Accurate appraisal of one’s own abilities is one metacognitive skill considered to be an important factor affecting learning and behavior in childhood. The present study measured self-appraisal accuracy in children using tasks of executive function, and investigated relations between self-appraisal and informant ratings of real world behaviors measured by the BRIEF. We examined self-appraisal accuracy on fluency tasks in 91 children ages 10-17. More accurate self-appraisal was correlated with fewer informant ratings of real world behavior problems in inhibition and shifting, independent of actual performance. Findings suggest that self-appraisal represents cognitive processes that are at least partially independent of other functions putatively dependent on the frontal lobes, and these self-appraisal-specific processes have unique implications for optimal daily function.
Self Assessment; Self Concept; Awareness; Child Behavior; Executive Function; Meta-cognition
White matter hyperintensities (WMH) and silent brain infarcts (SBI) have been associated with both vascular factors and cognitive decline. We examined among cognitively normal elderly, whether vascular factors predict cognitive decline and whether these associations are mediated by MRI measures of subclinical vascular brain injury.
Prospective multi-site longitudinal study of subcortical ischemic vascular diseases
Memory and aging centers in California
We studied 74 participants who were cognitively normal at entry and received at least 2 neuropsychological evaluations and 2 MRI exams over an average follow-up of 6.9 years.
Item response theory was used to create composite scores of global, verbal memory, and executive functioning. Volumetric MRI measures included WMH, SBI, hippocampus, and cortical gray matter (CGM). We used linear mixed effects models to examine the associations between vascular factors, MRI measures, and cognitive scores.
History of coronary artery disease (CAD) was associated with greater declines in global, verbal memory, and executive cognition. The CAD associations remained after controlling for changes in WMH, SBI, hippocampal and CGM volumes.
History of CAD may be a surrogate marker for clinically significant atherosclerosis which also affects the brain. Structural MRI measures of WMH and SBI do not fully capture the potential adverse effects of atherosclerosis on the brain. Future longitudinal studies of cognition should incorporate direct measures of atherosclerosis in cerebral arteries, as well as more sensitive neuroimaging measures.
cognitively normal elderly; coronary artery disease; cognitive decline; MRI
This study examined the relationship between individual differences in executive functions (EF; assessed by measures of working memory, Stroop, trail making, and verbal fluency) and ability to down-regulate and up-regulate responses to emotionally evocative film clips. To ensure a wide range of EF, 48 participants with diverse neurodegenerative disorders and 21 older neurologically normal aging participants were included. Participants were exposed to three different movie clips that were designed to elicit a mix of disgust and amusement. While watching the films they were either instructed to watch, down-regulate, and up-regulate their visible emotional responses. Heart-rate and facial behaviors were monitored throughout. Emotion regulatory ability was operationalized as changes in heart-rate and facial behavior in the down- and up-regulation conditions, controlling for responses in the watch condition. Results indicated that higher verbal fluency scores were related to greater ability to regulate emotion in both the down-regulation and up-regulation conditions. This finding remained significant even after controlling for age and general cognitive functioning. No relationships were found between emotion regulation and the other EF measures. We believe these results derive from differences among EF measures, with verbal fluency performance best capturing the complex sequence of controlled planning, activation, and monitoring required for successful emotion regulation. These findings contribute to our understanding of emotion-cognition interaction, suggesting a link between emotion-regulatory abilities and individual differences in complex executive functions.
emotion regulation; executive functions; emotional behavior; Stroop; trail making; verbal fluency; working memory; FTLD; AD; cognition-emotion interaction; cognitive influences on emotion
Recent research suggests a central role for inflammatory mechanisms in cognitive decline that may occur prior to evidence of neurodegeneration. Limited information exists, however, regarding the relationship between low-grade inflammation and cognitive function in healthy older adults. This study examined the relation between inflammation, verbal memory consolidation, and medial temporal lobe volumes in a cohort of older community-dwelling subjects. Subjects included 141 functionally intact, community dwelling older adults with detectable (n = 76) and undetectable (n= 65) levels of C-reactive protein. A verbal episodic memory measure was administered to all subjects, and measures of delayed recall and recognition memory were assessed. A semiautomated parcellation program was used to analyze structural MRI scans. On the episodic memory task, analysis of covariance revealed a significant CRP group by memory recall interaction, such that participants with detectable levels of CRP evidenced worse performance after a delay compared to those with undetectable levels of CRP. Individuals with detectable CRP also demonstrated lower performance on a measure of recognition memory. Imaging data demonstrated smaller left medial temporal lobe volumes in the detectable CRP group as compared with the undetectable CRP group. These findings underscore a potential role for inflammation in cognitive aging as a modifiable risk factor.
inflammation; memory; aging; cognition; temporal lobe; c-reactive protein; cytokines
We examined whether the effect of APOE genotype on functional brain connectivity is modulated by gender in healthy older human adults. Our results confirm significantly decreased connectivity in the default mode network in healthy older APOE ε4 carriers compared to ε3 homozygotes. More importantly, further testing revealed a significant interaction between APOE genotype and gender in the precuneus, a major default mode hub. Female ε4 carriers showed significantly reduced default mode connectivity compared to either female ε3 homozygotes or male ε4 carriers, whereas male ε4 carriers differed minimally from male ε3 homozygotes. An additional analysis in an independent sample of healthy elderly using an independent marker of Alzheimer’s disease, i.e. spinal fluid levels of tau, provided corresponding evidence for this gender by APOE interaction. Taken together, these results converge with previous work showing a higher prevalence of the ε4 allele among women with Alzheimer’s disease and, critically, demonstrate that this interaction between APOE genotype and gender is detectable in the preclinical period.
Cross-sectional studies of normal aging indicate an association between memory and hippocampal volume, and between executive functioning and subcortical-frontal circuits. Much less is known, however, about the relationship between longitudinal MRI changes and cognitive decline. The authors hypothesized that longitudinal change in memory would be best predicted by change in hippocampal volumes, whereas change in executive functioning would be best predicted by cortical atrophy and progression of MRI markers of cerebrovascular disease. For this study, 50 healthy elderly subjects underwent structural MRI and cognitive testing at baseline and again at follow-up, with a mean follow-up interval of 45 months. Volumetric MRI measures were hippocampus, cortical gray matter, white matter signal hyperintensity (WMSH), and lacunae. Neuropsychological measures were psychometrically robust composite scores of episodic memory (MEM) and executive functioning (EXEC). Hierarchical multiple regression indicated that a decrease in hippocampus was associated with a decline in MEM, whereas decreased cortical gray matter and increased WMSH were independently associated with a decline in EXEC. Results suggest that in normal aging, cognitive functioning declines as cortical gray matter and hippocampus decrease, and WMSH increases. The association between WMSH and EXEC further highlights the cognitive sequealae associated with cerebrovascular disease in normal elderly.
normal aging; memory; executive function; hippocampal volumes; white matter signal hyperintensity
The Stroop is a frequently used neuropsychological test, with poor performance typically interpreted as indicative of disinhibition and frontal lobe damage. This study tested those interpretations by examining relationships between Stroop performance, behavioral disinhibition, and frontal lobe atrophy.
Participants were 112 well-characterized patients with mild cognitive impairment or dementia, recruited through UCSF's Memory and Aging Center. Participants received comprehensive dementia evaluations including structural MRI, neuropsychological testing, and informant interviews. Freesurfer, a semi-automated parcellation program, was used to analyze 1.5T MRI scans. Behavioral disinhibition was measured using the Disinhibition scale of the Neuropsychiatric Inventory. The sample (n=112) mean age was 65.40 (SD=8.60) years, education was 16.64 (SD=2.54) years, and MMSE was 26.63 (SD=3.32). Hierarchical linear regressions were used for data analysis.
Controlling for age, MMSE, and Color Naming performance, Stroop performance was not significantly associated with behavioral disinhibition (β=0.01, ΔR2=0.01, p=0.29). Hierarchical regressions controlling for age, MMSE, Color Naming, intracranial volume, and temporal and parietal lobes, examined whether left hemisphere or right hemisphere regions predict Interference speed. Bilaterally, parietal lobes were the brain region in which atrophy best predicted poorer Stroop (left: β=0.0004, ΔR2=0.02, p=0.002; right: β=0.0004, ΔR2=0.02, p=0.002). Of frontal regions, only dorsolateral prefrontal cortex atrophy predicted poorer Stroop (β=0.001, ΔR2=0.01, p=0.03); left and right anterior cingulate cortex (ACC) atrophy predicted better Stroop (left: β=−0.003, ΔR2=0.01, p=0.02; right: β=−0.004, ΔR2=0.01, p=0.02).
These findings suggest Stroop performance is a poor measure of behavioral disinhibition and frontal lobe atrophy even among a relatively high-risk population.
Stroop; disinhibition; MRI; frontal; neuropsychological
Based on the recent literature and collective experience, an international consortium developed revised guidelines for the diagnosis of behavioural variant frontotemporal dementia. The validation process retrospectively reviewed clinical records and compared the sensitivity of proposed and earlier criteria in a multi-site sample of patients with pathologically verified frontotemporal lobar degeneration. According to the revised criteria, ‘possible’ behavioural variant frontotemporal dementia requires three of six clinically discriminating features (disinhibition, apathy/inertia, loss of sympathy/empathy, perseverative/compulsive behaviours, hyperorality and dysexecutive neuropsychological profile). ‘Probable’ behavioural variant frontotemporal dementia adds functional disability and characteristic neuroimaging, while behavioural variant frontotemporal dementia ‘with definite frontotemporal lobar degeneration’ requires histopathological confirmation or a pathogenic mutation. Sixteen brain banks contributed cases meeting histopathological criteria for frontotemporal lobar degeneration and a clinical diagnosis of behavioural variant frontotemporal dementia, Alzheimer’s disease, dementia with Lewy bodies or vascular dementia at presentation. Cases with predominant primary progressive aphasia or extra-pyramidal syndromes were excluded. In these autopsy-confirmed cases, an experienced neurologist or psychiatrist ascertained clinical features necessary for making a diagnosis according to previous and proposed criteria at presentation. Of 137 cases where features were available for both proposed and previously established criteria, 118 (86%) met ‘possible’ criteria, and 104 (76%) met criteria for ‘probable’ behavioural variant frontotemporal dementia. In contrast, 72 cases (53%) met previously established criteria for the syndrome (P < 0.001 for comparison with ‘possible’ and ‘probable’ criteria). Patients who failed to meet revised criteria were significantly older and most had atypical presentations with marked memory impairment. In conclusion, the revised criteria for behavioural variant frontotemporal dementia improve diagnostic accuracy compared with previously established criteria in a sample with known frontotemporal lobar degeneration. Greater sensitivity of the proposed criteria may reflect the optimized diagnostic features, less restrictive exclusion features and a flexible structure that accommodates different initial clinical presentations. Future studies will be needed to establish the reliability and specificity of these revised diagnostic guidelines.
behavioural variant frontotemporal dementia; diagnostic criteria; frontotemporal lobar degeneration; FTD; pathology
The hippocampus and frontal lobes both contribute to episodic memory performance. In the present study, the authors evaluated the relative contributions of hippocampus, frontal lobes, anterior temporal cortex, and posterior cortex to memory performance in neurodegenerative patients and normal older controls. Subjects (n = 42) were studied with structural MRI and a memory paradigm that measured delayed recall, semantic clustering during recall, recognition discriminability, and recognition response bias. Data were analyzed with multiple regression. Consistent with the authors’ hypotheses, hippocampal volumes were the best predictor of delayed recall and recognition discriminability, whereas frontal volumes were the best predictor of semantic clustering and response bias. Smaller frontal volumes were associated with less semantic clustering during recall and a more liberal response bias. Results indicate that hippocampal and frontal contributions to episodic memory can be dissociated, with the hippocampus more important for memory accuracy, and frontal structures more important for strategic processing and decision making.
memory; hippocampus; frontal lobes; organization; response bias
To determine if socioemotional disinhibition and executive dysfunction are related to dissociable patterns of brain atrophy in neurodegenerative disease. Previous studies have indicated that behavioral and cognitive dysfunction in neurodegenerative disease are linked to atrophy in different parts of the frontal lobe, but these prior studies did not establish that these relationships were specific, which would best be demonstrated by a double dissociation.
Subjects included 157 patients with neurodegenerative disease. A semi-automated parcellation program (Freesurfer) was used to generate regional cortical volumes from structural MRI scans. Regions of interest (ROIs) included anterior cingulate cortex (ACC), orbitofrontal cortex (OFC), middle frontal gyrus (MFG) and inferior frontal gyrus (IFG). Socioemotional disinhibition was measured using the Neuropsychiatric Inventory. Principal component analysis including three tasks of executive function (EF; verbal fluency, Stroop Interference, modified Trails) was used to generate a single factor score to represent EF.
Partial correlations between ROIs, disinhibition, and EF were computed after controlling for total intracranial volume, MMSE, diagnosis, age, and education. Brain regions significantly correlated with disinhibition (ACC, OFC, IFG, and temporal lobes) and EF (MFG) were entered into separate hierarchical regressions to determine which brain regions predicted disinhibition and EF. OFC was the only brain region to significantly predict disinhibition and MFG significantly predicted executive functioning performance. A multivariate general linear model demonstrated a significant interaction between ROIs and cognitive-behavioral functions.
These results support a specific association between orbitofrontal areas and behavioral management as compared to dorsolateral areas and EF.
Brain behaviour and relationships; prefrontal; emotion regulation; executive control
Elderly patients who have an acute illness or who undergo surgery often experience cognitive decline. The pathophysiologic mechanisms that cause neurodegeneration resulting in cognitive decline, including protein deposition and neuroinflammation, also play a role in animal models of surgery-induced cognitive decline. With the aging of the population, surgical candidates of advanced age with underlying neurodegeneration are encountered more often, raising concerns that, in patients with this combination, cognitive function will precipitously decline postoperatively. This special article is based on a symposium that the University of California, San Francisco, convened to explore the contributions of surgery and anesthesia to the development of cognitive decline in the aged patient. A road map to further elucidate the mechanisms, diagnosis, risk factors, mitigation, and treatment of postoperative cognitive decline in the elderly is provided.
A randomized pilot experiment examined the neural substrates of response to cognitive training in participants with mild cognitive impairment (MCI). Participants performed exercises previously demonstrated to improve verbal memory and an active control group performed other computer activities. An auditory-verbal fMRI task was conducted before and after the two-month training program. Verbal memory scores improved significantly and left hippocampal activation increased significantly in the experimental group (gains in 5 of 6 participants) relative to the control group (reductions in all 6 participants). Results suggest that the hippocampus in MCI may retain sufficient neuroplasticity to benefit from cognitive training.
MRI; dementia; cognition; MCI; mild cognitive impairment; fMRI; functional MRI; cognitive training; hippocampus; medial temporal lobe
Figure copy is the most common method of visual spatial assessment in dementia evaluations, but performance on this test may be multifactorial. We examined the neuroanatomical substrates of figure copy performance in 46 patients with Alzheimer’s disease (AD) and 48 patients with the behavioral variant of Frontotemporal dementia (bvFTD). A group of 94 neurologically healthy controls were studied for comparison. In AD, poor figure copy correlated significantly with right parietal cortex volumes but not with right dorsolateral prefrontal cortex volumes, whereas in bvFTD, figure copy performance correlated significantly with right dorsolateral prefrontal cortex volumes and there was only a trend with right parietal cortex volumes. The cognitive processes associated with figure copy performance also differed by diagnostic group such that figure copy was associated with spatial perception and attention in AD and with spatial planning and working memory in bvFTD. Spatial planning accounted for unique variance in the figure copy performance of bvFTD even after accounting for spatial perception, attention, and working memory. These results suggest that figure copy performance in AD and bvFTD is not anatomically-specific and is differentially impacted by bottom-up and top-down aspects of visual spatial processing. Alternative methods of visual spatial assessment for dementia evaluations are proposed.
Visuospatial; Parietal; Prefrontal; Dementia; Neurodegenerative; Neuropsychological Assessment; Visuoconstruction
To determine the prevalence of mild cognitive impairment (MCI), dementia and subtypes among oldest old women.
Prospective cohort study
Women, Cognitive Impairment Study of Exceptional Aging
1299 oldest old (≥ 85 years) women
Main Outcome Measures
All women completed a neuropsychological test battery. Those who screened positive for possible cognitive impairment (n=634) were further assessed for a diagnosis of dementia, MCI, or normal by an expert panel. Remaining women were considered cognitively normal. Dementia and MCI subtypes were determined using standard criteria.
The women had a mean age of 88.2 years and 27.0% were ≥90 years; 231 women (17.8%) were diagnosed with dementia and 301 (23.2%) with MCI for a combined cognitive impairment prevalence of 41.0%. Clinical features consistent with Alzheimer’s disease and mixed dementia were most common, each accounting for 40% of dementia cases. Amnestic multiple domain and non-amnestic single domain were the most common MCI types, accounting for 33.9% and 28.9% of cases respectively. Cognitive impairment was more frequent among women ≥90 years compared to those 85–89 years (dementia 28.2% vs. 13.9%, p<0.0001, and MCI 24.5% v. 22.7%, p=0.02) and more common among women with less education, history of stroke, and prevalent depression.
In this large sample of oldest old women, approximately 40% had clinically adjudicated cognitive impairment. Subtypes of dementia and MCI were similar to younger populations. Our results suggest that women in the fastest growing demographic, the oldest old, should be carefully screened for cognitive disorders, especially high risk groups.
There are few studies that evaluate the clinical outcomes of individuals with non-amnestic mild cognitive impairment (MCI). The purpose of this study was to evaluate baseline predictors of clinical progression after 2 years for patients with dysexecutive MCI (dMCI), a single-domain non-amnestic MCI subgroup.
We evaluated clinical progression in a sample of 31 older adults with dMCI. Clinical progression was defined as a worsening on the Clinical Dementia Rating sum of boxes at the 2-year visit, whereas patients were classified as stable if the score did not worsen over 2 years. We compared baseline brain MRI, neuropsychological tests, and health risk factors.
Twelve individuals with dMCI progressed clinically, and 19 individuals remained stable over 2 years. Compared to the stable dMCI patients, the dMCI patients who progressed showed brain atrophy in the bilateral insula and left lateral temporal lobe on MRI. dMCI patients who progressed were also older, had lower baseline performance on category fluency and a spatial location task, and reported fewer dysexecutive symptoms. Health risk factors, except hypertension, did not differ between groups.
The results suggest that dMCI patients who progress relatively quickly over 2 years may have unique clinical and brain MRI features.
Executive function; Non-amnestic mild cognitive impairment; Dysexecutive mild cognitive impairment
Most MRI studies of Alzheimer's disease (AD) and frontotemporal dementia (FTD) have assessed structural, perfusion and diffusion abnormalities separately while ignoring the relationships across imaging modalities. This paper aimed to assess brain gray (GM) and white matter (WM) abnormalities jointly to elucidate differences in abnormal MRI patterns between the diseases. Twenty AD, 20 FTD patients, and 21 healthy control subjects were imaged using a 4 Tesla MRI. GM loss and GM hypoperfusion were measured using high-resolution T1 and arterial spin labeling MRI (ASL-MRI). WM degradation was measured with diffusion tensor imaging (DTI). Using a new analytical approach, the study found greater WM degenerations in FTD than AD at mild abnormality levels. Furthermore, the GM loss and WM degeneration exceeded the reduced perfusion in FTD whereas, in AD, structural and functional damages were similar. Joint assessments of multimodal MRI have potential value to provide new imaging markers for improved differential diagnoses between FTD and AD.
Resting-state or intrinsic connectivity network functional magnetic resonance imaging provides a new tool for mapping large-scale neural network function and dysfunction. Recently, we showed that behavioural variant frontotemporal dementia and Alzheimer’s disease cause atrophy within two major networks, an anterior ‘Salience Network’ (atrophied in behavioural variant frontotemporal dementia) and a posterior ‘Default Mode Network’ (atrophied in Alzheimer’s disease). These networks exhibit an anti-correlated relationship with each other in the healthy brain. The two diseases also feature divergent symptom-deficit profiles, with behavioural variant frontotemporal dementia undermining social-emotional function and preserving or enhancing visuospatial skills, and Alzheimer’s disease showing the inverse pattern. We hypothesized that these disorders would exert opposing connectivity effects within the Salience Network (disrupted in behavioural variant frontotemporal dementia but enhanced in Alzheimer’s disease) and the Default Mode Network (disrupted in Alzheimer’s disease but enhanced in behavioural variant frontotemporal dementia). With task-free functional magnetic resonance imaging, we tested these ideas in behavioural variant frontotemporal dementia, Alzheimer’s disease and healthy age-matched controls (n = 12 per group), using independent component analyses to generate group-level network contrasts. As predicted, behavioural variant frontotemporal dementia attenuated Salience Network connectivity, most notably in frontoinsular, cingulate, striatal, thalamic and brainstem nodes, but enhanced connectivity within the Default Mode Network. Alzheimer’s disease, in contrast, reduced Default Mode Network connectivity to posterior hippocampus, medial cingulo-parieto-occipital regions and the dorsal raphe nucleus, but intensified Salience Network connectivity. Specific regions of connectivity disruption within each targeted network predicted intrinsic connectivity enhancement within the reciprocal network. In behavioural variant frontotemporal dementia, clinical severity correlated with loss of right frontoinsular Salience Network connectivity and with biparietal Default Mode Network connectivity enhancement. Based on these results, we explored whether a combined index of Salience Network and Default Mode Network connectivity might discriminate between the three groups. Linear discriminant analysis achieved 92% clinical classification accuracy, including 100% separation of behavioural variant frontotemporal dementia and Alzheimer’s disease. Patients whose clinical diagnoses were supported by molecular imaging, genetics, or pathology showed 100% separation using this method, including four diagnostically equivocal ‘test’ patients not used to train the algorithm. Overall, the findings suggest that behavioural variant frontotemporal dementia and Alzheimer’s disease lead to divergent network connectivity patterns, consistent with known reciprocal network interactions and the strength and deficit profiles of the two disorders. Further developed, intrinsic connectivity network signatures may provide simple, inexpensive, and non-invasive biomarkers for dementia differential diagnosis and disease monitoring.
functional magnetic resonance imaging; frontotemporal dementia; Alzheimer’s disease; functional connectivity; biomarker
Depressed mood is a frequent co-morbidity of dementia suggesting that they might share a common neuropathological substrate. Gray matter (GM) atrophy and white matter lesions (WML) have been described in both conditions. Our aims were to determine the relationship of GM and WML with cognition and depressed mood in the same population. Structural brain images were obtained from 42 controls, 20 Alzheimer’s disease (AD) patients and 32 subjects with cognitive impairment/dementia due to subcortical cerebrovascular disease (vascCIND/IVD) and segmented to obtain lobar GM, white matter and WML volumes. Lobar WML had a negative effect on GM in all lobes in controls, on frontal, parietal and occipital GM in AD and on frontal GM in vascCIND/IVD. Frontal, temporal and hippocampal GM were associated with cognitive functions and frontal WML load with depressed mood. Cognitive function is associated with GM atrophy and depressed mood is associated with frontal WML. This indicates that although both often occur together depressed mood and cognitive impairment are caused by different pathological correlates.
white matter lesion; gray matter atrophy; depression; mood; cognition; MRI
This study investigated the neurobiological basis of attentional control dysfunction in neurodegenerative disease by determining the effect of regional brain atrophy on Flanker task performance of neurodegenerative patients. We hypothesized that atrophy in DLPFC and ACC would be significantly associated with decreased attentional control performance on the Flanker task. We used voxel-based morphometry (VBM) to measure the relationship between MRI measures of regional grey matter atrophy and performance on a version of the Flanker task, measured by accuracy and response time. Sixty-five subjects participated, including patients with frontotemporal dementia, Alzheimer’s disease, mild cognitive impairment, non-fluent progressive aphasia, corticobasal degeneration, progressive supranuclear palsy, semantic dementia, and healthy controls. Accuracy measures of attentional control and response time measures of attentional control were associated with two different patterns of regional atrophy across subjects. First, there was an association between left hemisphere DLPFC and ACC atrophy and poorer attentional control accuracy. Second, right hemisphere temporal-parietal junction (TPJ) and ventrolateral prefrontal cortex (VLPFC) and DLPFC atrophy were associated with slower response times during attentional control on accurate trials, which may reflect emergent involvement due to deficits in the DLPFC-ACC network.
This study compared rates of regional atrophy in Alzheimer's disease (AD), frontotemporal dementia (FTD), and semantic dementia (SD). Cross-sectional studies have shown that different dementia syndromes are associated with different patterns of regional brain tissue loss. Rates of atrophy over time may be useful for differential diagnosis, and could be used to monitor disease progression, serving as an outcome measure for clinical trials. We studied patients with AD (n=12), FTD (n=13), SD (n=20), and normal controls (n=23) longitudinally with structural MRI, using BRAINS2 software to measure frontal, temporal and parietal lobe volumes. In FTD the rate of frontal lobe atrophy over one year was greater than in any other group, while SD showed the highest rate in the temporal lobes. Atrophy in these regions progressed twice as quickly in FTD and SD compared with AD. Atrophy was not significantly faster for AD in any brain region compared with the other groups. Regional atrophy over time was significantly faster in FTD and SD compared with AD, and the regions of greatest atrophy were specific for each syndrome. Measuring specific regions of cerebral volume changes by serial neuroimaging may serve as a useful biomarker outcome measure for clinical trials in neurodegenerative diseases.
longitudinal; MRI; alzheimer's disease; frontotemporal dementia
Parkinson's Disease (PD), multiple system atrophy (MSA) and dementia with Lewy Bodies (DLB) share α-synuclein immunoreactivity 1. These “synucleinopathies” have overlapping signs and symptoms, but less is known about similarities and differences in their cognitive and neuropsychiatric profiles. We compared the cognitive and neuropsychiatric profiles of individuals with PD, MSA and DLB. Overall, the DLB group showed the most cognitive impairment, the MSA group demonstrated milder impairment and the PD group was the least cognitively impaired. The DLB and MSA groups showed worse executive function and visuospatial skills than PD, while DLB showed impaired memory relative to both PD and MSA. On the neuropsychiatric screening, all groups endorsed depression and anxiety; the DLB group alone endorsed delusions and disinhibition. Consistent with their greater level of cognitive and neuropsychiatric impairment, the DLB group showed the greatest amount of functional impairment on a measure of instrumental ADLs (FAQ). We found that MSA subjects had cognitive difficulties that fell between the mild deficits of the PD group and the more severe deficits of the DLB group. PD, MSA and DLB groups have similar neuropsychiatric profiles of increased depression and anxiety. Similar underlying α-synuclein pathology may contribute to these shared features.
Parkinson's Disease; Dementia with Lewy Bodies; multiple system atrophy; dementia; alpha-synuclein
This study examined relationships between lobar volumes and performance on the D-KEFS Sorting Test, a standardized measure of concept formation. Participants included 89 subjects, 19 patients with probable Alzheimer's disease, 25 patients with frontotemporal dementia, 13 patients with semantic dementia, 12 patients with progressive nonfluent aphasia, 9 patients with probable progressive supranuclear palsy, 2 patients with possible progressive supranuclear palsy, and 9 healthy participants. We used BRAINS2 software to generate volumes of the right and left frontal, temporal, and parietal lobes. Multiple regression analysis indicated that, after controlling for Mini-Mental State Examination scores, intracranial volume, and demographic variables, only the left frontal lobe significantly predicted performance on the D-KEFS Sorting test.
D-KEFS; Frontal lobes; Executive functioning; Card Sorting; Concept Formation
We performed a pilot randomized, controlled trial of intensive, computer-based cognitive training in 47 subjects with mild cognitive impairment (MCI). The intervention group performed exercises specifically designed to improve auditory processing speed and accuracy for 100 minutes/day, 5 days/week for 6 weeks; the control group performed more passive computer activities (reading, listening, visuospatial game) for similar amounts of time. Subjects had a mean age of 74 years and 60% were men; 77% successfully completed training. On our primary outcome, Repeatable Battery for Assessment of Neuropsychological Status (RBANS) total scores improved 0.36 standard deviations (SD) in the intervention group (p=0.097) compared to 0.03 SD in the control group (p=0.88) for a non-significant difference between the groups of 0.33 SD (p=0.26). On 12 secondary outcome measures, most differences between the groups were not statistically significant. However, we observed a pattern in which effect sizes for verbal learning and memory measures tended to favor the intervention group while effect sizes for language and visuospatial function measures tended to favor the control group, which raises the possibility that these training programs may have domain-specific effects. We conclude that intensive, computer-based mental activity is feasible in subjects with MCI and that larger trials are warranted.
human; aged; cognition; cognitive rehabilitation; memory; neuropsychological tests; randomized controlled trial; mild cognitive impairment
Although early studies on mild cognitive impairment (MCI) focused on memory dysfunction; more recent studies suggest that MCI is clinically heterogeneous. The objective of this study is to examine patterns of cerebral perfusion in anmestic (N=12) and non-amnestic (N=12) single-domain MCI patients from four a priori regions of interest (ROI): middle and superior frontal cortex, posterior cingulate, and precuneus, to compare them relative to healthy controls (N=12), and to correlate perfusion with neuropsychological measures. Relative to controls, all MCI patients had hypoperfusion in the posterior cingulate, bilaterally. MCI patients with executive dysfunctions also showed hypoperfusion in bilateral middle frontal cortex and the left precuneus relative to controls and in the left middle frontal cortex, left posterior cingulate, and left precuneus relative to amnestic MCI patients. Perfusion in the posterior cingulate correlated positively with memory performance while perfusion in all four a priori ROIs, predominately on the left side, correlated with executive function performance. The finding that single-domain MCI patients with prominent deficits in different cognitive domains exhibited different patterns of hypoperfusion relative to controls supports the existence of distinct subgroups of MCI. These data further suggest that cognitive impairment in MCI is related to cerebral hypoperfusion.
There is increasing recognition that set-shifting, a form of cognitive control, is mediated by different neural structures. However, these regions have not yet been carefully identified as many studies do not account for the influence of component processes (e.g., motor speed). We investigated gray matter correlates of set-shifting while controlling for component processes. Using the Design Fluency (DF), Trail Making Test (TMT), and Color Word Interference (CWI) subtests from the Delis-Kaplan Executive Function System (D-KEFS), we investigated the correlation between set-shifting performance and gray matter volume in 160 subjects with neurodegenerative disease, mild cognitive impairment, and healthy older adults using voxel-based morphometry. All three set-shifting tasks correlated with multiple, widespread gray matter regions. After controlling for the component processes, set-shifting performance correlated with focal regions in prefrontal and posterior parietal cortices. We also identified bilateral prefrontal cortex and the right posterior parietal lobe as common sites for set-shifting across the three tasks. There was a high degree of multicollinearity between the set-shifting conditions and the component processes of TMT and CWI, suggesting DF may better isolate set-shifting regions. Overall, these findings highlight the neuroanatomical correlates of set-shifting and the importance of controlling for component processes when investigating complex cognitive tasks.
D-KEFS; Design fluency; Trail making test; Color word interference; Executive function; Voxel-based morphometry