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Biomedical subjects

L S Forno

Publications and source records attributed to L S Forno.

At least 19 recordsLinked to original sources
PubMed2000

February 2000: Dementia with motor dysfunction in a patient with liver disease.

Acquired (non-Wilsonian) hepatocerebral degeneration (AHCD) is an irreversible neurological condition characterized by dementia, dysarthria, and motor disturbances. It has been described in patients with severe liver disease of many causes, and notably in patients with surgically or spontaneously created porto-systemic shunts. We report a case of AHCD in a patient with end-stage liver disease due to alcohol abuse and hepatitis C. In addition, this patient showed pathologic evidence of the less commonly reported "shunt myelopathy" in the absence of a surgically created porto-systemic shunt. The myelopathy was associated with a dramatic vacuolation involving especially the deep motor cortex. Electron microscopy suggested that the vacuolation was due mainly to disruption of abnormal astrocytes.

Aged↗
PubMed1999

Evidence of active nerve cell degeneration in the substantia nigra of humans years after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine exposure.

This report provides the first detailed neuropathological study of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced parkinsonism in humans. All 3 subjects self-administered the drug under the impression it was "synthetic heroin" and subsequently developed severe and unremitting parkinsonism, which was L-dopa responsive, at least in the earlier stages of illness. Survival times ranged from 3 to 16 years. Neuropathological examination revealed moderate to severe depletion of pigmented nerve cells in the substantia nigra in each case. Lewy bodies were not present. In Patients 1 and 2, there was gliosis and clustering of microglia around nerve cells. Patient 3 had a similar picture and also showed large amounts of extraneuronal melanin. These findings are indicative of active, ongoing nerve cell loss, suggesting that a time-limited insult to the nigrostriatal system can set in motion a self-perpetuating process of neurodegeneration. Although the mechanism by which this occurs is far from clear, the precedent set by the cases could have broad implications for human neurodegenerative disease.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1998

No neuropathologic evidence for an increased frequency of Alzheimer's disease among elderly schizophrenics.

BACKGROUND: There is currently controversy as to the frequency of Alzheimer's disease (AD) in elderly persons with schizophrenia. Several studies have reported an increased frequency of AD in elderly schizophrenics, whereas others have found no increase. This issue is important because it has been hypothesized that medications used to treat schizophrenia may exacerbate AD histopathology. METHODS: We examined autopsy cases from a state psychiatric hospital and a Veterans Affairs medical center. Charts were reviewed on 166 subjects to determine if the history warranted a DSM-IV diagnosis of schizophrenia. All subjects had complete gross and microscopic neuropathologic evaluations, which were reviewed for evidence of Alzheimer's disease. RESULTS: Retrospective chart review identified 51 subjects over the age of 55 who met DSM-IV criteria for schizophrenia (mean age = 71.7 years, SD = 8.6, range 56-95 years). Of these 51, only I met neuropathologic criteria for AD, a frequency of 2%. CONCLUSIONS: The frequency of subjects meeting neuropathologic criteria for Alzheimer's disease in our sample of schizophrenics was equal to or less than that found in the general population. Because institutionalized populations may contain an excess of elderly schizophrenic patients with severe behavioral pathologies, which may in turn reflect the presence of neurodegenerative processes such as Alzheimer's disease, our results may actually overestimate the frequency of Alzheimer's in the entire schizophrenic population. The frequency of Alzheimer's disease in the elderly with schizophrenia may be less than that in the general population.

Aged↗
PubMed1998

Hereditary form of parkinsonism--dementia.

In four generations of a family, 13 members were afflicted with an autosomal dominant disorder characterized by young age at onset, early weight loss, and rapidly progressive dopa-responsive parkinsonism, followed later by dementia and, in some, by hypotension. Intellectual dysfunction began with subjective memory loss and objective visuospatial dysfunction and was followed later by decline of frontal lobe cognitive and memory functions. Neuropathological examination in 4 autopsied cases showed neuronal loss in the substantia nigra and locus ceruleus and widespread Lewy bodies, many of them in the cerebral cortex; those in the hypothalamus and locus ceruleus were often of bizarre shapes. Other findings were vacuolation of the temporal cortex, unusual neuronal loss and gliosis in the hippocampus (CA 2/3), and neuronal loss in the nucleus basalis. There were no neuritic plaques, neurofibrillary tangles, or amyloid deposits. Positron emission tomography in 3 patients showed decreased striatal uptake of fluorodopa. Neurochemical analysis of an autopsied brain showed a pronounced decrease in choline acetyltransferase activity in the frontal and temporal cortices and hippocampus and a severe depletion of striatal dopamine with a pattern not typical of classic Parkinson's disease.

Adult↗
PubMed1998

Novel alpha-synuclein-immunoreactive proteins in brain samples from the Contursi kindred, Parkinson's, and Alzheimer's disease.

A specific mutation (A53T) in the encoding region for alpha-synuclein has been identified in a large multigenerational family with an autosomal dominant parkinsonism known as the Contursi kindred. In this study, we used a monoclonal antibody directed against alpha-synuclein in order to identify novel proteins in the brain of an affected member of this kindred who had come to autopsy. Homogenates from the frontal cortex and caudate nucleus were examined using Western blot techniques and compared to matched autopsy specimens from control subjects and patients with various forms of parkinsonism. Western blots, using a 15-min exposure time, revealed the expected 19-kDa band representing alpha-synuclein in all brain samples examined. However, a novel band in the 36-kDa range was also present in the Contursi brain which was not seen in cortex or caudate from control brains or in frontal cortex from 14 cases of typical Parkinson's disease. With a 24-h exposure time, this band was faintly seen in the caudate nucleus of three of the Parkinson's disease cases. Surprisingly, the 36-kDa band (as well as other high-molecular-weight bands) was also present in frontal cortex and caudate nucleus in 3 additional cases that met diagnostic criteria for both Parkinson's disease and Alzheimer's disease. A preliminary analysis of samples from the frontal cortex of 10 Alzheimer's disease cases revealed a 36-kDa band in only one instance. The identification of novel alpha-synuclein-immunoreactive bands in these various forms of parkinsonism may open new research avenues for exploring the relationship between abnormal protein deposition in the brain and one or more neurodegenerative disorders, including the Contursi form of familial parkinsonism.

Adult↗
PubMed1998

Absence of mutations in the coding region of the alpha-synuclein gene in pathologically proven Parkinson's disease.

A missense mutation of the alpha-synuclein gene has been associated with parkinsonism in a large Italian kindred. Recently, alpha-synuclein was also identified in Lewy bodies. Using reverse transcribed-polymerase chain reaction (RT-PCR) technique, we sequenced the entire coding region of the alpha-synuclein gene using brain tissue from 24 pathologically proven Parkinson's disease cases. No mutations were found in any of the patients, suggesting that a mutation at the coding region of the alpha-synuclein gene is unlikely to be responsible for nigrostriatal degeneration in typical sporadic Parkinson's disease.

Adult↗
PubMed1997

No association between the alpha 1-antichymotrypsin A allele and Alzheimer's disease.

The alpha 1-antichymotrypsin (ACT) A allele was recently associated with Alzheimer's disease (AD), and the ACT AA genotype was reported to be more frequent in AD subjects with the apolipoprotein E (APOE) epsilon4 allele. We examined ACT and APOE genotypes in a sample of 160 subjects with probable AD and in 102 elderly control subjects. ACT A allele frequencies were similar in AD subjects (0.503) and elderly controls (0.519). In addition, we found no evidence that in AD the AA genotype is more frequent in subjects with the APOE epsilon4 allele than in those without it. Our results do not support an association between the ACT A allele and AD.

Adult↗
PubMed1996

Autopsy-proven progressive supranuclear palsy in two siblings.

Progressive supranuclear palsy (PSP) is a neurodegenerative disorder that is generally considered to be nonfamilial. We report a brother and sister with clinical and pathologic findings characteristic of PSP. Both developed parkinsonism in the eighth decade of life and within 5 years exhibited severe postural instability, bradykinesia, rigidity, dystonia, dysarthria, dysphagia, urinary incontinence, pseudobulbar palsy, and supranuclear oculomotor dysfunction but no tremor. Neither responded to levodopa and/or carbidopa. Their mother and, possibly, maternal grandfather reportedly suffered from a parkinsonian syndrome. Essential tremor occurred in the siblings' father and in two of the brother's three children. Autopsy in the brother at age 81 years and sister at age 79 years revealed changes typical of PSP with atrophy and neurofibrillary tangles in the globus pallidus, subthalamic nucleus, and rostral tegmental brainstem. No Lewy bodies were present. These cases are the first pair of relatives reported with autopsy confirmation of PSP in both and raise the question of genetic predisposition to PSP.

Aged↗
PubMed1996

P3 beta-amyloid peptide has a unique and potentially pathogenic immunohistochemical profile in Alzheimer's disease brain.

The presence of beta-amyloid in brain tissue is characteristic of Alzheimer's disease (AD). A naturally occurring derivative of the beta-amyloid peptide, p3, possesses all of the structural determinants required for fibril assembly and neurotoxicity. p3-specific antibodies were used to examine the distribution of this peptide in brain. p3 reactivity was absent or sparse in aged non-AD brains but was prevalent in selected areas of AD brain in diffuse deposits and in a subset of dystrophic neurites. p3-reactive dystrophic neurites were found both independent in the neuropil and associated with plaques. Little or no reactivity was observed to amyloid cores in classical plaques or to amyloid in the cerebral vasculature. The exclusive appearance of p3 reactivity in AD brain plus the selective localization of p3 reactivity to abnormal structures in the temporal lobe limbic system suggests that p3 may be a contributing factor to AD pathology.

Alzheimer Disease↗
PubMed1996

Antibodies to presenilin proteins detect neurofibrillary tangles in Alzheimer's disease.

Mutations in the presenilin (PS)-1 and PS-2 genes have been shown to be linked with the development of Alzheimer's disease (AD). We examined Alzheimer's brain tissue by immunohistochemistry using a set of antibodies raised to sequences shared between PS-1 and PS-2 proteins. These antibodies reacted exclusively with a subset of neurofibrillary tangles and not with neuropil threads or dystrophic neurites. Detection of the presenilin epitope in neurofibrillary tangles was observed in sporadic Alzheimer's disease brain samples and in samples from individuals carrying PS-1 and PS-2 mutations with no qualitative difference. These data indicate that both wild-type and mutant PS proteins are involved in a common pathogenic pathway in AD.

Alzheimer Disease↗
PubMed1995

Ultrastructure of eosinophilic inclusion bodies in the amygdala-parahippocampal region of aged squirrel monkeys treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, a dopaminergic neurotoxin.

Eosinophilic neuronal inclusions resembling cortical Lewy bodies have been observed in the amygdala-parahippocampal region of aged 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated squirrel monkeys. Electron microscopy in six monkeys revealed a composition of curving bundles of 16-17 nm filaments, arranged in a ball shape or as a cap adjacent to the nerve cell nucleus. The main difference between the monkey inclusions and human cortical Lewy bodies was the random orientation of the filaments in the human inclusion bodies.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1994

Aging and the nigrostriatal dopamine system: a non-human primate study.

The present study examined neurochemical, morphological and functional markers of the nigrostriatal dopamine system in young, intermediate-aged and old squirrel monkeys. Striking reductions in motoric activity were observed with advancing age. significant age-related loss of dopamine occurred in the substantia nigra (70%) and the putamen (30%) but not in the caudate. There was a strong correlation between the reductions in motoric activity and the loss of putamen dopamine. However, nigrostriatal dopamine loss did not appear to be the consequence of age-related loss of dopaminergic nigral neurons since the number of tyrosine immunoreactive cells was not significantly different among the three age groups. These results suggest that the aging squirrel monkey demonstrates the age-related loss of nigrostriatal dopamine thought to occur in humans and identify this non-human primate as a useful model to further investigate the underlying mechanism(s) and functional consequences of age-related decline of the nigrostriatal dopamine system. In addition, the selective loss of dopamine in the putamen but not the caudate parallels the regional vulnerability observed in Parkinson's disease, an age-related neurodegenerative disorder, raising the possibility of a relationship between normal aging and the development of this disease. Finally, because the number of tyrosine hydroxylase (TH) positive cells remains constant with age, these results raise the possibility that therapeutic strategies aimed at increasing dopamine concentrations may benefit elderly individuals.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1994

Development of a monoclonal antibody specific for the COOH-terminal of beta-amyloid 1-42 and its immunohistochemical reactivity in Alzheimer's disease and related disorders.

The beta-amyloid peptide (beta AP) has been characterized by protein sequencing techniques as a 39-43 amino acid protein with heterogeneous COOH-termini. Controversy exists regarding the predominant form of beta AP in neuritic plaques (NP) and cerebral vasculature of Alzheimer's disease (AD) brain. A monoclonal antibody was developed that selectively recognizes the free COOH-terminal of beta AP 1-42 but not beta AP species with shorter or longer COOH-termini. Brain sections from AD and related disorders were examined using this antibody. In AD samples, the antibody stained diffuse amyloid and NP cores, many intraneuronal and extraneuronal neurofibrillary tangles (NFT), but not cerebrovascular amyloid. Pick and Lewy bodies lacked immunoreactivity. These findings suggest that beta AP 1-42 is present in early and mature amyloid deposits and NFT, but that species of beta AP other than 1-42 comprise human vascular deposits.

Adult↗
PubMed1993

Similarities and differences between MPTP-induced parkinsonsim and Parkinson's disease. Neuropathologic considerations.

The MPTP monkey model for PD has continued to display similarities as well as differences from the human disease, also in respect to its neuropathology. In 65 MPTP-treated squirrel monkeys with survival for more than 2 days, the main similarities consisted of nerve cell degeneration, not only of SN, but also, in the majority of cases, of the LC. In 13 animals that survived for from 1 to 7 years after their first exposure to MPTP, the nerve cells in the ventrolateral portion of the SN compacta were particularly vulnerable, just as in PD. The principal differences were the lack of progression of the disease process in these long-term animals (although this has yet to be systematically tested) and the absence of formation of typical Lewy bodies in the SN, LC, and other predilection sites for Lewy bodies. Since inclusion bodies, now observed in 16 monkeys, could be produced fairly consistently in aged MPTP-treated squirrel monkeys, they appeared to represent a bridge between these similarities and differences. They had some features, especially their location in predilection sites for Lewy bodies, such as the SN, in common with Lewy bodies, but did not display the fully convincing morphological and immunocytochemical features, characteristics of the human inclusion bodies in PD. Overall, these studies continue to provide tantalizing hints that this model could lead to important new insights into the pathologic process that underlies PD.

Animals↗
PubMed1992

Neuropathologic features of Parkinson's, Huntington's, and Alzheimer's diseases.

Some of the similarities and differences between the neuropathology of Parkinson's disease, Huntington's disease, and Alzheimer's disease have been reviewed, and the relationship between the three diseases has been discussed. Although interconnected and reciprocally innervated structures are affected in PD and HD, they appear less closely related than in PD and AD. Different neurotoxins may play a part in their pathogenesis, as also suggested from other evidence. Neuropathologic features of PD, HD and AD are entirely compatible with a role for neurotoxins in their pathogenesis, but do not by themselves make a strong case for a neurotoxic hypothesis. However, additional neuropathologic studies of experimental neurotoxins may further strengthen arguments in favor of a neurotoxic etiology, as the MPTP animal model is doing for Parkinson's disease. Such experimental studies along with further molecular biological and other sophisticated new methods may open the way for exciting new developments in the near future.

Alzheimer Disease↗
PubMed1992

EAE cerebrospinal fluid augments in vitro phagocytosis and metabolism of CNS myelin by macrophages.

Previous studies from this laboratory have shown that CNS myelin is phagocytized and metabolized by cultured rat macrophages to a much larger extent when myelin is pretreated with serum containing antibodies to myelin constituents than when it is left untreated or pretreated with non-specific serum. In this study the effect of cerebrospinal fluid (CSF) from rabbits with experimental allergic encephalomyelitis (EAE) in promoting myelin phagocytosis was examined. Fourteen rabbits were immunized with purified myelin in Freund's complete adjuvant, seven of which developed clinical EAE symptoms. Serum and CSF were collected from EAE and control rabbits, and the CSF was centrifuged to remove cells. Sera and CSF from these rabbits and from Freund's adjuvant-immunized controls and untreated controls were measured for IgG content by radial diffusion assay, their myelin antibody characteristics were analyzed by immunoblots, and the ability of these serum and CSF samples to promote myelin phagocytosis when used for myelin opsonization was examined. The ability of a CSF sample to enhance radioactive myelin uptake and phagocytosis by cultured macrophages as measured by the appearance of radioactive cholesterol ester was linearly proportional to its total IgG titer, and correlated approximately both with clinical symptoms of the animal and the presence of antibody against the myelin constituents myelin basic protein, proteolipid protein, and galactocerebroside. The cholesterol esterification activities of EAE sera correlated to a lesser extent with IgG levels and clinical symptoms.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗