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D P Perl

Publications and source records attributed to D P Perl.

At least 73 records · Page 4Linked to original sources
PubMed1994

Amyotrophic lateral sclerosis and parkinsonism-dementia from Guam: differences in neurofibrillary tangle distribution and density in the hippocampal formation and neocortex.

Amyotrophic lateral sclerosis/parkinsonism-dementia complex is a highly prevalent neurodegenerative disorder among the native Chamorro population of Guam, and is characterized by widespread formation of neurofibrillary tangles. In the present study, the distribution of neurofibrillary tangles was quantitatively assessed in the cerebral cortex of cases presenting with either predominant amyotrophic lateral sclerosis or parkinsonism-dementia symptomatology. Results show that although the regional and laminar lesion distribution is qualitatively similar in both groups, cases with predominant parkinsonism-dementia generally have higher lesion densities than cases with amyotrophic lateral sclerosis. Interestingly, layer II of the entorhinal cortex was affected to the same degree in both conditions. In both groups, the CA1 field of the hippocampus, subiculum, and entorhinal cortex were the most affected areas. In the neocortex, the perirhinal and inferior temporal cortex consistently had higher lesion densities than the frontal, parietal, and cingulate cortex, whereas the visual cortex was practically devoid of lesions. Also, most of the neurofibrillary tangles were located in the supragranular layers of the neocortex, with relatively low densities in the infragranular layers, in both brain groups. Interestingly, the primary motor cortex contained more neurofibrillary tangles in parkinsonism-dementia than in amyotrophic lateral sclerosis cases. It is possible that the differences in regional neurofibrillary tangle densities reflect the variable severity of the dementing process observed between the two groups of patients. Several studies on Alzheimer's disease and related disorders indicate that the regional and laminar cortical localization of neurofibrillary tangles may parallel the degeneration of specific corticocortical projections. The present data suggest that the population of corticocortical projections involved in Guamanian cases differs substantially from that affected in Alzheimer's disease. The differential distribution and densities of the lesions may contribute to the differences in symptomatology and severity of dementia among Alzheimer's disease and Guamanian cases, although these neurodegenerative disorders as well as related illnesses may share certain etiopathogenetic mechanisms.

Adult↗
PubMed1994

Pathological alterations of the cerebral microvasculature in Alzheimer's disease and related dementing disorders.

Alterations of the cerebral microvasculature have been reported in aging and in neurodegenerative disorders such as Alzheimer's disease. However, the exact role of microvascular alterations in the pathogenesis of neurodegeneration remains unknown. In the present report, the cerebral cortex microvasculature was studied by immunohistochemistry using a monoclonal antibody against vascular heparan sulfate proteoglycan protein core in normal aging controls. Alzheimer's disease, Down syndrome, Guam amyotrophic lateral sclerosis/parkinsonian dementia complex, Pick's disease and dementia pugilistica. In all dementing illnesses, increased microvascular pathology was evident compared to normal controls. Decreased microvascular density and numerous atrophic vessels were the primary abnormalities observed in all dementing disorders. These microvascular abnormalities demonstrated regional and laminar selectivity, and were primarily found in layers III and V of frontal and temporal cortex. Quantitative analysis employing computer-assisted microscopy demonstrated that the decrease in microvascular density in Alzheimer's disease was statistically significant compared to age-matched controls. In addition, extracellular heparan sulfate proteoglycan deposits were observed which colocalized with thioflavine S-positive senile plaques in Alzheimer's disease, Down syndrome and selected Guam dementia cases. In some cases, heparan sulfate proteoglycan was seen in senile plaques that appeared to be diffuse or primitive plaques that stained weakly with thioflavine. Heparan sulfate proteoglycan-containing neurons were also observed in Alzheimer's disease, as well as in Down syndrome and Guam cases. Glial staining for heparan sulfate proteoglycan was never observed. Our data support previous observations that microvascular pathology is found in aging and in Alzheimer's disease. The changes in Alzheimer's disease exceed those found in normal aging controls. We also found microvascular pathology in all other dementing disorders studied. Our studies further demonstrated that the microvascular pathology displays regional and laminar patterns which parallel patterns of neuronal loss. Finally, we also found that heparan sulfate proteoglycan is present in senile plaques and neurons not only as previously reported in Alzheimer's disease, but also in Down syndrome and Guam cases. Heparan sulfate proteoglycan in senile plaques may be derived from either the degenerating microvasculature or from degenerating neurons.(ABSTRACT TRUNCATED AT 400 WORDS)

Aged↗
PubMed1994

Quantitative neuropathologic analysis of Pick's disease cases: cortical distribution of Pick bodies and coexistence with Alzheimer's disease.

Pick's disease is characterized morphologically by severe atrophy of the frontal and temporal lobes and the presence in the cerebral cortex of degenerative neuronal lesions referred to as Pick bodies. In the present study, we analyzed the regional and laminar distribution of Pick bodies in a series of 16 Pick's disease cases. These distribution and density patterns were compared with those observed for neurofibrillary tangles in Alzheimer's disease. Very high densities of Pick bodies were observed Ammon's horn, subiculum, entorhinal cortex, and in the granule cell layer of the dentate gyrus. In the frontal and temporal neocortex, they were preferentially distributed in layers II and VI. All of the Pick's disease cases also exhibited neurofibrillary tangles in the frontal and temporal areas and in the hippocampal formation, with higher densities in layers II-III than in layers V-VI of the neocortical regions. Interestingly, this laminar distribution of neurofibrillary tangles was strikingly different from that observed in Alzheimer's disease cases, where they were more numerous in the infragranular layers than in the supragranular layers. In addition, a few Pick's disease cases also had cortical senile plaques. These results suggest that the presence of neurofibrillary tangles in Pick's disease may be more frequent than previously reported, and that Pick's disease and Alzheimer's disease may coexist in certain cases. The lesion distribution patterns suggest that different populations of cortical neurons are affected in Pick's and Alzheimer's disease, and that alterations of select corticocortical and corticosubcortical projections may distinguish these forms of dementia. It is also possible that these two disorders share certain pathogenetic mechanisms, even though both display specific patterns of regional and neuronal vulnerability to the degenerative processes.

Aged↗
PubMed1994

Cortical cholinergic markers in schizophrenia.

Cortical cholinergic deficits have been implicated in the cognitive deficits produced by a variety of neurodegenerative diseases including Alzheimer's disease (AD). Recent studies have suggested that many of the chronically institutionalized geriatric schizophrenic patients are also cognitively impaired. In this postmortem study we compared cholinergic marker activity in six different cortical regions derived from elderly controls, chronically institutionalized geriatric schizophrenic patients, and AD patients. All of the Alzheimer's disease cases met neuropathological criteria for AD, while none of the schizophrenic cases met criteria for AD. Cholinergic marker activity (choline acetyltransferase and acetylcholinesterase) was significantly diminished in the AD cohort but not in the schizophrenic cohort. Additionally, cortical choline acetyltransferase activity was significantly and negatively correlated with Clinical Dementia Rating scores (CDR), whereas no such correlations were evident in the schizophrenic cohort. These results suggest that cognitive deficits in geriatric schizophrenics are not due to diminished cortical cholinergic activity.

Acetylcholine↗
PubMed1994

Galanin-like immunoreactivity is increased in the postmortem cerebral cortex from patients with Alzheimer's disease.

Galanin is a peptide that is associated with cholinergic neurons of the basal forebrain, and, thus, of interest for the neuropathology of Alzheimer's disease. In the present study, human galanin-like immunoreactivity was measured in postmortem human cerebral cortical tissues by using a homologous radioimmunoassay. In an initial study, six cerebral cortical regions were evaluated from nine elderly controls, 13 neuropathologically verified Alzheimer's disease patients, and 19 elderly schizophrenics. A significant 65% increase in galanin was found in frontal cortex Brodmann area 8 of Alzheimer's disease patients compared with controls. In contrast, cerebral cortical tissues from elderly schizophrenics were not different from those from elderly controls in any region. In a second study, 10 cerebral cortical regions were evaluated from 50 neuropathologically verified Alzheimer's disease patients and nine elderly controls. Concentrations of galanin were increased significantly 26-61% in six of 10 cerebral cortical regions examined (Brodmann areas F8, F44, T20, T21, T36, and P22). Purification of brain extracts by size-exclusion Sephadex G-50 chromatography revealed that human galanin-like immunoreactivity eluted in two peaks of different molecular weights. These studies reveal increased concentrations of galanin in the cerebral cortex of Alzheimer's disease, similar to previous findings in basal forebrain tissue. Because galanin inhibits cholinergic neurotransmission, these findings may have important implications in the understanding of Alzheimer's disease neuropathology and associated cognitive deficits.

Alzheimer Disease↗
PubMed1994

Projected neurodegenerative disease mortality among minorities in the United States, 1990-2040.

Between 1992 and 2040, the United States nonwhite elderly population is expected to grow from 3.3 to 14.1 million. In order to assess the implications of this increase on the mortality from neurodegenerative diseases in the United States, we used Census Bureau population estimates to formulate projections of the annual number of deaths from neurodegenerative diseases and from six comparison conditions (liver cirrhosis, colon cancer, lung cancer, cancer of the female breast, multiple sclerosis, and malignant melanoma), assuming that the United States disease-age-gender-specific death rates for 1985-1988 remain constant between 1990 and 2040. We find that neurodegenerative disease mortality increases by 281-524%, depending on the model of population growth used. For the 'middle' population growth model, the increase in annual neurodegenerative disease mortality is 373%. The major component of this increase is the rise in deaths attributed to dementia. For the six comparison diseases, the increases in mortality range from 130 (multiple sclerosis) to 288% (colon cancer). Given the current level of underascertainment of neurodegenerative disease mortality, particularly among minorities, and the conservative nature of the Census Bureau estimates of future population, it is likely that these projections are under-estimates. The implications of these data are discussed.

Dementia↗
PubMed1994

Age-associated and cell-type-specific neurofibrillary pathology in transgenic mice expressing the human midsized neurofilament subunit.

Alterations in neurofilaments are a common occurrence in neurons of the human nervous system during aging and diseases associated with aging. Such pathologic changes may be attributed to species-specific properties of human neurofilaments as well as cell-type-specific regulation of this element of the cytoskeleton. The development of transgenic animals containing human neurofilament subunits offers an opportunity to study the effects of aging and other experimental conditions on the human-specific form of these proteins in a rodent model. The present study shows that mice from the transgenic line NF(M)27, which express the human midsized neurofilament subunit at low levels (2-25% of the endogenous NF-M), develop neurofilamentous accumulations in specific subgroups of neurons that are age dependent, affecting 78% of transgenic mice over 12 months of age. Similar accumulations do not occur in age-matched, wild-type littermates or in 3-month-old transgenic mice. In 12-month-old transgenic mice, somatic neurofilament accumulations resembling neurofibrillary tangles were present predominantly in layers III and V of the neocortex, as well as in select subpopulations of subcortical neurons. Intraperikaryal, spherical neurofilamentous accumulations were particularly abundant in cell bodies in layer II of the neocortex, and neurofilament-containing distentions of Purkinje cell proximal axons occurred in the cerebellum. These pathological accumulations contained mouse as well as human NF subunits, but could be distinguished by their content of phosphorylation-dependent NF epitopes. These cytoskeletal alterations closely resemble the cell-type-specific alterations in neurofilaments that occur during normal human aging and in diseases associated with aging, indicating that these transgenic animals may serve as models of some aspects of the pathologic features of human neurodegenerative diseases.

Aging↗
PubMed1993

Widespread deficits in somatostatin but not neuropeptide Y concentrations in Alzheimer's disease cerebral cortex.

Somatostatin-like immunoreactivity (SLI) and neuropeptide Y-like immunoreactivity (NPYLI) were measured in the cerebral cortex of 49 patients with Alzheimer's disease (AD), and 9 elderly controls. Concentrations of SLI were lower in AD patients relative to controls in 9 of 10 cortical regions. In contrast, no significant differences in NPYLI concentrations between the two groups were observed in any of 10 regions. These studies suggest a dissociation between SLI deficits and NPYLI concentrations in the postmortem cerebral cortex of AD patients. The apparent sparing of NPYLI-containing neurons suggests that neuropeptide Y may be located within a separate group of neurons compared to somatostatin.

Aged↗
PubMed1993

Severe cognitive impairment in elderly schizophrenic patients: a clinicopathological study.

The severe cognitive impairment that affects many of the elderly schizophrenic patients could represent the outcome of schizophrenia in old age for the very severe and chronically ill patients or may be the result of lengthy institutionalization and somatic treatment. Alternatively, it could be due to the presence of concurrent dementing disorders, such as Alzheimer's disease (AD) or multi-infarct dementia. Using an identical neuropathological protocol, brain specimens from schizophrenic patients who showed evidence of severe cognitive impairment were compared with 12 age-matched control cases and the same number of age-matched cases of neuropathologically confirmed patients with AD. Despite their relatively advanced age (mean age 77.1 years +/- 2.8), none of the schizophrenia cases showed sufficient degree of senile plaques and neurofibrillary tangle formations to confirm a diagnosis of AD. Other neurodegenerative disorders associated with dementia were also not identified. These studies suggest that alternative explanations need to be sought for the severe cognitive impairment commonly encountered in elderly schizophrenic patients.

Age Factors↗
PubMed1993

Sequencing of exons 16 and 17 of the beta-amyloid precursor protein gene reveals the beta-amyloid sequence to be normal in cases of the parkinson dementia complex of Guam.

Exons 16 and 17 of the beta-amyloid precursor protein gene has been sequenced in individuals with the amyotropic lateral sclerosis/Parkinson's dementia complex of Guam to test the hypothesis that this disease is an allelic variant of Alzheimer's disease and to test whether sequence differences within beta-amyloid in this population contributes to the non-deposition of this peptide in the disorder. The sequence was normal.

Aged↗
PubMed1993

Post-mortem examination of dopaminergic parameters in Alzheimer's disease: relationship to noncognitive symptoms.

Dopaminergic mechanisms have been implicated in depression, agitation, and psychosis--symptoms that are frequently observed in patients with Alzheimer's disease (AD). In a longitudinal study, 23 prospectively assessed AD patients underwent autopsies in which concentrations of dopamine, homovanillic acid, and dihydroxyphenylacetic acid were assayed in the temporal lobe (Brodmann areas 20 and 21). Data-reduction techniques were used to minimize the number of relationships tested. For this series of AD patients, no significant correlation was found between indices of dopaminergic neurotransmission and maximal severity of psychosis, depression, or agitation.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1993

Projected neurodegenerative disease mortality in the United States, 1990-2040.

Between 1990 and 2040, the United States elderly population is expected to grow from 31.6 to 68.1 million. In order to assess the implications of this increase on the mortality from neurodegenerative diseases in the United States, we used Census Bureau population estimates to formulate projections of the annual number of deaths from neurodegenerative diseases and from six comparison conditions (liver cirrhosis, colon cancer, lung cancer, cancer of the female breast, multiple sclerosis, and malignant melanoma), assuming that the United States disease-age-gender-race-specific death rates for 1985-1988 remain constant between 1990 and 2040. We find that neurodegenerative disease mortality increases by 119-231%, depending on the model of population growth used. For the 'middle' population growth model, the increase in annual neurodegenerative disease mortality is 166%. The major component of this increase is the rise in deaths attributed to dementia. For the six comparison diseases, the increases in mortality range from 52 (multiple sclerosis) to 130% (colon cancer). Given the current level of under ascertainment of neurodegenerative disease mortality and the conservative nature of the Census Bureau estimates of future population, it is likely that these projections are underestimates. The implications of these data are discussed.

Alzheimer Disease↗
PubMed1993

Investigation of a fatality from nonoccupational aluminum phosphide exposure: measurement of aluminum in tissue and body fluids as a marker of exposure.

This case study reports our clinical and laboratory investigation of the accidental death of a pregnant rural woman related to phosphine exposure from stored grain fumigated with aluminum phosphide (AIP3) pellets. Environmental data (housing proximity to fumigated grain and meteorologic conditions at the time) coupled with clinical data (tachycardia and the rapid development of pulmonary edema with no antecedent clinical abnormalities) suggested possible toxicant effects. Gross and microscopic autopsy findings demonstrated pulmonary edema. Because phosphine generated from the phosphide is highly reactive and unstable, our laboratory strategy for this investigation focused on the quantitative analysis of aluminum (AI) in blood, gastric contents, and in lung tissue to test the possibility of fumigant intoxication. We recovered 713 ng/ml Al from blood (normal laboratory range 2 to 42 ng/ml). Laser mass spectral analysis of lung tissue demonstrated high concentrations of Al in alveolar macrophages (> 200 ppm) with little or no Al in adjacent lung tissue. Control lung tissue from an urban autopsy case matched by age, sex, and smoking habits showed no demonstrable Al. We conclude that Al may be a useful marker for AIP3 exposure.

Adult↗
PubMed1992

Neuromelanin-containing neurons of the substantia nigra accumulate iron and aluminum in Parkinson's disease: a LAMMA study.

The Laser Microprobe Mass Analyzer (LAMMA) is a sensitive instrument for identifying and localizing trace elements in tissue samples. Using LAMMA, we have examined melanin-containing neurons of the substantia nigra in patients with Parkinson's disease (PD) and controls. We found that iron significantly accumulates within neuromelanin granules of patients with PD compared to controls. Increased aluminum was found in the neuromelanin granules of 2 of 3 PD cases but in no controls. The accumulation of iron and aluminum, which are known to promote oxidant stress, may account for the selective degeneration of neuromelanin-containing neurons in PD.

Aluminum↗
PubMed1992

Distribution of neurofibrillary tangles and senile plaques in the cerebral cortex in postencephalitic parkinsonism.

Postencephalitic parkinsonism is characterized neuropathologically by severe loss of pigmented neurons in the substantia nigra and the presence of high densities of neurofibrillary tangles in several brainstem structures. In 5 cases of postencephalitic parkinsonism, we observed that the neurofibrillary tangle distribution in the cerebral cortex predominated in the hippocampus and entorhinal cortex. In the prefrontal and inferior temporal cortex, neurofibrillary tangles were preferentially localized in layers II and III. This pattern contrasts with the neurofibrillary tangle distribution observed in neocortical areas of Alzheimer's disease cases, where neurofibrillary tangles are denser in layer V than in layer III. These results suggest that specific elements of the cortical circuitry might be differentially affected in postencephalitic parkinsonism as compared to Alzheimer's disease, and that cortical involvement is likely to be a common feature of this condition.

Aged↗
PubMed1992

Evidence for early vulnerability of the medial and inferior aspects of the temporal lobe in an 82-year-old patient with preclinical signs of dementia. Regional and laminar distribution of neurofibrillary tangles and senile plaques.

Detailed neuropathologic studies of neurofibrillary tangle and senile plaque distribution have shown that key elements of certain neocortical and hippocampal circuits are either compromised or lost in Alzheimer's disease. It has been suggested that a global corticocortical disconnection underlies dementia and leads to the dramatic disruption of integrated functions exhibited by patients with Alzheimer's disease. To investigate the distribution of lesions associated with the earliest indications of incipient dementia, we performed a quantitative neuropathologic evaluation of a non-demented 82-year-old patient demonstrating globally intact intellectual function but initial signs of impairment of specific cognitive functions before death. We observed densities of senile plaques comparable to those found in Alzheimer's disease throughout the cerebral cortex, whereas extensive neurofibrillary tangle formation was restricted to selective areas of the temporal lobe. The results of this systematic quantitative and comparative analysis of medial and inferior temporal lobe structures suggest a functional relationship between the degree of cognitive decline evidenced in the earliest stages of Alzheimer's disease and the anatomic progression of Alzheimer's disease-related pathologic changes along specific elements of the cortical circuitry.

Aged↗