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The clock drawing test (CDT) is an inexpensive tool to screen for dementia. In this study, we examined if a variational autoencoder (VAE) with only two latent variables can capture and encode clock drawing anomalies from a large dataset of unannotated CDTs (n = 13,580) using self-supervised pre-training and use them to classify dementia CDTs (n = 18) from non-dementia CDTs (n = 20). The model was independently validated using a larger cohort consisting of 41 dementia and 50 non-dementia clocks. The classification model built with the parsimonious VAE latent space adequately classified dementia from non-dementia (0.78 area under receiver operating characteristics (AUROC) in the original test dataset and 0.77 AUROC in the secondary validation dataset). The VAE-identified atypical clock features were then reviewed by domain experts and compared with existing literature on clock drawing errors. This study shows that a very small number of latent variables are sufficient to encode important clock drawing anomalies that are predictive of dementia., (© 2022. The Author(s).)

Tests of everyday action semantics were developed and piloted in a group of healthy adults (n = 53) and then administered to individuals with Alzheimer's disease (AD; n = 17) or Parkinson's disease dementia (PDD; n = 20). Relations between everyday action knowledge and everyday function were explored. Three action semantic tests were developed: Probe Test - 45 forced-choice questions regarding task sequences, objects, and steps; Picture Sequencing Test - sequential ordering of 4-5 cards depicting task steps; Script Test - open-ended verbal description of the steps required to complete everyday tasks. Cognitive tests, informant reports of functioning, and the Naturalistic Action Test (NAT), a performance-based test of function, also were administered to AD and PDD participants. NAT performance was scored for omission (failure to complete steps) and commission (inaccurate performance of step) errors. The AD and PDD groups performed worse than healthy participants on all action semantic tasks. AD and PDD groups significantly differed on only the Script Test - AD participants generated fewer correct steps. Performance on each of the action semantic tests significantly correlated with NAT omission errors. Only the Sequencing Test significantly predicted omissions, commissions, and informant report of everyday functioning. In sum, task knowledge is associated with omissions in everyday tasks and is impaired in both AD and PDD. The ability to accurately sequence task steps is associated with multiple aspects of everyday function and may be easily assessed with picture arrangement., (© 2017 The British Psychological Society.)

Background: Neuropsychological deficits, neuropsychiatric symptoms, and problems with instrumental activities of daily living are common in participants with mild cognitive impairment (MCI)., Objectives: To assess how subtle to mildly impaired instrumental activities of daily living (IADLs) might be related to neuropsychological abilities (including executive control and episodic memory) and neuropsychiatric symptoms (including apathy and depression) among participants with a diagnosis of MCI., Methods: Participants were evaluated for MCI and possible dementia at an outpatient memory clinic on the basis of a comprehensive neuropsychological evaluation, a geriatric psychiatry evaluation, a magnetic resonance image of the brain, and serum studies to evaluate for a possible reversible cause of cognitive decline. A series of stepwise regression analyses were conducted whereby IADL ability was the dependent variable and neuropsychological abilities, such as executive control and episodic memory, or neuropsychiatric symptoms, including apathy and depression, were the independent or predictor variables. The presence and severity of neuropsychiatric symptoms was assessed using a modified version of the Neuropsychiatric Inventory (mNPI). Participants were grouped by MCI diagnosis status (amnestic MCI, combined dysexecutive/mixed MCI, and no MCI)., Results: Twenty-six participants were in the amnestic MCI group, 19 in the combined dysexecutive/mixed MCI group, and 36 participants did not meet criteria for MCI (non-MCI group). Groups did not differ in age, education, Mini-Mental State Examination performance, IADL abilities, estimated premorbid general intellectual abilities, or mNPI ratings for apathy and depression. Stepwise regression analyses found a robust relationship between mild IADL impairment and greater apathy (R=0.497, r21,69=0.247, P<.001; β=-0.497, P<.001). Depression did not enter the final model. A weaker-but statistically significant-relationship was found between mild IADL impairment and worse executive control test performance (R=0.271, r21,68=0.073, P<.023; β=0.271, P<.23). Episodic memory did not enter the final model. When both apathy and executive control were assessed as related to IADL impairment, only apathy entered the final model (R=0.497, R21,69=0.247, P<.001; β=-0.497, P<.001)., Conclusion: Mildly impaired IADL functioning can negatively affect quality of life. Moreover, apathy may be amenable to treatment. In a primary geriatric care setting, neuropsychiatric symptoms and neuropsychological abilities should be routinely assessed.

Background/aims: Mild cognitive impairment (MCI) lacks a "gold standard" operational definition. The Jak/Bondi actuarial neuropsychological criteria for MCI are associated with improved diagnostic stability and prediction of progression to dementia compared to conventional MCI diagnostic approaches, although its utility in diagnosing MCI in old-old individuals (age 75+) is unknown. Therefore, we investigated the applicability of neuropsychological MCI criteria among old-old from the Framingham Heart Study., Methods: A total of 347 adults (ages 79-102) were classified as cognitively normal or MCI via Jak/Bondi and conventional Petersen/Winblad criteria, which differ on cutoffs for cognitive impairment and number of impaired scores required for a diagnosis. Cox models examined MCI status in predicting risk of progression to dementia., Results: MCI diagnosed by both the Jak/Bondi and Petersen/Winblad criteria was associated with incident dementia; however, when both criteria were included in the regression model together, only the Jak/Bondi criteria remained statistically significant. At follow-up, the Jak/Bondi criteria had a lower MCI-to-normal reversion rate than the Petersen/Winblad criteria., Conclusions: Our findings are consistent with previous research on the Jak/Bondi criteria and support the use of a comprehensive neuropsychological diagnostic approach for MCI among old-old individuals., (© 2018 S. Karger AG, Basel.)

Objective: Analysis sought to determine whether Wechsler Memory Scale-Logical Memory (LM)-correct responses and errors were related to magnetic resonance imaging (MRI) brain volume measurements., Methods: The LM immediate (LM-I) and LM delay (LM-D) free recall correct responses and related and unrelated errors were scored. Principal components analysis yielded a 3-factor solution: LM-I and LM-D correct responses, LM-I and LM-D-unrelated errors, and LM-I/-D-related errors. The MRI total cerebral brain volume, frontal brain volume, temporal horn volume (THV), and white matter hyperintensities volume (WMHIV) were obtained., Results: Increasing THV (suggesting greater regional atrophy) was associated with lower scores on the LM-correct responses factor. Extensive WMHIV was associated with higher scores on the LM-related errors factor., Conclusion: These results suggest that LM-correct responses could relate to emerging brain alterations. Longitudinal research might enhance the sensitivity of this test to identify preclinical impairment and persons at risk of mild cognitive impairment and dementia., (© The Author(s) 2015.)

Objective: Prior research has shown that individuals with Parkinson's disease dementia (PDD) show a different pattern of error types on everyday tasks compared with individuals with Alzheimer's disease (AD). This study evaluated whether these groups would respond differently to cues designed to remind participants of task goals and improve performance of everyday tasks (i.e., goal cues)., Method: Participants with PDD (n = 20) and AD (n = 20), and a comparison group of individuals with Parkinson's disease and no dementia (n = 20), were administered performance-based tasks of everyday functioning that allowed for the quantification of errors before and after the presentation of goal cues., Results: AD participants showed a significantly greater response to the goal cues as compared with individuals with PDD. The goal cues facilitated the completion of task goals but did not promote error correction (i.e., the undoing of errors that had been made earlier during the task)., Conclusions: Not all dementia patients respond similarly to cues designed to improve everyday functioning. Understanding patients' specific form of everyday action impairment is crucial for developing individualized interventions that target specific functional deficits., ((c) 2015 APA, all rights reserved).)

This study examined everyday action impairment in participants with Parkinson's disease dementia (PDD) by comparison with participants with Parkinson's disease-no dementia (PD) or Alzheimer's disease (AD) and in reference to a neuropsychological model. Participants with PDD (n = 20), PD (n = 20), or AD (n = 20) were administered performance-based measures of everyday functioning that allowed for the quantification of overall performance and error types. Also, caregiver ratings of functional independence were obtained. On performance-based tests, the PDD group exhibited greater functional impairment than the PD group but comparable overall impairment relative to the AD group. Error patterns did not differ between PDD and PD participants but the PDD group demonstrated a higher proportion of commission errors and lower proportion of omission errors relative to the AD group. Hierarchical regression analyses showed omission errors were significantly predicted by neuropsychological measures of episodic memory, whereas commission errors were predicted by both measures of general dementia severity (MMSE) and executive control. Everyday action impairment in PDD differs quantitatively from PD but qualitatively from AD and may be characterized by a relatively high proportion of commission errors-an error type associated with executive control deficits. (JINS, 2012, 18, 1-12).

Objective: To examine the concept of leukoaraiosis thresholds on working memory, visuoconstruction, memory, and language in dementia., Methods: A consecutive series of 83 individuals with insidious onset/progressive dementia clinically diagnosed with Alzheimer disease (AD) or small vessel vascular dementia (VaD) completed neuropsychological measures assessing working memory, visuoconstruction, episodic memory, and language. A clinical MRI scan was used to quantify leukoaraiosis, total white matter, hippocampus, lacune, and intracranial volume. We performed analyses to detect the lowest level of leukoaraiosis associated with impairment on the neuropsychological measures., Results: Leukoaraiosis ranged from 0.63% to 23.74% of participants' white matter. Leukoaraiosis explained a significant amount of variance in working memory performance when it involved 3% or more of the white matter with curve estimations showing the relationship to be nonlinear in nature. Greater leukoaraiosis (13%) was implicated for impairment in visuoconstruction. Relationships between leukoaraiosis, episodic memory, and language measures were linear or flat., Conclusions: Leukoaraiosis involves specific threshold points for working memory and visuoconstructional tests in AD/VaD spectrum dementia. These data underscore the need to better understand the threshold at which leukoaraiosis affects and alters the phenotypic expression in insidious onset dementia syndromes.

The current study aimed to address error monitoring impairments in dementia using an intervention for execution deficits. Thirty-eight participants completed the Naturalistic Action Test (NAT) under two conditions: Standard and User-Centered. The Standard NAT followed the manual procedures; in the User-Centered NAT, objects were arranged sequentially, and distractor items were separated from target objects. While participants committed fewer errors in the User-Centered condition, there was no difference in the proportion of errors detected. However, the neuropsychological processes associated with monitoring differed across conditions. The results have implications for a neuropsychological model of error monitoring in dementia.

Objective: Research suggests that dementia patients detect fewer action errors than age-matched controls; however, little is known about the derivation of their error-monitoring difficulties. The aims of the study are to evaluate a novel, task-training action intervention (TT-NAT) designed to increase error monitoring in dementia patients and to pinpoint the relation between error monitoring and neuropsychological processes., Method: Participants (n = 45) with dementia were administered the Standard NAT, a performance-based test requiring completion of three everyday tasks. A second group (n = 42) was administered the TT-NAT, which includes a brief training session prior to the commencement of each task. All participants were compared on the following variables: total errors, proportion of errors detected, and proportion of errors corrected. Correlations between error-monitoring variables and neuropsychological tests of executive functioning and language were performed., Results: TT-NAT participants produced fewer total errors and detected significantly more errors than Standard NAT participants (z = 3.0; t = 3.36; p < .05). Error detection was strongly related to only the language composite index (r = .57, p = .00) in the TT-NAT, whereas it was moderately related to both the language (r = .31, p = .04) and executive composite (r = .36, p = .02) indices in the Standard NAT condition., Conclusion: Review of task steps and objects before task performance may be a promising intervention for error-monitoring deficits in dementia patients; this finding has implications for neuropsychological rehabilitation of functional deficits in this population.

The Philadelphia Brief Assessment of the Cognition (PBAC) is a brief dementia-screening instrument. The PBAC assesses five cognitive domains: working memory/executive control; lexical retrieval/language; visuospatial/visuoconstructional operations; verbal/visual episodic memory; and behavior/social comportment. A revised version of the PBAC was administered to 198 participants including patients with Alzheimer's disease (AD) (n=46) and four groups of patients with frontotemporal dementia (FTD) syndromes: behavioral-variant FTD (bvFTD; n=65), semantic-variant primary progressive aphasia (PPA) (svPPA; n=22), non-fluent/agrammatic-variant PPA (nfaPPA; n=23), and corticobasal syndrome (CBS; n=42), and a group of normal controls (n=15). The total PBAC score was highly correlated with the MMSE. The criterion validity of the PBAC was assessed relative to standard neuropsychological test performance. Using standard neuropsychological test performance as a criterion, the total PBAC score accurately identified the presence and severity of dementia. Intra-class correlations between PBAC subscales and standard neuropsychological tests were highly significant. PBAC subscales demonstrated good clinical utility in distinguishing AD and FTD subtypes using receiver operating characteristic analysis and standard diagnostic performance statistics to determine optimal subscale cut scores. The PBAC is a valid tool and able to assesses differential patterns neuropsychological/behavioral impairment in a broad range of neurodegenerative conditions.

Background: Clock drawing is part of the Montreal Cognitive Assessment (MoCA) test but may have administration and scoring limitations. We assessed (1) the reliability of the MoCA clock criteria relative to a published error scoring approach, (2) whether command-only administration could distinguish dementia from cognitively intact individuals and (3) the value of adding a clock copy condition to the MoCA., Methods: Three novice raters and clocks from dementia and control participants were used to assess the 3 aims., Results: MoCA interrater and intrarater reliability were low (i.e. intraclass correlation coefficient = 0.12-0.31) and required repeat training. Clocks drawn to command classified dementia at chance. Inclusion of a copy condition demonstrated expected dementia subgroup patterns., Conclusion: Reliable clock scoring with MoCA criteria requires practice. Supplementing a clock copy to the standard MoCA test (takes <1 min) will improve dementia assessment., (Copyright © 2011 S. Karger AG, Basel.)

This study evaluated the impact of distractor objects and their similarity to target objects on everyday task performance in dementia. Twenty participants with dementia due to Alzheimer's disease (n = 12) or subcortical vascular disease (n = 8) were videotaped while they performed 3 discrete tasks: (1) make a cup of coffee, (2) wrap a gift, and (3) pack a lunch under two conditions that were counterbalanced across participants. The conditions differed in terms of the type of distractor objects included in the workspace: (1) Target-Related Distractor Condition - distractor objects were functionally and visually similar to target objects (e.g., salt for sugar) (2) Unrelated Distractor Condition - distractors were neither visually nor functionally similar to targets (e.g., glue for sugar). Participants touched (t = 4.19; p < .01) and used (z = 3.00; p < .01) significantly more distractors, made more distractor errors (i.e., substitutions; t = 2.93; p < .01), and took longer to complete tasks (t = 2.27; p < .05) in the Target-Related Distractor condition. The percent of steps accomplished and non-distractor errors did not differ across conditions (t < 1.26; p > .05 for both). In summary, distractors that were similar to targets elicited significant interference effects circumscribed to object selection.

Everyday action performance is impaired as a consequence of dementia. Omissions (i.e., not performing task steps) are a frequent source of error in everyday tasks among dementia patients. External cues or notes are often suggested to improve everyday functioning and might specifically address omission errors; however, the efficacy of such strategies has not been evaluated. Thus, the primary aim of this study was to assess the efficacy of goal cues (i.e., reminders of everyday task objectives) for improving dementia patients' everyday action performance. Forty-four participants with mild to moderate dementia were administered the Naturalistic Action Test (NAT), a performance-based test that includes three everyday tasks. After participants indicated that they had completed each task, they were presented with a cue card restating the task goals. Videotapes were used to code task performance as well as responses to the cues. Most participants checked their work and showed significant improvement in task accomplishment/omission errors, but not commission errors, after the cues. However, effect sizes for the differences were small, and the proportion of cases in the impaired range did not differ before versus after the cues. Therefore, although statistically significant, we concluded that the goal cues did not meaningfully or clinically improve everyday functioning.

In patients with dementia, leukoaraiosis (LA) was hypothesized to result in differential patterns of impairment on a verbal serial list-learning test. Using a visual rating scale, 144 dementia patients with ischemic scores <4 were re-categorized as having mild (n = 73), moderate (n = 44), or severe LA (n = 27). Mild LA was predicted to be associated with an amnestic list-learning profile, while severe LA was predicted to be associated with a dysexecutive profile. List-learning performances were standardized to a group of healthy older adults (n = 24). Analyses were conducted on a set of four factors derived from the list-learning paradigm, as well as error scores. Data indicate that LA severity is an important marker for understanding list learning in dementia.

We hypothesized that specific neuropsychological deficits were associated with specific patterns of atrophy. A magnetic resonance imaging volumetric study and a neuropsychological protocol were obtained for patients with several frontotemporal lobar dementia phenotypes including a social/dysexecutive (SOC/EXEC, n = 17), progressive nonfluent aphasia (n = 9), semantic dementia (n = 7), corticobasal syndrome (n = 9), and Alzheimer's disease (n = 21). Blinded to testing results, patients were partitioned according to pattern of predominant cortical atrophy; our partitioning algorithm had been derived using seriation, a hierarchical classification technique. Neuropsychological test scores were regressed versus these atrophy patterns as fixed effects using the covariate total atrophy as marker for disease severity. The results showed the model accounted for substantial variance. Furthermore, the "large-scale networks" associated with each neuropsychological test conformed well to the known literature. For example, bilateral prefrontal cortical atrophy was exclusively associated with SOC/EXEC dysfunction. The neuropsychological principle of "double dissociation" was supported not just by such active associations but also by the "silence" of locations not previously implicated by the literature. We conclude that classifying patients with degenerative dementia by specific pattern of cortical atrophy has the potential to predict individual patterns of cognitive deficits.

Few studies have assessed whether the patterns of neuropsychological impairment in patients with different frontotemporal lobar degeneration (FTLD) subtypes remain distinct over the duration of their illness or devolve into a common, undifferentiated neuropsychological state. A longitudinal neuropsychological analysis was obtained over 100 months assessing executive control, language/naming, and visuoconstruction in 441 patients diagnosed with Alzheimer's disease (AD) and four FTLD subtypes, i.e., a social comportment/dysexecutive (SOC/EXEC) disorder; progressive non-fluent aphasia (PNFA); semantic dementia (SemD); and corticobasal degeneration (CBD). Initial group differences on each measure were maintained over the duration of illness, including several double dissociations. For example, AD patients exhibited a decline in 'animal' fluency; PNFA patients had difficulty on tests of executive control, SemD maintained their impairment on tests of naming, and CBD had presented with performance on visuoconstructional tests. None of the group by neuropsychological task interactions evaluating longitudinal decline was significant, suggesting that performance does not converge onto a common subtype over time. These data indicate that distinct patterns of neuropsychological impairment are maintained longitudinally, reflecting the unique anatomic distribution of relative disease burden in AD and FTLD.

Objective: To investigate the neural basis for the behavioral symptoms of frontotemporal lobar degeneration (FTLD) that cause the greatest caregiver distress., Background: FTLD is a progressive neurodegenerative disease associated with behavioral disturbances. Group studies have related these behaviors to volume loss on MRI., Methods: Forty caregivers of patients with the clinical diagnosis of FTLD completed the Neuropsychiatric Inventory. Twelve neuropsychiatric symptoms and the associated caregiver distress were assessed. Optimized voxel-based morphometry identified significant atrophy in subgroups of FTLD patients with isolated behavioral symptoms corresponding to the most distressing behaviors, and we correlated cortical atrophy directly with these distressing behavioral disorders in an unbiased group analysis., Results: The greatest stressors for caregivers were apathy and disinhibition (p < 0.005 for both contrasts). Partially distinct areas of cortical atrophy were associated with these behaviors in both individual patients with these symptoms and group-wide analyses, including the dorsal anterior cingulate cortex and dorsolateral prefrontal cortex in apathetic patients, and the medial orbital frontal cortex in disinhibited patients., Conclusions: Caregiver stress in families of FTLD patients is due in large part to apathy and disinhibition. The anatomic distribution of cortical loss corresponding to these distressing social behaviors includes partially distinct areas within the frontal lobe.

Background and Purpose: Leukoaraiosis (LA) might interrupt intra- and interhemispheric communication and thus induce cognitive impairments and dementia. It remains unclear, however, if there is a volume threshold of LA that is needed before either the signs of dementia and/or a specific pattern of neuropsychological impairment become manifest. Roman et al has suggested that 25% of white matter may need to be involved before white matter alterations influence the clinical signs associated with dementia. The purpose of this study is to ascertain the threshold of MRI-LA as measured with a visual rating scale needed to induce specific patterns of neuropsychological impairment associated with dementia., Methods: One hundred fifteen patients with dementia received a comprehensive neuropsychological examination and the severity of MRI-LA was measured using a 40-point LA scale., Results: Patients were categorized into low (mean LA=4.21+/-2.92; 3.22%-17.82%), moderate (mean LA=12.58+/-2.54; 25.01%-37.80%), and severe (mean LA=22.36+/-4.04; 45.80%-66.00%) LA groups. Patients in the mild LA group obtained markedly lower scores on tests of episodic memory compared with working memory, a neuropsychological profile often associated with Alzheimer disease. Patients with moderate LA displayed equal impairment on neuropsychological tests. Patients in the severe LA group obtained significantly lower scores on tests of working memory as compared with episodic memory., Conclusions: These data provide evidence that a threshold of moderate MRI-LA as measured with a visual rating scale is associated with greater and/or equal impairment on tests of working memory versus episodic memory and provides a benchmark to assess the effect of MRI-LA on the clinical presentation of dementia.

Background: Clinical-pathologic studies are crucial to understanding brain-behavior relations and improving diagnostic accuracy in neurodegenerative diseases., Objective: To establish clinical, neuropsychological, and imaging features of clinically diagnosed patients with frontotemporal dementia (FTD) that help discriminate between pathologically determined tau-positive FTD, tau-negative FTD, and frontal-variant Alzheimer disease., Design: Retrospective clinical-pathologic survey., Setting: Academic medical center. Patients Sixty-one participants with the clinical diagnosis of a frontotemporal spectrum disorder who underwent a neuropsychological evaluation and had an autopsy-confirmed disease., Main Outcome Measures: Neuropsychological performance and high-resolution structural magnetic resonance imaging (MRI)., Results: Distinguishing features of patients with tau-positive FTD include visual perceptual-spatial difficulty and an extrapyramidal disorder significantly more often than other patients, significant cortical atrophy in the frontal and parietal regions as evidenced on MRI, and the burden of pathology is greatest in the frontal and parietal regions. Patients with tau-negative FTD are distinguished by their greater difficulties with social, language, and verbally mediated executive functions, significant cortical atrophy in the frontal and temporal regions as evidenced on MRI, and significant frontal and temporal pathology. Patients with Alzheimer disease at autopsy have significantly impaired delayed recall during episodic memory testing; atrophy that involves temporal areas, including the hippocampus, as evidenced on MRI; and widely distributed pathology including the medial temporal structures. A discriminant function analysis grouped patients on the basis of clinical and neuropsychological features with 87.5% accuracy., Conclusion: Clinical, neuropsychological, and imaging profiles can contribute to accurate antemortem diagnosis in FTD.

Dementia research suggests executive dysfunction is best understood within the context of disease-specific neuropathology. Leukoaraiosis (LA) results in executive dysfunction yet little is known about its impact on specific aspects of working memory (WM). This study aimed to investigate the relationship between MRI LA severity and WM in dementia. A visual rating scale was used to assign patients with dementia into groups with minimal-mild LA (Low LA; n=34) and moderate-severe LA (High LA; n=32). A modified Digit Span Backward Task consisting of 3-, 4-, and 5-span trials measured specific components of WM. Short-term storage and rehearsal in WM were assessed by the total number of digits reported regardless of recall order (ANY-ORDER; e.g., 47981 recalled '18943', score=4). Mental manipulation in the form of disengagement and temporal re-ordering was assessed by the total number of digits recalled in correct position (SERIAL-ORDER; e.g., 47981 recalled '18943', score=3). There was no difference between LA groups on ANY-ORDER comparisons. The High LA group obtained lower SERIAL-ORDER scores than the Low LA group. Stepwise regression analyses were conducted that first entered MMSE scores then composite z-scores reflecting executive functioning, language and memory. ANY-ORDER performance variance was explained solely by dementia severity. SERIAL-ORDER performance variance was further explained by executive dysfunction. Results suggest that high degrees of LA do not interfere with immediate (digit) recall but do interfere with disengagement and temporal re-ordering. LA may disconnect the frontal lobes from subcortical and cortical structures that form the neuronal networks critical for these WM functions.

Background: A neuropsychological screening instrument sensitive to neuropsychological deficits associated with Alzheimer's disease (AD) and patients with frontotemporal dementia (FTD) would be valuable for diagnostic evaluation., Methods: The Philadelphia Brief Assessment of Cognition (PBAC) assesses working memory/executive control, language, visuospatial operations, verbal/visual episodic memory, and behavior/social comportment and can be administered and scored in 15-20 min. Participants included 149 patients with AD and four groups of FTD patients - i.e., patients with a decline in social comportment, personality, and executive functioning (SOC/EXEC), semantic dementia (SemD), progressive nonfluent aphasia (PNFA), and corticobasal syndrome (CBS)., Results: The total PBAC score correlated with the Mini-Mental State Examination. Between-group analysis of PBAC subscales and the results of logistic regression analyses produced substantial between-group differences, emphasizing the sensitivity of the test to differentiate dementia subtypes. AD patients were impaired on tests of episodic memory, SOC/EXEC patients were impaired on a measure of social comportment/behavioral disturbance, PNFA patients obtained low scores on tests of working memory/executive control, SemD patients obtained lower scores on language-mediated measures, and CBS patients were impaired on visuospatial/visual memory tests., Conclusion: These data support the usefulness of the PBAC as a relatively brief screening test of overall dementia severity across a wide range of dementia patients., ((c) 2007 S. Karger AG, Basel.)

Reports of semantic dementia patients have shown more accurate identification and use for personal objects than unfamiliar analogs of the same objects (e.g., personal comb versus experimenter's comb) [Bozeat, S., Lambon Ralph, M. A., Patterson, K., & Hodges, J. R. (2002). The influence of personal familiarity and context on object use in semantic dementia. Neurocase, 8, 127-134; Snowden, J. S., Griffiths, H., & Neary, D. (1994). Semantic dementia: Autobiographical contribution to preservation of meaning. Cognitive Neuropsychology, 11, 265-288]. Despite potential clinical implications, the personal object advantage has not been explored in various dementia populations. Sixteen mild to moderate dementia patients were tested with 12-15 of their personal objects and laboratory analog objects. Four tasks were administered: Naming, Gesture, Semantic/Script Generation, and Personal Object Decision (i.e., Is this yours?). Although 25% of the sample performed at chance in identifying personal objects as their own, participants generated more specific information (t=2.3, p=.03) and more accurate gestures (t=2.4, p=.03) for personal objects. Thus, the personal object advantage was observed for script/semantic knowledge and movement sequences, and should be considered in residential planning for various dementia patients.

Objective: To determine the association between neuropsychiatric symptoms and the presence of medical illness among outpatients with mild dementia., Method: The Neuropsychiatric Inventory (NPI) was used to assess neuropsychiatric symptoms, and the Cumulative Illness Rating Scale (CIRS) was used to evaluate physical impairment, in 44 outpatients diagnosed as having dementia (Alzheimer disease, n=22; vascular dementia, n=13; mixed dementia, n=9). The tests used were standard parts of a memory assessment program at a college of osteopathic medicine. Pearson product moment correlations were used to assess any associations between NPI and CIRS scores., Results: Significant associations were identified between several NPI-assessed symptoms and degree of medical illness as measured by the CIRS. Neurobehavioral problems were significantly correlated (P<.05) with illness in the following body organ systems: gastrointestinal (lower), genitourinary, neurologic, ophthalmologic/otolaryngologic, psychiatric, and respiratory., Conclusion: The authors' preliminary data underscore the importance of primary care physicians assessing patients with dementia for comorbidity of psychiatric illnesses when conducting medical examinations.

The current research sought to test the hypothesis that psychotic symptoms in patients with dementia might be due to relatively greater executive control and visuoperceptual deficits. Twenty-four dementia patients with psychosis and 24 outpatients without psychosis diagnosed with either probable Alzheimer's disease (AD) or possible/probable Ischemic Vascular Dementia (IVD) were studied. Groups did not differ with respect to age, education, severity of dementia, or depression. Presence and severity of psychosis was measured with a modification of the Neuropsychiatric Inventory (NPI; Cummings, J. L., Mega, M., Gray, K., Rosenberg-Thompson, S., Carusi, D. A., & Gorbein, J. (1994). The neuropsychiatric inventory: Comprehensive assessment of psychopathology in dementia. Neurology, 44, 2308-2314). Between-group and regression analyses found a consistent relationship such that patients with psychosis obtained low scores on the Boston Revision Wechsler Memory Scale-Mental Control subtest (WMS-MC subtest), a test of executive control. On some analyses patients with psychosis also made more perceptual errors on tests of naming and obtained higher scores on tests of delayed recognition memory. However, the relationship between severity of psychosis and performance on visuoperceptual and memory measures was considerably less robust. These data suggest a strong relationship between severity of psychosis and poor performance on executive control. Less evidence was obtained to support our contention that psychotic symptoms in dementia may arise from an interaction of neuropsychological deficits involving greater impairment in executive and visuoperceptual functioning.

The neuropathology associated with chronic alcohol abuse varies across studies, though research suggests generalized reductions in cortical and subcortical grey and white matter. Neuropsychological findings also differ within the literature. The inconsistent findings with respect to the neuropathology and neurobehavior of patients with histories of alcohol abuse may be due, at least in part, to differing nosology and the highly variable inclusion/exclusion criteria employed by researchers. Oslin et al. [Int J Geriatr Psychiatry 1998;13:203-212] have proposed and recently validated specific criteria for probable alcohol-related dementia (ARD). We were interested in comparing the neuropsychological profile of ARD patients with the neurocognitive profiles of typical cortical and subcortical dementia patients. Participants included 14 ARD patients, 15 patients diagnosed with Alzheimer's disease (AD), 13 patients diagnosed with subcortical vascular dementia (VaD), and 20 normal controls. Patient subgroups were similar with respect to age (mean = 79), education (mean = 12 years) and dementia severity (MMSE; mean = 22.1). The three dementia patient subgroups demonstrated significantly worse performance than the normal controls subgroup on all neuropsychological tests. The ARD subgroup exhibited very similar executive control deficits to VaD patients. However, the different neurocognitive profiles of the patient subgroups suggest that ARD patients may also, in fact, demonstrate some degree of amnesia given that they perform slightly worse than subcortical patients on delayed verbal free recall and recognition. Nonetheless, the ARD patients did not display as severe impairment as the AD patients on the memory tasks. No significant differences between the three patient groups were identified on language tests. In sum, we present preliminary evidence of a distinct neuropsychological profile for ARD patients that includes impairment on both executive control and memory tests. This pattern of performance suggests that long-term alcohol abuse, in comparison to AD and VaD, may be associated with both cortical and subcortical neuropathology.

Sixteen patients with Alzheimer's disease (AD) and 15 patients with vascular dementia (VaD) associated with subcortical white matter lesions or subcortical cardiovascular accidents (CVAs) were treated with donepezil for 16 weeks. Within-group analyses for the AD group revealed significant improvement on some tests of working memory, and marginal improvement on the Mini-Mental State Examination and on tests of immediate free recall from a serial list-learning task. Identical analyses for the VaD group revealed substantial gains on tests of working memory and delayed recognition memory. These data suggest that medication such as donepezil may act to improve the working memory deficits known to be associated with dementia patients with subcortical vascular lesions. The clinical implications of these findings are discussed.

Objectives: A clock drawing test scoring system is presented to explore the neuropsychological/neuroanatomic components underlying clock drawing in patients initially diagnosed with Alzheimer disease, ischemic vascular dementia associated with white matter alterations, and Parkinson disease., Methods: Fourteen clock drawing test errors were scored to create 4 clock drawing test subscales that assess different underlying cognitive operations., Results: In the command condition, errors on the Time subscale were correlated with impairment on executive control measures. In the copy condition, errors on the Perseveration/Pull to Stimulus subscale was also correlated with executive control measures. Patients presenting with mild (low) magnetic resonance imaging white matter alterations, significant (high) white matter alterations, and Parkinson disease were compared. In the command condition, the low white matter alterations group made fewer total errors than the Parkinson disease group. In the copy condition, the low white matter alterations group made fewer errors on the Time, Spatial Layout, and Perseveration/Pull to Stimulus clock drawing test subscales than the high white matter alterations or Parkinson disease groups. Few differences were noted between the high white matter alterations and Parkinson disease groups., Discussion: Our data suggest that heavy demands on executive control associated with the interruption of large-scale cortical-subcortical neural networks underlie impairment in clock drawing in mild dementia.

Differential patterns of executive function deficits (EFD) exist in cortical and subcortical dementia; however, little work exists attempting to integrate these findings into a conceptual framework. The current study aimed to characterize EFD in cortical and subcortical dementia. Patients with Alzheimer's disease (AD; n = 65), subcortical ischemic vascular dementia (IVD; n = 64), or Parkinson's disease with dementia (dPD; n = 21) completed a variety of measures purported to require executive systems. We extracted variables of interest from measures shown in a growing body of literature to be associated with EFD in dementia. These measures included the Boston Revision of the WMS Mental Control subtest, letter fluency, WAIS-R Similarities subtest, CVLT, the Graphical Sequence Test-Dementia version, and Clock Drawing. When submitted to a PCA with varimax rotation, these variables produced a four-component solution (62% of the variance). Component 1 appeared to reflect adequacy of working memory, Component 2 irrelevant or context nonspecific interference, Component 3 reflected response preparation and Component 4 relevant or context-specific interference. Post hoc analyses of z-transformed composite scores revealed that AD differentially affected context-specific interference, IVD and dPD disrupted working memory and response preparation while IVD differentially affected context non-specific interference. EFD in dementia can be divided into specific components that are differentially impaired by cortical and subcortical dementias. Implications for an overall conceptual framework of EFD in dementia are discussed.

Clinical methods used to determine unawareness in dementia exist; however, their applicability to empirical research is limited. The authors present a statistically derived approach to determining unawareness that addresses these limitations. Dementia patients (n=32) completed an awareness questionnaire. On an identical questionnaire, collateral sources (relatives or friends; n=32) provided their best estimate of participants' abilities. The authors compared cluster analysis, the proposed empirical approach, to a currently used standard deviation cutoff score approach. Cluster analysis included all participants, displayed sound statistical properties, and was more sensitive to between-group differences in psychotic symptoms than standard deviation cutoff. Cluster analysis appears more appropriate for understanding the overall spectrum of unawareness in dementia research.

Unawareness of deficit is a common feature of degenerative dementia. The present study explored awareness and correction of naturalistic action errors in 54 dementia participants and 10 healthy controls while they performed a series of everyday tasks, such as toast preparation and gift-wrapping. Awareness for everyday task performance and cognitive functioning was also assessed with questionnaire discrepancy scores, and a neuropsychological test protocol was administered. Dementia participants were aware of and corrected a significantly smaller proportion of errors compared to controls (z = -4.59, p < .001). Awareness and correction of action errors was not significantly correlated with the number of naturalistic errors committed, questionnaire discrepancy scores, or neuropsychological test data. Within-group analyses showed awareness differed across error types, such that participants were aware of a greater proportion of substitution and sequence errors compared to omissions, perseverations, and action addition (i.e., utilization behavior) errors (z < or = -3.2, p < or = .002 for all analyses). Taken together these data suggest that error awareness and correction during the course of action is not related to error production or awareness measured via questionnaire discrepancy scores. Rather, direct assessment of error detection and correction may provide novel information about behavioral monitoring that can not be extrapolated from measures of dementia severity or traditional neuropsychological assessment.

The nine-word California Verbal Learning Test (CVLT-9; Libon et al., 1996; Spreen & Strauss, 1998) is a verbal list learning task used to assess declarative memory impairment among dementia patients. The present study sought to investigate the neuro-cognitive mechanisms that underlie the production of intrusions and perseverations on the list A, free recall learning trials, and the false positive responses made on the delayed recognition condition. Patients with probable Alzheimer's disease (AD), Ischaemic Vascular Dementia associated with periventricular and deep white matter changes (IVD), and individuals without dementia (NC) were studied. Between-group analyses showed that AD participants produced more initial intrusion errors, and perseverated on those same intrusion errors across list A learning trials than IVD or NC participants. Also, as participants with dementia produced initial free recall intrusion errors, the semantic organization of their responses on the 'animal' word list generation task declined (Giovannetti-Carew, Lamar, Cloud, Grossman, & Libon, 1997). On the delayed recognition test condition, within-group analyses revealed that the IVD group endorsed more list B interference foils, than other errors. AD participants endorsed semantically related foils and list B interference foils. In addition, as participants with dementia endorsed more list B interference foils, more perseverations were produced on the Graphical Sequence Test - Dementia Version (Lamar et al., 1997). These results were interpreted within the context of the semantic knowledge, and executive functions deficits that typify AD and IVD, respectively.

Two experiments investigating the capacity to sustain mental set in dementia were conducted. Experiment 1 analyzed performance of a non-demented control group (NC), participants with Alzheimer's disease (AD) and participants with ischemic vascular dementia (IVD) on the Boston Revision of the Wechsler Memory Scale Mental Control subtest (MC). On simple tasks there were no between-group differences after controlling for time to completion. On complex tasks, NC participants outperformed both dementia groups and AD participants obtained higher accuracy indices than IVD participants. The IVD group produced a disproportionate number of commission errors regardless of task complexity. The AD group tended to produce more omission errors on more difficult measures of mental set. Individual task performance was divided into three sections-first, middle, and last. IVD participants made fewer and fewer correct responses over all three sections, whereas performance of AD participants leveled off by the middle section with no further decline. Experiment 2 compared letter fluency performance among NC, AD and IVD groups, and participants with dementia secondary to idiopathic Parkinson's disease (PD). For all letter cues, IVD and PD participants generated fewer responses than NC and AD participants. However, IVD and PD participants generated a larger proportion of words than AD and NC participants within the first 15 s. As the task progressed, the output of IVD and PD participants dropped precipitously. These findings indicate that failure to maintain mental set is not a diffuse or general cognitive disability. Rather, failure to maintain mental set in dementia may be best understood within the context of predictable and specific within-task time epochs.

ObjectivePreclinical Alzheimer's disease (AD) defined by a positive AD biomarker in the presence of normal cognition is presumed to precede mild cognitive impairment (MCI). Subtle cognitive deficits and cognitive inefficiencies in preclinical AD may be detected through process and error scores on neuropsychological tests in those at risk for progression to MCI.MethodCognitively normal participants (n = 525) from the Alzheimer's Disease Neuroimaging Initiative were followed for up to 5 years and classified as either stable normal (n = 305) or progressed to MCI (n = 220). Cox regressions were used to determine whether baseline process scores on the Rey Auditory Verbal Learning Test (AVLT; intrusion errors, learning slope, proactive interference, retroactive interference) predicted progression to MCI and a Clinical Dementia Rating (CDR) score of 1 after considering demographic characteristics, apolipoprotein E ε4 status, cerebrospinal fluid AD biomarkers, ischemia risk, mood, functional difficulty, and standard neuropsychological total test scores for the model.ResultsBaseline AVLT intrusion errors predicted progression to MCI (hazard ratio = 1.04, 95% confidence interval 1.01-1.07, p = .008) and improved model fit after the other valuable predictors were already in the model, χ2(df = 1) = 6.330, p = .012. AVLT intrusion errors also predicted progression to CDR = 1 (hazard ratio = 1.10, 95% confidence interval 1.02-1.18, p = .016) and again improved model fit, χ2(df = 1) = 4.682, p = .030.ConclusionsIntrusion errors on the AVLT contribute unique value for predicting progression from normal cognition to MCI and normal cognition to mild dementia (CDR = 1). Intrusion errors appear to reflect subtle change and inefficiencies in cognition that precede impairment detected by neuropsychological total scores. (PsycINFO Database Record

IntroductionWe examined associations between magnetic resonance imaging (MRI) markers of cerebrovascular disease and neurodegeneration with mild cognitive impairment (MCI) diagnosis at baseline and conversion from normal cognition to MCI at follow-up.MethodsFramingham Offspring participants underwent brain MRI and neuropsychological assessment at baseline (n=1049) and follow-up (n=561). Participants were classified at baseline and at follow-up as cognitively normal or MCI using sensitive neuropsychological criteria. White matter hyperintensity (WMH) volume, covert brain infarcts, hippocampal volume, and total cerebral brain volume were quantified.ResultsBaseline measures of WMH and hippocampal volume were associated with MCI status cross-sectionally and also with conversion from normal cognition to MCI at 6.5-year follow-up. Annualized change rates in total cerebral brain volume and hippocampal volume were associated with conversion from normal cognition to MCI to follow-up.DiscussionBaseline WMH and hippocampal volume are markers that are both associated with conversion from normal cognition to MCI, highlighting the role of both vascular lesions and neurodegeneration in MCI.

BackgroundWorking memory (WM) is often assessed with serial order tests such as repeating digits backward. In prior dementia research using the Backward Digit Span Test (BDT), only aggregate test performance was examined.ObjectiveThe current research tallied primacy/recency effects, out-of-sequence transposition errors, perseverations, and omissions to assess WM deficits in patients with mild cognitive impairment (MCI).MethodsMemory clinic patients (n = 66) were classified into three groups: single domain amnestic MCI (aMCI), combined mixed domain/dysexecutive MCI (mixed/dys MCI), and non-MCI where patients did not meet criteria for MCI. Serial order/WM ability was assessed by asking participants to repeat 7 trials of five digits backwards. Serial order position accuracy, transposition errors, perseverations, and omission errors were tallied.ResultsA 3 (group)×5 (serial position) repeated measures ANOVA yielded a significant group×trial interaction. Follow-up analyses found attenuation of the recency effect for mixed/dys MCI patients. Mixed/dys MCI patients scored lower than non-MCI patients for serial position 3 (p

Elevated blood glucose and the apolipoprotein (APOE) ɛ4 allele have both been associated with increased dementia risk; however, the neuropathological mechanisms underlying these associations remain unclear. We examined the impact of APOE genotype and midlife blood glucose on post-mortem vascular and Alzheimer's disease (AD) neuropathology. Ninety-four participants from the Framingham Heart Study without diagnosed diabetes underwent health examination at midlife and brain autopsy at death. Histopathological measures of vascular and AD neuropathology were obtained and analyzed. Results demonstrated that, among APOE ɛ4 carriers, elevated blood glucose was associated with more severe AD pathology. There was no such relationship with vascular pathology. In a relatively healthy sample with low vascular risk burden, midlife elevated blood glucose was associated with greater AD pathology among APOE ɛ4 carriers. A better understanding of interactive effects of APOE genotype and vascular risk on neuropathology has implications for identification of individuals at risk for decline and long-term preventive treatment.

We investigated whether midlife pulse pressure is associated with brain atrophy and cognitive decline, and whether the association was modified by apolipoprotein-E ε4 (APOE-ε4) and hypertension. Participants (549 stroke-free and dementia-free Framingham Offspring Cohort Study participants, age range=55.0 to 64.9 y) underwent baseline neuropsychological and magnetic resonance imaging (subset, n=454) evaluations with 5- to 7-year follow-up. Regression analyses investigated associations between baseline pulse pressure (systolic-diastolic pressure) and cognition, total cerebral volume and temporal horn ventricular volume (as an index of smaller hippocampal volume) at follow-up, and longitudinal change in these measures. Interactions with APOE-ε4 and hypertension were assessed. Covariates included age, sex, education, assessment interval, and interim stroke. In the total sample, baseline pulse pressure was associated with worse executive ability, lower total cerebral volume, and greater temporal horn ventricular volume 5 to 7 years later, and longitudinal decline in executive ability and increase in temporal horn ventricular volume. Among APOE-ε4 carriers only, baseline pulse pressure was associated with longitudinal decline in visuospatial organization. Findings indicate arterial stiffening, indexed by pulse pressure, may play a role in early cognitive decline and brain atrophy in mid to late life, particularly among APOE-ε4 carriers.

We examined cortical amyloid-β (Aβ) levels and interactions with apolipoprotein (APOE) ɛ4 genotype status across empirically-derived mild cognitive impairment (MCI) subgroups and cognitively normal older adults. Participants were 583 ADNI participants (444 MCI, 139 normal controls [NC]) with baseline florbetapir positron emission tomography (PET) amyloid imaging and neuropsychological testing. Of those with ADNI-defined MCI, a previous cluster analysis [1] classified 51% (n = 227) of the current sample as amnestic MCI, 8% (n = 37) as dysexecutive/mixed MCI, and 41% (n = 180) as cluster-derived normal (cognitively normal). Results demonstrated that the dysexecutive/mixed and amnestic MCI groups showed significantly greater levels of amyloid relative to the cluster-derived normal and NC groups who did not differ from each other. Additionally, 78% of the dysexecutive/mixed, 63% of the amnestic MCI, 42% of the cluster-derived normal, and 34% of the NC group exceeded the amyloid positivity threshold. Finally, a group by APOE genotype interaction demonstrated that APOE ɛ4 carriers within the amnestic MCI, cluster-derived normal, and NC groups showed significantly greater amyloid accumulation compared to non-carriers of their respective group. Such an interaction was not revealed within the dysexecutive/mixed MCI group which was characterized by both greater cognitive impairment and amyloid accumulation compared to the other participant groups. Our results from the ADNI cohort show considerable heterogeneity in Aβ across all groups studied, even within a group of robust NC participants. Findings suggest that conventional criteria for MCI may be susceptible to false positive diagnostic errors, and that onset of Aβ accumulation may occur earlier in APOE ɛ4 carriers compared to non-carriers.

Clock Drawing Test performance was examined alongside other neuropsychological tests in mild cognitive impairment (MCI). We tested the hypothesis that clock-drawing errors are related to executive impairment. The current research examined 86 patients with MCI for whom, in prior research, cluster analysis was used to sort patients into dysexecutive (dMCI, n = 22), amnestic (aMCI, n = 13), and multidomain (mMCI, n = 51) subtypes. First, principal components analysis (PCA) and linear regression examined relations between clock-drawing errors and neuropsychological test performance independent of MCI subtype. Second, between-group differences were assessed with analysis of variance (ANOVA) where MCI subgroups were compared to normal controls (NC). PCA yielded a 3-group solution. Contrary to expectations, clock-drawing errors loaded with lower performance on naming/lexical retrieval, rather than with executive tests. Regression analyses found increasing clock-drawing errors to command were associated with worse performance only on naming/lexical retrieval tests. ANOVAs revealed no differences in clock-drawing errors between dMCI versus mMCI or aMCI versus NCs. Both the dMCI and mMCI groups generated more clock-drawing errors than the aMCI and NC groups in the command condition. In MCI, language-related skills contribute to clock-drawing impairment.

BackgroundWe assessed whether mild cognitive impairment (MCI) subtypes could be empirically derived within the Alzheimer's Disease Neuroimaging Initiative (ADNI) MCI cohort and examined associated biomarkers and clinical outcomes.MethodsCluster analysis was performed on neuropsychological data from 825 MCI ADNI participants.ResultsFour subtypes emerged: (1) dysnomic (n = 153), (2) dysexecutive (n = 102), (3) amnestic (n = 288), and (4) cluster-derived normal (n = 282) who performed within normal limits on cognitive testing. The cluster-derived normal group had significantly fewer APOE ε4 carriers and fewer who progressed to dementia compared with the other subtypes; they also evidenced cerebrospinal fluid Alzheimer's disease biomarker profiles that did not differ from the normative reference group.ConclusionsIdentification of empirically derived MCI subtypes demonstrates heterogeneity in MCI cognitive profiles that is not captured by conventional criteria. The large cluster-derived normal group suggests that conventional diagnostic criteria are susceptible to false-positive errors, with the result that prior MCI studies may be diluting important biomarker relationships.

We compared two methods of diagnosing mild cognitive impairment (MCI): conventional Petersen/Winblad criteria as operationalized by the Alzheimer's Disease Neuroimaging Initiative (ADNI) and an actuarial neuropsychological method put forward by Jak and Bondi designed to balance sensitivity and reliability. 1,150 ADNI participants were diagnosed at baseline as cognitively normal (CN) or MCI via ADNI criteria (MCI: n = 846; CN: n = 304) or Jak/Bondi criteria (MCI: n = 401; CN: n = 749), and the two MCI samples were submitted to cluster and discriminant function analyses. Resulting cluster groups were then compared and further examined for APOE allelic frequencies, cerebrospinal fluid (CSF) Alzheimer's disease (AD) biomarker levels, and clinical outcomes. Results revealed that both criteria produced a mildly impaired Amnestic subtype and a more severely impaired Dysexecutive/Mixed subtype. The neuropsychological Jak/Bondi criteria uniquely yielded a third Impaired Language subtype, whereas conventional Petersen/Winblad ADNI criteria produced a third subtype comprising nearly one-third of the sample that performed within normal limits across the cognitive measures, suggesting this method's susceptibility to false positive diagnoses. MCI participants diagnosed via neuropsychological criteria yielded dissociable cognitive phenotypes, significant CSF AD biomarker associations, more stable diagnoses, and identified greater percentages of participants who progressed to dementia than conventional MCI diagnostic criteria. Importantly, the actuarial neuropsychological method did not produce a subtype that performed within normal limits on the cognitive testing, unlike the conventional diagnostic method. Findings support the need for refinement of MCI diagnoses to incorporate more comprehensive neuropsychological methods, with resulting gains in empirical characterization of specific cognitive phenotypes, biomarker associations, stability of diagnoses, and prediction of progression. Refinement of MCI diagnostic methods may also yield gains in biomarker and clinical trial study findings because of improvements in sample compositions of 'true positive' cases and removal of 'false positive' cases.

Background: Increased blood-brain barrier (BBB) permeability and amyloid-β (Aβ) peptides (especially Aβ1–42) (Aβ42) have been linked to Alzheimer's disease (AD) pathogenesis, but the nature of their involvement in AD-related neuropathological changes leading to cognitive changes remains poorly understood. Objective: To test the hypothesis that chronic extravasation of bloodborne Aβ42 peptide and brain-reactive autoantibodies and their entry into the brain parenchyma via a permeable BBB contribute to AD-related pathological changes and cognitive changes in a mouse model. Methods: The BBB was rendered chronically permeable through repeated injections of Pertussis toxin (PT), and soluble monomeric, fluorescein isothiocyanate (FITC)-labeled or unlabeled Aβ42 was injected into the tail-vein of 10-month-old male CD1 mice at designated intervals spanning ∼3 months. Acquisition of learned behaviors and long-term retention were assessed via a battery of cognitive and behavioral tests and linked to neuropathological changes. Results: Mice injected with both PT and Aβ42 demonstrated a preferential deficit in the capacity for long-term retention and an increased susceptibility to interference in selective attention compared to mice exposed to PT or saline only. Immunohistochemical analyses revealed increased BBB permeability and entry of bloodborne Aβ42 and immunoglobulin G (IgG) into the brain parenchyma, selective neuronal binding of IgG and neuronal accumulation of Aβ42 in animals injected with both PT and Aβ42 compared to controls. Conclusion: Results highlight the potential synergistic role of BBB compromise and the influx of bloodborne Aβ42 into the brain in both the initiation and progression of neuropathologic and cognitive changes associated with AD. [ABSTRACT FROM AUTHOR]

The clock drawing test is a simple and inexpensive method to screen for cognitive frailties, including dementia. In this study, we used the relevance factor variational autoencoder (RF-VAE), a deep generative neural network, to represent digitized clock drawings from multiple institutions using an optimal number of disentangled latent factors. The model identified unique constructional features of clock drawings in a completely unsupervised manner. These factors were examined by domain experts to be novel and not extensively examined in prior research. The features were informative, as they distinguished dementia from non-dementia patients with an area under receiver operating characteristic (AUC) of 0.86 singly, and 0.96 when combined with participants' demographics. The correlation network of the features depicted the "typical dementia clock" as having a small size, a non-circular or "avocado-like" shape, and incorrectly placed hands. In summary, we report a RF-VAE network whose latent space encoded novel constructional features of clocks that classify dementia from non-dementia patients with high performance. [ABSTRACT FROM AUTHOR]

The current study presents a rapid review of the psychometric features of the standard Montreal Cognitive Assessment (MoCA), and the proposal for a modified version of the test, informed by the methodology of the Boston Process Approach to neuropsychological assessment. In order to aid the process of identification of the primary underlying neurocognitive mechanism responsible for defective test performance, the MoCA-Process-Based Approach (MoCA-PA) adds complementary or satellite test conditions in some of its subtests, includes "new" qualitative indices to capture the cognitive processes involved in each cognitive task, and incorporates new qualitative classifications of error subtypes. It provides concurrent assessment of multiple cognitive processes within each task, without significantly increasing administration time or placing significant additional burden upon the respondent. We present preliminary results obtained from an initial sample of 45 community-dwelling older adults attending a University program for seniors. Results suggest the usefulness of additional indices in providing additional information on cognitive deterioration that may be overlooked with the only consideration of quantitative scores. Future research will aim to collect normative data for different clinical populations using the newly developed indices in order to determine the validity and clinical utility of the relatively novel qualitative process-based methods used in the MoCA-PA. [ABSTRACT FROM AUTHOR]

Background: Relative to the abundance of publications on dementia and clock drawing, there is limited literature operationalizing 'normal' clock production.Objective: To operationalize subtle behavioral patterns seen in normal digital clock drawing to command and copy conditions.Methods: From two research cohorts of cognitively-well participants age 55 plus who completed digital clock drawing to command and copy conditions (n = 430), we examined variables operationalizing clock face construction, digit placement, clock hand construction, and a variety of time-based, latency measures. Data are stratified by age, education, handedness, and number anchoring.Results: Normative data are provided in supplementary tables. Typical errors reported in clock research with dementia were largely absent. Adults age 55 plus produce symmetric clock faces with one stroke, with minimal overshoot and digit misplacement, and hands with expected hour hand to minute hand ratio. Data suggest digitally acquired graphomotor and latency differences based on handedness, age, education, and anchoring.Conclusion: Data provide useful benchmarks from which to assess digital clock drawing performance in Alzheimer's disease and related dementias. [ABSTRACT FROM AUTHOR]

Background: Advantages of digital clock drawing metrics for dementia subtype classification needs examination.Objective: To assess how well kinematic, time-based, and visuospatial features extracted from the digital Clock Drawing Test (dCDT) can classify a combined group of Alzheimer's disease/Vascular Dementia patients versus healthy controls (HC), and classify dementia patients with Alzheimer's disease (AD) versus vascular dementia (VaD).Methods: Healthy, community-dwelling control participants (n = 175), patients diagnosed clinically with Alzheimer's disease (n = 29), and vascular dementia (n = 27) completed the dCDT to command and copy clock drawing conditions. Thirty-seven dCDT command and 37 copy dCDT features were extracted and used with Random Forest classification models.Results: When HC participants were compared to participants with dementia, optimal area under the curve was achieved using models that combined both command and copy dCDT features (AUC = 91.52%). Similarly, when AD versus VaD participants were compared, optimal area under the curve was, achieved with models that combined both command and copy features (AUC = 76.94%). Subsequent follow-up analyses of a corpus of 10 variables of interest determined using a Gini Index found that groups could be dissociated based on kinematic, time-based, and visuospatial features.Conclusion: The dCDT is able to operationally define graphomotor output that cannot be measured using traditional paper and pencil test administration in older health controls and participants with dementia. These data suggest that kinematic, time-based, and visuospatial behavior obtained using the dCDT may provide additional neurocognitive biomarkers that may be able to identify and tract dementia syndromes. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) and vascular dementia (VaD) are the two most common types of dementia. Although the combination of these disorders, called 'mixed' dementia, is recognized, the prevailing clinical and research perspective continues to consider AD and VaD as independent disorders. A review of recent neuropathological and neuropsychological literature reveals that these two disorders frequently co-occur and so-called 'pure' AD or VaD is comparatively rare. In addition, recent research shows that vascular dysfunction not only potentiates AD pathology, but that pathological changes in AD may subsequently induce vascular disorders. On the basis of these data, we propose that the neurobiological underpinnings underlying AD/VaD dementia and their neuropsychological phenotypes are best understood as existing along a clinical/pathological continuum or spectrum. We further propose that in conjunction with current diagnostic criteria, statistical modeling techniques using neuropsychological test performance should be leveraged to construct a system to classify AD/VaD spectrum dementia in order to test hypotheses regarding how mechanisms related to AD and VaD pathology interact and influence each other. [ABSTRACT FROM AUTHOR]