Yves Robitaille

The Neuropathology of CAG Repeat Diseases: Review and Update of Genetic and Molecular Features

Classification of inherited neurodegenerative diseases is increasingly based on their genetic features, which supplement, clarify, and sometimes replace the older clinical and pathologic schemata. This change has been particularly rapid and impressive for the CAG repeat disorders. In Huntingtons disease, X‐linked spinobulbar muscular atrophy, dentatorubropallidoluysian atrophy, and a series of autosomal dominant cerebellar atrophies, genetic advances have resolved many nosologic issues, and opened new avenues for exploration of pathogenesis. In this review, we summarize classic and current concepts in neuropathology of these CAG repeat diseases.

Phylogenetic analysis of the mitochondrial genome indicates significant differences between patients with Alzheimer disease and controls in a French-Canadian founder population

The activity of cytochrome oxidase (CO), the terminal enzyme of the mitochondrial electron transport chain, has been reported to be lower in the brains of Alzheimer disease (AD) patients. This suggests that a modification of mitochondrial DNA (mtDNA) may be responsible for this decrease of CO activity. Many mtDNA variants were found by different studies at a higher frequency in AD patients, suggesting that mtDNA variants could confer a genetic susceptibility to AD. In this study, we sequenced the entire mitochondrial genome region that encompasses the three CO genes and the 22 mitochondrial tRNA in 69 AD patients and 83 age-matched controls. We detected a total of 95 mtDNA variants. The allele frequencies of the majority of these variants were similar in patients and controls. However, a haplotype composed of three different modifications (positions: 5633, 7476, and 15812) was present in three of the 69 late-onset AD patients (4.3%) and also in 1 of 16 early-onset AD patients (6.2%) but not in control individuals. Given that one of these variants (15812) has already been shown to be associated with another neurodegenerative disease and that all three modifications are relatively conserved and their frequencies in the general population is only 0.1%, our data suggest that the presence of this haplotype may represent a risk factor for AD. We also found a significant association (P < 0.05) of two other variants at positions 709 (rRNA 12S) and 15928 (tRNA(Thr)). These two mtDNA variants are three times more frequent in control individuals compared with AD patients, suggesting that they may be protective against AD.

Distribution of brain cytochrome oxidase activity in various neurodegenerative diseases

Cytochrome oxidase (CO) is the terminal complex of the mitochondrial respiratory chain which generates ATP by oxidative phosphorylation. We have measured CO activity in six different brain regions of patients with senile dementia of Alzheimer type (SDAT, n = 10), presenile dementia of Alzheimer type (PDAT, n = 10), Lewy body dementia with SDAT (LBD, n = 5), cerebrovascular dementia (CVD, n = 10), Parkinson dementia (PD, n = 5), and in controls (n = 8), as all confirmed by neuropathological evaluation. CO activity was lower in the frontal and parietal cortex of SDAT patients compared to controls. Patients with PDAT, LBD, CVD or PD showed no significant reduction of the enzymatic activity in the six regions studied. Our results show that reduced CO activity might play a role in the physiopathology of senile dementia of Alzheimer type.

Immunohistochemical studies of adult human glial cells

n Abstractn n Using immunohistochemical techniques, we examined major histocompatibility complex (MHC) antigen expression on astrocytes, oligodendrocytes, and macrophages-microglia derived from surgically resected tissue from young adults and maintained in dissociated cell cultures supplemented with either fetal calf or human AB serum. The majority of these cells in culture expressed class I MHC antigens. MHC class II expression was observed on only a restricted proportion of astrocytes either under basal or induction conditions (γ-interferon, activated lymphocyte supernatants), on the majority of macrophages-microglia under inducing conditions, and not on oligodendrocytes. MHC class II expression on astrocytes in culture did not correlate with the extent of in situ gliosis or with in vitro cell morphology. MHC antigen expression was not detected in situ immunohistochemically. These data extend observations on the dissociation of in vivo and in vitro expression of MHC antigens on glial cells. The apparent greater expression of MHC class II antigens on macrophages-microglia compared to astrocytes raises the issue of the relative roles of each of these cell types in promoting immune reactivity under pathologic conditions.n n

Apo E allele frequencies in Alzheimer's disease, Lewy body dementia, Alzheimer's disease with cerebrovascular disease and vascular dementia.

Apolipoprotein (Apo E) was genotyped using a fluorescent PCR-RFLP assay in 187 patients with a probable or possible clinical diagnosis of sporadic Alzheimers disease (AD) and in 166 autopsied patients with dementia (21 presenile AD, 70 senile AD, 18 Lewy body dementia (LBD), 38 AD with cerebrovascular disease (AD-CVD), 19 vascular dementia). The relative epsilon 4 allele frequency was 0.472 in LBD, 0.513 in AD-CVD, 0.405 in presenile AD, 0.364 in senile AD, and 0.079 in vascular dementia. The relative epsilon 2 allele frequency was 0.211 in vascular dementia, 0.083 in LBD, 0.047 in presenile AD, 0.100 in senile AD and 0.039 in AD with CVD. We infer that apo E is a major risk factor for structural phenotypes of dementia involving AD, alone or in conjunction with another pathology. In addition, the epsilon 2 allele is likely to represent a risk factor for vascular morbidity, as the relative epsilon 2 allele frequency was 0.211 in patients with vascular dementia compared with 0.144 in elderly controls.

Deficits in the somatostatin SS1 receptor sub-type in frontal and temporal cortices in Alzheimer's disease

The aim of this study was to evaluate the possible differential alterations of somatostatin (SRIF) receptor sub-types in Alzheimers disease (AD). Consequently the binding profile of cortical SRIF receptors were examined in normal and AD brains using non-selective ([125I]Tyr0, D-Trp8-SRIF14) and SS1 receptor sub-type-selective ([125I]SMS204-090) radioligands. Maximal binding capacities, but not affinities, were reduced for both ligands in the temporal cortex. In contrast, only the maximal binding capacity of [125I]SMS204-090 was significantly reduced (68%) in the frontal cortex; no alterations were detected using the non-selective probe. This reveals that while the maximal binding capacity of the SS1 receptor sub-type is altered in frontal and temporal cortices in AD, other putative cortical SRIF receptor classes (such as SS2 sites) are not as broadly affected. This could be of significance for eventual therapeutic approaches using SRIF-related analogues.

Selective delayed alternation deficits in dominantly inherited olivopontocerebellar atrophy

In order to characterize more completely the nature of the frontal lobe-type cognitive changes in patients with dominantly inherited olivopontocerebellar atrophy (OPCA) we administered two tasks sensitive to frontal system dysfunction, delayed alternation (DA) and delayed response (DR), to 12 patients from one OPCA family. Affected members from this family have previously been shown to have a marked and widespread cerebral (including frontal) cortical cholinergic reduction as severe as that observed in Alzheimers disease. Performance on DA, but not on DR, was significantly impaired in the OPCA patients compared to that in the controls. We suggest that the DA deficits in OPCA could be a consequence of a loss of cholinergic innervation to orbitofrontal or possibly temporal cortical areas and/or damage to the integrity of the cerebello-frontal neuronal connections.

Lymphangiomyomatosis syndrome with hyperparathyroidism. A case report

A 48‐year‐old woman presented with the classical clinicopathological features of the lymphangiomyomatosis syndrome. After a three year stable period, there was the onset of a rapidly progressive downhill course unresponsive to dietary, bronchodilator and corticosteroid therapy. Pathological findings were characterized by widespread pulmonary, thoracic duct and lymph node involvement. There was a mediastinal lymphangiomyoma growing within the distal thoracic duct, and a similar lesion within the left kidney which could clinically mimic an angiomyolipoma. Comments are also made on the finding of a parathyroid adenoma. The physiopathology and possible resemblance to “formes frustes” of tuberous sclerosis are discussed.

New Patterns of Intraneuronal Accumulation of the Microtubular Binding Domain of tau in Granulovacuolar Degeneration

Sixteen brains from Alzheimers disease (AD) patients with varying duration of dementia were studied using the monoclonal antibody (mAb) 6.423 raised against the three repeated domains of the tau protein, and named the paired helical filament (PHF) core. In Ammons horns of the AD cases 6.423 mAb, in addition to immunoreacting with neurofibrillary tangles (NFTs), dystrophic neurites, and plaquelike structures, also recognized a subpopulation of granulovacuolar degeneration elements (GVD). A new immunoreactive structure, a spherical inclusion, was also stained by 6.423. The immunoreactive GVD elements and the spherical inclusion were found in the aged controls (> 65 years of age) and in non-AD dementia cases, as well. The staining of the GVD was markedly decreased when the tissue was preincubated with alkaline phosphatase. In contrast, NFTs and the spherical inclusions resisted dephosphorylation. Neurons containing the spherical inclusion frequently lacked immunoreactive intracellular NFTs. Due to the similar immunohistochemical properties between the spherical bodies and immunoreactive NFTs, we named this new inclusion PHF core body. Our results suggest that the PHF core body may represent a successful attempt by hippocampal neurons to restrict the PHF core expression. Thus, the failure of this mechanism may lead to the NFT formation in a range of dementing processes. Alternatively, the PHF core body may be an early stage in the NFT formation. (J Geriatr Psychiatry Neurol 1992;5:132–141).

Calcium Channel Binding Sites in Human Braina

The existence of highly specific binding sites for various classes of calcium channel blockers has been demonstrated in various tissues including brain.- It now appears that different classes of calcium antagonists such as the 1,4-dihydropyridines, the phenylalkylamines, and diltiazem interact with different binding sites that are allosterically coupled to induce their effects.- In the mammalian nervous system, calcium antagonist binding sites are heterogeneously distributed being mostly concentrated in areas enriched with synaptic contacts such as the hippocampus and the cortex.- However, these sites have not been characterized in much detail in human brain. Only a few reports have described their existence and autoradiographic distribution in postmortem tiss~es.6*.~ We report here on the presence of calcium channel binding sites in human brain using postmortem as well as fresh cortical biopsied tissues.