Deafferentation-induced abnormal neurofilament phosphorylation in red nucleus neurones.

Hippocampal deafferentation has been proposed as a pathogenetic mechanism for neurofibrillary tangle (NFT) formation in human mesolimbocortical dementia. We previously developed a rodent model of hippocampal deafferentation involving bilateral destructive lesions of the ventrotegmental area (VTA), septum of the medial forebrain and entorhinal cortex combined with pharmacological inhibition of serotonin 5-HT2 and dopamine D1 receptors. Unexpectedly, we observed an alteration in phosphorylated neurofilament protein immunoreactivity and argyrophilia in magnocellular neurones of the red nucleus.

Neuronal argyrophilia and phosphorylated neurofilament accumulation secondary to deafferentation.

This work tests the hypothesis that deafferentation caused by experimental brain lesions leads to the appearance of perikaryal argyrophilia and the accumulation of phosphorylated cytoskeletal proteins which are potential precursors for neurofibrillary tangle formation. Destructive lesions of the ventral tegmental area, the septum of the medial forebrain and the entorhinal cortex, when combined with systemic administration of a D-1 dopamine receptor antagonist, produced transsynaptic changes in neurons of the hippocampal formation in the midbrain. Abnormally phosphorylated neurofilament protein was demonstrated immunohistochemically in the cytoplasm of mesencephalic pyramidal neurons, particularly in the red nucleus.

Denervation induced abnormal phosphorylation in hippocampal neurons.

This study demonstrates that combined dopaminergic and cholinergic denervation of the hippocampus results in the appearance of morphologically altered, Tau reactive, apical dendrites of granule cells in the rat dentate gyrus. The denervated granule cells and their apical dendrites also display immunoreactivity to a mitogen-activated protein kinase, ERK-1, and also evidence of abnormal phosphorylation of these dendrites as revealed by SMI-31 immunoreactivity. Dopaminergic denervation alone also causes mitogen activated protein kinase reactivity without the Tau-reactive apical dendrities.

Immunoreactive changes resulting from dopaminergic denervation of the dentate gyrus of the rat hippocampal formation.

The hypothesis that dopaminergic denervation is a factor in the development of hippocampal neurofibrillary tangles was tested in the rat with bilateral stereotaxic 6-hydroxydopamine (6-OHDA) lesions of the ventral tegmental area (VTA). This led to the postsynaptic appearance of cytoplasmic immunoreactivity to ubiquitin in neurons of the dentate gyrus. An additional postsynaptic morphologic abnormality was seen when the animals were pretreated with the D1 dopaminergic antagonist SCH 23390 and the VTA lesions were combined with septal lesions affecting cholinergic and GABAergic neurons projecting to the dentate gyrus.

Analysis of the prion protein gene in thalamic dementia.

Thalamic degenerations or dementias are poorly understood conditions. The familial forms are (1) selective thalamic degenerations and (2) thalamic degenerations associated with multiple system atrophy. Selective thalamic degenerations share clinical and pathologic features with fatal familial insomnia, an autosomal dominant disease linked to a mutation at codon 178 of the prion protein (PrP) gene that causes the substitution of asparagine for aspartic acid (178Asn mutation).

Arrested maturation of cerebral neurons, axons and myelin: a new familial syndrome of newborns.

A new lethal familial syndrome of unknown etiology is described in two male siblings who died in the newborn period. Both had corneal edema and were hypotonic, requiring assisted ventilation at birth. Neuropathological findings included an immature appearance of neocortical neurons, with cortical architecture similar to that normally seen in an infant of 5 months gestational age.

Hippocampal pyramidal cell response to 6-hydroxydopamine lesions of the rat ventral tegmental area.

The occurrence of neurofibrillary tangles (NFT) in the perforant pathway in association with dopaminergic cell loss in the ventral tegmental area (VTA) in human mesolimbic dementia, raises the possibility that denervation is a cause of NFT formation. This was tested in the rat by lesioning dopaminergic neurons which project to the hippocampus from the ventral tegmental area by means of stereotaxic injections of 6-hydroxydopamine. This resulted in the appearance of immunoreactivity to the paired helical filament protein plus an increase of tau and MAP-2 proteins in pyramidal neurons of CA-1 and CA-2.

A lethal syndrome resembling branchio-oculo-facial syndrome.

Branchio-oculo-facial syndrome, a recently delineated autosomal dominant condition, is characterized by branchial cleft sinuses, ocular anomalies, and unusual facial appearance. A patient with branchial cleft fistulae, microphthalmia, nasomaxillary dysplasia, in addition to cardiac and CNS malformation (holoprosencephaly and meningo-encephalocele), is described. Although many features of this lethal malformation complex resemble those seen in the branchio-oculo-facial syndrome, the complex may represent a new multiple malformation syndrome.

Tyrosine hydroxylase-like (TH) immunoreactivity in Parkinson's disease and Alzheimer's disease.

We used tyrosine hydroxylase immunoreactivity (TH) to mark dopaminergic fibers in cerebral tissue from adult persons with Parkinson's disease (PD) or Alzheimer's disease (AD). In the PD cases we found a loss of dopaminergic neurons in the ventral tegmental area (VTA), severely reduced TH fibers in dopaminergic terminal fields (particularly in the hippocampal perforant pathway) and neurofibrillary tangles (NFT), that occurred only in the perforant pathway. In contrast, AD cases were characterized by a lack of significant neuron loss in the VTA and by mild loss of TH fibers.

Tyrosine hydroxylase-like (TH) immunoreactivity in human mesolimbic system.

A practical methodology has been described for the use of human postmortem brain tissue in both tyrosine hydroxylase and dopamine beta-hydroxylase immunohistochemistry in which in situ perfusion with paraformaldehyde is followed by immersion fixation in Bouin's fixative. These studies indicate that TH-like immunoreactive fibers and terminals are not uniformly distributed in the human hippocampal complex. A distinctive lesser innervation is noted for the structures that compose the perforant pathway and may be important for the predilection of these areas for pathological change particularly as occurs in Alzheimer's disease.

Focal signal-intensity variations in the posterior internal capsule: normal MR findings and distinction from pathologic findings.

Cranial magnetic resonance (MR) imaging studies in 117 control patients were reviewed to evaluate for focal signal-intensity variations in the posterior internal capsule. Rounded foci of increased signal intensity were found near the junction of the posterior limb and retrolenticular portion of the internal capsule on axial T2-weighted images in 56% of patients imaged at 1.5 T and in 50% imaged at 0.

Vascular glycosaminoglycans in periventricular leukoencephalopathy.

Three cases of adult dementia with periventricular leukoencephalopathy demonstrated staining with alcian blue dye (alcianophilia) in thickened cerebral arteries and arterioles of the abnormal white matter. The property of alcianophilia identifies glycosaminoglycans (GAGs); retention of alcian blue staining at high MgCl2 concentrations (0.7 M) in these cases indicates that the GAGs are highly sulfated and are likely to represent heparan sulfate.

Validation of clinical diagnostic criteria for Alzheimer's disease.

Clinical investigations of Alzheimer's disease (AD) have been limited by diagnostic inaccuracy. We employed explicit clinical inclusion and exclusion criteria to identify subjects with senile dementia of the Alzheimer type (SDAT). In a consecutive series of 26 postmortem examinations from this sample, AD was histologically verified in all subjects and was the primary dementing illness.

The association of ventral tegmental area histopathology with adult dementia.

Six cases of adult dementia with mesolimbic pathology are reported. The core clinical syndrome consists of parkinsonism, progressive dementia, and behavioral disturbances (generally depression). The histopathologic findings uniformly include a loss of pigmented neurons in the ventral tegmental area plus neurofibrillary tangles and/or cell loss in the entorhinal cortex and pyramidal cell layer of the hippocampus (perforant pathway).

T-lymphocyte function in Alzheimer's disease.

T-lymphocyte function in Alzheimer's disease (AS) was evaluated by means of delayed type hypersensitivity (DTH) and mitogen responsiveness using concanavalin A (Con A) and BCG vaccine as stimulators. DTH and the response to Con A was significantly lower in AD than in normal aging. The Con A response included one group in which the thymidine uptake was lower than the minimum normal response while another group was within the normal range.

The pathogenetic significance of congophilic angiopathy.

Congophilic angiopathy has been separated into two forms. A primary vasculopathy is described in which amyloid deposition is the initial morphological brain change and is of pathogenetic importance in the development of dementia or brain hemorrhage. Another form occurs in Alzheimer's disease and is incidental to the brain damage resulting from senile plaques.

Historical aspects of normal and abnormal brain fluids. III. Cerebral edema.

The early life, death, and revival of the concept of cerebral edema are discussed. This unusual sequence has been related to a clinical syndrome, a vascular hypothesis, a unique brain circulation, and a new investigative technique: electron microscopy.

Historical aspects of normal and abnormal brain fluids. II. Hydrocephalus.

A history of internal hydrocephalus from Vesalius to the present has been presented. Several intriguing aspects of hydrocephalus have been explored, including the existence of this disorder before tha 16th century and the possibility of medical management. The exciting promise and discouraging failure of experimentally devised choroid plexectomy has been recounted.

Computed tomography and stroke edema: case report with an analysis of water in acute infarction.

An index case and 13 other cases of acute ischemic cerebral infarction have been examined following the occurrence of death 1-6 days postictus. Histologic studies and water content assay involved both the infarct and peri-infarct tissue. The primary site of fluid accumulation was the infarcted white matter; however, after 3 days, edema in the adjacent white matter may be significant.

Delayed hypersensitivity in Alzheimer's disease following BCG immunostimulation.

Forty-four patients with Alzheimer's disease were evaluated for delayed hypersensitivity responses using five ubiquitous antigens. Compared with a nondemented age-matched population, these patients evidenced a large number of deficient responses, especially in the zero-response group. Twenty-three patients were randomly selected for immunostimulation using BCG vaccine.

Cytochemistry of brain amyloid in adult dementia.

A cytochemical study of 14 cases of adult dementia revealed the presence of gamma globulin in the amyloid of three cases of congophilic angiopathy by means of immunofluorescence microscopy. In these cases, the additional identification of human albumin is regarded to indicate a non-specific macromolecular leak in the blood-brain barrier. Both reactions are inhibited by prior absorption with the appropriate serum protein.