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D Galasko

Publications and source records attributed to D Galasko.

At least 19 recordsLinked to original sources

Diagnosis and management of dementia with Lewy bodies: third report of the DLB Consortium.

The dementia with Lewy bodies (DLB) Consortium has revised criteria for the clinical and pathologic diagnosis of DLB incorporating new information about the core clinical features and suggesting improved methods to assess them. REM sleep behavior disorder, severe neuroleptic sensitivity, and reduced striatal dopamine transporter activity on functional neuroimaging are given greater diagnostic weighting as features suggestive of a DLB diagnosis. The 1-year rule distinguishing between DLB and Parkinson disease with dementia may be difficult to apply in clinical settings and in such cases the term most appropriate to each individual patient should be used. Generic terms such as Lewy body (LB) disease are often helpful. The authors propose a new scheme for the pathologic assessment of LBs and Lewy neurites (LN) using alpha-synuclein immunohistochemistry and semiquantitative grading of lesion density, with the pattern of regional involvement being more important than total LB count. The new criteria take into account both Lewy-related and Alzheimer disease (AD)-type pathology to allocate a probability that these are associated with the clinical DLB syndrome. Finally, the authors suggest patient management guidelines including the need for accurate diagnosis, a target symptom approach, and use of appropriate outcome measures. There is limited evidence about specific interventions but available data suggest only a partial response of motor symptoms to levodopa: severe sensitivity to typical and atypical antipsychotics in approximately 50%, and improvements in attention, visual hallucinations, and sleep disorders with cholinesterase inhibitors.

Brain↗

Rate of progression differs in frontotemporal dementia and Alzheimer disease.

OBJECTIVE: To compare survival and rates of cognitive and functional decline in patients with autopsy-confirmed frontotemporal dementia (FTD) and Alzheimer disease (AD) in a large multicenter study. BACKGROUND: Despite advances in the clinical characterization of FTD, little is known about its rate of progression. Characterizing survival and rate of decline in FTD is important because it can provide prognostic guidelines and benchmarks to use in the evaluation of disease-modifying drugs. METHODS: Seventy patients with FTD and 70 patients with AD who were followed by seven Alzheimer disease research centers until confirmation of diagnosis at autopsy were matched for overall age, education, and Mini-Mental State Examination (MMSE) score at initial evaluation. Survival and rates of cognitive and functional decline were compared. RESULTS: Patients with FTD had significantly shorter survival from initial evaluation to death than patients with AD (FTD = 4.2 years, AD = 6.0 years; log-rank test = 5.17, p < 0.05), and they declined significantly faster over one year on the MMSE (mean annual rate of change: -6.7 points for FTD vs -2.3 points for AD). A significantly greater proportion of patients with FTD were impaired in basic activities of daily living (ADLs) at initial evaluation, and lost the capacity for independent or minimally-assisted ADLs over the subsequent year. CONCLUSIONS: The results are consistent with shorter survival and faster rates of cognitive and functional decline in patients with frontotemporal dementia (FTD) compared to those with Alzheimer disease (AD). This suggests that FTD follows a more malignant disease course than AD once dementia is clinically recognized.

Activities of Daily Living↗

Detailed assessment of activities of daily living in moderate to severe Alzheimer's disease.

Patients with Alzheimer's Disease (AD) who have reached a stage of moderate to severe dementia are capable of completing a restricted range of cognitive tests and performing a limited range of activities of daily living (ADL). As part of an initiative to develop instruments to evaluate AD, we analyzed data describing the performance of a large number of ADL and scores on cognitive and global assessment measures in a cohort of patients with AD with moderate to severe cognitive impairment, defined as a Mini-Mental State Examination score ranging from 0-15 (out of 30). From the large pool of ADL, 19 met criteria of applicability, reliability, good scaling, concordant validity, and sensitivity to detect change in performance over 6-12 months. A total score derived from these 19 ADL ratings, comprising a scale termed the Alzheimer Disease Cooperative Study ADL-sev, correlated strongly with measures of cognition and of global dementia severity. Patients with moderate to severe AD showed a decline on the ADL-sev and cognitive measures over 6 and 12 months, consistent with the progression of AD. Detailed evaluation of ADL may provide a useful index to evaluate patients with moderate to severe AD and may complement cognitive assessment, especially for characterizing change in interventional or therapeutic studies.

Activities of Daily Living↗

Consensus paper of the WFSBP Task Force on Biological Markers of Dementia: the role of CSF and blood analysis in the early and differential diagnosis of dementia.

Aging of population, and increasing life expectancy result in an increasing number of patients with dementia. This symptom can be a part of a completely curable disease of the central nervous system (e.g, neuroinflammation), or a disease currently considered irreversible (e.g, Alzheimer's disease, AD). In the latter case, several potentially successful treatment approaches are being tested now, demanding reasonable standards of pre-mortem diagnosis. Cerebrospinal fluid and serum analysis (CSF/serum analysis), whereas routinely performed in neuroinflammatory diseases, still requires standardization to be used as an aid to the clinically based diagnosis of AD. Several AD-related CSF parameters (total tau, phosphorylated forms of tau, Abeta peptides, ApoE genotype, p97, etc.) tested separately or in a combination provide sensitivity and specificity in the range of 85%, the figure commonly expected from a good diagnostic tool. In this review, recently published reports regarding progress in neurochemical pre-mortem diagnosis of dementias are discussed with a focus on an early and differential diagnosis of AD. Novel perspectives offered by recently introduced technologies, e.g, fluorescence correlation spectroscopy (FCS) and surface enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF MS) are briefly discussed.

Aged↗

Abeta1-42 promotes cholinergic sprouting in patients with AD and Lewy body variant of AD.

BACKGROUND: The neurodegenerative process in Alzheimer's disease (AD) and in the Lewy body variant of AD (LBV) patients is characterized by cholinergic dysfunction and deposition of amyloid beta-peptide (Abeta) 1-40 and 1-42; however, the differential effects of Abeta species on the cholinergic system are not completely clear. OBJECTIVE: To better understand the relationship between levels of Abeta1-40 and 1-42 on cholinergic deficits in AD and LBV patients. METHODS: Levels of choline acetyltransferase (ChAT) activity and ChAT immunoreactivity in the plaques in the frontal cortex of patients with AD and LBV were correlated with Abeta1-42 and 1-40 levels determined by ELISA and with neuropathologic and neurologic markers. RESULTS: Although the overall levels of ChAT activity were reduced in AD and LBV cases, there was a direct correlation with Abeta1-42 levels. Furthermore, patients with high Abeta1-42 levels had more abundant cholinergic dystrophic neurites in the plaques than cases with lower Abeta1-42. CONCLUSION: Abeta1-42 may also trigger cholinergic dysfunction by promoting aberrant neuritic sprouting.

Aged↗

Influence of Alzheimer pathology on clinical diagnostic accuracy in dementia with Lewy bodies.

OBJECTIVE: To determine whether AD neurofibrillary pathology influences clinical diagnostic accuracy in dementia with Lewy bodies (DLB). BACKGROUND: Pathologic diagnosis of DLB mandates Lewy bodies but also allows for AD pathology in the form of plaques and tangles. Because clinical diagnostic accuracy of DLB remains low, the authors questioned whether the severity of AD pathology in the form of tangles might affect the clinician's ability to correctly diagnose DLB in life. DESIGN/METHODS: Ninety-eight subjects with autopsy-proven DLB who had been evaluated annually at the University of California San Diego AD Research Center were identified. The clinical diagnosis used was the last diagnosis before death. Pathologic diagnosis of DLB was made according to Consensus guidelines, and Braak staging was used to assess the degree of neurofibrillary AD pathology. The clinical characteristics of subjects with DLB with low vs high Braak stages were compared and the clinical diagnostic accuracy for subjects stratified according to Braak stage was determined. RESULTS: Only 27% of the subjects with DLB demonstrated both visual hallucinations and spontaneous extrapyramidal signs (EPS). The low Braak stage (0 to 2, n = 24) subjects had a higher frequency of visual hallucinations (65%) than did subjects with DLB with higher (3 to 6, n = 66) Braak stages (33%, p = 0.008), and showed a slightly greater but not significant degree of EPS. Although clinical diagnostic accuracy for DLB was relatively low (49%), it was higher for subjects with low (75%) compared to high (39%) Braak stages (p = 0.0039). CONCLUSIONS: The degree of concomitant AD tangle pathology has an important influence on the clinical characteristics and, therefore, the clinical diagnostic accuracy of DLB.

Aged↗

Performance on the dementia rating scale in Parkinson's disease with dementia and dementia with Lewy bodies: comparison with progressive supranuclear palsy and Alzheimer's disease.

BACKGROUND: The relation between dementia with Lewy bodies (DLB) and Parkinson's disease with dementia (PDD) is unknown. OBJECTIVES: To compare the cognitive profiles of patients with DLB and PDD, and compare those with the performance of patients with a subcortical dementia (progressive supranuclear palsy) and a cortical dementia (Alzheimer's disease). DESIGN: Survey of cognitive features. SETTING: General community in Rogaland county, Norway, and a university dementia and movement disorder research centre in the USA. PATIENTS: 60 patients with DLB, 35 with PDD, 49 with progressive supranuclear palsy, and 29 with Alzheimer's disease, diagnosed by either standardised clinical procedures and criteria (all PDD and Alzheimer cases and 76% of cases of progressive supranuclear palsy), or necropsy (all DLB cases and 24% of cases of progressive supranuclear palsy). Level of dementia severity was matched using the total score on the dementia rating scale adjusted for age and education. MAIN OUTCOME MEASURES: Dementia rating scale subscores corrected for age. RESULTS: No significant differences between the dementia rating scale subscores in the PDD and DLB groups were found in the severely demented patients; in patients with mild to moderate dementia the conceptualisation subscore was higher in PDD than in DLB (p = 0.03). Compared with Alzheimer's disease, PDD and DLB had higher memory subscores (p < 0.001) but lower initiation and perseveration (p = 0.008 and p=0.021) and construction subscores (p = 0.009 and p = 0.001). DLB patients had a lower conceptualisation subscore (p = 0.004). Compared with progressive supranuclear palsy, PDD and DLB patients had lower memory subscores (p < 0.001). CONCLUSIONS: The cognitive profiles of patients with DLB and PDD were similar, but they differed from those of patients with Alzheimer's disease and progressive supranuclear palsy. The cognitive pattern in DLB and PDD probably reflects the superimposition of subcortical deficits upon deficits typically associated with Alzheimer's disease.

Aged↗

Cognitive profiles differ in autopsy-confirmed frontotemporal dementia and AD.

BACKGROUND: Frontotemporal dementia (FTD) is currently distinguished from AD primarily on the basis of behavioral features because studies of cognition have shown negligible or inconsistent differences. However, the poor discriminability of cognitive measures may relate to reliance on imprecise clinically diagnosed groups. Therefore, a retrospective examination of neuropsychological test performance in autopsy-confirmed patients is warranted. OBJECTIVE: To compare the pattern of cognitive deficits exhibited by patients with autopsy-confirmed FTD and AD. METHODS: The profiles of cognitive deficits exhibited by patients with neuropathologic diagnosis of FTD (n = 14) or AD (n = 28) were compared. The Mattis Dementia Rating Scale (MDRS), letter and category fluency tests, Wechsler Intelligence Scale for Children-Revised block design test, Boston naming test, and clock drawing test were administered. RESULTS: Multivariate analysis of covariance controlling for age, education, and level of dementia revealed that patients with FTD performed significantly worse than patients with AD on letter and category fluency tests but significantly better on the MDRS memory subscale, block design test, and clock drawing test. A logistic regression model, validated in an independent clinical sample, used letter fluency, MDRS memory, and block design scores to correctly classify 91% of AD patients and 77% of FTD patients. CONCLUSIONS: A double dissociation in the pattern of cognitive deficits exhibited by FTD and AD patients was demonstrated. The FTD patients were more impaired than AD patients on word generation tasks (i.e., verbal fluency) that are sensitive to frontal lobe dysfunction but less impaired on tests of memory and visuospatial abilities sensitive to dysfunction of medial temporal and parietal association cortices.

Aged↗

Defective neuronal sprouting by human apolipoprotein E4 is a gain-of-negative function.

The apolipoprotein E (apoE) epsilon 4 allele (apoE4) is a major risk factor for neurodegenerative conditions, including Alzheimer's disease (AD). A role for apoE in regeneration of synaptic circuitry after neural injury has been shown in several in vitro studies in which apoE3 supports neuronal sprouting better than apoE4. We evaluated sprouting in an in vitro mouse organotypic hippocampal slice culture system derived from transgenic mice expressing apoE3 or apoE4, in which apoE-dependent granule cell mossy fiber sprouting in the presence of apoE4 is only 51% of the level of apoE3. Sprouting supported by apoE4 had a dose response opposite that by supported by apoE3: although increasing E3 expression increased sprouting, increasing E4 expression decreased sprouting, suggesting that the defect in E4 in supporting neuronal sprouting is a gain-of-negative activity. These results may have important pharmacogenomic implications for AD therapies that modulate apoE expression levels.

Alzheimer Disease↗

ALS and PDC of Guam: forty-year follow-up.

BACKGROUND: It was noticed in the mid-1950s that the incidence of ALS and parkinsonism--dementia complex (PDC) were much higher on Guam than anywhere else in the world. In 1958, a registry of patients and controls was established to ascertain the familial and genetic aspects of these diseases. Patients and individually matched controls and their relatives were registered from 1958 to 1963. The registry was updated and analyzed in 1998 through 1999. OBJECTIVE: To ascertain whether first-degree relatives of patients had a higher risk for developing ALS or PDC than relatives of controls. METHODS: During the period of 1958 to 1963, 126 new patients and 126 individually matched controls and their respective first-degree relatives and spouses were evaluated neurologically and registered. Forty years later, the number of new cases among the patient and control relatives were compared to an expected number of new cases based on the age- and sex-specific incidence of ALS and PDC in the population at large. RESULTS: From 1958 to 1999, there were 102 new ALS or PDC cases among relatives of patients and 33 among relatives of controls. These values were compared with the derived expected values. There were more observed than expected new cases among patients' relatives, and less observed cases than expected among the controls' relatives. CONCLUSIONS: Relatives of patients with ALS or PDC have significantly higher risks for developing the disease than the Guamanian population, whereas relatives of controls have significantly lower risks.

Aged↗

Clinical features and changing patterns of neurodegenerative disorders on Guam, 1997-2000.

BACKGROUND: In the 1950s, high-incidence ALS and Parkinson-dementia complex (PDC) were identified among Chamorros, the native inhabitants of Guam. Brains of patients with these syndromes showed widespread neurofibrillary tangles. Although ALS and PDC were reported to have dramatically declined in the 1980s, new cases are still encountered. Late-life dementia has received little study among Chamorros. METHODS: From 1997 to 2000, the authors evaluated newly referred and previously identified patients. They screened first-degree relatives of previous registries, and subjects aged 60 or older. Subjects who scored below a cognitive test cutoff or had symptoms or signs consistent with parkinsonism or ALS underwent psychometric testing, assessment by a neurologist, and laboratory studies as appropriate. Consensus diagnoses were made. RESULTS: The authors identified 194 Chamorros with ALS (n = 10), PD (n = 11), PDC (n = 90), or late-life dementia (n = 83). Mean ages at onset were 55 for ALS, 68 for PDC, 63 for PD, and 74 for dementia. Late-life dementia was more common in women, and met criteria for probable or possible AD. The APOE-epsilon 4 allele frequency was uniformly low regardless of neurologic diagnosis. CONCLUSIONS: The rapid decline of high-incidence ALS on Guam over the past 40 years suggests the contribution of a modifiable environmental factor. PDC remains relatively common, with an unchanged clinical picture apart from later age at onset. Dementia among elderly Chamorros (termed "Mariana dementia") resembles AD. Autopsy studies will clarify whether this dementia is related to AD pathology or represents a late-life neurofibrillary tangle syndrome more closely allied to PDC.

Age of Onset↗

Cholinergic deficits in the brains of patients with parkinsonism-dementia complex of Guam.

Patients with parkinsonism-dementia complex (PDC) of Guam showed moderate loss of choline acetyl transferase activity in the midfrontal and inferior parietal cortex, and severe loss in the superior temporal cortex. This deficit was similar to that seen in Alzheimer's disease and less severe than Lewy body disease. Thus, cholinergic deficits in the neocortex might contribute to some of the cognitive alterations in PDC of Guam.

Acetylcholine↗

Altered expression of the synuclein family mRNA in Lewy body and Alzheimer's disease.

The main objective of this study was to determine if levels of alpha-, beta- and/or gamma-synuclein mRNAs are differentially affected in brains of Lewy body disease (LBD) and Alzheimer's disease (AD) patients, compared to controls. In control cases, highest levels of expression were observed in the neocortex and the lowest in basal ganglia and substantia nigra. beta-Synuclein was the most abundant message (75-80%), followed by gamma-synuclein (10-15%) and alpha-synuclein (8-10%). Analysis of the superior temporal cortex, a region selectively affected in LBD and AD, showed that compared to controls, levels of alpha-synuclein were increased in cases of diffuse LBD (DLBD), levels of beta-synuclein were decreased in AD and DLBD, and levels of gamma-synuclein were increased in AD cases. This study suggests that a critical balance among products of the synuclein gene is important to maintain normal brain function and that alterations in this balance might be associated with neurodegenerative disorders.

Aged↗

TAU as a susceptibility gene for amyotropic lateral sclerosis-parkinsonism dementia complex of Guam.

BACKGROUND: A Guam variant of amyotrophic lateral sclerosis (ALS-G) and parkinsonism dementia complex (PDC-G) are found in the Chamorro people of Guam. Both disorders have overlapping neuropathologic findings, with neurofibrillary tangles in spinal cord and brain. The cause of ALS-G-PDC-G is unknown, although inheritance and environment appear important. Because neurofibrillary tangles containing tau protein are present in ALS-G-PDC-G, and because mutations in the tau gene (TAU) cause autosomal dominant frontotemporal dementia, TAU was examined as a candidate gene for ALS-G-PDC-G. METHODS: TAU was evaluated by DNA sequence analysis in subjects with ALS-G-PDC-G, by linkage analysis of TAU polymorphisms in an extended pedigree from the village of Umatac, and by evaluation of linkage disequilibrium with polymorphic markers flanking and within TAU. RESULTS: Linkage disequilibrium between ALS-G-PDC-G and the TAU polymorphism CA3662 was observed. For this 2-allele system, PDC and ALS cases were significantly less likely than Guamanian controls to have the 1 allele (4.9% and 2% vs 11.5%, respectively; Fisher exact P =.007). DNA sequence analysis of TAU coding regions did not demonstrate a mutation responsible for ALS-G-PDC-G. Analysis of TAU genotypes in an extended pedigree of subjects from Umatac showed obligate recombinants between TAU and ALS-G-PDC-G. Linkage analysis of the Umatac pedigree indicates that TAU is not the major gene for ALS-G-PDC-G. CONCLUSIONS: The genetic association between ALS-G-PDC-G implicates TAU in the genetic susceptibility to ALS-G-PDC-G. TAU may be a modifying gene increasing risk for ALS-G-PDC-G in the presence of another, as yet, unidentified gene.

Adult↗

Frequency of tau gene mutations in familial and sporadic cases of non-Alzheimer dementia.

BACKGROUND: Mutations in the tau gene have been reported in families with frontotemporal dementia (FTD) linked to chromosome 17. It remains uncertain how commonly such mutations are found in patients with FTD or non-Alzheimer dementia with or without a positive family history. OBJECTIVE: To determine the frequency of tau mutations in patients with non-Alzheimer dementia. PATIENTS AND METHODS: One hundred one patients with non-Alzheimer, nonvascular dementia, most thought to have FTD. Of these, 57 had a positive family history of dementia. Neuropathologic findings were available in 32. The tau gene was sequenced for all exons including flanking intronic DNA, portions of the 3' and 5' untranslated regions, and at least 146 base pairs in the intron following exon 10. RESULTS: Overall, the frequency of the tau mutations was low, being 5.9% (6/101) in the entire group. No mutations were found in the 44 sporadic cases. However, 6 (10.5%) of the 57 familial cases and 4 (33%) of the 12 familial cases with tau pathologic findings had mutations in the tau gene. The most common mutation was P301L. CONCLUSIONS: We conclude that tau mutations are uncommon in a neurology referral population with non-Alzheimer dementia, even in those with a clinical diagnosis of FTD. However, a positive family history and/or tau pathologic findings increase the likelihood of a tau mutation. There must be other genetic and nongenetic causes of FTD and non-Alzheimer dementia, similar to the etiologic heterogeneity present in Alzheimer disease.

Chromosomes, Human, Pair 17↗

Loss of brain tau defines novel sporadic and familial tauopathies with frontotemporal dementia.

Dementia lacking distinctive histopathology (DLDH) or frontotemporal lobe degeneration (FTLD) is the most common neuropathological diagnosis for sporadic frontotemporal dementias (FTDs). The hallmarks of DLDH are neuron loss and gliosis in the absence of any disease-specific brain lesion. Similar brain pathology is also seen in a familial FTD pedigree known as hereditary dysphasic disinhibition dementia 2 (HDDD2). Abnormality in the function or isoform composition of the microtubule binding protein tau is a prominent feature in the brains of many patients with sporadic and hereditary FTDs. Therefore, we studied the tau protein in different brain regions from DLDH and HDDD2 patients. Our results indicate that a selective loss of all six tau isoforms, but not tau mRNA, occurs in these brains compared to normal control and Alzheimer's disease brains. Loss of tau protein was identified by Western blot analysis of protein extracts from DLDH and HDDD2 brains in regions both with and without neuronal degeneration. Functionally, this loss of tau protein may be equivalent to pathogenic mutations in the tau gene identified in familial FTD with parkinsonism linked to chromosome 17 (FTDP-17). Thus, DLDH and HDDD2 are novel tauopathies with a unique mechanism of pathogenesis. The presence of tau mRNA in these brains suggests that the level of tau protein may be controlled posttranscriptionally, at the level of either translation or mRNA stability.

Aged↗

Lewy bodies and dementia.

The discovery of widely distributed Lewy bodies (LBs) in the brains of patients with dementia has stimulated much clinical and pathologic inquiry. This clinico-pathologic syndrome is now referred to as dementia with Lewy bodies (DLB). Diagnostic criteria for DLB proposed at a workshop in 1995 are receiving detailed scrutiny. The criteria are complex to apply, and appear to have high specificity, but variable sensitivity. Neuropathologic studies have been aided by the development of probes against alpha-synuclein, a key component of LBs. Widespread LBs in limbic or cortical areas contribute to dementia. Pharmacologic management of cognitive and behavioral symptoms in patients with DLB is being explored. There is evidence that cholinesterase inhibitors may have beneficial effects.

Humans↗

New approaches to diagnose and treat Alzheimer's disease: a glimpse of the future.

An explosion of scientific and clinical knowledge about Alzheimer's disease now provides a basis for selecting targets for treatment aimed at slowing progression of dementia or delaying the onset of or preventing Alzheimer's disease. The rationale that underlies several promising approaches to treatment are reviewed. Novel forms of treatment are most effective when combined with sensitive clinical methods to diagnose Alzheimer's disease as early as possible and to track its progression over time. Therefore, this article highlights findings concerning biological markers for Alzheimer's disease and the mild cognitive impairment syndrome and attempts to define a prodromal stage of Alzheimer's disease.

Aged↗