Showing papers by "Pietro Tiraboschi published in 2000"

Cholinergic dysfunction in diseases with Lewy bodies.

Abstract: Objective: To evaluate cholinergic activity in diseases with Lewy bodies (LB; LB variant of AD [LBV], diffuse LB disease [DLBD], and Parkinson’s disease [PD]) to determine if 1) AD changes are requisite to cholinergic dysfunction, 2) cholinergic activity declines to the same extent in neocortical and archicortical areas, and 3) cholinergic loss is influenced by APOE genotype. Background: Like AD, diseases with LB are associated with decreased choline acetyltransferase (ChAT) activity. Increased APOE e4 allele frequency has been reported in LBV. Whether APOE genotype affects cholinergic function in LBV remains unclear. Methods: An autopsy series of 182 AD (National Institute on Aging and Consortium to Establish a Registry for Alzheimer’s Disease criteria), 49 LBV, 11 PD, 6 DLBD, and 16 normal control (NC) subjects. APOE genotype and ChAT activity (nmol/h/100 mg) in the midfrontal and hippocampal cortices were determined. Results: Mean midfrontal ChAT activity was markedly reduced in diseases with LB (LBV: 53.3 ± 39.0; PD: 54.8 ± 35.7; DLBD: 41.3 ± 24.8) compared to NC (255.4 ± 134.6; p p with (LBV) and without (DLBD and PD) AD pathology. Although mean ChAT activity for LBV was less than half that for AD in the midfrontal cortex, it was similar to that for AD in the hippocampus (LBV: 243.5 ± 189.7; AD: 322.8 ± 265.6; p > 0.05). However, hippocampal ChAT activity for both AD and LBV was lower than that for NC (666.5 ± 360.3; p Conclusions: Marked losses in midfrontal ChAT activity occur in diseases with LB, independent of coexistent AD changes. A greater midfrontal, as opposed to hippocampal, cholinergic deficit may differentiate LBV from AD. The lack of a relationship between e4 allele dosage and midfrontal ChAT activity suggests that other factors may play a role in its decline in LBV.

Diagnostic accuracy of dementia with Lewy bodies.

Abstract: Background Diagnostic criteria for dementia with Lewy bodies (DLB) are still evolving. No data exist on prospective differentiation of DLB and Alzheimer disease (AD). Objective To examine the clinician's diagnostic accuracy for DLB and analyze factors contributing to false-positive DLB diagnoses. Methods A prospective series of 10 patients with clinically diagnosed DLB who came to autopsy was compared with 32 autopsy-confirmed cases of DLB (27 Lewy body variant, 5 diffuse Lewy body disease) and 20 autopsy-confirmed cases of AD (matched on age, sex, education, and initial Mini-Mental State Examination score) with regard to distinguishing and/or confounding clinical features. Results The clinical diagnostic accuracy for DLB was 50%, with 5 of the 10 patients clinically presumed to have DLB confirmed at autopsy. Of the 5 misdiagnosed cases, 4 had AD and 1 had progressive supranuclear palsy. The misdiagnosed DLB cases who had pure AD had fewer hallucinations (25%) than those with Lewy body variant (63%) or diffuse Lewy body disease (100%) (P= .048); however, an equal amount of spontaneous (in the absence of neuroleptics) extrapyramidal signs was found. There were no differences among groups with regard to daily fluctuations in cognition or falls. Compared with the AD control group, the misdiagnosed DLB cases with pure AD showed significantly more spontaneous extrapyramidal signs (P≤.02). Conclusions The clinician's diagnostic accuracy for DLB was poor. Early spontaneous extrapyramidal signs in AD were associated with false-positive clinical diagnoses of DLB. The distinction between DLB and AD may be improved by greater emphasis on hallucinations.

The decline in synapses and cholinergic activity is asynchronous in Alzheimer's disease.

Abstract: Objective: To determine the timing of cholinergic loss and reduction of synapses in AD. Background: Decrements in neocortical synapses and cholinergic function occur in AD and correlate with cognitive decline. However, how early in the disease process these changes appear remains unclear. Methods: An autopsy series of 89 demented patients with pathologically confirmed AD (National Institute on Aging and Consortium to Establish a Registry for Alzheimer’s Disease criteria) and 18 normal control subjects (NC). The AD cases were stratified according to their last Mini-Mental State Examination (MMSE) score prior to death as mild (MMSE = 20; n = 14), moderate (MMSE = 10 to 19; n = 20), severe (MMSE = 1 to 9; n = 29), and very severe (MMSE = 0; n = 26). Midfrontal (MF) synapse density was assessed by dot-immunobinding assay for synaptophysin (Syn), and MF choline acetyltransferase (ChAT) activity was determined using standard protocols. Results: Compared with those in NC, neither Syn nor ChAT was appreciably reduced in patients with mild AD at death. Decline of ChAT was significant only in AD patients who died in the late stages of the disease and was maximal in those who had more severely deteriorated. In contrast, decline of Syn was significant and almost maximal in patients in intermediate or moderate stages. Consequently, the last MMSE score prior to death correlated more strongly with ChAT than Syn when the AD cohort included more impaired patients ( r = 0.46 versus 0.40). The reverse occurred when only less impaired patients (MMSE = 10) were included in the analyses ( r = 0.28 versus 0.64). There was only a modest correlation between Syn and ChAT activity. Conclusions: The results imply an asynchronous pattern of decline of synapses and cholinergic activity, with Syn loss preceding ChAT decrements. However, neither MF synapse reduction nor cholinergic dysfunction appears to be an early event in AD.

E4 allele dosage does not predict cholinergic activity or synapse loss in Alzheimer's disease.

Abstract: Objective: To investigate the relationship between apolipoprotein E ( APOE ) genotype and both cholinergic dysfunction and synapse loss in AD. Background: A reduction in neocortical synapses and marked losses in the cholinergic system occur in AD. It has been suggested that the number of APOE e4 alleles is inversely related to choline acetyltransferase (ChAT) activity, thereby influencing cholinergic function. Whether APOE genotype may influence neocortical synapse loss remains unclear. Methods: An autopsy series of 182 patients with AD (National Institute on Aging and Consortium to Establish a Registry for Alzheimer’s Disease criteria) and 16 normal controls (NC). APOE genotype was determined in blood samples or in postmortem brain tissue. Midfrontal synapse counts (AU/μg) were quantified by a dot-immunobinding assay for synaptophysin (Syn). Midfrontal ChAT activity (nmol/h/100 mg) was assessed using standard assays. Results: Mean midfrontal ChAT activity and Syn were both significantly reduced in patients with AD compared with NC. The relationship between ChAT activity and number of e4 allele copies in AD was complex, with ChAT activity lower in patients with either two or no e4 alleles compared with those with one e4 allele. There was no relationship between APOE genotype and synapse loss in AD. Syn density was almost identical across the three genotypes. Conclusions: Unlike other studies, we failed to detect a linear relationship between ChAT activity and number of e4 allele copies in the midfrontal cortex of this large sample of patients with AD. Our data also show that the presence of e4 allele does not influence midfrontal synapse loss in AD. This suggests that factors other than APOE genotype may be operative in the decline in midfrontal cholinergic function and synapses seen in AD.

Apolipoprotein E and intronic polymorphism of presenilin 1 and alpha-1-antichymotrypsin in Alzheimer's disease and vascular dementia.

Abstract: Apolipoprotein E (ApoE) genotypes, presenilin 1 (PS-1) and α1-antichymotrypsin (ACT) polymorphism and the association of the genotypes were examined in patients with Alzheimer’s disease (AD