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Biomedical subjects

D Galasko

Publications and source records attributed to D Galasko.

At least 73 records · Page 4Linked to original sources
PubMed1996

Extrapyramidal motor signs in clinically diagnosed Alzheimer disease.

We reviewed clinical case series published over a 10-year period addressing the cross-sectional frequency, incidence, and diagnostic and prognostic significance of extrapyramidal signs (EPS) in Alzheimer disease (AD). The review was prompted by recent reports of Lewy body (LB) pathology in the brains of many AD patients and the association of LB pathology with clinical parkinsonism in AD. In the clinical case series reviewed, we evaluated several possible determinants of prevalent EPS, including neuroleptic use, EPS assessment technique, and dementia severity. Neuroleptics were a well recognized cause of parkinsonism in these reports, though some failed to document the frequency of neuroleptic use. Assessment methods were also important: Studies using structured clinical research scales to rate EPS reported higher frequencies than studies employing routine neurological examination. The relationship between parkinsonism and dementia severity was complex. Some studies found bradykinesia, facial masking, and parkinsonian postural changes even in mildly demented, neuroleptic-naive AD patients. Rigidity, on the other hand, became increasingly common as dementia progressed. AD patients with EPS showed faster cognitive and functional decline and earlier death than those without EPS, even after consideration of differences in initial dementia severity. In the differential diagnosis of dementia with parkinsonism, LB disease in its various forms, including AD with LB, is the principal diagnostic consideration. Future studies of parkinsonism in AD should employ standardized clinical rating scales and should exclude patients on neuroleptics or analyze their results separately. Investigators should report frequencies for individual parkinsonian signs in addition to the overall prevalence of EPS to facilitate meaningful comparisons across studies.

Alzheimer Disease↗
PubMed1996

Neocortical lewy body counts correlate with dementia in the Lewy body variant of Alzheimer's disease.

Patients with the Lewy body variant (LBV) of Alzheimer's disease (AD) meet diagnostic criteria for AD but have a lighter burden of plaque and tangle AD pathology despite comparable dementia. We quantified neocortical Lewy bodies (LB) in LBV patients (n = 14) using anti-ubiquitin polyclonal antibody, selecting for quantification those neocortical regions with the highest densities of LB. Neocortical neurofibrillary tangles (NFT) and neuritic plaques were evaluated with thioflavin- S. A group of classical AD patients (n = 12), matched for disease duration, was also studied. For most of these cases, entorhinal neurofibrillary pathology had previously been assessed by applying a modification of the Braak and Braak AD staging protocol. Although LBV and AD groups had similar mental test scores when last evaluated prior to death, lower neocortical NFT and plaque counts and lower modified Braak stages were observed in LBV. Neocortical NFT counts correlated with impaired neuropsychological test performance in AD but not in LBV. Plaque counts did not correlate with mental status in either group. Lewy body concentrations in four neocortical areas correlated significantly with dementia severity in LBV. The association of AD lesions in the neocortex with dementia in LBV was comparatively weaker than that observed for LB concentrations. These findings suggest that neocortical LB combined with entorhinal NFT or subcortical Parkinson's disease-type pathology may equalize the degree of dementia seen in LBV with that encountered in classical AD.

Aged↗
PubMed1996

Clinical and neuropsychological differences between patients with earlier and later onset of Alzheimer's disease: A CERAD analysis, Part XII.

To determine whether the age of the onset of Alzheimer's disease (AD) is related to the expression and rate of decline of this disorder, we examined the clinical and neuropsychological performance of 421 patients entered into the Consortium to Establish a Registry for Alzheimer's Disease and followed annually for up to 4 years. Statistical analyses were based on multivariable logistic regression analysis for dichotomous clinical measures and multivariable linear regression analysis for psychometric measures. All analyses examined the effect of age after controlling for gender, education, and stage of dementia. Clinical information obtained on entry into the study indicated that younger patients performed more poorly on measures of language and concentration, and older patients performed more poorly on measures of memory and orientation. On neuropsychological measures at entry, younger patients, performed more poorly on praxis and had significantly higher scores of confrontation naming. Younger age predicted a significantly faster rate of progression for all neuropsychological measures. These findings support the concept of age-related clinical subtypes of AD.

Age of Onset↗
PubMed1996

The apolipoprotein E epsilon 4 allele is associated with increased neuritic plaques and cerebral amyloid angiopathy in Alzheimer's disease and Lewy body variant.

OBJECTIVE: To determine the relationship between apolipoprotein E (apoE) genotype and neuropathologic lesions in Alzheimer's disease (AD) and Lewy body variant (LBV). DESIGN: Retrospective genetic-neuropathologic study of AD and LBV cases. The main neuropathologic outcome measures were modeled as a function of apoE genotype, neuropathologic diagnosis, and gender. Age at death and duration of symptom effects were controlled for by ANCOVA. PATIENTS: One hundred twenty-seven cases with neuropathologically diagnosed AD (n = 84) or LBV (n = 43). MAIN OUTCOME MEASURES: Quantitative scores of neuritic plaques (NPs), neurofibrillary tangles (NFTs), cerebral amyloid angiopathy (CAA) severity, and CAA prevalence were averaged across four brain regions: midfrontal, inferior parietal, superior temporal, and hippocampal. RESULTS: The apoE epsilon 4 allele was associated with increased NPs within both AD and LBV. The epsilon 4 allele was associated with an increased frequency of CAA in the AD and LBV groups combined groups combined and in and in LBV alone. While CAA severity and NETs were increased in the epsilon 4/4 homozygous case when AD and LBV were combined, there were no significant effects within AD or LBV alone. CONCLUSIONS: The apoE epsilon 4 allele is strongly associated with increased NPs, but not neocortical NFTs, in both AD and LBV.

Aged↗
PubMed1996

ApoE and CYP2D6 polymorphism with and without parkinsonism-dementia complex in the people of Chamorro, guam.

Parkinsonism-dementia complex (PDC), a neurodegenerative disorder in the Chamorro, Guam population, has been epidemiologically ascribed to the ingestion of the neurotoxin cycasin. This disease is characterized neuropathologically by the presence of abundant neurofibrillary tangles (NFTs). We analyzed a genetic risk factor of Alzheimer's disease (AD), apolipoprotein E, hypothesized to be linked to NFT formation, and a genetic risk factor of Parkinson's disease (PD), CYP2D6 mutation, linked to slower metabolism of exogenous toxins, in Chamorro, Guam individuals with and without PDC. The representation of the G-to-C mutation in exon 9 of the CYP2D6 gene was higher in Chamorro and Filipino than in Caucasian individuals, but this mutant allele had similar high frequencies in both PDC patients and healthy Chamorro individuals. We found no alleles of these genes associated with AD or PD to be overrepresented among those with PDC.

Adult↗
PubMed1996

Consensus guidelines for the clinical and pathologic diagnosis of dementia with Lewy bodies (DLB): report of the consortium on DLB international workshop.

Recent neuropathologic autopsy studies found that 15 to 25% of elderly demented patients have Lewy bodies (LB) in their brainstem and cortex, and in hospital series this may constitute the most common pathologic subgroup after pure Alzheimer's disease (AD). The Consortium on Dementia with Lewy bodies met to establish consensus guidelines for the clinical diagnosis of dementia with Lewy bodies (DLB) and to establish a common framework for the assessment and characterization of pathologic lesions at autopsy. The importance of accurate antemortem diagnosis of DLB includes a characteristic and often rapidly progressive clinical syndrome, a need for particular caution with neuroleptic medication, and the possibility that DLB patients may be particularly responsive to cholinesterase inhibitors. We identified progressive disabling mental impairment progressing to dementia as the central feature of DLB. Attentional impairments and disproportionate problem solving and visuospatial difficulties are often early and prominent. Fluctuation in cognitive function, persistent well-formed visual hallucinations, and spontaneous motor features of parkinsonism are core features with diagnostic significance in discriminating DLB from AD and other dementias. Appropriate clinical methods for eliciting these key symptoms are described. Brainstem or cortical LB are the only features considered essential for a pathologic diagnosis of DLB, although Lewy-related neurites, Alzheimer pathology, and spongiform change may also be seen. We identified optimal staining methods for each of these and devised a protocol for the evaluation of cortical LB frequency based on a brain sampling procedure consistent with CERAD. This allows cases to be classified into brainstem predominant, limbic (transitional), and neocortical subtypes, using a simple scoring system based on the relative distribution of semiquantitative LB counts. Alzheimer pathology is also frequently present in DLB, usually as diffuse or neuritic plaques, neocortical neurofibrillary tangles being much less common. The precise nosological relationship between DLB and AD remains uncertain, as does that between DLB and patients with Parkinson's disease who subsequently develop neuropsychiatric features. Finally, we recommend procedures for the selective sampling and storage of frozen tissue for a variety of neurochemical assays, which together with developments in molecular genetics, should assist future refinements of diagnosis and classification.

Dementia↗
PubMed1995

A fibroblast growth factor binding protein in human cerebral spinal fluid.

A soluble protein which binds basic fibroblast growth factor (FGF-2) has been detected in cerebral spinal fluid from normal individuals and patients with Alzheimer's disease and Parkinson's disease. This 70-85 kDa protein is recognized by an antibody to the extracellular domain of the high affinity FGF receptor and is not detected by an antibody to the intracellular domain of the FGF receptor, suggesting that it consists of a truncated portion of the extracellular domain of the high affinity FGF receptor. This FGF-BP appears to be identical to the two IgG-like loop form of FGFR-1 identified and purified from human and bovine blood. The possibility that this FGF-BP may play a role in transporting, sequestering, or even delivering the FGFs to target cells in the CNS is discussed.

Alzheimer Disease↗
PubMed1995

The CYP2D6B mutant allele is overrepresented in the Lewy body variant of Alzheimer's disease.

Approximately one-fourth of neuropathologically confirmed cases of Alzheimer's disease (AD) also have brainstem and neocortical Lewy bodies, constituting a Lewy body variant of AD. Because Lewy bodies are a pathologic hallmark of Parkinson's disease (PD), this subpopulation of AD subjects may have the same risk factors as PD subjects. Analyses of the cytochrome P450 CYP2D6-debrisoquine 4-hydroxylase mutant B allele, a susceptibility gene for PD, revealed a higher representation of this allele in the Lewy body variant of AD than in pure AD or non-AD without Lewy bodies.

Alleles↗
PubMed1995

Reduction of beta-amyloid peptide42 in the cerebrospinal fluid of patients with Alzheimer's disease.

In this clinical study the cerebrospinal fluid (CSF) level of a novel form of the beta-amyloid peptide (A beta) extending to position 42 (A beta 42) was determined in patients with Alzheimer's disease (AD) as well as controls. In addition to measurement of CSF A beta 42 levels, total A beta peptides, microtubule-associated protein tau, and apolipoprotein E (ApoE) genotype were also assessed. It is interesting that CSF A beta 42 levels were found to be significantly lower in AD patients relative to controls, whereas total A beta levels were not. A beta 42 has recently been shown to preferentially deposit in the brain tissue of patients with AD, suggesting that diminished clearance may account for its reduction in CSF. As previously reported, tau levels were increased in AD patients; however, neither A beta 42 nor tau levels were apparently influenced by the ApoE genotype.

Aged↗
PubMed1995

Genetic evidence that the Lewy body variant is indeed a phenotypic variant of Alzheimer's disease.

Lewy Body Variant (LBV) patients present as Alzheimer's disease (AD) clinically; about two-thirds also have mild extrapyramidal features. At autopsy, neocortical and brain stem Lewy bodies are present in addition to changes diagnostic of AD. We have found that the Apolipoprotein E4 allele is a major genetic risk factor for LBV as it is for "pure AD," in contrast to subjects with diffuse Lewy body disease or Parkinson's disease. This genetic evidence supports the concept that LBV--the second most common neurodegenerative form of dementia--is a phenotypic variant of AD.

Aged↗
PubMed1995

Episodic memory changes are associated with the APOE-epsilon 4 allele in nondemented older adults.

OBJECTIVE: To compare the memory performances of nondemented older adults with and without the epsilon 4 allele of the apolipoprotein E (APOE-epsilon 4). BACKGROUND: Few studies have examined the cognitive status of subjects at high risk for the development of dementia of the Alzheimer type (DAT). A newly reported risk factor for DAT allows for an examination of the cognitive performances of nondemented subjects who are at risk by virtue of being either heterozygous or homozygous for the APOE-epsilon 4 allele. METHODS: The California Verbal Learning Test (CVLT) was administered to 52 nondemented older adults. Subjects were divided into two groups on the basis of the presence (n = 17) or absence (n = 35) of one or two APOE-epsilon 4 alleles. RESULTS: APOE- epsilon 4 and non-epsilon 4 groups did not significantly differ in demographic, mental status, and functional characteristics. APOE-epsilon 4 subjects demonstrated significantly poorer mean performances than non-epsilon 4 subjects on nine CVLT variables. Seven group differences remained significant, and three approached significance (0.05 < p < 0.10), after the effects of age and gender were taken into account. Six of the 14 APOE-epsilon 4 subjects who completed annual follow-up evaluations developed either DAT or questionable DAT, whereas none of the 26 non-epsilon 4 subjects who received follow-up demonstrated any cognitive decline. CONCLUSIONS: Results suggest that episodic memory changes in older adults are associated with APOE-epsilon 4 allele; sensitive cognitive markers such as those of the CVLT may precede the subsequent development of DAT.

Aged↗
PubMed1995

The Consortium to Establish a Registry for Alzheimer's Disease (CERAD). Part XI. Clinical milestones in patients with Alzheimer's disease followed over 3 years.

The rate of cognitive decline, measured by psychometric testing, is widely used to track the progression of Alzheimer's disease (AD). As an alternative approach, we studied clinical measures as markers of the progression of dementia in 343 community-dwelling patients with probable AD enrolled in the multi-center Consortium to Establish a Registry for Alzheimer's Disease (CERAD) project. Subjects received standardized evaluations at entry and at annual follow-up. Decline on the Clinical Dementia Rating, loss of instrumental activities of daily living, failure to recall three words on the Mini-Mental State Examination (MMSE), and decline of the total MMSE score to below 10 were high-risk milestones, with cumulative frequencies exceeding 50% at 3 years. Loss of dressing and toileting activities occurred at intermediate rates, while loss of eating ability was rare. The risk of reaching clinical milestones and the annual rate of cognitive decline on the MMSE were directly correlated. Clinical milestones are useful indices of the progression of dementia in patients with AD.

Activities of Daily Living↗
PubMed1995

Adjunctive therapy in patients with Alzheimer's disease. A practical approach.

Alzheimer's disease (AD) primarily results in memory impairment and cognitive deficits in areas such as language, visuospatial function, calculation, praxis and judgement. However, over 30% of patients with dementia develop a group of secondary behavioural disturbances, including depression, hallucinations and delusions, agitation, insomnia and wandering. Because these secondary symptoms impair patients' function, increase their need for supervision, and often influence the decision to institutionalise them, the control of these symptoms is a priority in managing AD. Psychotropic drugs, particularly antipsychotics (neuroleptics), have been a mainstay in treating many of these symptoms, but carry a high risk of adverse effects. Patients with AD may be particularly vulnerable to adverse effects of medications because of changes in pharmacokinetics and neurotransmitter systems, related to both AD and aging. At present, treating secondary symptoms of AD is more of an art than a science. For virtually every group of symptoms, older and newer classes of medications are available, with proven efficacy in patients without dementia and less clear results in AD patients. We review current treatment options and suggest preferences for each symptom complex, based on a trade-off between efficacy and adverse effects. New agents, such as selective serotonin reuptake inhibitors and atypical antipsychotics, may herald the arrival of symptom- (and receptor-) specific drugs with minimal adverse effects.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1994

Apolipoprotein-E epsilon-4 is associated with increased neurofibrillary pathology in the Lewy body variant of Alzheimer's disease.

Brains from demented patients with both Alzheimer's disease (AD) pathology and brainstem and neocortical Lewy bodies have fewer neurofibrillary tangles than pure AD, but share with AD an increased apolipoprotein-E epsilon-4 (APOE4) allelic frequency. We applied the Braak and Braak AD neuropathology staging protocol, based on entorhinal and neocortical neurofibrillary pathology, to 40 such Lewy body variants of AD (LBV) and 97 cases of pure AD and compared the results in APOE4 positive and APOE4 negative subgroups. APOE4 was associated with more severe neurofibrillary pathology in LBV but not in pure AD, where a ceiling effect appears to be operative.

Aged↗