Biomedical subjects

Jean Paul G Vonsattel

Publications and source records attributed to Jean Paul G Vonsattel.

6 recordsLinked to original sources

PubMed2025

A rare genetic variant confers resistance to neurodegeneration across multiple neurological disorders by augmenting selective autophagy.

The study of disease modifiers is a powerful way to identify patho-mechanisms associated with disease. Using the strong genetic traits of Huntington's disease (HD), we identified a rare, single-nucleotide polymorphism (SNP) in WDFY3 associated with a delayed age of onset of up to 23 years. Remarkably, the introduction of the orthologous SNP into mice recapitulates this neuroprotection, significantly delaying neuropathological and behavioral dysfunction in two models of HD. The SNP increases expression of the protein autophagy-linked Fab1, YOTB, Vac1, and EEA1 (FYVE) protein (Alfy), an autophagy adaptor protein for the clearance of aggregated proteins, whose ectopic overexpression is sufficient to capture the neuroprotective effects of the variant. Increasing Alfy expression protects not only against HD but also against the toxicity due to phospho-α-synuclein and AT8-positive accumulation. By combining human and mouse genetics, we have uncovered a pathway that protects against multiple proteinopathies, revealing a much-sought-after, shared therapeutic target across a broad range of neurodegenerative diseases.

Animals↗

PubMed2006

Dementia with cerebrovascular disease.

In this case study, we review the symptoms, cognitive testing, brain imaging, and brain pathology of a woman with dementia, for whom the neuropathological findings suggest a prominent contribution of cerebrovascular disease. Vascular dementia is the term commonly used for persons with dementia resulting from strokes, either clinically evident or subclinical "silent" events. "Mixed dementia" is the term used when there is an admixture of pathological findings related to Alzheimer's disease (AD) and cerebrovascular disease, as in this situation. In some cases of mixed dementia, the pathological involvement of AD may be the principal contributory cause of the cognitive symptoms, and in others, the vascular changes may give the greater contribution.

Aged↗

PubMed2006

Essential tremor associated with pathologic changes in the cerebellum.

BACKGROUND: Although essential tremor (ET) is one of the most common neurologic disorders, there have been few postmortem studies. We recently reported postmortem changes (torpedoes and Bergmann gliosis) in the cerebellar cortex in a few ET cases. OBJECTIVE: To describe more extensive postmortem changes in the cerebellum in another ET case. DESIGN: Case report. RESULTS: A 90-year-old woman had a 30-year history of ET. At postmortem examination, there was segmental loss of Purkinje cells, presence of torpedoes, and Bergmann gliosis in the cerebellar cortex. Moreover, there were extensive changes in the dentate nucleus, in the form of neuronal loss, neuronal atrophy, microglial clusters, and reduction in the number of efferent fibers (ie, pallor of the hilum). CONCLUSIONS: The brain in the current case exhibited more marked cerebellar pathologic features than noted in previously reported ET cases and thereby extends the described cerebellar findings in this common, yet pathologically poorly characterized, neurologic disorder.

Aged, 80 and over↗

PubMed2006

Parkinsonism, dysautonomia, and intranuclear inclusions in a fragile X carrier: a clinical-pathological study.

A new tremor-ataxia syndrome, fragile X-associated tremor/ataxia syndrome (FXTAS), has been described among carriers of premutation expansions (55-200 CGG repeats) of the fragile X mental retardation 1 (FMR1) gene. The prevalence of FMR1 premutation alleles has been reported to be 1 in 813 among men. Patients with FXTAS may also have features of parkinsonism. Postmortem findings have been described in eight patients with FXTAS and detailed descriptions of the pathological features of this syndrome have been published in two of these. We present a detailed description of the postmortem findings in a third patient. The patient had parkinsonism and was a carrier of a premutation expansion in the FMR1 gene. As in previous reports, the most prominent finding was the presence of eosinophilic nuclear inclusions in neurons and astrocytes, loss of Purkinje cells, and regional vacuolation of the cerebral white matter. As in one previous report, nuclear inclusions were also present in ependymal and choroid plexus cells. A new finding is that of nuclear inclusions in both the adeno- and neurohypophysis. These findings confirm the diffuse nature of this pathology. Further studies of clinical-pathological correlation in a larger sample of brains would provide additional insight into the mechanisms of the tremor, ataxia, and parkinsonism in these patients.

Aged↗

PubMed2005

Essential tremor associated with focal nonnigral Lewy bodies: a clinicopathologic study.

BACKGROUND: Essential tremor is one of the most common neurological diseases. Its links with Parkinson disease (PD) are often debated. There have been few published postmortem studies. OBJECTIVE: To study our first case of essential tremor through the recently established Essential Tremor Centralized Brain Repository. DESIGN: Report of a case of a patient with a diagnosis of severe essential tremor for 46 years who exhibited no signs of parkinsonism. RESULTS: On postmortem examination, gross brain sections showed no abnormalities. Results of microscopic examination of hematoxylin-eosin-stained sections revealed that the locus coeruleus contained multiple Lewy bodies (LBs), although none were found in the substantia nigra, dorsal vagal nuclei, thalamus, substantia innominata, inferior olivary nucleus, or cerebellum. Immunochemical staining using antibodies directed against alpha-synuclein confirmed the presence of many LBs in the locus ceruleus and showed rare LBs in the substantia innominata and dorsal vagal nuclei. There were no LBs in the substantia nigra. CONCLUSIONS: Our patient had a very focal presence of LBs in the locus ceruleus, an anatomically restricted form of LB disease. This study provides support for the link between essential tremor and LB disease and raises the question as to what proportion of patients with essential tremor might have unusual forms of LB disease.

Aged↗

PubMed2004

Late-life action tremor in a southern sea otter (enhydris lutris nereis).

Although tremor is highly prevalent in human beings, there are few reports of tremor occurring in other mammals. Such tremor can further our insight into the mechanisms and anatomical basis of human tremor disorders. We report on a southern sea otter with a slowly progressive 6.5 to 8.5 Hz action tremor of late life that shared several clinical characteristics with essential tremor. The main pathological finding was in the cerebellum, where there was extensive vacuolation of Purkinje cells.

Age Factors↗