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This study describes the development and validation of the Activities of Daily Living Questionnaire (ADLQ), an informant-based assessment of functional abilities, in patients with probable Alzheimer disease and other forms of dementia.... more
This study describes the development and validation of the Activities of Daily Living Questionnaire (ADLQ), an informant-based assessment of functional abilities, in patients with probable Alzheimer disease and other forms of dementia. The ADLQ measures functioning in six areas: self-care, household care, employment and recreation, shopping and money, travel, and communication. The ADLQ was administered to 140 caregivers followed longitudinally in the Northwestern Alzheimer's Disease Center. In a subset of 28 participants, the total ADLQ score and each of the subscales were found to be highly reproducible, with average concordance coefficients of 0.86. Concurrent validity was established by comparing the ADLQ with the Record of Independent Living, a previously validated measure of level of dependency in daily living activities. The ADLQ was also compared with other measures of dementia severity on the initial and annual follow-up visits and was found to be significantly and nega...
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Magnetic resonance images of the brain acquired in relationship to the commissural plane have been analyzed in twenty cases classified as Probable Alzheimer's disease (Pr. AD). These examinations have been compared to normal aged... more
Magnetic resonance images of the brain acquired in relationship to the commissural plane have been analyzed in twenty cases classified as Probable Alzheimer's disease (Pr. AD). These examinations have been compared to normal aged matched subjects. All examinations have been made in strict correlation with the planes defined by Talairach and Tournoux (1988). The analysis of brain cortical damage was made by evaluating the sulci of the brain mainly on coronal sections correlated with simultaneous image review of the same area on the two other orthogonal planes. In Pr. AD, an asymmetric atrophic pattern was found mainly on the following areas: amygdaloid nucleus, para hippocampal gyrus, hippocampus, areas 22 and 21, temporal pole, insula, dorso frontal cortex, angular gyrus, superior parietal lobule. The primary motor and visual areas were normal in all cases.
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Research Interests: Biological Sciences, Melatonin, Humans, Circadian Rhythm, Female, and 7 moreMale, Light, Body Temperature, Aged, Middle Aged, Adult, and Age Factors
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Frontotemporal dementia (FTD) has been linked to the microtubule associated protein tau (MAPT) gene region of chromosome 17. However, many chromosome-17 linked FTLDs do not have MAPT mutations or tau protein deposits, but have ubiquitin... more
Frontotemporal dementia (FTD) has been linked to the microtubule associated protein tau (MAPT) gene region of chromosome 17. However, many chromosome-17 linked FTLDs do not have MAPT mutations or tau protein deposits, but have ubiquitin positive, tau and alpha-synuclein negative inclusions. Mutations in the progranulin (PGRN) gene, located 1.7 Mb from MAPT at 17q21.31, were recently discovered in some of these individuals. The pathologic phenotype in all cases has thus far included ubiquitinated neuronal intranuclear inclusions (NIIs) and neuronal cytoplasmic inclusions (NCIs). PGRN mutation analysis was performed in 12 individuals. Informed consent was obtained from next of kin under an IRB-approved protocol. We compared clinical and pathologic findings in those cases with and without PGRN mutations. PGRN mutations were found in four patients, two with clinical FTD and a positive family history, and two with clinical primary progressive aphasia (PPA), one with and one without a family history. All four cases with, and five of eight cases without, PGRN mutations had ubiquitinated NCIs and NIIs. Brains of individuals with PGRN mutations are associated with more frequent frontal NCIs and dystrophic neurites, less frequent dentate gyrus NCIs, and more frequent striatal NIIs than FTLD-U cases without PGRN mutations. PGRN mutations at 17q21 may occur in apparently sporadic frontotemporal lobar dementia with ubiquitinated inclusions cases and in cases presenting with either primary progressive aphasia or the behavioral variant of frontotemporal dementia. Some cases without PGRN mutations also have ubiquitinated neuronal intranuclear inclusions. Clinicopathologic differences are observed among individuals with and without PGRN mutations.
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To study the effects of bromocriptine, a dopamine agonist, on visual search. The anatomic substrate of spatial attention takes the form of a distributed network with interconnected cortical (frontal, parietal, and cingulate) and... more
To study the effects of bromocriptine, a dopamine agonist, on visual search. The anatomic substrate of spatial attention takes the form of a distributed network with interconnected cortical (frontal, parietal, and cingulate) and subcortical (striatal and thalamic) components. Dopamine appears to exert a modulatory effect on the function of this network. Seven consecutive right-handed subjects with right-sided cerebral lesions were studied using a computerized target search paradigm. Eye movements were recorded. Bromocriptine caused the subjects to spend more time exploring the ipsilesional hemispace and therefore increased the relative neglect of the contralesional left hemispace. However, target detection accuracy did not change. Bromocriptine thus had a differential impact on the exploratory-motor versus sensory-perceptual components of directed attention. Our results show that bromocriptine may worsen some aspects of hemispatial neglect in patients with lesions that include the postsynaptic components of ascending dopaminergic pathways.
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The authors screened for tau gene mutations and polymorphisms to determine whether genetic variation at or near the tau locus contributes to the development of primary progressive aphasia (PPA). No mutations were detected in 25 patients... more
The authors screened for tau gene mutations and polymorphisms to determine whether genetic variation at or near the tau locus contributes to the development of primary progressive aphasia (PPA). No mutations were detected in 25 patients with PPA. However, a significant overrepresentation of the tau H1/H1 genotype, also found in progressive supranuclear palsy and corticobasal degeneration, was found in the PPA group. Whether tau haplotypes have a primary causal role or whether they affect the topology of neurodegeneration remains to be determined.
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Visual cortical surface area varies two- to threefold between human individuals, is highly heritable, and has been correlated with visual acuity and visual perception. However, it is still largely unknown what specific genetic and... more
Visual cortical surface area varies two- to threefold between human individuals, is highly heritable, and has been correlated with visual acuity and visual perception. However, it is still largely unknown what specific genetic and environmental factors contribute to normal variation in the area of visual cortex. To identify SNPs associated with the proportional surface area of visual cortex, we performed a genome-wide association study followed by replication in two independent cohorts. We identified one SNP (rs6116869) that replicated in both cohorts and had genome-wide significant association (P(combined) = 3.2 × 10(-8)). Furthermore, a metaanalysis of imputed SNPs in this genomic region identified a more significantly associated SNP (rs238295; P = 6.5 × 10(-9)) that was in strong linkage disequilibrium with rs6116869. These SNPs are located within 4 kb of the…
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Research Interests: Cognitive Science, Dementia, Archives, Brain, Humans, and 16 moreGenetic Testing, Mutation, Female, Male, Phosphorylation, Clinical Sciences, Introns, Aged, Middle Aged, Genotype, Single Nucleotide Polymorphism, Frontotemporal Dementia, Alzheimer Disease, Genetic Markers, Neurosciences, and Case Control Studies
Research Interests: Magnetic Resonance Imaging, Language, Speech, Humans, Female, and 15 moreVoxel Based Morphometry, Male, Magnetic Resonance, Reaction Time, Motor Cortex, Task Performance, Primary Progressive Aphasia, Clinical Sciences, Aged, Middle Aged, Parietal Lobe, Fusiform Gyrus, Annals, Neurosciences, and Gray Matter
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Our goal in this study was to determine whether donepezil, an acetylcholinesterase inhibitor, would improve cognitive functioning in 19 subjects with Down syndrome and no dementia. They were assigned to either a donepezil or placebo... more
Our goal in this study was to determine whether donepezil, an acetylcholinesterase inhibitor, would improve cognitive functioning in 19 subjects with Down syndrome and no dementia. They were assigned to either a donepezil or placebo group. Cognitive functioning and caregiver ratings were measured at baseline, 4 weeks, and 12 weeks. With the exception of one area (language), no improvement was noted in any of the cognitive subtests, behavioral scores, or caregiver ratings. Subjects in the donepezil group showed an improvement in language scores compared to subjects in the placebo group. The results suggest that donepezil may improve language performance in subjects with Down syndrome and no dementia, but further studies need to be done on a larger group to confirm this result.
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There is little information regarding the usefulness of the Mini-Mental State Examination (MMSE) for tracking progression of... more
There is little information regarding the usefulness of the Mini-Mental State Examination (MMSE) for tracking progression of non-Alzheimer's disease dementias. This study examined the utility of the MMSE in capturing disease severity in the behavioral variant frontotemporal dementia (bvFTD) and primary progressive aphasia (PPA), 2 nonamnestic clinical dementia syndromes. Retrospective data from 41 bvFTD and 30 PPA patients were analyzed. bvFTD patients' change in MMSE scores over time was significantly correlated with change over time on a measure of activities of daily living. In contrast, PPA patients' MMSE scores showed greater decline over time than scores on the activities of daily living scale. Results suggest that the MMSE score, heavily dependent on language skill, overestimates dementia severity in PPA patients. However, the score may be a more accurate measure of functional impairment in bvFTD due to the influence of their executive function and attentional deficits on MMSE performance.
Research Interests: Psychometrics, Dementia, Executive Function, Activities of Daily Living, Humans, and 19 moreLanguage Skills, Female, Male, Follow-up studies, Disease Severity, Functional impairment, American, Differential Diagnosis, Mental Disorders, Primary Progressive Aphasia, Clinical Sciences, Mini Mental State Examination, Aged, Middle Aged, Frontotemporal Dementia, Retrospective Studies, Disease Progression, Attention Deficit, and Activity of Daily Living
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Progressive decline in cognition is a hallmark feature of dementia, and the rate and profile of cognitive decline has been well characterized in Alzheimer disease (AD). Less is known about decline in cognition over time in other forms of... more
Progressive decline in cognition is a hallmark feature of dementia, and the rate and profile of cognitive decline has been well characterized in Alzheimer disease (AD). Less is known about decline in cognition over time in other forms of dementia such as the behavioral variant of frontotemporal dementia (FTD) and primary progressive aphasia (PPA). The present study examined rate of cognitive decline across domains of memory, language, and executive function measured by neuropsychologic tests, in AD (n=84), FTD (n=66), and PPA (n=44). Patients were in the mild stages of dementia, with comparable duration of illness at the baseline evaluation. A best linear unbiased predictor (BLUP) analysis was used in which the slope of the relationship between a cognitive measure and time was estimated for each person. AD subjects demonstrated a floor effect on measures of memory at baseline and a decline on measures of language and executive functioning over time. FTD showed the greatest decline over time on the Mini-Mental State Examination, executive functioning, and naming. PPA patients demonstrated prominent decline on language measures, verbal memory measures, and attention. Results suggest that the profile of rate of change over time has unique features on the basis of the type of dementia syndrome. However, there is overlap in the profiles of decline likely influenced by the overlap in cognitive constructs measured by neuropsychologic tests. The comparison of the rate of decline in FTD and PPA may also reflect the neuroanatomic overlap in these syndromes over time.
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Memory impairment, characterized by a pattern of rapid forgetting, is the hallmark deficit in... more
Memory impairment, characterized by a pattern of rapid forgetting, is the hallmark deficit in Alzheimer's disease (AD). Memory deficits have also been reported in frontotemporal dementia (FTD), and are thought to reflect diminished organizational and attentional abilities leading to a pattern of decreased acquisition of new information. The present study compared patients with AD, the behavioral variant of FTD, and cognitively intact elderly control subjects on two types of memory tests: story memory and word list recall. The percent of information recalled immediately (encoded), after a delay, and the percent retention between these conditions was calculated for both tests. The results showed that FTD patients encoded and recalled more information from the story than AD patients. No difference was found between FTD and AD patients for encoding of the word list. However, FTD patients recalled more words after a delay than AD patients. Percent retention on both tasks was also greater for the FTD group. The results suggest that patterns of performance on different tests of memory, and, in particular, measures of retention, can be useful in differentiating memory impairment in AD from that of FTD on cognitive testing.