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1.
Brain Behav ; 4(2): 201-14, 2014 Mar.
Article in English | MEDLINE | ID: mdl-24683513

ABSTRACT

BACKGROUND: Neuroimaging studies examining neural substrates of impaired self-awareness in patients with neurodegenerative diseases have shown divergent results depending on the modality (cognitive, emotional, behavioral) of awareness. Evidence is accumulating to suggest that self-awareness arises from a combination of modality-specific and large-scale supramodal neural networks. METHODS: We investigated the structural substrates of patients' tendency to overestimate or underestimate their own capacity to demonstrate empathic concern for others. Subjects' level of empathic concern was measured using the Interpersonal Reactivity Index, and subject-informant discrepancy scores were used to predict regional atrophy pattern, using voxel-based morphometry analysis. Of the 102 subjects, 83 were patients with neurodegenerative diseases such as behavioral variant frontotemporal dementia (bvFTD) or semantic variant primary progressive aphasia (svPPA); the other 19 were healthy older adults. RESULTS: bvFTD and svPPA patients typically overestimated their level of empathic concern compared to controls, and overestimating one's empathic concern predicted damage to predominantly right-hemispheric anterior infero-lateral temporal regions, whereas underestimating one's empathic concern showed no neuroanatomical basis. CONCLUSIONS: These findings suggest that overestimation and underestimation of one's capacity for empathic concern cannot be interpreted as varying degrees of the same phenomenon, but may arise from different pathophysiological processes. Damage to anterior infero-lateral temporal regions has been associated with semantic self-knowledge, emotion processing, and social perspective taking; neuropsychological functions partly associated with empathic concern itself. These findings support the hypothesis that-at least in the socioemotional domain-neural substrates of self-awareness are partly modality-specific.


Subject(s)
Awareness/physiology , Empathy/physiology , Frontotemporal Lobar Degeneration/pathology , Frontotemporal Lobar Degeneration/physiopathology , Self-Assessment , Temporal Lobe/pathology , Aged , Female , Humans , Male , Middle Aged
2.
PLoS One ; 7(11): e50425, 2012.
Article in English | MEDLINE | ID: mdl-23185621

ABSTRACT

Cognitive processing slows with age. We sought to determine the importance of white matter integrity, assessed by diffusion tensor imaging (DTI), at influencing cognitive processing speed among normal older adults, assessed using a novel battery of computerized, non-verbal, choice reaction time tasks. We studied 131 cognitively normal adults aged 55-87 using a cross-sectional design. Each participant underwent our test battery, as well as MRI with DTI. We carried out cross-subject comparisons using tract-based spatial statistics. As expected, reaction time slowed significantly with age. In diffuse areas of frontal and parietal white matter, especially the anterior corpus callosum, fractional anisotropy values correlated negatively with reaction time. The genu and body of the corpus callosum, superior longitudinal fasciculus, and inferior fronto-occipital fasciculus were among the areas most involved. This relationship was not explained by gray or white matter atrophy or by white matter lesion volume. In a statistical mediation analysis, loss of white matter integrity mediated the relationship between age and cognitive processing speed.


Subject(s)
Aging , Cognition/physiology , Corpus Callosum/physiology , Frontal Lobe/physiology , Parietal Lobe/physiology , Perforant Pathway/physiology , Reaction Time/physiology , Aged , Aged, 80 and over , Anisotropy , Brain Mapping , Choice Behavior , Corpus Callosum/anatomy & histology , Cross-Sectional Studies , Diffusion Tensor Imaging , Female , Frontal Lobe/anatomy & histology , Humans , Male , Middle Aged , Parietal Lobe/anatomy & histology , Perforant Pathway/anatomy & histology , Task Performance and Analysis
3.
J Int Neuropsychol Soc ; 18(5): 834-44, 2012 Sep.
Article in English | MEDLINE | ID: mdl-22835330

ABSTRACT

On tests of design fluency, an examinee draws as many different designs as possible in a specified time limit while avoiding repetition. The neuroanatomical substrates and diagnostic group differences of design fluency repetition errors and total correct scores were examined in 110 individuals diagnosed with dementia, 53 with mild cognitive impairment (MCI), and 37 neurologically healthy controls. The errors correlated significantly with volumes in the right and left orbitofrontal cortex (OFC), the right and left superior frontal gyrus, the right inferior frontal gyrus, and the right striatum, but did not correlate with volumes in any parietal or temporal lobe regions. Regression analyses indicated that the lateral OFC may be particularly crucial for preventing these errors, even after excluding patients with behavioral variant frontotemporal dementia (bvFTD) from the analysis. Total correct correlated more diffusely with volumes in the right and left frontal and parietal cortex, the right temporal cortex, and the right striatum and thalamus. Patients diagnosed with bvFTD made significantly more repetition errors than patients diagnosed with MCI, Alzheimer's disease, semantic dementia, progressive supranuclear palsy, or corticobasal syndrome. In contrast, total correct design scores did not differentiate the dementia patients. These results highlight the frontal-anatomic specificity of design fluency repetitions. In addition, the results indicate that the propensity to make these errors supports the diagnosis of bvFTD. (JINS, 2012, 18, 1-11).


Subject(s)
Brain Mapping , Frontal Lobe/pathology , Frontotemporal Dementia/complications , Speech Disorders/etiology , Speech Disorders/pathology , Aged , Alzheimer Disease/complications , Alzheimer Disease/psychology , Cognition Disorders/diagnosis , Cognition Disorders/psychology , Female , Frontotemporal Dementia/psychology , Frontotemporal Lobar Degeneration/complications , Frontotemporal Lobar Degeneration/psychology , Functional Laterality , Humans , Image Processing, Computer-Assisted , Language Tests , Magnetic Resonance Imaging , Male , Middle Aged , Neuropsychological Tests , ROC Curve , Regression Analysis , Supranuclear Palsy, Progressive/complications , Supranuclear Palsy, Progressive/psychology
4.
Neuropsychology ; 25(5): 655-65, 2011 Sep.
Article in English | MEDLINE | ID: mdl-21574716

ABSTRACT

OBJECTIVE: The Stroop (Stroop, 1935) 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. METHOD: Participants were 112 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 semiautomated parcellation program, was used to analyze 1.5T MRI scans. Behavioral disinhibition was measured using the Neuropsychiatric Inventory (Cummings, 1997; Cummings et al., 1994) Disinhibition Scale. The sample (n = 112) mean age was 65.40 (SD = 8.60) years, education was 16.64 (SD = 2.54) years, and Mini-Mental State Examination (MMSE; Folstein et al., 1975) was 26.63 (SD = 3.32). Hierarchical linear regressions were used for data analysis. RESULTS: Controlling for age, MMSE, and color naming, Stroop performance was not significantly associated with disinhibition (ß = 0.01, ΔR² = 0.01, p = .29). Hierarchical regressions controlling for age, MMSE, color naming, intracranial volume, and temporal and parietal lobes, examined whether left or right hemisphere regions predict Stroop performance. Bilaterally, parietal lobe atrophy best predicted poorer Stroop (left: ß = 0.0004, ΔR² = 0.02, p = .002; right: ß = 0.0004, ΔR² = 0.02, p = .002). Of frontal regions, only dorsolateral prefrontal cortex atrophy predicted poorer Stroop (ß = 0.001, ΔR² = 0.01, p = .03); left and right anterior cingulate cortex atrophy predicted better Stroop (left: ß = -0.003, ΔR² = 0.01, p = .02; right: ß = -0.004, ΔR² = 0.01, p = .02). CONCLUSION: These findings suggest Stroop performance is a poor measure of behavioral disinhibition and frontal lobe atrophy even among a relatively high-risk population.


Subject(s)
Brain Mapping , Cognitive Dysfunction/physiopathology , Dementia/physiopathology , Frontal Lobe/physiopathology , Inhibition, Psychological , Stroop Test , Aged , Cognitive Dysfunction/diagnostic imaging , Cognitive Dysfunction/psychology , Dementia/diagnostic imaging , Dementia/psychology , Frontal Lobe/pathology , Humans , Magnetic Resonance Imaging , Middle Aged , Neuropsychological Tests , Organ Size , Radiography , Reaction Time
5.
Neuropsychology ; 25(2): 249-59, 2011 Mar.
Article in English | MEDLINE | ID: mdl-21381829

ABSTRACT

OBJECTIVE: To determine whether 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 lobes, but these prior studies did not establish that these relationships were specific, which would best be demonstrated by a double dissociation. METHOD: Subjects included 157 patients with neurodegenerative disease. A semiautomated 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 3 tasks of executive function (EF; verbal fluency, Stroop Interference, modified Trails) was used to generate a single-factor score to represent EF. RESULTS: Partial correlations between ROIs, disinhibition, and EF were computed after controlling for total intracranial volume, Mini-Mental State Examination, 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 EF performance. A multivariate general linear model demonstrated a significant interaction between ROIs and cognitive-behavioral functions. CONCLUSIONS: These results support a specific association between orbitofrontal areas and behavioral management as compared with dorsolateral areas and EF.


Subject(s)
Affective Symptoms/etiology , Cerebral Cortex/pathology , Cognition Disorders , Dementia , Executive Function/physiology , Social Behavior , Affective Symptoms/diagnosis , Aged , Analysis of Variance , Brain Mapping , Cognition Disorders/etiology , Cognition Disorders/pathology , Cognition Disorders/psychology , Dementia/complications , Dementia/pathology , Dementia/psychology , Female , Functional Laterality , Humans , Image Processing, Computer-Assisted , Magnetic Resonance Imaging , Male , Middle Aged , Neuropsychological Tests , Psychiatric Status Rating Scales , Regression Analysis
6.
Neuropsychologia ; 49(1): 43-8, 2011 Jan.
Article in English | MEDLINE | ID: mdl-21029744

ABSTRACT

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.


Subject(s)
Brain Mapping , Cognition Disorders/etiology , Cognition Disorders/pathology , Psychomotor Performance/physiology , Aged , Alzheimer Disease/complications , Alzheimer Disease/pathology , Female , Frontotemporal Dementia/complications , Frontotemporal Dementia/pathology , Humans , Image Processing, Computer-Assisted , Imitative Behavior/physiology , Magnetic Resonance Imaging/methods , Male , Mental Status Schedule , Middle Aged , Neuropsychological Tests , Photic Stimulation/methods , Space Perception/physiology
7.
J Neurol Neurosurg Psychiatry ; 82(2): 196-203, 2011 Feb.
Article in English | MEDLINE | ID: mdl-20562461

ABSTRACT

BACKGROUND: Frontotemporal dementia-amyotrophic lateral sclerosis (FTD-ALS) is a heritable form of FTD, but the gene(s) responsible for the majority of autosomal dominant FTD-ALS cases have yet to be found. Previous studies have identified a region on chromosome 9p that is associated with FTD and ALS. METHODS: The authors report the clinical, volumetric MRI, neuropathological and genetic features of a new chromosome 9p-linked FTD-ALS family, VSM-20. RESULTS: Ten members of family VSM-20 displayed heterogeneous clinical phenotypes of isolated behavioural-variant FTD (bvFTD), ALS or a combination of the two. Parkinsonism was common, with one individual presenting with a corticobasal syndrome. Analysis of structural MRI scans from five affected family members revealed grey- and white-matter loss that was most prominent in the frontal lobes, with mild parietal and occipital lobe atrophy, but less temporal lobe atrophy than in 10 severity-matched sporadic bvFTD cases. Autopsy in three family members showed a consistent and unique subtype of FTLD-TDP pathology. Genome-wide linkage analysis conclusively linked family VSM-20 to a 28.3 cM region between D9S1808 and D9S251 on chromosome 9p, reducing the published minimal linked region to a 3.7 Mb interval. Genomic sequencing and expression analysis failed to identify mutations in the 10 known and predicted genes within this candidate region, suggesting that next-generation sequencing may be needed to determine the mutational mechanism associated with chromosome 9p-linked FTD-ALS. CONCLUSIONS: Family VSM-20 significantly reduces the region linked to FTD-ALS on chromosome 9p. A distinct pattern of brain atrophy and neuropathological findings may help to identify other families with FTD-ALS caused by this genetic abnormality.


Subject(s)
Amyotrophic Lateral Sclerosis/genetics , Amyotrophic Lateral Sclerosis/pathology , Chromosomes, Human, Pair 9/genetics , Frontotemporal Dementia/genetics , Frontotemporal Dementia/pathology , Adult , Amyotrophic Lateral Sclerosis/complications , Autopsy , Brain/pathology , DNA Mutational Analysis , Family , Female , Frontotemporal Dementia/complications , Genetic Linkage , Genetic Predisposition to Disease , Genome-Wide Association Study , Haplotypes , Humans , Immunohistochemistry , Lod Score , Magnetic Resonance Imaging , Male , Middle Aged , Parkinson Disease/genetics , Pedigree
8.
Acta Neuropathol ; 119(3): 365-74, 2010 Mar.
Article in English | MEDLINE | ID: mdl-19876635

ABSTRACT

Sporadic corticobasal syndrome (CBS) has been associated with diverse pathological substrates, but frontotemporal lobar degeneration with TDP-43 immunoreactive inclusions (FTLD-TDP) has only been linked to CBS among progranulin mutation carriers. We report the clinical, neuropsychological, imaging, genetic, and neuropathological features of GS, a patient with sporadic corticobasal syndrome. Genetic testing revealed no mutations in the microtubule associated protein tau or progranulin (PGRN) genes, but GS proved homozygous for the T allele of the rs5848 PGRN variant. Autopsy showed ubiquitin and TDP-43 pathology most similar to a pattern previously associated with PGRN mutation carriers. These findings confirm that FTLD-TDP should be included in the pathological differential diagnosis for sporadic CBS.


Subject(s)
Basal Ganglia Diseases/complications , Frontotemporal Lobar Degeneration/pathology , TDP-43 Proteinopathies/pathology , Basal Ganglia Diseases/genetics , Brain/pathology , Enzyme-Linked Immunosorbent Assay , Female , Frontotemporal Lobar Degeneration/complications , Frontotemporal Lobar Degeneration/genetics , Humans , Immunohistochemistry , Intercellular Signaling Peptides and Proteins/genetics , Intercellular Signaling Peptides and Proteins/metabolism , Magnetic Resonance Imaging , Middle Aged , Neurodegenerative Diseases/genetics , Neurodegenerative Diseases/pathology , Neuropsychological Tests , Progranulins , TDP-43 Proteinopathies/complications , TDP-43 Proteinopathies/genetics , tau Proteins/genetics , tau Proteins/metabolism
9.
Neuroimage ; 47(4): 1558-67, 2009 Oct 01.
Article in English | MEDLINE | ID: mdl-19501654

ABSTRACT

Degeneration of language regions in the dominant hemisphere can result in primary progressive aphasia (PPA), a clinical syndrome characterized by progressive deficits in speech and/or language function. Recent studies have identified three variants of PPA: progressive non-fluent aphasia (PNFA), semantic dementia (SD) and logopenic progressive aphasia (LPA). Each variant is associated with characteristic linguistic features, distinct patterns of brain atrophy, and different likelihoods of particular underlying pathogenic processes, which makes correct differential diagnosis highly clinically relevant. Evaluation of linguistic behavior can be challenging for non-specialists, and neuroimaging findings in single subjects are often difficult to evaluate by eye. We investigated the utility of automated structural MR image analysis to discriminate PPA variants (N=86) from each other and from normal controls (N=115). T1 images were preprocessed to obtain modulated grey matter (GM) images. Feature selection was performed with principal components analysis (PCA) on GM images as well as images of lateralized atrophy. PC coefficients were classified with linear support vector machines, and a cross-validation scheme was used to obtain accuracy rates for generalization to novel cases. The overall mean accuracy in discriminating between pairs of groups was 92.2%. For one pair of groups, PNFA and SD, we also investigated the utility of including several linguistic variables as features. Models with both imaging and linguistic features performed better than models with only imaging or only linguistic features. These results suggest that automated methods could assist in the differential diagnosis of PPA variants, enabling therapies to be targeted to likely underlying etiologies.


Subject(s)
Aphasia/classification , Aphasia/diagnosis , Artificial Intelligence , Brain/pathology , Image Interpretation, Computer-Assisted/methods , Magnetic Resonance Imaging/methods , Pattern Recognition, Automated/methods , Aged , Algorithms , Female , Humans , Image Enhancement/methods , Male , Middle Aged , Reproducibility of Results , Sensitivity and Specificity
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