASUREMENTS: Depression was diagnosed at baseline and after 3 months using NIMH-dAD criteria and the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) Axis I Disorders. Depressive symptoms also were assessed with the Cornell Scale for Depression in Dementia (CSDD), the Geriatric Depression Scale (GDS), and the Neuropsychiatric Inventory Questionnaire. RESULTS: The baseline frequency of depression using NIMH-dAD criteria (44%) was higher than that obtained using DSM-IV criteria for major depression (14%; Z = -5.50, df = 101, p <0.001) and major or minor depression (36%; Z = -2.86, df = 101, p = 0.021) or using established cut-offs for the CSDD (30%; Z = -2.86, df = 101, p = 0.004) or GDS (33%; Z = -2.04, df = 101, p = 0.041). The NIMH-dAD criteria correctly identified all patients meeting DSM-IV criteria for major depression, and correlated well with DSM-IV criteria for major or minor depression (kappa = 0.753, p <0.001), exhibiting 94% sensitivity and 85% specificity. The higher rates of depression found with NIMH-dAD criteria derived primarily from its less stringent requirements for the frequency and duration of symptoms. Remission rates at 3 months were similar across instruments. CONCLUSIONS: The NIMH-dAD criteria identify a greater proportion of AD patients as depressed than several other established tools.

Communicating mild cognitive impairment diagnoses with and without amyloid imaging.

BACKGROUND: Mild cognitive impairment (MCI) has an uncertain etiology and prognosis and may be challenging for clinicians to discuss with patients and families. Amyloid imaging may aid specialists in determining MCI etiology and prognosis, but creates novel challenges related to disease labeling. METHODS: We convened a workgroup to formulate recommendations for clinicians providing care to MCI patients. RESULTS: Clinicians should use the MCI diagnosis to validate patient and family concerns and educate them that the patient's cognitive impairment is not normal for his or her age and education level. The MCI diagnosis should not be used to avoid delivering a diagnosis of dementia. For patients who meet Appropriate Use Criteria after standard-of-care clinical workup, amyloid imaging may position specialists to offer more information about etiology and prognosis. Clinicians must set appropriate expectations, including ensuring that patients and families understand the limitations of amyloid imaging. Communication of negative results should include that patients remain at elevated risk for dementia and that negative scans do not indicate a specific diagnosis or signify brain health. Positive amyloid imaging results should elicit further monitoring and conversations about appropriate advance planning. Clinicians should offer written summaries, including referral to appropriate social services. CONCLUSIONS: In patients with MCI, there is a need to devote considerable time and attention to patient education and shared decision-making. Amyloid imaging may be a tool to aid clinicians. Careful management of patient expectations and communication of scan results will be critical to the appropriate use of amyloid imaging information.

Practice effects on motor control in healthy seniors and patients with mild cognitive impairment and Alzheimer's disease.

This research was designed to test the hypothesis that motor practice can enhance the capabilities of motor control in healthy controls (NC) and patients with a diagnosis of probable Alzheimer's disease (AD) and mild cognitive impairment (MCI), and consequently results in better motor performance. Approximately half of the subjects in the NC (n = 31), AD (n = 28), and MCI (n = 29) either received or did not receive practice on a task of fast and accurate arm movement with a digitizer. Changes in movement time (MT), movement smoothness (jerk), and percentage of primary submovement (PPS) were recorded and compared among the three groups across six blocks of trials (baseline and five training sessions). For all subjects, practice improved motor functions as reflected by faster and smoother motor execution, as well as a greater proportion of programming control. Compared to unaffected matched controls, AD and MCI subjects exhibited a greater reduction in movement jerk due to practice. Movement time and PPS data revealed that motor practice appeared to reduce the use of "on-line" correction adopted by the AD or MCI patients while performing the aiming movements. Evidently, their arm movements were quicker, smoother, and temporally more consistent than their untrained peers. The findings of this study shed light on how MCI and AD may affect motor control mechanisms, and suggest possible therapeutic interventions aimed at improving motor functioning in these impaired individuals.

Facilitating acquisition and transfer of a continuous motor task in healthy older adults and patients with Alzheimer's disease.

This study examined the acquisition and transfer of a fine motor skill, namely the rotary pursuit, in 99 patients with Alzheimer's disease (AD) and 100 normal controls (NCs). To identify optimal learning strategies, the authors had participants practice the rotary pursuit under constant, blocked, random, or no training conditions. Transfer was assessed using speeds that were different from those practiced during acquisition. AD patients and NCs receiving constant practice outperformed their peers in the blocked and random conditions during acquisition. Whereas all 3 types of practice facilitated transfer in the NCs, AD patients only benefited from constant practice. The inability of the AD patients to benefit from variable practice suggests that these individuals may have difficulty accessing and/or forming motor schemas.

Memory for unfamiliar faces differentiates mild cognitive impairment from normal aging.

Memory for unfamiliar faces has received little attention in the effort to identify neuropsychological measures that could differentiate mild cognitive impairment (MCI) from normal aging and/or predict conversion from MCI to dementia. We used the Wechsler Memory Scale-III Faces test to investigate facial memory in normal aging (n = 58), MCI (n = 74), and mild Alzheimer's disease (n = 22). After adjustment for age, gender, and years of education, MCI patients demonstrated significantly poorer memory for unfamiliar faces than their healthy peers. Lower scores were also associated with worsening cognition and functional abilities but not an increased risk of dementia.

Frontal cortex neuropathology in dementia pugilistica.

Dementia pugilistica (DP) is associated with chronic traumatic brain injury (CTBI), and leads to a "punch drunk" syndrome characterized by impairments in memory and executive function, behavioral changes, and motor signs. Microscopic features include the accumulation of neurofibrillary tangles (NFTs), beta-amyloid (Aß), and TAR DNA binding protein 43 (TDP-43) pathology. Here we describe detailed clinical and neuropathological data about a 55-year-old retired boxer (ApoE3/4), who presented with executive dysfunction and behavioral impairments. At autopsy, significant Aß pathology was seen, primarily in the form of diffuse plaques. Tau pathology was extensive and was determined to be of Braak and Braak stage VI. Frontal white matter showed evidence of glial tau inclusions (astrocytes and oligodendroglia). Cerebrovascular pathology was minimal with patchy amyloid angiopathy. Inflammation was another key feature, including microglial activation and significant C1q labeling of neurons, along with NFTs. TDP-43-positive pathology was also observed. Inflammation may be a key inciting as well as propagating feature of DP neuropathology.

Neuropsychological data in nondemented oldest old: the 90+ Study.

Although the oldest old are the fastest growing segment of the population, little is known about their cognitive performance. Our aim was to compile a relatively brief test battery that could be completed by a majority of individuals aged 90 or over, compensates for sensory losses, and incorporates previously validated, standardized, and accessible instruments. Means, standard deviations, and percentiles for 10 neuropsychological tests covering multiple cognitive domains are reported for 339 nondemented members of the 90+ Study. Cognitive performance declined with age for two-thirds of the tests. Performance on some tests was also affected by gender, education, and depression scores.

Differential regulation of inhibitors of apoptosis proteins in Alzheimer's disease brains.

Neuronal degeneration linked to apoptosis can be inhibited by a family of proteins known as inhibitors of apoptosis proteins (IAPs). We examined three members of the IAP family that are implicated in the regulation of neuronal death. We assessed NAIP, XIAP, and cIAP-2 protein levels in the entorhinal cortex of non-demented, cognitively impaired and Alzheimer's disease cases. Levels of paired helical filament-1 (PHF-1), a marker of neurofibrillary tangles, were assessed to determine their relationship to IAP levels. NAIP was decreased in AD cases compared to mildly impaired and unimpaired cases, and this decrease was associated with increased PHF-1 levels. Low NAIP levels were associated with higher Braak and Braak tangle stage and cognitive dysfunction. XIAP levels were higher in AD cases and cIAP-2 levels did not vary with clinical status. Our data suggest that decreased NAIP may place neurons at risk for the development of tangles and apoptosis.

Relapsing polychondritis with features of dementia with Lewy bodies.

We describe a 72-year old man with clinical features suggestive of dementia with Lewy bodies (DLB) who proved neuropathologically to have degeneration induced by relapsing polychondritis (RP), an autoimmune inflammatory disorder of cartilaginous tissues. There was lymphocytic infiltration of the leptomeninges, perivascular cuffing, reactive astrocytosis, and activation of microglia in multiple brain areas all consistent with an immunologically mediated process. There was widespread neuronal loss within the hippocampus, entorhinal cortex, and amygdala as well as diffuse myelin pallor of cortical pathways. Elevated levels of complement proteins and endothelial markers of inflammation were observed, which are similar to previous reports in DLB. This study demonstrates that qualitatively similar inflammation-associated neurodegeneration is present in widespread regions of the brain in a RP case presenting clinically as DLB.

Caspase-cleaved tau accumulation in neurodegenerative diseases associated with tau and alpha-synuclein pathology.

Alzheimer's disease (AD), Pick's disease (PiD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD) and dementia with Lewy bodies (DLB) are diseases associated with the accumulation of tau or alpha-synuclein. In AD, beta-amyloid (Abeta)-associated caspase activation and cleavage of tau at Asp421 (DeltaTau) may be an early step in neurofibrillary tangle (NFT) formation. To examine whether DeltaTau accumulates in other diseases not characterized by extracellular Abeta accumulation, we examined PiD, PSP, and CBD cases in comparison to those without extensive tau accumulation including frontotemporal lobar degeneration without Pick bodies (FTLD) and control cases. Additionally, we studied DeltaTau accumulation in DLB cases associated with intracellular alpha-synuclein. DeltaTau was observed in all disease cases except non-PiD FTLD and controls. These results demonstrate that the accumulation of DeltaTau may represent a common pathway associated with abnormal accumulation of intracellular tau or alpha-synuclein and may be relatively less dependent on the extracellular accumulation of Abeta in non-AD dementias.

Methods to improve the detection of mild cognitive impairment.

We examined whether the performance of the National Institute of Aging's Consortium to Establish a Registry for Alzheimer's Disease's 10-word list (CWL), part of the consortium's neuropsychological battery, can be improved for detecting Alzheimer's disease and related disorders early. We focused on mild cognitive impairment (MCI) and mild dementia because these stages often go undetected, and their detection is important for treatment. Using standardized diagnostic criteria combined with history, physical examination, and cognitive, laboratory, and neuroimaging studies, we staged 471 community-dwelling subjects for dementia severity by using the Clinical Dementia Rating Scale. We then used correspondence analysis (CA) to derive a weighted score for each subject from their item responses over the three immediate- and one delayed-recall trials of the CWL. These CA-weighted scores were used with logistic regression to predict each subject's probability of impairment, and receiver operating characteristic analysis was used to measure accuracy. For MCI vs. normal, accuracy was 97% [confidence interval (C.I.) 97-98%], sensitivity was 94% (C.I. 93-95%), and specificity was 89% (C.I. 88-91%). For MCI/mild dementia vs. normal, accuracy was 98% (C.I. 98-99%), sensitivity was 96% (C.I. 95-97%), and specificity was 91% (C.I. 89-93%). MCI sensitivity was 12% higher (without lowering specificity) than that obtained with the delayed-recall total score (the standard method for CWL interpretation). Optimal positive and negative predictive values were 100% and at least 96.6%. These results show that CA-weighted scores can significantly improve early detection of Alzheimer's disease and related disorders.