Digital Clock Drawing as an Alzheimer's Disease Susceptibility Biomarker: Associations with Genetic Risk Score and APOE in Older Adults.

BACKGROUND: Alzheimer's disease (AD) is the leading cause of dementia in older adults, but most people are not diagnosed until significant neuronal loss has likely occurred along with a decline in cognition. Non-invasive and cost-effective digital biomarkers for AD have the potential to improve early detection. OBJECTIVE: We examined the validity of DCTclockTM (a digitized clock drawing task) as an AD susceptibility biomarker. DESIGN: We used two primary independent variables, Apolipoprotein E (APOE) ε4 allele carrier status and polygenic risk score (PRS). We examined APOE and PRS associations with DCTclockTM composite scores as dependent measures. SETTING: We used existing data from the Framingham Heart Study (FHS), a community-based study with the largest dataset of digital clock drawing data to date. PARTICIPANTS: The sample consisted of 2,398 older adults ages 60-94 with DCTclockTM data (mean age of 72.3, 55% female and 92% White). MEASUREMENTS: PRS was calculated using 38 variants identified in a recent large genome-wide association study (GWAS) and meta-analysis of late-onset AD (LOAD). RESULTS: Results showed that DCTclockTM performance decreased with advancing age, lower education, and the presence of one or more copies of APOE ε4. Lower DCTclockTM Total Score as well as lower composite scores for Information Processing Speed (both command and copy conditions) and Drawing Efficiency (command condition) were significantly associated with higher PRS levels and more copies of APOE ε4. APOE and PRS associations displayed similar effect sizes in both men and women. CONCLUSIONS: Our results indicate that higher AD genetic risk is associated with poorer DCTclockTM performance in older adults without dementia. This is the first study to demonstrate significant differences in clock drawing performance on the basis of APOE status or PRS.

Impairment in category fluency in ischemic vascular dementia.

The underlying mechanisms for impaired output on letter (F, A, and S) and category (e.g., animal) word list generation (WLG) tasks in subcortical ischemic vascular dementia (IVD) were investigated. Normal control (NC) and Alzheimer's disease (AD) participants were also studied. IVD and NC participants performed better on category than letter WLG tasks, whereas the opposite was observed among AD participants. IVD participants produced fewer responses than AD participants on letter WLG tasks, but there was no difference between AD and IVD participants on the "animal" WLG task. AD participants scored lower than IVD and NC participants on animal WLG indexes measuring semantic knowledge. There were few differences between IVD and NC participants. The reduced output on the animal WLG task for IVD participants is consistent with search-retrieval deficits. The reduced output of AD participants may be caused by degraded semantic knowledge.

Visuoconstructional problems in dementia: contribution of executive systems functions.

Visuoconstructional ability was assessed by asking patients diagnosed with Alzheimer's disease (AD), ischaemic vascular dementia (IVD), and Parkinson's disease (PD) and a normal control group (NC) to copy a modification of the Rey-Osterrieth Complex Figure (M-ROCF). The drawings of the NC group were superior to all dementia participants. AD patients generally outperformed IVD and PD patients; however, there were few differences between IVD and PD groups. Nonetheless, the drawings of IVD and PD patients were very fragmented and contained numerous perseverations and omissions. Despite these errors, patients with IVD and PD obtained higher delayed recognition memory scores than AD patients. Correlational analyses among dementia patients between neuropsychological tests and the copy of the M-ROCF found that accurate figure copy was most consistently correlated with tests of working memory, that is, tests requiring patients to monitor their behavior and sustain a complex mental set while performing mental manipulations. By contrast, no relationship between executive function tests related to measures of response selection/inhibition or other domains of neuropsychological functioning was found.

Perseverative behavior in Alzheimer's disease and subcortical ischemic vascular dementia.

Perseverative behavior has not been extensively studied in patients with dementia. In this study, perseverative behavior was elicited with the dementia version of the Graphical Sequence Test. A control group and participants with Alzheimer's disease (AD) and subcortical ischemic vascular dementia (IVD) were studied. A factor analysis revealed a 3-factor model consisting of perseverations related to semantic knowledge, motor functioning, and a third, intermediary factor. IVD participants made more total perseverations than did AD participants. Perseverations made by AD participants were correlated with deficits on tests of semantic knowledge, whereas the perseverations made by IVD participants were correlated with motor and frontal systems tests. Results are consistent with the view that perseverative behavior is hierarchically arranged in terms of specific levels of cognitive complexity and the overall pattern of cognitive deficits associated with each type of dementia.

Binswanger's disease: some neuropsychological considerations.

The literature regarding Binswanger's disease is reviewed. Emphasis is placed on reviewing the neuropsychological literature related to Binswanger's disease. In addition, a retrospective analysis was carried out among four groups of subjects (N = 61) who were divided according to the presence or absence of dementia and deep white-matter alterations. A main effect for deep white-matter alterations was found for almost all measures of diastolic and systolic blood pressure. Among the two nondemented groups there was an effect of deep white matter alteration on neuropsychological functioning. Subjects with deep white matter changes performed worse on tests of immediate and delayed recall of a prose passage. Among the two demented groups there were no differences on any of the neuropsychological measures, although subjects with deep white matter alterations exhibited a higher incidence of focal neurologic signs and stroke. We conclude that Binswanger's disease is probably more prevalent than currently appreciated. Also, among clinically nondemented individuals periventricular white-matter alterations may be associated with subtle but definable neuropsychological deficits, and these individuals may be at risk for developing a dementing illness.

A case of late-onset psychosis: integrating neuropsychological and SPECT data.

We report the case of a 67-year-old woman who experienced a sudden onset of psychotic illness (i.e., prominent delusions and hallucinations) that has endured for approximately 3 years. As part of her neurobehavioral work-up, a SPECT scan revealed right frontal and left anterior temporal-lobe hypoperfusion. Serial neuropsychological evaluations obtained 2 years apart demonstrated a steady decline on tests of executive control (monitoring, allocation of attention, perseveration) and visuospatial abilities, whereas performance in other areas of cognitive functioning have remained steady and in the normal range for the patient's age. Over this same period of time, serial EEG, MRI, and neurology examinations have been within normal limits. Thus, there was little evidence with which to diagnose dementia. It is suggested that concomitant impairment in executive control, coupled with a degraded capacity to process perceptual information, can give rise to enduring psychotic behavior.

Clock drawing as an assessment tool for dementia.

Clock drawing has recently been shown to lie useful in differentiating Alzieimer's disease patients from normal controls. Our procedure for clock drawing differed from other published reports in that a copy condition was employed and patients were asked to set clock hands to read "ten after eleven". We found both clock drawing procedures to be correlated with tests related to executive and visuospatial functioning. In both conditions, nondemented controls performed significantly better than demented patients. In the command condition there was no difference between Alzheimer patients and patients with cerebrovascular dementia. In the copy condition, patients with cerebrovascular dementia performed significantly worse than Alzheimer patients. The inclusion of a copy condition appears to greatly expand the utility of this test. Although our scoring system did not differentiate between various dementing disorders in the command condition, if clock drawing is used as a screening instrument, lack of improvement in the copy condition in comparison to the command condition may be a sign of a vascular involvement.

Further analyses of clock drawings among demented and nondemented older subjects.

In a previous article we described a 10-point scoring system (i.e., scale 1) to grade clock drawings to command and copy with hands set for "ten after 11" among demented patients. Alzheimer's subjects (AD) improved from the command to copy conditions, whereas subjects with ischaemic vascular dementia (IVD) did not. To investigate the underlying cognitive deficits responsible for this profile, an additional scale was developed (scale 2) that tallied errors in graphomotor functioning, hand/number placement, and executive control. On an independent sample of subjects, AD subjects, again, made significant improvement on scale 1 from the command to copy condition, whereas no such improvement occurred among the IVD subjects. On scale 2, IVD subjects made more graphomotor errors in the command condition, and more executive control and more total errors in the copy conditions than AD subjects. A number of positive correlations were noted between tests of language and memory on scale 1. By contrast, scores on tests of executive control declined as scale 2 errors increased. In addition, a principal component analysis indicated that scale 2 test performance loaded on a factor with other tests related to executive control. These results suggest that impairment in frontal systems functioning may explain why IVD subjects do not improve from the command to copy conditions on scale 1. Such a pattern of performance in clock drawing may also be helpful in making a differential diagnosis between AD and IVD.

Different underlying mechanisms for deficits in concept formation in dementia.

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.

Dementia associated with periventricular and deep white matter alterations: a subtype of subcortical dementia.

This research examined the neuropsychological functioning of demented patients with periventricular and deep white matter alterations. Thirty-three outpatients with NINCDS-ADRDA probable Alzheimer's disease (AD) and 27 outpatients with probable/ possible ischaemic vascular dementia (IVD, Chui et al., 1992) associated with periventricular and deep white matter alterations matched for age, education, level of dementia, and functional disability were studied. White matter alterations were measured using a 40-point scale previously described by Junque et al. (1990). Subjects with cortical CVAs were excluded. On executive control tests, IVD subjects made more preservations on tests of mental control and response set, and produced fewer responses on phonemic controlled oral word association tests (letters: F,A,S). IVD subjects also made more preservations and graphomotor errors on clock drawings. On the California Verbal Learning Test the IVD group performed better than AD subjects on the short delay free recall test condition, the recognition discriminability index, and made fewer intrusion errors on both free and cued recall conditions. We conclude that neuropsychological assessment can differentiate AD from IVD associated with white matter alterations, and that the neuropsychological profile of demented subjects with significant periventricular and deep white matter alterations is similar to other subcortical dementing illnesses.

Neuropsychological profiles associated with subcortical white matter alterations and Parkinson's disease: implications for the diagnosis of dementia.

Despite the emergence of a number of new classification systems, the diagnosis of cerebrovascular dementia remains controversial. Also controversial is the significance of periventricular and deep white matter alterations (WMA) as seen on magnetic resonance imaging (MRI). To further clarify this issue, MRI scans were used to regroup patients clinically diagnosed with Alzheimer's disease (AD) or subcortical ischemic vascular dementia (IVD) into cohorts presenting with either little versus significant WMA on MRI. These two groups were then compared to demented patients diagnosed with idiopathic Parkinson's disease (PD) using a comprehensive neuropsychological protocol. Neuropsychological assessment failed to distinguish between patients with PD and significant WMA. By contrast, both of these patient groups exhibited disproportionate impairment on tests of executive systems functioning, whereas patients with little WMA showed greater impairment on tests of declarative memory and semantic knowledge. These findings constitute further evidence that the pattern of cognitive impairment associated with significant WMA is distinctly different when compared to AD. These results are discussed within the context of a growing body of literature suggesting that elements of the underlying neuropathologies in AD and IVD are linked. Implications for the diagnosis of dementia are also discussed.

The effect of maternal smoking during pregnancy on sleep respiratory and arousal patterns in neonates.

Ten term infants who were exposed to maternal smoking during pregnancy and 10 age- and sex-matched control infants participated in the study. At the age of 48 hours (+/- 10), all infants underwent a 150- to 200-minute polygraphic study in a soundproof laboratory. Respiratory and heart rates, distribution of sleep states, and oxygen saturation were comparable in the two groups. The number and length of apneic events were similarly distributed in the two groups. The proportion of obstructive apneic events followed by arousal was significantly higher in the control group especially during quiet sleep (p = 0.001). It appears that exposure to smoking during pregnancy is associated with a higher arousal threshold in term infants. This finding could be of relevance in the assessment of maternal smoking as a risk factor for sudden infant death syndrome.

Neuroimaging correlates of everyday action in dementia.

The everyday, functional impairments associated with dementia remain poorly understood from a neuropsychological perspective. This study investigated relations between brain structure volumes and two measures of everyday action-caregiver questionnaire and direct assessment-in 57 participants with dementia. Results showed that caregiver ratings reflecting more functional impairment were strongly associated with smaller volumes of deep white matter. Direct assessment of everyday task performance in a subsample revealed relations between unique neurological substrates and discrete everyday action error types. Findings emphasize differences in functional assessment methods and highlight the role of white matter in functional deficits in dementia.

White matter imaging contributes to the multimodal diagnosis of frontotemporal lobar degeneration.

OBJECTIVE: To evaluate the distribution of white matter (WM) disease in frontotemporal lobar degeneration (FTLD) and Alzheimer disease (AD) and to evaluate the relative usefulness of WM and gray matter (GM) for distinguishing these conditions in vivo. METHODS: Patients were classified as having FTLD (n = 50) or AD (n = 42) using autopsy-validated CSF values of total-tau:ß-amyloid (t-tau:Aß(1-42)) ratios. Patients underwent WM diffusion tensor imaging (DTI) and volumetric MRI of GM. We employed tract-specific analyses of WM fractional anisotropy (FA) and whole-brain GM density analyses. Individual patient classification was performed using receiver operator characteristic (ROC) curves with FA, GM, and a combination of the 2 modalities. RESULTS: Regional FA and GM were significantly reduced in FTLD and AD relative to healthy seniors. Direct comparisons revealed significantly reduced FA in the corpus callosum in FTLD relative to AD. GM analyses revealed reductions in anterior temporal cortex for FTLD relative to AD, and in posterior cingulate and precuneus for AD relative to FTLD. ROC curves revealed that a multimodal combination of WM and GM provide optimal classification (area under the curve = 0.938), with 87% sensitivity and 83% specificity. CONCLUSIONS: FTLD and AD have significant WM and GM defects. A combination of DTI and volumetric MRI modalities provides a quantitative method for distinguishing FTLD and AD in vivo.

Multimodal predictors for Alzheimer disease in nonfluent primary progressive aphasia.

OBJECTIVE: Alzheimer disease (AD) and frontotemporal lobar degeneration (FTLD) are hypothesized to cause clinically distinct forms of primary progressive aphasia (PPA) that predominantly affect expressive speech. AD is thought to cause logopenic progressive aphasia (LPA), and FTLD may cause progressive nonfluent aphasia (PNFA). We sought to determine the value of clinical characterization, neuropsychological analysis, and MRI atrophy in predicting pathology of LPA and PNFA. METHODS: Patients with LPA (n = 19) and patients with PNFA (n = 19) were evaluated with neuropsychological assessments, structural MRI, CSF analysis, and neuropathologic examination. RESULTS: Twelve of 19 patients with LPA (63%) and 6 of 19 patients with PNFA (32%) had neuropathologic findings or CSF biomarkers consistent with AD. Neuropsychological testing showed that naming was more impaired in patients with AD, and letter-guided fluency was more affected in patients with a non-AD disorder. Voxel-based morphometry analysis revealed that in patients with AD, patients with LPA and PNFA had significant posterior-superior temporal atrophy; in patients with non-AD, patients with LPA had peri-Sylvian atrophy and patients with PNFA had dorsolateral prefrontal and insular atrophy. Receiver operator characteristic curve analysis showed that combining neuropsychological testing with MRI atrophy pattern had 90% specificity for pathology or CSF biomarkers consistent with AD, and combining clinical features with neuropsychological analysis had 100% sensitivity for pathology or CSF biomarkers consistent with AD. CONCLUSIONS: Neither PPA phenotyping nor imaging alone is a reliable predictor of pathology. Multimodal predictors, such as combining neuropsychological testing with MRI analysis, can improve noninvasive prediction of underlying pathology in nonfluent forms of PPA.

Neurocognitive contributions to verbal fluency deficits in frontotemporal lobar degeneration.

OBJECTIVE: To test the hypothesis that different neurocognitive networks underlie verbal fluency deficits in frontotemporal lobar degeneration (FTLD). METHODS: Letter ("FAS") and semantic ("animal") fluency tests were administered to patients with a behavioral/dysexecutive disorder (bvFTLD; n = 71), semantic dementia (SemD; n = 21), and progressive nonfluent aphasia (PNFA; n = 26). Tests measuring working memory, naming/lexical retrieval, and semantic knowledge were also obtained. MRI voxel-based morphometry (VBM) studies were obtained on a subset of these patients (bvFTLD, n = 51; PNFA, n = 11; SemD, n = 10). RESULTS: Patients with SemD were disproportionately impaired on the semantic fluency measure. Reduced output on this test was correlated with impaired performance on naming/lexical retrieval tests. VBM analyses related reduced letter and semantic fluency to anterior and inferior left temporal lobe atrophy. Patients with bvFTLD were equally impaired on both fluency tests. Poor performance on both fluency tests was correlated with low scores on working memory and naming/lexical retrieval measures. In this group, MRI-VBM analyses related letter fluency to bilateral frontal atrophy and semantic fluency to left frontal/temporal atrophy. Patients with PNFA were also equally impaired on fluency tests. Reduced semantic fluency output was correlated with reduced performance on naming/lexical retrieval tests. MRI-VBM analyses related semantic fluency to the right frontal lobe and letter fluency to left temporal atrophy. CONCLUSIONS: Distinct neurocognitive networks underlie impaired performance on letter and semantic fluency tests in frontotemporal lobar degeneration subgroups.

Longitudinal decline in autopsy-defined frontotemporal lobar degeneration.

BACKGROUND: The natural history of patients with pathologically proven frontotemporal lobar degeneration (FTLD) is important from clinical and biologic perspectives, but is not well documented quantitatively. METHODS: We examine longitudinal decline in cognitive functioning in an autopsy-proven cohort of patients with the clinical diagnosis of a FTLD spectrum disorder or FTLD pathology using a panel of neuropsychological measures. Patients are categorized according to findings at autopsy into tau-positive FTLD, tau-negative FTLD, and frontal variant-Alzheimer disease (fvAD) subgroups. RESULTS: Patients decline significantly over time on all neuropsychological measures. Moreover, several measures differentiate between histopathologically distinct subgroups throughout the course of the disease process. This includes a significant double dissociation involving relative difficulty on a visual constructional measure in tau-positive patients compared to relatively impaired visual confrontation naming in tau-negative patients. Longitudinal measures of FAS naming fluency and animal naming fluency also distinguish tau-positive patients and tau-negative patients with FTLD from patients with fvAD. Other measures show significant decline but do not distinguish between histopathologic groups longitudinally. CONCLUSION: Our findings suggest different longitudinal patterns of cognitive decline in pathologically defined subgroups of patients. Measures consistently distinguishing between patient subgroups can be used to bolster diagnostic accuracy throughout the course of these diseases, while measures demonstrating undifferentiated longitudinal decline may serve as useful endpoints in treatment trials.

Patterns of neuropsychological impairment in frontotemporal dementia.

OBJECTIVE: To differentiate frontotemporal dementia (FTD) subtypes from each other and from probable Alzheimer disease (AD) using neuropsychological tests. METHODS: Patients with FTD and AD (n = 109) were studied with a comprehensive neuropsychological protocol at first contact. Data were subjected to a principal components analysis (PCA) to extract core neuropsychological features. A five-factor solution accounted for 72.89% of the variance and yielded factors related to declarative memory, working memory/visuoconstruction, processing speed/mental flexibility, lexical retrieval, and semantic memory. RESULTS: Between- and within-group analyses revealed that patients with AD obtain their lowest scores on tests of declarative memory while semantic dementia (SemD) patients are particularly disadvantaged on tests of semantic memory. On tests of processing speed/mental flexibility time to completion was faster for social comportment/dysexecutive (SOC/EXEC) patients, but these patients made more errors on some tests. Patients with corticobasal degeneration (CBD) and progressive nonfluent aphasia (PNFA) were impaired on tests of working memory. Logistic regression analyses using factor scores successfully assigned FTD subgroups and AD patients into their respective diagnostic categories. CONCLUSION: Patients with differing frontotemporal dementia phenotypes can be distinguished from each other and from Alzheimer disease using neuropsychological tests.

Subcortical vascular dementia: integrating neuropsychological and neuroradiologic data.

BACKGROUND: Research criteria for subcortical vascular dementia are based on radiologic evidence of vascular pathology and greater impairment on tests of executive control than memory. The relationship(s) between neuroradiological evidence of subcortical vascular disease and neuropsychological impairments has not been specified. OBJECTIVE: To define these research criteria, the authors rated the severity of MRI white matter abnormalities (WMAs) and neuropsychological data from patients with dementia. METHODS: Sixty-nine outpatients who met the criteria for dementia were studied with neuropsychological tests that assessed executive (mental) control, declarative memory, visuoconstruction (clock drawing), and language (semantic category fluency). MRI-WMAs were rated using a leukoaraiosis (LA) scale (range 0 to 40). RESULTS: First, regression analyses demonstrated that neuropsychological measures accounted for 60.7% of the variance in WMA severity (47.3% of this variance attributable to executive/visuoconstructive test performance, 13.4% attributable to memory/language test performance). Second, patients were grouped according to the severity of WMAs (i.e., low, moderate, and severe white matter groups). Only patients with mild WMA (mean LA = 3.61 +/- 2.63, approximately 2.4 to 15.6% of the subcortical white matter) presented with greater impairment on memory/language tests vs executive control/visuoconstructive tests, a neuropsychological profile typically associated with Alzheimer disease. Patients with moderate WMA (mean LA = 12.76 +/- 2.49, approximately 25.6 to 38.1% of the subcortical white matter) presented with equal impairment on executive/visuoconstructional vs memory/language tests. Patients with severe WMA (mean LA = 21.76 +/- 2.97, approximately 46.9 to 62.4% of the subcortical white matter) displayed a profile of greater executive/visuoconstructional impairment relative to memory/language disabilities. CONCLUSION: A profile of equal impairment on tests of executive control and memory along with radiologic evidence involving about one-fourth of the cerebral white matter as measured by the Leukoaraiosis Scale may be sufficient for a diagnosis of subcortical vascular dementia.

Neuropsychological functioning in treated phenylketonuria.

Comprehensive neuropsychological assessment was performed on a series of patients with treated classical phenylketonuria. All patients showed a similar cluster of performance deficits in motor and visual-motor functions, spatial operations, academic skill areas, and select areas of higher level reasoning. The results are consistent with other neuropsychological studies of patients with early and late diet termination that have used differing assessment methods, thus allowing for greater confidence in the findings. Examination of underlying factors indicates that poor motor coordination, limits in the complexity of spatial problem solving, and limits in the amount of information that can be "processed" simultaneously may account for most or all of the performance deficits observed among these patients. Suggestions for future research and both clinical and theoretical implications of the findings are discussed.