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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.

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.

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.

We examined the construct of mental planning by quantifying digital clock drawing digit placement accuracy in command and copy conditions, and by investigating its underlying neuropsychological correlates and functional connectivity. We hypothesized greater digit misplacement would associate with attention, abstract reasoning, and visuospatial function, as well as functional connectivity from a major source of acetylcholine throughout the brain: the basal nucleus of Meynert (BNM). Participants (n = 201) included non-demented older adults who completed all metrics within 24 h of one another. A participant subset met research criteria for mild cognitive impairment (MCI; n = 28) and was compared to non-MCI participants on digit misplacement accuracy and expected functional connectivity differences. Digit misplacement and a comparison dissociate variable of total completion time were acquired for command and copy conditions. a priori fMRI seeds were the bilateral BNM. Command digit misplacement is negatively associated with semantics, visuospatial, visuoconstructional, and reasoning (p's < 0.01) and negatively associated with connectivity from the BNM to the anterior cingulate cortex (ACC; p = 0.001). Individuals with MCI had more misplacement and less BNM-ACC connectivity (p = 0.007). Total completion time involved posterior and cerebellar associations only. Findings suggest clock drawing digit placement accuracy may be a unique metric of mental planning and provide insight into neurodegenerative disease. [ABSTRACT FROM AUTHOR]

Technology has transformed the science and practice of medicine. In this special mini-forum, data using digital neuropsychological technology are reported. All of these papers demonstrate how coupling digital technology with standard paper and pencil neuropsychological tests are able to extract behavior not otherwise obtainable. As digital assessment methods mature, early identification of persons with emergent neurodegenerative and other neurological illness may be possible. [ABSTRACT FROM AUTHOR]

Background: A digital version of the clock drawing test (dCDT) provides new latency and graphomotor behavioral measurements. These variables have yet to be validated with external neuropsychological domains in non-demented adults. Objective: The current investigation reports on cognitive constructs associated with selected dCDT latency and graphomotor variables and compares performances between individuals with mild cognitive impairment (MCI) and non-MCI peers. Methods: 202 non-demented older adults (age 68.79 ± 6.18, 46% female, education years 16.02 ± 2.70) completed the dCDT and a comprehensive neuropsychological protocol. dCDT variables of interest included: total completion time (TCT), pre-first hand latency (PFHL), post-clock face latency (PCFL), and clock face area (CFA). We also explored variables of percent time drawing (i.e., 'ink time') versus percent time not drawing (i.e., 'think time'). Neuropsychological domains of interest included processing speed, working memory, language, and declarative memory. Results: Adjusting for age and premorbid cognitive reserve metrics, command TCT positively correlated with multiple cognitive domains; PFHL and PCFL negatively associated with worse performance on working memory and processing speed tests. For Copy, TCT, PCFL, and PFHL negatively correlated with processing speed, and CFA negatively correlated with language. Between-group analyses show MCI participants generated slower command TCT, produced smaller CFA, and required more command 'think' (% Think) than 'ink' (% Ink) time. Conclusion: Command dCDT variables of interest were primarily processing speed and working memory dependent. MCI participants showed dCDT differences relative to non-MCI peers, suggesting the dCDT may assist with classification. Results document cognitive construct validation to digital metrics of clock drawing. [ABSTRACT FROM AUTHOR]

A cognitive assessment strategy that is not limited to examining a set of summary test scores may be more helpful for early detection of emergent illness such as Alzheimer's disease (AD) and may permit a better understanding of cognitive functions and dysfunctions in those with AD and other dementia disorders. A revisit of the work already undertaken by Kaplan and colleagues using the Boston Process-Approach provides a solid basis for identifying new opportunities to capture data on neurocognitive processes, test-taking strategies and response styles. Thus, this critical review will combine traditional process-based assessment strategies with support provided or offered by newer technologies that have the potential to add value to data collection and interpretation. There is now considerable interest in neuropsychological test administration using computer/digital technology, both in research and in clinical settings. To add value, any computerized version of an existing cognitive test should respect the administration procedure for which normative data were obtained, should be time-saving in terms of scoring and interpretation, and should, we argue, facilitate gathering information about the processes and strategies followed in test completion. This article will offer an overview of the steps needed when implementing computerization of neuropsychological tests using a Process-Based Approach (PBA) to these technology-based adaptations and will discuss further developments in this area by linking it to future technological developments that may be possible in the area of neuropsychological assessment. Additionally, an overview of neuropsychological tests that may benefit from computerization will be presented, together with suggestions on the specific processes, strategies and features that may be captured with the aid of such computerization. Finally, hypotheses on how virtual reality could be an asset for the future of the PBA to neuropsychological assessment will also be discussed. [ABSTRACT FROM AUTHOR]

Evolutionary divergence of the mitochondrial genome has given rise to distinct haplogroups. These haplogroups have arisen in specific geographical locations and are responsible for subtle functional changes in the mitochondria that may provide an evolutionary advantage in a given environment. Based on these functional differences, haplogroups could define disease susceptibility in chronic settings. In this study, we undertook a detailed neuropsychological analysis of a cohort of long-term HIV-1-infected individuals in conjunction with sequencing of their mitochondrial genomes. Stepwise regression analysis showed that the best model for predicting both working memory and declarative memory were age and years since diagnosis. In contrast, years since diagnosis and sub-haplogroup were significantly predictive of psychomotor speed. Consistent with this, patients with haplogroup L3e obtained better scores on psychomotor speed and dexterity tasks when compared to the remainder of the cohort, suggesting that this haplogroup provides a protective advantage when faced with the combined stress of HIV-1 infection and long-term antiretroviral therapies. Differential performance on declarative memory tasks was noted for individuals with other sub-L haplogroups, but these differences were not as robust as the association between L3e and psychomotor speed and dexterity tasks. This work provides evidence that mitochondrial haplogroup is related to neuropsychological test performance among patients in chronic disease settings such as HIV-1 infection. [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]

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]

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]

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]

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) [ABSTRACT FROM PUBLISHER]

This study examined whether distinct neuropsychological profiles could be delineated in a sample with Mild Cognitive Impairment (MCI) and whether white matter lesion (WML) burden contributed to MCI group differences. A heterogeneous, clinical sample of 70 older adults diagnosed with MCI was assessed using cognitive scores, and WML was quantified using a semi-automated, volumetric approach on T2-weighted fluid-attenuated inversion recovery (FLAIR) images. Using cluster and discriminant analyses, three distinct groups (Memory/Language, Executive/Processing Speed, and Pure Memory ) were empirically derived based on cognitive scores. Results also showed a dose dependent relationship of WML burden to MCI subgroup, with the Executive/Processing Speed subgroup demonstrating significantly higher levels of WML pathology when compared to the other subgroups. In addition, there was a dissociation of lesion type by the two most impaired subgroups (Memory/Language and Executive/Processing Speed) such that the Memory/ Language subgroup showed higher periventricular lesion (PVL) and lower deep white matter lesion (DWML) volumes, whereas the Executive/Processing Speed demonstrated higher DWML and lower PVL volumes. Results demonstrate that distinct MCI subgroups can be empirically derived and reliably differentiated from a heterogeneous MCI sample, and that these profiles differ according to WML burden. Overall, findings suggest different underlying pathologies within MCI and contribute to our understanding of MCI subtypes. [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]

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]

Vascular dementia (VaD) is a heterogeneous term that has evolved to describe the behavioral syndromes associated with a variety of clinical and neuropathologic changes. As such, the VaD literature lacks a clear consensus regarding the neuropsychological and other constituent characteristics associated with various cerebrovascular changes. We address the issues articulated by Paul and colleagues (Paul, Garrett,&Cohen, 2003), by offering four recommendations to refine the clinical assessment and diagnostic decision-making process of individuals with suspected cerebrovascular changes: (a) Describing the nature of vascular changes may facilitate predictions regarding the neuropsychological profile of subtypes of VaD; (b) employ a process approach to assessment, measuring cognitive constructs in addition to test scores to describe the neuropsychological profiles of types of VaD; (c) integrate direct MRI observations of the brain and other collateral data in the diagnostic process; and (d) consider using"vascular cognitive impairment, no dementia"for suspected prodromal VaD. [ABSTRACT FROM AUTHOR]

Naturalistic actions are everyday tasks (e.g. cooking) that require one to use multiple objects and sequence steps to achieve a goal. Naturalistic action impairment has been attributed to executive dysfunction [Higher cortical functions in man. New York: Basic Books, 1966], semantic knowledge degradation [Brain 111 (1988) 1173], and, more recently, general limitations in cognitive resources [Neuropsychology 12 (1998) 13]. Action impairments were explored in 51 dementia participants with the short form of the multi-level action test (MLAT-S). A clinical neuropsychological test protocol was also administered. Regression analyses including measures of executive functioning, semantic knowledge, and global cognitive functioning showed that global cognitive functioning was the best predictor of MLAT-S errors. Furthermore, task demands significantly influenced the type and frequency of errors, and dementia participants showed a pattern of errors similar to that reported in other clinical populations [Cognitive Neuropsychology 15 (1998) 617; Neuropsychologia 37 (1999) 51; Neuropsychology 12 (1998) 13]. Taken together, the present findings are inconsistent with semantic and executive accounts, but support the limited-capacity resource theory of naturalistic action impairment. [Copyright &y& Elsevier]

Background: When performing the clock-drawing test healthy participants often draw the clock face using a counter clockwise movement. The reason for this circular directional bias is not known. These actions may be related to the development of motor or attentional programs that associate leftward with downward movements, and rightward with upward movements.Methods: To further examine this down-left, up-right programming hypothesis, we examined the direction of circular movements made during cursive writing by dividing the first curved movements into the following pairs, up versus down, and leftward versus rightward.Results and Conclusions: With almost all the letters analyzed, when initially moving upward there was a simultaneous rightward movement and when initially moving downward a leftward movement. The results suggest that there appears to be a relationship between downward and leftward movements as well as between upward and right rightward movements. In addition, there is some evidence to suggest that the right-upward movements may be mediated by the left hemisphere and left-downward movements by the right hemisphere. Although our results suggest motor or spatial attentional programs may account for counter clockwise face drawing, activities such as learned writing direction may influence this spatial bias. Therefore, additional research is needed to better understand if these spatial biases are learned or intrinsic and the neuropsychological mechanisms that might account for these asymmetries. [ABSTRACT FROM AUTHOR]

Graphomotor and time-based variables from the digital Clock Drawing Test (dCDT) characterize cognitive functions. However, no prior publications have quantified the strength of the associations between digital clock variables as they are produced. We hypothesized that analysis of the production of clock features and their interrelationships, as suggested, will differ between the command and copy test conditions. Older adults aged 65+ completed a digital clock drawing to command and copy conditions. Using a Bayesian hill-climbing algorithm and bootstrapping (10,000 samples), we derived directed acyclic graphs (DAGs) to examine network structure for command and copy dCDT variables. Although the command condition showed moderate associations between variables ( μ | β z | = 0.34) relative to the copy condition ( μ | β z | = 0.25), the copy condition network had more connections (18/18 versus 15/18 command). Network connectivity across command and copy was most influenced by five of the 18 variables. The direction of dependencies followed the order of instructions better in the command condition network. Digitally acquired clock variables relate to one another but differ in network structure when derived from command or copy conditions. Continued analyses of clock drawing production should improve understanding of quintessential normal features to aid in early neurodegenerative disease detection. [ABSTRACT FROM AUTHOR]