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Biomedical subjects

N L Foster

Publications and source records attributed to N L Foster.

At least 19 recordsLinked to original sources
PubMed1997

Frontotemporal dementia and parkinsonism linked to chromosome 17: a consensus conference. Conference Participants.

We held an international consensus conference on frontotemporal dementia, behavioral disturbances, and parkinsonism linked to chromosome 17 to determine whether these are homogeneous or heterogeneous disorders, to agree on terminology, and to develop strategies for further research. The group identified 13 kindreds with sufficient evidence for linkage, finding in common to all a critical 2 cM between markers D17S791 and D17S800. There was agreement that (1) despite previous descriptions that have emphasized one or another clinical or neuropathological feature, the kindreds share clinical and neuropathological features; (2) until more specific information about the genetic defects becomes available, this disorder is best termed frontotemporal dementia and parkinsonism linked to chromosome 17; and (3) further research will be enhanced by identifying the gene or genes responsible for this disorder, detecting additional cases within known families and, in new families, correlating mutations with phenotypes and more fully delineating the clinical, neuropsychological, and neuropathological characteristics of this disorder.

Brain↗
PubMed1997

Metabolic reduction in the posterior cingulate cortex in very early Alzheimer's disease.

This study investigated cerebral glucose metabolism in very early Alzheimer's disease, before a clinical diagnosis of probable Alzheimer's disease is possible, using [18F]fluorodeoxyglucose positron emission tomography. First, 66 patients with probable Alzheimer's disease with a spectrum of dementia severity (Mini-Mental State Examination score, 0-23) were recruited and studied. Cortical metabolic activity was analyzed topographically using three-dimensional stereotactic surface projections. Regression analysis was performed for each brain pixel to predict metabolic patterns of very early disease. Predictions were tested prospectively in a group of 8 patients who complained only of memory impairment without general cognitive decline (Mini-Mental State Examination score, 25 +/- 1) at the time of scanning but whose condition later progressed to probable Alzheimer's disease. Both results were compared to cerebral metabolic activity in 22 age-similar normal control subjects. Prediction and analysis of actual patients consistently indicated marked metabolic reduction (21-22%) in the posterior cingulate cortex and cinguloparietal transitional area in patients with very early Alzheimer's disease. Mean metabolic reduction in the posterior cingulate cortex was significantly greater than that in the lateral neocortices or parahippocampal cortex. The result suggests a functional importance for the posterior cingulate cortex in impairment of learning and memory, which is a feature of very early Alzheimer's disease.

Aged↗
PubMed1997

Cognitive, behavioral, and motor effects of the NMDA antagonist ketamine in Huntington's disease.

BACKGROUND: Excitotoxicity may contribute to neuronal degeneration in Huntington's disease (HD). N-methyl-D-aspartate (NMDA) receptor antagonists can prevent neuronal degeneration caused by excitotoxicity, but their effects in HD patients are not known. METHODS: We investigated the acute cognitive, behavioral, and motor effects of the NMDA-receptor antagonist ketamine in HD patients. Double-blind infusions of 0.10, 0.40, and 0.60 mg/kg/hr ketamine were given to 10 HD patients on one test day and compared with placebo infusions on a second, identical testing day. Linear mixed-effects models and randomization tests were used to identify whether, and at which dose, a significant change from baseline occurred in outcome variables. RESULTS: We demonstrated that ketamine is well tolerated at low and intermediate subanesthetic doses. Intermediate ketamine doses produced specific decline in memory and verbal fluency. Higher subanesthetic doses caused a significant increase in psychiatric symptoms and impairment of eye movements. CONCLUSIONS: These results describe the spectrum of clinical effects produced by increasing NMDA receptor blockade in HD patients. The clinical effects appearing with higher levels of NMDA receptor blockade can identify the range of doses used in clinical trials of NMDA receptor antagonists.

Adult↗
PubMed1997

Cerebral metabolic differences in Parkinson's and Alzheimer's diseases matched for dementia severity.

UNLABELLED: Despite controversial clinicopathological distinctions between Parkinson's disease with dementia (PDD) and Alzheimer's disease (AD), similar patterns of metabolic reduction in the posterior brain were reported previously using PET with [18F]fluorodeoxyglucose. The current study was designed to examine more specific regional differences in cerebral glucose metabolism between PDD and AD using accurate and objective brain mapping techniques. METHODS: This study included nine normal subjects, nine PDD patients and nine AD patients. PDD and AD groups were matched carefully for age, sex and general dementia severity as measured by Mini-Mental State Examination and Clinical Dementia Rating scales. Each subject underwent [18F]fluorodeoxyglucose-PET and neuropsychological testing. After anatomic standardization of PET image sets and stereotactic data extraction, absolute and normalized cerebral metabolic rates were assessed by region of interest and pixel-by-pixel analyses. RESULTS: PDD and AD showed global glucose metabolic reduction with similar regional accentuation involving the lateral parietal, lateral temporal and lateral frontal association cortices and posterior cingulate cortex in comparison to normal controls. When comparing between PDD and AD, however, PDD showed greater metabolic reduction in the visual cortex and relatively preserved metabolism in the medial temporal cortex. CONCLUSION: Although a common feature of metabolic abnormalities in the posterior brain exists in PDD and AD, the presence of regional metabolic differences suggests different degrees and combinations of disease specific underlying pathological and neurochemical processes.

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PubMed1996

The neuropathology of chromosome 17-linked dementia.

We recently described a family with chromosome 17-linked dementia, characterized clinically by disinhibition-dementia-parkinsonism-amyotrophy complex. We report now the neuropathology of 6 affected family members. This included semiquantitative scoring of neuronal loss, gliosis, and spongiosis and immunocytochemical and ultrastructural characterization of neuronal and glial inclusions. The changes consisted of circumscribed neuronal loss, gliosis, and spongiosis of limbic neocortical areas and frontal, temporal, and occipital association areas. Similar changes were present in subcortical nuclei, most severe in the substantia nigra, but also involved the ventral striatum and amygdala. The hippocampus was spared except for degeneration of the afferent perforant tract, secondary to entorhinal nerve cell loss. Argyrophilic neuronal inclusions, with a characteristic immunocytochemical profile, were found in brainstem nuclei, hypothalamus and basal ganglia. Ultrastructurally, in 3 patients these inclusions showed hitherto undescribed abnormally assembled filaments. Glial cytoplasmic inclusions were widespread in white matter structures. Immunocytochemistry failed to demonstrate the protease-resistant prion protein. The pathology appears to be unique, involving various cortical and subcortical structures, and is consistent with the clinical findings of Kluver-Bucy-like syndrome, parkinsonism, and frontal lobe dementia. For this entity we suggest the term "chromosome 17-linked dementia."

Brain↗
PubMed1996

In vivo mapping of cholinergic terminals in normal aging, Alzheimer's disease, and Parkinson's disease.

To map presynaptic cholinergic terminal densities in normal aging (n = 36), Alzheimer's disease (AD) (n = 22), and Parkinson's disease (PD) (n = 15), we performed single-photon emission computed tomography using [123I]iodobenzovesamicol (IBVM), an in vivo marker of the vesicular acetylcholine transporter. We used coregistered positron emission tomography with [18F]fluorodeoxyglucose for metabolic assessment and coregistered magnetic resonance imaging for atrophy assessment. In controls (age, 22-91 years), cortical IBVM binding declined only 3.7% per decade. In AD, cortical binding correlated inversely with dementia severity. In mild dementia, binding differed according to age of onset, but metabolism did not. With an onset age of less than 65 years, binding was reduced severely throughout the entire cerebral cortex and hippocampus (about 30%), but with an onset age of 65 years or more, binding reductions were restricted to temporal cortex and hippocampus. In PD without dementia, binding was reduced only in parietal and occipital cortex, but demented PD subjects had extensive cortical binding decreases similar to early-onset AD. We conclude that cholinergic neuron integrity can be monitored in living AD and PD patients, and that it is not so devastated in vivo as suggested by postmortem choline acetyltransferase activity (50-80%).

Aged↗
PubMed1996

The caffeine breath test does not identify patients susceptible to tacrine hepatotoxicity.

Therapy with tacrine, a promising new treatment for Alzheimer's disease, must be discontinued in up to 15% of patients because of hepatocellular toxicity. Recent studies using human liver microsomes have suggested that a single liver enzyme, cytochrome P450 1A2 (CYP1A2), catalyzes the major route of metabolism and elimination of tacrine, and also catalyzes the pathway(s) involved in the generation of reactive metabolites capable of covalent protein binding and cytotoxicity. Because CYP1A2 activity has been shown to vary up to 60-fold among patients, we proposed that a convenient measure of CYP1A2 activity, the [(13)C 3-methyl] caffeine breath test (CBT), might be clinically useful in identifying patients most susceptible to tacrine liver toxicity. To test this hypothesis, we administered the CBT to 37 patients with Alzheimer's disease before they began treatment with tacrine. Twenty patients received 2 mg/kg of [(13)C 3-methyl] caffeine. The remaining 17 patients received the commercially available CBT kit, which employs a constant 200-mg dose. The activities of two other major drug-metabolizing enzymes (cytochrome P450 3A4 and 2D6 [CYP3A4 and CYP2D6]) were also measured in these 17 patients. We found that the results obtained from the CBT protocol did not predict the peak serum alanine transaminase (ALT) observed in the patients. The measured CYP3A4 and CYP2D6 activities also failed to predict the susceptible patients. However, the result of the standardized-dose CBT correlated well with the logarithm of the steady-state plasma tacrine level obtained in 10 patients (R(2) = .69, P = .003). We conclude that the CBT will not be clinically useful in determining the subset of patients most susceptible to tacrine hepatotoxicity. However, the correlation we observed between CBT results and tacrine blood levels is the first evidence supporting a critical role for CYP1A2 activity in the disposition of the drug in vivo.

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PubMed1996

Visual-spatial deficits expalin visual symptoms in Alzheimer's disease.

PURPOSE: To determine whether the visual symptoms of patients with Alzheimer's disease are related to visual-spatial dysfunction. METHODS: We administered a test battery modified from existing neuropsychometric materials that taxed visual-spatial skills, form identification, color vision, and visual memory. We tested 14 patients with Alzheimer's disease who had visual symptoms prominent enough to prompt ophthalmologic consultation, 11 patients with Alzheimer's disease who lacked such visual symptoms, and a control group of 53 subjects without Alzheimer's disease. The groups with Alzheimer's disease were matched for Wechsler Adult Intelligence Scale-Revised scores. RESULTS: Patients with Alzheimer's disease who had prominent visual symptoms differed significantly from those without prominent visual symptoms only in their relatively poor visual-spatial test scores. CONCLUSIONS: Visual symptoms in Alzheimer's disease are related primarily to visual-spatial deficits. These findings are consistent with previous evidence that patients with Alzheimer's disease who have prominent visual symptoms have accentuated histologic and metabolic abnormalities in the parieto-occipital regions known to process visual-spatial information. The findings support the view that pathways mediating visual-spatial and form identification are at least partially segregated in the brain, and emphasize that tests used to screen visually symptomatic patients with Alzheimer's disease will be more effective if they prominently assess visual-spatial skills.

Aged↗
PubMed1996

Neuropsychological subgroups of patients with Alzheimer's disease.

Neuropsychological data from 134 patients diagnosed with probable Alzheimer's disease (AD) were studied retrospectively to investigate whether subgroups of patients with qualitatively distinct profiles could be identified. Three empirical classification approaches were undertaken in this regard: Q-type factor analysis, hierarchical agglomerative cluster analysis, and iterative partitioning. Three subgroups were consistently identified across the clustering methods. Subgroup 1, the largest of the groups, was marked by moderate to severe anomia and constructional dyspraxia. Individuals in subgroup 2 displayed relatively spared visual-perceptual/constructional functioning but severe anomia. Members of subgroup 3 exhibited intact naming and nonverbal reasoning and moderate difficulty in copying overlapping figures. The three subgroups did not differ with respect to age, age at disease onset, duration of illness, educational level, or Hamilton depression rating. Detailed description of the data analyses are provided as a tutorial outlining subtyping methodology. Results are discussed in terms of the subgroup and the stage model approaches to the conceptualization of AD.

Aged↗
PubMed1996

Familial Creutzfeldt-Jakob disease with a five-repeat octapeptide insert mutation.

We report a familial form of Creutzfeldt-Jakob disease, associated with a unique insert mutation of the PRNP gene in an American family of Ukrainian origin. Ten family members exhibited early age at onset and long-duration illnesses characterized primarily by personality changes, cognitive impairment, and spasticity. The proband, presenting at age 42 years, exhibited a fairly stable, nonprogressive course over 7 years, followed by precipitous decline and death in the eighth year. Other affected family members exhibited marked clinical heterogeneity. Each tested affected member had an insert mutation consisting of five extra octapeptide repeats between codons 51 and 91 of the PRNP gene on chromosome 20. Examination of two autopsy cases showed classic spongiform change, neuronal loss and astrocytosis in one case, and minimal pathologic abnormality in the other case. This report documents a new insert mutation of the PRNP gene, and confirms the early age of onset, characteristically prolonged clinical course, and clinical and pathologic heterogeneity seen in such mutations.

Adult↗
PubMed1995

Positron emission tomography measures of benzodiazepine binding in Alzheimer's disease.

OBJECTIVE: To evaluate the integrity of neurons and neuropil in metabolically affected association cortices of patients with Alzheimer's disease by measuring central benzodiazepine binding sites with the use of positron emission tomography. DESIGN: In patients with Alzheimer's disease, we determined the cerebral distribution of flumazenil tagged with carbon 11 ([11C]flumazenil), a ligand that binds to the gamma-aminobutyric acid A (GABAA) receptor complex, and the distribution of fludeoxyglucose tagged with fluorine 18 fludeoxyglucose F 18), a measure of local cerebral glucose metabolism. Tracer kinetic analysis was applied to quantify data in regions of interest. These data were compared with those of normal control subjects. SUBJECTS: Patients with probable Alzheimer's disease ([11C]flumazenil, n = 13; fludeoxyglucose F 18, n = 11) and normal elderly control subjects ([11C]flumazenil, n = 6; fludeoxyglucose F 18, n = 10). RESULTS: Significant decreases of the [11C]flumazenil transport rate were found in hypometabolic parietal and temporal association cortices, but [11C]flumazenil binding was not significantly decreased. CONCLUSIONS: When measured in living patients, association cortical benzodiazepine binding sites are relatively preserved, suggesting structurally intact cortical neuropil underlying the glucose hypometabolism identified in Alzheimer's disease.

Aged↗
PubMed1995

Maintenance of balance, gait patterns, and obstacle clearance in Alzheimer's disease.

Patients with cognitive impairment, particularly as a result of Alzheimer's disease (AD), are at increased risk for falls, but it is unclear how, or if, they differ from normal adults in their balance, gait, or ability to clear an obstacle in their path. Using an optoelectronic camera system, we compared body motions and force output at the feet in patients with probable AD (n = 17) with those in healthy older adults (n = 15) while they stood on a force plate or on a beam attached to the force plate that was either stationary or accelerating. Using the same camera system and comparing this AD group with another group of healthy older adults (n = 24), we observed the AD patients during normal walking and while clearing 25- and 152-mm-high obstacles. None of the AD patients had extrapyramidal signs or musculoskeletal impairments. Compared with healthy older adults, normal walking speed was significantly slower in the AD group (p < 0.0001). While clearing either obstacle, the AD patients were significantly slower in their approach (p < 0.0001) and crossing (p < 0.0001) speeds and landed closer to the obstacle after having crossed it (p < 0.02). Moreover, the percent of trials in which a subject made contact with an obstacle was significantly higher in patients with AD (p < 0.005).(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1995

A diagnostic approach in Alzheimer's disease using three-dimensional stereotactic surface projections of fluorine-18-FDG PET.

UNLABELLED: To improve the diagnostic performance of PET as an aid in evaluating patients suspected of having Alzheimer's disease, we developed a fully automated method which generates comprehensive image presentations and objective diagnostic indices. METHODS: Fluorine-18-fluorodeoxyglucose PET image sets were collected from 37 patients with probable Alzheimer's disease (including questionable and mild dementia), 22 normal subjects and 5 patients with cerebrovascular disease. Following stereotactic anatomic standardization, metabolic activity on an individual's PET image set was extracted to a set of predefined surface pixels (three-dimensional stereotactic surface projection, 3D-SSP), which was used in the subsequent analysis. A normal database was created by averaging extracted datasets of the normal subjects. Patients' datasets were compared individually with the normal database by calculating a Z-score on a pixel-by-pixel basis and were displayed in 3D-SSP views for visual inspections. Diagnostic indices were then generated based on averaged Z-scores for the association cortices. RESULTS: Patterns and severities of metabolic reduction in patients with probable Alzheimer's disease were seen in the standard 3D-SSP views of extracted raw data and statistical Z-scores. When discriminating patients with probable Alzheimer's disease from normal subjects, diagnostic indices of the parietal association cortex and unilaterally averaged parietal-temporal-frontal cortex showed sensitivities of 95% and 97%, respectively, with a specificity of 100%. Neither index yielded false-positive results for cerebrovascular disease. CONCLUSION: 3D-SSP enables quantitative data extraction and reliable localization of metabolic abnormalities by means of stereotactic coordinates. The proposed method is a promising approach for interpreting functional brain PET scans.

Aged↗
PubMed1995

PET of peripheral benzodiazepine binding sites in the microgliosis of Alzheimer's disease.

UNLABELLED: Animal and human autoradiographic studies have shown increased in vitro binding of the peripheral benzodiazepine binding site antagonist PK 11195 in areas of microgliosis, including the temporal association cortex of patients with Alzheimer's disease. To further elucidate the role of cellular inflammation and microgliosis in Alzheimer's disease during life, we used PET and [11C]PK 11195, a peripheral benzodiazepine receptor ligand known to bind avidly to microglia. METHODS: Eight patients with a diagnosis of probable Alzheimer's disease underwent PET of the brain using [11C]PK 11195 and, for comparison, with [18F]FDG to determine cerebral glucose metabolism. Uptake of [11C]PK 11195 in various brain regions was expressed relative to that in the cerebellum and compared to values determined in one normal elderly subject and in clinically and anatomically unaffected hemispheres of seven patients with small unilateral gliomas. RESULTS: No increases in peripheral benzodiazepine binding were identified in patients with probable Alzheimer's disease, and binding was lowest in regions that were most hypometabolic. CONCLUSION: The peripheral benzodiazepine binding sites associated with microgliosis and cellular inflammation in Alzheimer's disease at postmortem are undetectable by PET using [11C]PK 11195 in patients with mild-to-moderate dementia.

Aged↗
PubMed1994

Clinical characteristics of a family with chromosome 17-linked disinhibition-dementia-parkinsonism-amyotrophy complex.

We studied the clinical features, pathology, and molecular genetics of a family (Mo) with an autosomal dominant disinhibition, frontal lobe dementia, parkinsonism, and amyotrophy. We examined seven affected members and gathered clinical information on another six. The mean onset was at age 45 years. Personality and behavioral changes (disinhibition, withdrawal, alcoholism, hyperphagia) were the first symptoms in twelve. There was early memory loss, anomia, and poor construction with preservation until late of orientation, speech, and calculations. All affected members examined had rigidity, bradykinesia, and postural instability. Mean duration to death was 13 years. We studied the neuropathology of six individuals, five of whom had been examined in life. There was atrophy and spongiform change in the frontotemporal cortex, and neuronal loss and gliosis in the substantia nigra and amygdala. Two individuals, including one with fasciculations and muscle wasting, had anterior horn cell loss. There were no Lewy bodies, neurofibrillary tangles, or amyloid plaques. We call this disorder the "disinhibition-dementia-parkinsonism-amyotrophy complex" (DDPAC), based on the clinical syndrome found in this family and linkage to chromosome 17.

Adult↗
PubMed1993

Services for persons with dementia and their families: a survey of information and referral agencies in Michigan.

In planning a statewide Dementia Program, Michigan agencies (N = 244) providing geriatric information and referral (I&R) were surveyed to determine service availability, families' needs, and problems providing I&R for persons with dementia and their families. Home-delivered meals, nursing and social work assessments were considered more available. Medical assessment, however, was considered "very available" by only 60%. Respite and adult day care were least available and most needed. Least was known about autopsy and financial services. For several services, non-urban areas reported less availability than urban areas. With additional information and training, existing agencies could provide more available and extensive I&R for persons with dementia and their families, forming a statewide network.

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