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Introduction: A rapid and reliable neuropsychological protocol is essential for the efficient assessment of neurocognitive constructs related to emergent neurodegenerative diseases. We developed an AI-assisted, digitally administered/scored neuropsychological protocol that can be remotely administered in -10min. This protocol assesses the requisite neurocognitive constructs associated with emergent neurodegenerative illnesses. Methods: The protocol was administered to 77 ambulatory care/memory clinic patients (56.40% women; 88.50% Caucasian). The protocol includes a 6-word version of the Philadelphia (repeatable) Verbal Learning Test [P(r)VLT], three trials of 5 digits backward fromthe Backwards Digit Span Test (BDST), and the "animal" fluency test. The protocol provides a comprehensive set of traditional "core" measures that are typically obtained through paper-and-pencil tests (i.e., serial list learning, immediate and delayed free recall, recognition hits, percent correct serial order backward digit span, and "animal" fluency output). Additionally, the protocol includes variables that quantify errors and detail the processes used in administering the tests. It also features two separate, norm-referenced summary scores specifically designed to measure executive control and memory. Results: Using four core measures, we used cluster analysis to classify participants into four groups: cognitively unimpaired (CU; n = 23), amnesticmild cognitive impairment (MCI; n = 17), dysexecutive MCI (n = 23), and dementia (n = 14). Subsequent analyses of error and process variables operationally defined key features of amnesia (i.e., rapid forgetting, extra-list intrusions, profligate responding to recognition foils); key features underlying reduced executive abilities (i.e., BDST items and dysexecutive errors); and the strength of the semantic association between successive responses on the "animal" fluency test. Executive and memory index scores effectively distinguished between all four groups. There was over 90% agreement between how cluster analysis of digitally obtained measures classified patients compared to classification using a traditional comprehensive neuropsychological protocol. The correlations between digitally obtained outcome variables and analogous paper/pencil measures were robust. Discussion: The digitally administered protocol demonstrated a capacity to identify patterns of impaired performance and classification similar to those observed with standard paper/pencil neuropsychological tests. The inclusion of both core measures and detailed error/process variables suggests that this protocol can detect subtle, nuanced signs of early emergent neurodegenerative illness efficiently and comprehensively. [ABSTRACT FROM AUTHOR]

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.

Background/aimsMild 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.MethodsA 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.ResultsMCI 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.ConclusionsOur 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.

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.

ObjectiveAnalysis sought to determine whether Wechsler Memory Scale-Logical Memory (LM)-correct responses and errors were related to magnetic resonance imaging (MRI) brain volume measurements.MethodsThe 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.ResultsIncreasing 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.ConclusionThese 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.

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]

Introduction: Screening for neurocognitive impairment and psychological distress in ambulatory primary and specialty care medical settings is an increasing necessity. The Core Cognitive EvaluationTM (CCE) is administered/ scored using an iPad, requires approximately 8 min, assesses 3- word free recall and clock drawing to command and copy, asks questions about lifestyle and health, and queries for psychological distress. This information is linked with patients' self-reported concerns about memory and their cardiovascular risks. Methods: A total of 199 ambulatory patients were screened with the CCE as part of their routine medical care. The CCE provides several summary indices, and scores on 44 individual digital clock variables across command and copy tests conditions. Results: Subjective memory concerns were endorsed by 41% of participants. Approximately 31% of participants reported psychological distress involving loneliness, anxiety, or depression. Patients with self-reported memory concerns scored lower on a combined delay 3- word/ clock drawing index (p < 0.016), the total summary clock drawing command/ copy score (p < 0.050), and clock drawing to command Drawing Efficiency (p < 0.036) and Simple and Complex Motor (p < 0.029) indices. Patients treated for diabetes and atherosclerotic cardiovascular disease (ASCVD) scored lower on selected CCE outcome measures (p < 0.035). Factor analyses suggest that approximately 10 underlying variables can explain digital clock drawing performance. Discussion: The CCE is a powerful neurocognitive assessment tool that is sensitive to patient's subjective concerns about possible decline in memory, mood symptoms, possible cognitive impairment, and cardiovascular risk. iPad administration ensures total reliability for test administration and scoring. The CCE is easily deployable in outpatient ambulatory primary care settings. [ABSTRACT FROM AUTHOR]

Background: Greater cardiovascular burden and peripheral inflammation are associated with dysexecutive neuropsychological profiles and a higher likelihood of conversion to vascular dementia. The digital clock drawing test (dCDT) is useful in identifying neuropsychological dysfunction related to vascular etiology. However, the specific cognitive implications of the combination of cardiovascular risk, peripheral inflammation, and brain integrity remain unknown. Objective: We aimed to examine the role of cardiovascular burden, inflammation, and MRI-defined brain integrity on dCDT latency and graphomotor metrics in older adults. Methods: 184 non-demented older adults (age 69±6, 16±3 education years, 46% female, 94% white) completed dCDT, vascular assessment, blood draw, and brain MRI. dCDT variables of interest: total completion time (TCT), pre-first hand latency, digit misplacement, hour hand distance from center, and clock face area. Cardiovascular burden was calculated using the Framingham Stroke Risk Profile (FSRP-10). Peripheral inflammation markers included interleukin (IL)-6, IL-8, IL-10, tumor necrosis factor-alpha, and high sensitivity C-reactive protein. Brain integrity included bilateral entorhinal cortex volume, lateral ventricular volume, and whole brain leukoaraiosis. Results: FSRP-10, peripheral inflammation, and brain integrity explained an additional 14.6% of the variance in command TCT, where FSRP-10 was the main predictor. FSRP-10, inflammatory markers, and brain integrity explained an additional 17.0% in command digit misplacement variance, with findings largely driven by FSRP-10. Conclusion: Subtle graphomotor behavior operationalized using dCDT metrics (i.e., TCT and digit misplacement) is partly explained by cardiovascular burden, peripheral inflammation, and brain integrity and may indicate vulnerability to a disease process. [ABSTRACT FROM AUTHOR]

Background: The theory of executive attention (Fuster, 2015) suggests considerable plasticity regarding when specific neurocognitive operations are recruited to bring executive tasks to fruition. Objective: We tested the hypothesis that differing neurocognitive operations are recruited upon the initiation of a response, but that other distinct neurocognitive operations are recruited towards the middle or end of a response. Methods: The Backward Digit Span Test (BDST) was administered to 58 memory clinic patients (MCI, n = 22; no-MCI, n = 36). Latency to generate all correct 5-span responses was obtained. Statistical analyses found that optimal group classification was achieved using the first and third digit backward. First and third response latencies were analyzed in relation to verbal working memory (WM), visual WM, processing speed, visuospatial operations, naming/lexical access, and verbal episodic memory tests. Results: For the first response, slower latencies were associated with better performance in relation to verbal WM and visuospatial test performance. For the third response, faster latencies were associated with better processing speed and visuospatial test performance. Conclusion: Consistent with the theory of executive attention, these data show that the neurocognitive operations underlying successful executive test performance are not monolithic but can be quite nuanced with differing neurocognitive operations associated with specific time epochs. Results support the efficacy of obtaining time-based latency parameters to help disambiguate successful executive neurocognitive operations in memory clinic patients. [ABSTRACT FROM AUTHOR]

Background: Individuals with Alzheimer's disease (AD) often present with coexisting vascular pathology that is expressed to different degrees and can lead to clinical heterogeneity. Objective: To examine the utility of unsupervised statistical clustering approaches in identifying neuropsychological (NP) test performance subtypes that closely correlate with carotid intima-media thickness (cIMT) in midlife. Methods: A hierarchical agglomerative and k-means clustering analysis based on NP scores (standardized for age, sex, and race) was conducted among 1,203 participants (age 48±5.3 years) from the Bogalusa Heart Study. Regression models assessed the association between cIMT ≥50th percentile and NP profiles, and global cognitive score (GCS) tertiles for sensitivity analysis. Results: Three NP profiles were identified: Mixed-low performance [16%, n = 192], scores ≥1 SD below the mean on immediate, delayed free recall, recognition verbal memory, and information processing; Average [59%, n = 704]; and Optimal [26%, n = 307] NP performance. Participants with greater cIMT were more likely to have a Mixed-low profile [OR = 3.10, 95% CI (2.13, 4.53), p < 0.001] compared to Optimal. After adjusting for education and cardiovascular (CV) risks, results remained. The association with GCS tertiles was more attenuated [lowest (34%, n = 407) versus highest (33%, n = 403) tertile: adjusted OR = 1.66, 95% CI (1.07, 2.60), p = 0.024]. Conclusion: As early as midlife, individuals with higher subclinical atherosclerosis were more likely to be in the Mixed-low profile, underscoring the potential malignancy of CV risk as related to NP test performance, suggesting that classification approaches may aid in identifying those at risk for AD/vascular dementia spectrum illness. [ABSTRACT FROM AUTHOR]

Background: Evidence for the universal presence of IgG autoantibodies in blood and their potential utility for the diagnosis of Alzheimer's disease (AD) and other neurodegenerative diseases has been extensively demonstrated by our laboratory. The fact that AD-related neuropathological changes in the brain can begin more than a decade before tell-tale symptoms emerge has made it difficult to develop diagnostic tests useful for detecting the earliest stages of AD pathogenesis. Objective: To determine the utility of a panel of autoantibodies for detecting the presence of AD-related pathology along the early AD continuum, including at pre-symptomatic [an average of 4 years before the transition to mild cognitive impairment (MCI)/AD)], prodromal AD (MCI), and mild-moderate AD stages. Methods: A total of 328 serum samples from multiple cohorts, including ADNI subjects with confirmed pre-symptomatic, prodromal, and mild-moderate AD, were screened using Luminex xMAP® technology to predict the probability of the presence of AD-related pathology. A panel of eight autoantibodies with age as a covariate was evaluated using randomForest and receiver operating characteristic (ROC) curves. Results: Autoantibody biomarkers alone predicted the probability of the presence of AD-related pathology with 81.0% accuracy and an area under the curve (AUC) of 0.84 (95% CI = 0.78–0.91). Inclusion of age as a parameter to the model improved the AUC (0.96; 95% CI = 0.93–0.99) and overall accuracy (93.0%). Conclusion: Blood-based autoantibodies can be used as an accurate, non-invasive, inexpensive, and widely accessible diagnostic screener for detecting AD-related pathology at pre-symptomatic and prodromal AD stages that could aid clinicians in diagnosing AD. [ABSTRACT FROM AUTHOR]

Neuropsychological assessment using the Boston Process Approach (BPA) suggests that an analysis of the strategy or the process by which tasks and neuropsychological tests are completed, and the errors made during test completion convey much information regarding underlying brain and cognition and are as important as overall summary scores. Research over the last several decades employing an analysis of process and errors has been able to dissociate between dementia patients diagnosed with Alzheimer's disease, vascular dementia associated with MRI-determined white matter alterations, and Parkinson's disease; and between mild cognitive impairment subtypes. Nonetheless, BPA methods can be labor intensive to deploy. However, the recent availability of digital platforms for neuropsychological test administration and scoring now enables reliable, rapid, and objective data collection. Further, digital technology can quantify highly nuanced data previously unobtainable to define neurocognitive constructs with high accuracy. In this paper, a brief review of the BPA is provided. Studies that demonstrate how digital technology translates BPA into specific neurocognitive constructs using the Clock Drawing Test, Backward Digit Span Test, and a Digital Pointing Span Test are described. Implications for using data driven artificial intelligence-supported analytic approaches enabling the creation of more sensitive and specific detection/diagnostic algorithms for putative neurodegenerative illness are also discussed. [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]

Objective: To determine how well machine learning algorithms can classify mild cognitive impairment (MCI) subtypes and Alzheimer's disease (AD) using features obtained from the digital Clock Drawing Test (dCDT). Methods: dCDT protocols were administered to 163 patients diagnosed with AD(n = 59), amnestic MCI (aMCI; n = 26), combined mixed/dysexecutive MCI (mixed/dys MCI; n = 43), and patients without MCI (non-MCI; n = 35) using standard clock drawing command and copy procedures, that is, draw the face of the clock, put in all of the numbers, and set the hands for "10 after 11." A digital pen and custom software recorded patient's drawings. Three hundred and fifty features were evaluated for maximum information/minimum redundancy. The best subset of features was used to train classification models to determine diagnostic accuracy. Results: Neural network employing information theoretic feature selection approaches achieved the best 2-group classification results with 10-fold cross validation accuracies at or above 83%, that is, AD versus non-MCI = 91.42%; AD versus aMCI = 91.49%; AD versus mixed/dys MCI = 84.05%; aMCI versus mixed/dys MCI = 84.11%; aMCI versus non-MCI = 83.44%; and mixed/dys MCI versus non-MCI = 85.42%. A follow-up two-group non-MCI versus all MCI patients analysis yielded comparable results (83.69%). Two-group classification analyses were achieved with 25–125 dCDT features depending on group classification. Three- and four-group analyses yielded lower but still promising levels of classification accuracy. Conclusion: Early identification of emergent neurodegenerative illness is criterial for better disease management. Applying machine learning to standard neuropsychological tests promises to be an effective first line screening method for classification of non-MCI and MCI subtypes. [ABSTRACT FROM AUTHOR]

Introduction: The Oblique Effect denotes superior performance for perceiving horizontal or vertical rather than diagonal or oblique stimuli. The current research investigated responding to oblique test stimuli in patients with mild cognitive impairment (MCI). Method: Four statistically-determined groups (n = 112) were studied; patients with little to no cognitive impairment (non-MCI, n = 39); subtle cognitive impairment (SCI, n = 15); amnestic MCI (aMCI, n = 28); and a combined mixed/dysexecutive MCI (mixed/dys MCI, n = 30). The ability to respond to oblique versus non-oblique test stimuli was assessed using the Judgment of Line Orientation Test (JOLO). Comprehensive neuropsychological assessment was also obtained. Between-group differences for JOLO oblique and non-oblique test stimuli were analyzed. Hierarchical linear regression models were constructed to identify relations between accuracy for oblique and non-oblique test items and neurocognitive domains. Results: The mixed/dys MCI group demonstrated lower accuracy for oblique test items compared to non-MCI patients. Accurate responding to oblique test items was associated with better performance on tests measuring executive control, processing speed, naming/lexical retrieval, and verbal concept formation. No between-group differences were seen for non-oblique items and these items were not associated with cognition. Conclusions:Significant impairment on oblique test items distinguished patients with multi-domain/dysexecutive MCI from non-MCI patients. Accurate responding to oblique test items was associated with a complex array of neuropsychological tests suggesting that multidimensional neuropsychological skills underlie the visuospatial reasoning abilities necessary for successful oblique line identification. Research associating responding to oblique versus non-oblique test stimuli using additional neuropsychological test paradigms, and MRI-defined neuroanatomical regions of interest may provide additional information about the brain-behavior relations that underlie MCI subtypes. [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]

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. [ABSTRACT FROM AUTHOR]

Objective Competitive Queuing (CQ) models of memory for serial order comprise two layers: parallel planning where target items are activated and competitive choice where serial order is specified. The application of CQ models regarding healthy and pathological aging has received little attention. Method Participants included patients with Alzheimer's disease (AD; n = 26), vascular dementia (VaD; n = 29), and healthy controls (HC; n = 35). Memory for serial order in the visual domain was assessed using the Object Span Task, where participants briefly viewed then drew a sequence of four figures. Percent correct and total errors (omissions, intrusions, repetitions, transpositions) were computed for each serial position. Results Significant primacy effects were detected in each group. AD and VaD participants were less accurate and showed more omission and between-trial repetition errors than HC (HC < AD = VaD, p <.05). VaD participants produced more transposition and intrusion errors than the AD and HC groups (HC < AD < VaD, p <.05). A group × position interaction was significant for omissions (p <.05), with AD and VaD participants producing more omissions in later serial positions (SP1 < SP2 < SP3 < SP4, all p values <.05). Conclusions Analysis of accuracy and errors by serial position identified unique patterns of performance across groups that suggest involvement of distinct layers of response activation and selection. Serial order difficulties in AD may be due to weakened activation of task items affecting later serial positions, whereas poor performance in VaD may be due to weakened activation plus interference from extraneous stimuli at all serial positions. [ABSTRACT FROM AUTHOR]

Background: Vascular health factors frequently co-occur with Alzheimer's disease (AD). A better understanding of how systemic vascular and cerebrovascular health intersects with clinical and pathological AD may inform prevention and treatment opportunities.Objective: To establish the Vanderbilt Memory & Aging Project, a case-control longitudinal study investigating vascular health and brain aging, and describe baseline methodology and participant characteristics.Methods: From September 2012 to November 2014, 335 participants age 60- 92 were enrolled, including 168 individuals with mild cognitive impairment (MCI, 73±8 years, 41% female) and 167 age-, sex-, and race-matched cognitively normal controls (NC, 72±7 years, 41% female). At baseline, participants completed a physical and frailty examination, fasting blood draw, neuropsychological assessment, echocardiogram, cardiac MRI, and brain MRI. A subset underwent 24-hour ambulatory blood pressure monitoring and lumbar puncture for cerebrospinal fluid (CSF) collection.Results: As designed, participant groups were comparable for age (p = 0.31), sex (p = 0.95), and race (p = 0.65). MCI participants had greater Framingham Stroke Risk Profile scores (p = 0.008), systolic blood pressure values (p = 0.008), and history of left ventricular hypertrophy (p = 0.04) than NC participants. As expected, MCI participants performed worse on all neuropsychological measures (p-values < 0.001), were more likely to be APOEɛ4 carriers (p = 0.02), and had enhanced CSF biomarkers, including lower Aβ42 (p = 0.02), higher total tau (p = 0.004), and higher p-tau (p = 0.02) compared to NC participants.Conclusion: Diverse sources of baseline and longitudinal data will provide rich opportunities to investigate pathways linking vascular and cerebrovascular health, clinical and pathological AD, and neurodegeneration contributing to novel strategies to delay or prevent cognitive decline. [ABSTRACT FROM AUTHOR]

Background: There is remarkable heterogeneity in clinical Alzheimer's disease (AD) or vascular dementia (VaD).Objectives: 1) To statistically examine neuropsychological data to determine dementia subgroups for individuals clinically diagnosed with AD or VaD and then 2) examine group differences in specific gray/white matter regions of interest.Methods: A k-means cluster analysis requested a 3-group solution from neuropsychological data acquired from individuals diagnosed clinically with AD/VaD. MRI measures of hippocampal, caudate, ventricular, subcortical lacunar infarction, whole brain volume, and leukoaraiosis (LA) were analyzed. Three regions of LA volumes were quantified and these included the periventricular (5 mm around the ventricles), infracortical (5 mm beneath the gray matter), and deep (between periventricular and infracortical) regions.Results: Cluster analysis sorted AD/VaD patients into single domain amnestic (n = 41), single-domain dysexecutive (n = 26), and multi-domain (n = 26) phenotypes. Multi-domain patients exhibited worst performance on language tests; however, multi-domain patients were equally impaired on memory tests when compared to amnestic patients. Statistically-determined groups dissociated using neuroradiological parameters: amnestic and multi-domain groups presented with smaller hippocampal volume while the dysexecutive group presented with greater deep, periventricular, and whole brain LA. Neither caudate nor lacunae volume differed by group. Caudate nucleus volume negatively correlated with total LA in the dysexecutive and multi-domain groups.Conclusions: There are at least three distinct subtypes embedded within patients diagnosed clinically with AD/VaD spectrum dementia. We encourage future research to assess a) the neuroradiological substrates underlying statistically-determined AD/VaD spectrum dementia and b) how statistical modeling can be integrated into existing diagnostic criteria. [ABSTRACT FROM AUTHOR]

Background: Epidemiologic autopsy studies show mixed Alzheimer's disease (AD)/vascular pathology in many patients. Moreover, clinical research shows that it is not uncommon for AD and vascular dementia (VaD) patients to be equally impaired on memory, executive, or other neurocognitive tests. However, this clinical heterogeneity has not been incorporated into the new diagnostic criteria for AD (Dubois et al., 2010; McKhann et al., 2011). Objective: The current research applied Latent Class Analysis (LCA) to a protocol of six neuropsychological parameters to identify phenotypic subtypes from a large group of AD/VaD participants. Follow-up analyses examined difference between groups on neuroradiological parameters and neuropsychological measures of process and errors. Methods: 223 AD/VaD patients were administered a comprehensive neuropsychological protocol. Measures of whole brain and hippocampal volume were available for a portion of the sample (n = 76). Results: LCA identified four distinct groups: moderate/mixed dementia (n = 54; 24.21%), mild/mixed dementia (n = 91; 40.80%); dysexecutive (n = 49, 21.97%), and amnestic (n = 29, 13.00%). Follow-up analyses comparing the groups on neuropsychological process and error scores showed that the dysexecutive group exhibited difficulty sustaining mental set. The moderate/mixed group evidenced pronounced impairment on tests of lexical retrieval/naming along with significant amnesia. Amnestic patients also presented with gross amnesia, but showed relative sparing on other neuropsychological measures. Mild/mixed patients exhibited milder memory deficits that were intermediary between the amnestic and moderate/mixed groups. Conclusions: There are distinct neuropsychological profiles in patients independent of clinical diagnosis, suggesting that the two are not wholly separate and that this information should be integrated into new AD diagnostic paradigms. [ABSTRACT FROM AUTHOR]

The history including some of the intellectual origins of the Boston Process Approach and some misconceptions about the Boston Process Approach are reviewed. The influence of Gestalt psychology and Edith Kaplan’s principal collaborators regarding the development of the Boston Process Approach is discussed. [ABSTRACT FROM AUTHOR]

Patients with the semantic variant of primary progressive aphasia, also known as semantic dementia, and Alzheimer's disease have deficits in semantic memory. However, few comparative studies have been performed to determine whether these patient groups have distinct semantic memory impairments. We asked 15 patients with semantic variant primary progressive aphasia and 57 patients with Alzheimer's disease to judge semantic category membership of coloured photos and printed words that are members of familiar natural and manufactured categories, and we related performance to grey matter atrophy. We found that both semantic variant primary progressive aphasia and Alzheimer's disease are significantly impaired on this task. Moreover, patients with semantic variant primary progressive aphasia had a significantly more prominent deficit for natural objects than their own deficit judging manufactured objects. Both semantic variant primary progressive aphasia and Alzheimer's disease had atrophy that included portions of the left temporal lobe. Regression analyses related performance in semantic variant primary progressive aphasia to ventral and medial portions of the left temporal lobe, while regression analyses in Alzheimer's disease related performance to these ventral and medial temporal areas as well as lateral temporal-parietal regions in the left hemisphere. We conclude that both semantic variant primary progressive aphasia and Alzheimer's disease are significantly impaired in a simple category membership judgement task and the selective impairment for natural kinds in semantic variant primary progressive aphasia is related in part to disease in visual association cortex in ventral-medial portions of the left temporal lobe. We discuss factors that may contribute to the semantic memory deficit in semantic variant primary progressive aphasia. [ABSTRACT FROM AUTHOR]

Given the importance of identifying dementia prodromes for future treatment efforts, we examined two methods of diagnosing mild cognitive impairment (MCI) and determined whether empirically-derived MCI subtypes of these diagnostic methods were consistent with one another as well as with conventional MCI subtypes (i.e., amnestic, non-amnestic, single-domain, multi-domain). Participants were diagnosed with MCI using either conventional Petersen/Winblad criteria (n = 134; >1.5 SDs below normal on one test within a cognitive domain) or comprehensive neuropsychological criteria developed by Jak et al. (2009) (n = 80; >1 SD below normal on two tests within a domain), and the resulting samples were examined via hierarchical cluster and discriminant function analyses. Results showed that neuropsychological profiles varied depending on the criteria used to define MCI. Both criteria revealed an Amnestic subtype, consistent with prodromal Alzheimer's disease (AD), and a Mixed subtype that may capture individuals in advanced stages of MCI. The comprehensive criteria uniquely yielded Dysexecutive and Visuospatial subtypes, whereas the conventional criteria produced a subtype that performed within normal limits, suggesting its susceptibility to false positive diagnostic errors. Whether these empirically-derived MCI subtypes correspond to dissociable neuropathologic substrates and represent reliable prodromes of dementia will require additional follow-up. (JINS, 2013, 19, 1–11) [ABSTRACT FROM PUBLISHER]

Objective Previous work investigating deficits in selfappraisal in behavioural-variant frontotemporal degeneration (bvFTD) has focused on a single domain: social/behavioural processes. We examined whether a domain-specific versus multi-domain model best explains degraded self-appraisal in bvFTD. Methods 49 patients with bvFTD and 73 patients with Alzheimer's disease (AD) were administered quantitative assessments of episodic memory, naming and grammatical comprehension. Self-appraisal of cognitive test performance was assessed by asking patients to rate their performance immediately after completing each neuropsychological test. A discrepancy score was created to reflect the difference between patient performance on neuropsychological tests and selfappraisal of their test performance. Self-appraisal for each neuropsychological measure was related to grey matter (GM) density in each group using voxel-based morphometry. Results bvFTD patients were poor at evaluating their own performance on all cognitive tests, with no significant correlations between self-appraisal and actual performance. By contrast, poor self-appraisal in AD was restricted to episodic memory performance. Poor selfappraisal on each task in bvFTD and AD was related to reduced GM density in several ventral and rostral medial prefrontal regions. Crucially, poor self-appraisal for all domains in bvFTD was related to a specific area of reduced GM density in the subgenual cingulate (BA 25). Conclusion Poor self-appraisal in bvFTD affects multiple domains, and this multi-domain impairment pattern is associated with frontal disease in the subgenual cingulate. [ABSTRACT FROM AUTHOR]

Memory tests are sensitive to early identification of Alzheimer's disease (AD) but less useful as the disease advances. However, assessing particular types of recognition memory may better characterize dementia severity in later stages of AD. We sought to examine patterns of recognition memory deficits in individuals with AD and mild cognitive impairment (MCI). Memory performance and global cognition data were collected from participants with AD (n = 37), MCI (n = 37), and cognitively intact older adults (normal controls, NC; n = 35). One-way analyses of variance (ANOVAs) examined differences between groups on yes/no and forced-choice recognition measures. Individuals with amnestic MCI performed worse than NC and nonamnestic MCI participants on yes/no recognition, but were comparable on forced-choice recognition. AD patients were more impaired across yes/no and forced-choice recognition tasks. Individuals with mild AD (≥120 Dementia Rating Scale, DRS) performed better than those with moderate-to-severe AD (<120 DRS) on forced-choice recognition, but were equally impaired on yes/no recognition. There were differences in the relationships between learning, recall, and recognition performance across groups. Although yes/no recognition testing may be sensitive to MCI, forced-choice procedures may provide utility in assessing severity of anterograde amnesia in later stages of AD. Implications for assessment of insufficient effort and malingering are also discussed. [ABSTRACT FROM AUTHOR]

Medial temporal lobe and temporoparietal brain regions are among the earliest neocortical sites to undergo pathophysiologic alterations in Alzheimer's disease (AD), although the underlying white matter changes in these regions is less well known. We employed diffusion tensor imaging to evaluate early alterations in regional white matter integrity in participants diagnosed with mild cognitive impairment (MCI). The following regions of interests (ROIs) were examined: 1) anterior cingulum (AC); 2) posterior cingulum (PC); 3) genu of the corpus callosum; 4) splenium of the corpus callosum; and 5) as a control site for comparison, posterior limb of the internal capsule. Forty nondemented participants were divided into demographically-similar groups based on cognitive status (MCI: n = 20; normal control: n = 20), and fractional anisotropy (FA) estimates of each ROI were obtained. MCI participants showed greater posterior white matter (i.e., PC, splenium) but not anterior white matter (i.e., AC, genu) changes, after adjusting for age, stroke risk, and whole brain volume. FA differences of the posterior white matter were best accounted for by changes in radial but not axial diffusivity. PC FA was also significantly positively correlated with hippocampal volume as well as with performance on tests of verbal memory, whereas stroke risk was significantly correlated with genu FA and was unrelated to PC FA. When investigating subtypes of our MCI population, amnestic MCI participants showed lower PC white matter integrity relative to those with non-amnestic MCI. Findings implicate involvement of posterior microstructural white matter degeneration in the development of MCI-related cognitive changes and suggest that reduced FA of the PC may be a candidate neuroimaging marker of AD risk. [ABSTRACT FROM AUTHOR]

Libon et al. (2010) provided evidence for three statistically determined clusters of patients with mild cognitive impairment (MCI): amnesic (aMCI), dysexecutive (dMCI), and mixed (mxMCI). The current study further examined dysexecutive impairment in MCI using the framework of Fuster's (1997) derailed temporal gradients, that is, declining performance on executive tests over time or test epoch. Temporal gradients were operationally defined by calculating the slope of aggregate letter fluency output across 15-s epochs and accuracy indices for initial, middle, and latter triads from the Wechsler Memory Scale-Mental Control subtest (Boston Revision). For letter fluency, slope was steeper for dMCI compared to aMCI and NC groups. Between-group Mental Control analyses for triad 1 revealed worse dMCI performance than NC participants. On triad 2, dMCI scored lower than aMCI and NCs; on triad 3, mxMCI performed worse versus NCs. Within-group Mental Control analyses yielded equal performance across all triads for aMCI and NC participants. mxMCI scored lower on triad 1 compared to triads 2 and 3. dMCI participants also performed worse on triad 1 compared to triads 2 and 3, but scored higher on triad 3 versus triad 2. These data suggest impaired temporal gradients may provide a useful heuristic for understanding dysexecutive impairment in MCI. (JINS, 2012, 18, 20–28) [ABSTRACT FROM PUBLISHER]

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. [ABSTRACT FROM PUBLISHER]

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. [ABSTRACT FROM AUTHOR]

A group of 94 nondemented patients self-referred to an outpatient memory clinic for memory difficulties were studied to determine the incidence of single versus multi-domain mild cognitive impairment (MCI) using Petersen criteria. Fifty-five community dwelling normal controls (NC) participants without memory complaints also were recruited. Tests assessing executive control, naming/lexical retrieval, and declarative memory were administered. Thirty-four patients exhibited single-domain MCI, 43 patients presented with multi-domain MCI. When the entire MCI sample ( n = 77) was subjected to a cluster analysis, 14 patients were classified with amnesic MCI, 21 patients with dysexecutive MCI, and 42 patients were classified into a mixed/multi-domain MCI group involving low scores on tests of letter fluency, "animal" fluency, and delayed recognition discriminability. Analyses comparing the three cluster-derived MCI groups versus a NC group confirmed the presence of memory and dysexecutive impairment for the amnesic and dysexecutive MCI groups. The mixed MCI group produced lower scores on tests of letter fluency compared with the amnesic MCI and NC groups and lower scores on tests of naming and memory compared with the NC group. In summary, multi-domain MCI is quite common. These data suggest that MCI is a highly nuanced and complex clinical entity. [ABSTRACT FROM AUTHOR]

Recent evidence suggests that patients with Alzheimer's disease (AD) and vascular comorbidities (VC) perform worse across measures of verbal reasoning and abstraction when compared to patients with AD alone. We performed a qualitative error analysis of Wechsler Adult Intelligence Scale-III Similarities zero-point responses in 45 AD patients with varying numbers of VC, including diabetes, hypertension, and hypercholesterolemia. Errors were scored in set if the answer was vaguely related to how the word pair was alike (e.g., dog-lion: "they can be trained") and out of set if the response was unrelated ("a lion can eat a dog"). AD patients with 2-3 VC did not differ on Similarities total score or qualitative errors from AD patients with 0-1 VC. When analyzing the group as a whole, we found that increasing numbers of VC were signifi cantly associated with increasing out of set errors and decreasing in set errors in AD. Of the vascular diseases investigated, it was only the severity of diastolic blood pressure that signifi cantly correlated with out of set responses. Understanding the contribution of VC to patterns of impairment in AD may provide support for directed patient and caregiver education concerning the presentation of a more severe pattern of cognitive impairment in affected individuals. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Aims: To evaluate the degree and pattern of functional difficulties in mild cognitive impairment (MCI) via direct observation of everyday task performance. Methods: MCI (n = 25), mild Alzheimer’s disease (AD; n = 25), and control (n = 18) participants performed three everyday tasks of increasing complexity. Results: Although caregivers reported no functional difficulties in MCI, direct observation measures of overall impairment and total errors showed MCI participants performed worse than controls, but better than AD participants, even on simple tasks. MCI and control participants exhibited significantly more difficulty performing steps accurately (i.e. commission errors) than completing task steps (i.e. omission errors), but AD participants showed an even distribution of commissions and omissions. Conclusions: Diagnostic criteria for MCI should specify mild functional deficits due to the inefficient and imprecise execution of task steps. Functional deficits characterized by omission of major task segments may indicate a diagnosis of dementia. Copyright © 2008 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

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. Copyright © 2007 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Abstract: 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. [Copyright &y& Elsevier]

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. Copyright © 2005 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Abstract: 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. [Copyright &y& Elsevier]

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. [ABSTRACT FROM AUTHOR]

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, WAJS-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 non- specific 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. [ABSTRACT FROM AUTHOR]

We investigated the different mechanisms that may underlie deficits in verbal concept formation among patients with Alzheimer's disease (AD) and ischaemic vascular dementia (IVD) associated with periventricular and deep white matter alterations. Concept formation was assessed with the WAIS-R Similarities subtest (SIM). Two types of errors were re-coded from the 0-point responses as scored by the WAIS-R manual. In set errors (e.g., dog–lion “they're alive”) were coded when patients reported a very vague superordinate concept for the word pair. Out of set responses (e.g., dog–lion “the lion roars and the dog barks”) were coded when a response was clearly out of mental set, i.e., when participants were unable to provide a superordinate concept for the word pair. Between-group comparisons demonstrated no difference in SIM test performance according to the scoring system described in the WAIS-R manual. Nonetheless, AD patients produced a greater proportion of in set errors, while IVD patients produced a greater proportion of out of set errors. Out of set errors were highly associated with measures of executive function, while in set errors were associated with measures related to delayed recognition memory and semantic intrusion errors. We conclude that the underlying deficits that contribute to poor concept formation differ between AD and IVD patients. In IVD impaired concept formation is related to deficits in the executive systems necessary to monitor responses and sustain mental set. In AD, by contrast, the deficit appears to be secondary to impaired verbal response selection. [ABSTRACT FROM PUBLISHER]

Background and Objective Prior research with patients with mild cognitive impairment (MCI) suggests that visual versus verbal episodic memory test performance may be more sensitive to emergent illness. However, little research has examined visual versus verbal episodic memory performance as related to MCI subtypes. Research Design and Methods Patients were diagnosed with non-MCI, amnestic MCI (aMCI), and combined mixed/dysexecutive MCI (mixed/dys MCI). Visual and verbal episodic memory were assessed with the Brief Visuospatial Memory Test-Revised (BVMT-R) and the 12-word Philadelphia (repeatable) Verbal Learning Test (P[r]VLT), respectively. Results BVMT-R and P(r)VLT scores yielded similar between-group patterns of performance. Non-MCI patients scored better than other groups on all parameters. aMCI and mixed/dys MCI did not differ on immediate or delayed free recall. Both delayed BVMT-R and P(r)VLT recognition test performance dissociated all three groups. Logistic regression analyses found that BVMT-R delayed free recall and delayed recognition scores correctly classified more patients with MCI (75.40%) than analogous P(r)VLT scores (66.20%). Visual versus verbal memory within-group analyses found no differences among non-MCI patients; P(r)VLT immediate free recall was worse among aMCI patients, but BVMT-R immediate free recall and delayed recognition were worse among mixed/dys MCI patients. Discussion and Implications Between-group analyses found convergent patterns of performance such that both tests identified elements of amnesia. However, logistic and within-group analyses found differing performance patterns suggesting that impaired visual episodic memory performance may be specific to emergent illness in mixed/dys MCI. Complementary but divergent neurocognitive networks may underlie visual versus verbal episodic memory performance in some patients with MCI. [ABSTRACT FROM AUTHOR]

Abstract: 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. [Copyright &y& Elsevier]