Constantin Bouras

A mutation in a case of early onset narcolepsy and a generalized absence of hypocretin peptides in human narcoleptic brains

We explored the role of hypocretins in human narcolepsy through histopathology of six narcolepsy brains and mutation screening of Hcrt, Hcrtr1 and Hcrtr2 in 74 patients of various human leukocyte antigen and family history status. One Hcrt mutation, impairing peptide trafficking and processing, was found in a single case with early onset narcolepsy. In situ hybridization of the perifornical area and peptide radioimmunoassays indicated global loss of hypocretins, without gliosis or signs of inflammation in all human cases examined. Although hypocretin loci do not contribute significantly to genetic predisposition, most cases of human narcolepsy are associated with a deficient hypocretin system.

Correlation of Alzheimer Disease Neuropathologic Changes With Cognitive Status: A Review of the Literature

Abstract Clinicopathologic correlation studies are critically important for the field of Alzheimer disease (AD) research. Studies on human subjects with autopsy confirmation entail numerous potential biases that affect both their general applicability and the validity of the correlations. Many sources of data variability can weaken the apparent correlation between cognitive status and AD neuropathologic changes. Indeed, most persons in advanced old age have significant non-AD brain lesions that may alter cognition independently of AD. Worldwide research efforts have evaluated thousands of human subjects to assess the causes of cognitive impairment in the elderly, and these studies have been interpreted in different ways. We review the literature focusing on the correlation of AD neuropathologic changes (i.e. &bgr;-amyloid plaques and neurofibrillary tangles) with cognitive impairment. We discuss the various patterns of brain changes that have been observed in elderly individuals to provide a perspective forunderstanding AD clinicopathologic correlation and conclude that evidence from many independent research centers strongly supports the existence of a specific disease, as defined by the presence of A&bgr; plaques and neurofibrillary tangles. Although A&bgr; plaques may play a key role in AD pathogenesis, the severity of cognitive impairment correlates best with the burden of neocortical neurofibrillary tangles.

Evidence supporting the existence of an activity-dependent astrocyte-neuron lactate shuttle

Mounting evidence from in vitro experiments indicates that lactate is an efficient energy substrate for neurons and that it may significantly contribute to maintain synaptic transmission, particularly during periods of intense activity. Since lactate does not cross the blood-brain barrier easily, blood-borne lactate cannot be a significant source. In vitro studies by several laboratories indicate that astrocytes release large amounts of lactate. In 1994, we proposed a mechanism whereby lactate could be produced by astrocytes in an activity-dependent, glutamate-mediated manner. Over the last 2 years we have obtained further evidence supporting the notion that a transfer of lactate from astrocytes to neurons might indeed take place. In this article, we first review data showing the presence of mRNA encoding for two monocarboxylate transporters, MCT1 and MCT2, in the adult mouse brain. Second, by using monoclonal antibodies selectively directed against the two distinct lactate dehydrogenase isoforms, LDH1 and LDH5, a specific cellular distribution between neurons and astrocytes is revealed which suggests that a population of astrocytes is a lactate ‘source’ while neurons may be a lactate ‘sink’. Third, we provide biochemical evidence that lactate is interchangeable with glucose to support oxidative metabolism in cortical neurons. This set of data is consistent with the existence of an activity-dependent astrocyte-neuron lactate shuttle for the supply of energy substrates to neurons.

Down patients: Extracellular preamyloid deposits precede neuritic degeneration and senile plaques

Using anti-SP28 (a polyclonal antibody to a 28 residue synthetic peptide homologous to the NH2-terminal region of the Alzheimer amyloid beta-protein) to investigate the cerebral cortex of 6 Down patients aged 6-55 y, we found that, besides senile plaques and congophilic vessels, extracellular deposits unrelated to degenerating neurites, tangle-bearing neurons or congophilic vessels were labelled. These deposits were similar to the extracellular deposits previously observed in the cerebral cortex of Alzheimer patients and non-demented individuals. The material accumulated in the deposits did not react with Congo red, thioflavine S or, on some occasions, silver salts and therefore might have been constituted by beta-protein precursors lacking the molecular conformation of amyloid fibrils. Age-related analysis of the cortical lesions in Down patients suggested that such extracellular deposits precede degenerating neurites and evolve into senile plaques.

Atypical form of Alzheimer's disease with prominent posterior cortical atrophy: A review of lesion distribution and circuit disconnection in cortical visual pathways

In recent years, the existence of visual variants of Alzheimers disease characterized by atypical clinical presentation at onset has been increasingly recognized. In many of these cases post-mortem neuropathological assessment revealed that correlations could be established between clinical symptoms and the distribution of neurodegenerative lesions. We have analyzed a series of Alzheimers disease patients presenting with prominent visual symptomatology as a cardinal sign of the disease. In these cases, a shift in the distribution of pathological lesions was observed such that the primary visual areas and certain visual association areas within the occipito-parieto-temporal junction and posterior cingulate cortex had very high densities of lesions, whereas the prefrontal cortex had fewer lesions than usually observed in Alzheimers disease. Previous quantitative analyses have demonstrated that in Alzheimers disease, primary sensory and motor cortical areas are less damaged than the multimodal association areas of the frontal and temporal lobes, as indicated by the laminar and regional distribution patterns of neurofibrillary tangles and senile plaques. The distribution of pathological lesions in the cerebral cortex of Alzheimers disease cases with visual symptomatology revealed that specific visual association pathways were disrupted, whereas these particular connections are likely to be affected to a less severe degree in the more common form of Alzheimers disease. These data suggest that in some cases with visual variants of Alzheimers disease, the neurological symptomatology may be related to the loss of certain components of the cortical visual pathways, as reflected by the particular distribution of the neuropathological markers of the disease.

Selective Disconnection of Specific Visual Association Pathways in Cases of Alzheimer's Disease Presenting with Balint's Syndrome

During a recent clinical and neuropathological evaluation of a large autopsy population of brains our attention was drawn to a subset of patients with Alzheimers disease (AD) presenting with a major impairment of visuospatial skills referred to as Balints syndrome. In this subset a shift in the distribution of certain pathological profiles had occurred in that the visual areas of the occipital and posterior parietal regions had an increased number of lesions, whereas the prefrontal cortex had fewer lesions than usually observed in AD. Previous quantitative analyses have shown that generally in AD, primary sensory cortical areas are less damaged than association areas of the frontal and temporal lobes, as demonstrated by the laminar and regional distribution of two neuropathological features of the disease, neurofibrillary tangles and neuritic (senile) plaques. The distribution of pathological lesions in the AD cases with Balints syndrome revealed that specific visual association pathways were disrupted, which are normally spared in AD. These data suggest that in some cases of AD, the particular psychological and neurological symptomatology may be caused by the selective loss of specific corticocortical systems, as reflected in the differential distribution of the neuropathological markers of the disease

Balint's syndrome in Alzheimer's disease : specific disruption of the occipito-parietal visual pathway

Previous quantitative neuropathologic analyses have shown that the association cortices of the temporal and frontal lobes are more damaged than the visual regions of the occipital lobe in Alzheimers disease. In the present paper, we report on a subpopulation of Alzheimers disease patients presenting a visual defect referred to as Balints syndrome, and displaying a global caudal shift in pathology. Balints syndrome is a defect in visuospatial skills, and the distribution of pathology suggests that the connections underlying this functional component of the visual system are devastated, whereas they are normally spared in Alzheimers disease. These results suggest that multiple subtypes of Alzheimers disease exist with differential distribution of pathology and corresponding neurologic symptomatology, and that neuritic plaque and neurofibrillary tangle formation involve the loss of specific corticocortical projections associated with specific functional deficits and identifiable neurologic syndromes.

Cerebral cortex pathology in aging and Alzheimer's disease: a quantitative survey of large hospital-based geriatric and psychiatric cohorts

In order to explore the relationships between the involvement of specific neuronal populations and cognitive deterioration, and to compare the hierarchical patterns of cortical involvement in normal brain aging and Alzheimers disease, over 1200 brains from elderly subjects without cognitive deficits, as well as from patients with age-associated memory impairment and Alzheimers disease, were examined. Our results suggest that the neuropathological changes associated with normal brain aging and Alzheimers disease affect select cortical circuits at different points in time. Extensive hippocampal alterations are correlated with age-associated memory impairment, whereas substantial neurofibrillary tangle formation in neocortical association areas of the temporal lobe is a prerequisite for the development of Alzheimers disease. Despite several lines of evidence involving amyloid deposit in the pathogenesis of Alzheimers disease and Downs syndrome, our observations indicate that there is no correlation between senile plaque densities and degree of dementia in both disorders. In contrast to younger elderly cases, in the ninth and tenth decades of life, there is a differential cortical involvement in that parietal and cingulate areas are early affected in the course of Alzheimers disease, and neocortical senile plaques densities are strongly correlated with the severity of dementia. Moreover, Alzheimers disease symptomatology is characterized in these very old patients by high neurofibrillary tangle densities in the anterior CA1 field, but not in the entorhinal cortex and inferior temporal cortex. These observations are discussed in the light of the hypothesis of global corticocortical disconnection and with respect to the notion of selective neuronal vulnerability in Alzheimers disease.

A monoclonal antibody to non-phosphorylated neurofilament protein marks the vulnerable cortical neurons in Alzheimer's disease

Various cytoskeletal proteins have been implicated in the formation of neurofibrillary tangles in Alzheimers disease. A monoclonal antibody to non-phosphorylated neurofilament protein labels a distinct subset of pyramidal cells in the normal human cortex which have a distribution very similar to that of neurofibrillary tangles in brains from patients with Alzheimers disease. In addition, regions and layers that normally contain a high density of such cells, in Alzheimers disease, have large numbers of neurofibrillary tangles and few remaining immunoreactive cells.

Differential distribution of neurofibrillary tangles in the cerebral cortex of dementia pugilistica and Alzheimer's disease cases.

SummaryHead trauma has been associated with the occurrence of Alzhiemers disease and plays a clear role in the etiopathogenesis of the boxers encephalopathy referred to as dementia pugilistica. Neurofibrillary tangles (NFT), one of the pathological hallmarks of Alzheimers disease are observed in very high densities in the brains of former professional boxers suffering from dementia pugilistica. In Alzheimers disease, NFT display striking regional and laminar distribution patterns that have been correlated with the localization of neurons forming specific corticocortical connections. In dementia pugilistica cases, NFT were concentrated in the superficial layers in the neocortex, whereas in Alzheimers disease they predominated in the deep layers. Thus, the association cortex of brains from dementia pugilistica patients demonstrated an inverse NFT distribution as compared to Alzheimers disease. This finding suggests that a more circumscribed population of cortical pyramidal neurons might be affected in dementia pugilistica than in Alzheimers disease.