Jean Constantinidis

Pick’s Disease

Study of 32 cases of Pick’s lobar atrophy offers evidence that one must distinguish some particular histopathological forms, characterized by the presence or absence of argyrophilic inclusions and/or

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

Vascular dementia: A clinicopathological study

We have reviewed the clinical and pathological records of 40 aged patients who showed only vascular lesions on histological examination. They were followed up for 3.5 +/- 6.3 years before death, and in 28 cases the diagnosis of dementia was done during life. Demographic data, vascular and systemic illnesses, psychiatric neurological and neuropsychological disturbances, and pathological findings were compared between demented and non-demented patients. The number of strokes, several neurological and almost all neuropsychological disturbances, the volume of macroscopic cerebral infarct, especially in frontal, occipital and basal regions, the lacunar state and the white matter lesions, were significantly greater in demented patients. However most of them had less than 100 ml3 of brain infarct. The relative influence of each type of cerebral vascular lesion upon the dementia syndrome was determined by means of multivariate analysis. The volume of macroscopic cerebral infarct, the white matter lesion and the lacunar state showed quite similar contributions to mental deterioration.

Neurofibrillary pathology in brains of elderly schizophrenics treated with neuroleptics

Summary The clinical histories of 102 schizophrenics who died at 70 years of age or older were reviewed. The incidence of neurofibrillary tangles (NFTs) was two times higher in the patients who received (74%) than in those who did not receive (36%) treatment with neuroleptics. The development of NFTs started earlier in the treated group. Further studies comparing brains of nine schizophrenics (average age, 86 years) who did not receive treatment with neuroleptics and seven age-matched cases who received neuroleptics, both with neurofibrillary pathology and neuritic plaques, showed characteristic differences. The numerical density of NFTs was slightly greater in the cornu Ammonis (CA1 and CA2) and subiculum of treated patients. Significantly lower numerical density and lower percentage of pretangles (stage 0) and early and mature tangles (stages 1 and 2) and increased number of end-stage tangles (stage 3) were found in the CA, subicular complex, and cerebral cortex of the treated group. These changes suggest accelerated neurofibrillary degeneration in neurons. A significant increase in the numerical density of τ-1-positive plaques was observed in sector CA1 of the CA (from 0.15/mm2 to 17.36/mm2), subiculum (from 0/mm2 to 16.62/mm2), temporal cortex (from 0.14/mm2 to 9.46/mm2), and occipital cortex (from 0.08/mm2 to 0.39/mm2). The higher numerical density of τ-1—positive plaques, but not of 4G8-positive plaques, indicates acceleration of neurofibrillary changes in the plaques of patients treated with neuroleptics. The significant decrease (20–25%) in the numerical density of neurons in the pyramidal layer of sectors 2–4 in the CA appears to be associated with accelerated neurofibrillary changes in neurons and plaques in the treated group. This study demonstrates that chronic treatment with neuroleptics—not schizophrenia itself—significantly increases the risk of more frequent, earlier, and accelerated development of neurofibrillary pathology in the brains of elderly schizophrenics.

An improved immunohistostaining procedure for peptides in human brain

Floating sections from human brains immersed for more than forty years in formalin, or from brains freshly fixed for a short time are treated by KMnO4-Pals modified solutions to suppress the endogenous peroxidase activity before using the peroxidase-antiperoxidase method (PAP), or to remove the autofluorescence of lipofuscin, which is very intense in brains from old patients, before using the immunofluorescence method. Following this, immersion of sections in NaOH and H2O2 allows for the demasking of antigenic sites. These treatments enhance the immunolabelling considerably, with results comparable to those obtained with freshly fixed tissues, and facilitate the discrimination between specifically and unspecifically stained structures.

Delta Sleep-Inducing Peptide in the Rat Brain: An Immunohistological Microscopic Study

The authors have developed a method which makes it possible, for the first time, to visualize the delta sleep-inducing peptide in histological preparations and study it under the light and fluorescence microscope. Their research builds on Monnier s discovery, in 1963, of a humoral hypnogenic factor in rabbits which was subsequently isolated and identified as a nonapeptide. Dubbed delta sleep-inducing peptide (DSIP), this factor was later detected in rat brain by radioimmunoassay but has eluded histological visualization until recently. In their work, the authors used an anti-DSIP antiserum suitable for immunohistological purposes. Two indirect immunohistological methods (PAP and immunofluorescence) allowed them to visualize, for the first time, structures containing specific DSIP-like immunoreactivity in some areas of the rat brain: indusium griseum, nucleus septi lateralis, hippocampus, striae longitudinales of Lancisi , bandeletta diagnalis of Broca, pallidum, hypothalamus, hypophysis and neocortex. Some DSIP pathways seem likely: (1) indusium griseum - striae longitudinales - hippocampus; (2) nucleus septi lateralis - striae longitudinales , bandeletta diagonalis - hippocampus; (3) neurons of the pyramidal layer of the hippocampus - gyrus dentatus; (4) pallidum - commissura of Ganser - hypothalamus. The possible correlations between DSIP neurons and neurons with other neurotransmitters are discussed. In preliminary clinical trials, DSIP has shown promise for the treatment of insomnia and the opiate and alcohol withdrawal syndromes.(ABSTRACT TRUNCATED AT 250 WORDS)

Paradoxical sleep and brain catecholamines in the rat after single and repeated administration of alpha-methyl-paratyrosine

This study is concerned with the role of catecholamines (CA) in the regulation of paradoxical sleep (PS) in the rat. Alpha-methyl-paratyrosine (alphaMPT), an inhibitor of tyrosine hydroxylase, was used in a multiple administration schedule in order to avoid toxic effects. From 2 to 10 doses of 75 mg/kg of alphaMPT, a progressive reduction of green fluorescence occurred in CA cell bodies as well as in terminals. The green fluorescence reduction was faster in dopaminergic than in noradrenergic neurons, and faster in cell bodies than in terminals. Sleep recordings showed a slight increase of PS after one or two doses of 75 mg/kg of alphaMPT, and a dose-related decrease after 3-7 injections. After two doses of 75 mg/kg, the number of PS phases was significantly increased. This can be due to the release of a non-CA PS primer mechanism. These experiments support the view that an intact synaptic transmission in CA neurons is necessary for the realization of PS.

Substance P immunoreactivity in Alzheimer disease: a study in cases presenting symmetric or asymmetric cortical atrophy.

Substance P-like immunoreactivity was visualized by immunohistochemical methods in 20 postmortem brains: 6 senile, 4 presenile Alzheimer dementia (AD), 3 AD with interhemispheric asymmetric cortical atrophy, and 7 control cases. For all pathological cases, the SP-like immunoreactivity was significantly reduced in the neocortical areas and in the hippocampus. This contrasted with an enhanced SP-like immunoreactivity in the pallidum and the substantia nigra in AD brains and a more pronounced SP-like immunoreactivity in the more atrophic side in the asymmetrically atrophied brains.

Tyrosine hydroxylase-immunoreactive neurons in paraventricular and supraoptic nuclei of the human brain demonstrated by a method adapted to prolonged formalin fixation

We studied the distribution of tyrosine hydroxylase (TH) immunoreactive (IR) neurons in the adult human hypothalamus using a modification of the peroxidase-antiperoxidase immunohistochemical method which can be applied on autopsy brain material following prolonged formalin fixation. We observed that most of the TH-IR perikarya localized within the paraventricular (PVN) and supraoptic (SON) nuclei were large and showed homogeneous staining over the entire cytoplasm and processes. These results show that in the human brain a large population of neurons within the neurosecretory nuclei are able to synthesize a catecholamine.

Hypothesis regarding amyloid and zinc in the pathogenesis of Alzheimer disease: potential for preventive intervention.

Summary:In Alzheimer disease (AD) the “primum movens” is amyloid (AM) production within the cerebral cortex. Cerebral AM alone may be asymptomatic. Clinical symptoms (amnesia, instrumental disorders) appear when AM induces neighboring neuritic alterations: paired hellical filaments (PHF), and distant neuronal body lesions: neurofibrillary tangles (NFT), i.e. pathologic synthesis of abnormal proteins. The timing for these inductions should be equal to the survival after the onset of amnesia: a mean of 14 months for the induction of the peri-AM neuritic alterations and a mean of 52 months for the induction of the distant to AM NFT in the hippocampic neuronal bodies. We postulate that the AM induces this neuronal pathology by producing functional zinc deficiency. The hippocampal zinc decreases in AD. The mechanism of the AM-induced zinc deficiency may be the following: the AM is formed within the walls of capillaries (senile plaques), disturbs the blood-brain barrier (BBB) and toxic metals (i.e., iron, aluminum, mercury) may enter in the cerebral cortex, where they displace the zinc in some enzymes. NFT and neuronal dysfunction may be produced by deficiency of the following zinc enzymes: (a) those of DNA metabolism, inducing abnormal DNA in the neurons and therefore abnormal protein synthesis, PHF-NFT; (b) those of glutamate (GLU) dehydrogenase (which catabolizes GLU), resulting in an excitotoxic increase of GLU; (c) those of neuronal detoxification, superoxydedismutase, carbonic anhydrase, and lactate dehydrogenase leading to neuronal toxicity. During the window between AM formation and PHF-NFT production (14-52 months), a zinc complex crossing the BBB may be useful to prevent AM of producing PHF-NFT, and also to normalize neuronal detoxification. By the zinc treatment, AM should remain asymptomatic and clinical dementia should be prevented.