Biomedical subjects

Mark S Forman

Publications and source records attributed to Mark S Forman.

26 records · Page 2Linked to original sources

PubMed2003

Initiation and synergistic fibrillization of tau and alpha-synuclein.

Alpha-synuclein (alpha-syn) and tau polymerize into amyloid fibrils and form intraneuronal filamentous inclusions characteristic of neurodegenerative diseases. We demonstrate that alpha-syn induces fibrillization of tau and that coincubation of tau and alpha-syn synergistically promotes fibrillization of both proteins. The in vivo relevance of these findings is grounded in the co-occurrence of alpha-syn and tau filamentous amyloid inclusions in humans, in single transgenic mice that express A53T human alpha-syn in neurons, and in oligodendrocytes of bigenic mice that express wild-type human alpha-syn plus P301L mutant tau. This suggests that interactions between alpha-syn and tau can promote their fibrillization and drive the formation of pathological inclusions in human neurodegenerative diseases.

Amyloid↗

PubMed2003

Bilateral subthalamic nucleus deep brain stimulation for advanced PD: correlation of intraoperative MER and postoperative MRI with neuropathological findings.

This postmortem study correlated intraoperative subthalamic nucleus (STN) deep brain stimulation (DBS) placement and postoperative magnetic resonance imaging (MRI) with autopsy findings in a patient who died suddenly 4 days postoperatively from a pulmonary embolism. The study demonstrates that (1) MRI stereotactic localization combined with microelectrode recording (MER) is an accurate way to target STN; (2) multiple MER tracts do not cause significant injury to the brain; and (3) postoperative MRI accurately demonstrates location of the DBS electrodes.

Electric Stimulation Therapy↗

PubMed2003

'Unfolding' pathways in neurodegenerative disease.

The endoplasmic reticulum responds to stress by initiating a cascade of events known as the 'unfolded-protein response' (UPR). The accumulation of misfolded proteins in the leukodystrophy Pelizaeus-Merzbacher disease activates this stress response, resulting in apoptosis of oligodendrocytes. Although it remains uncertain whether the UPR plays a mechanistic role in prototypical neurodegenerative disorders such as Alzheimer's disease, this is plausible because misfolded proteins are directly implicated in the pathogenesis of these disorders.

Adaptation, Physiological↗

PubMed2003

Fatal subacute cytomegalovirus encephalitis associated with hypogammaglobulinemia and thymoma.

Parathymic syndromes are systemic disorders that occur in association with thymoma. One such parathymic syndrome, hypogammaglobulinemia, was initially identified by Good in 1954 and has been referred to as Good syndrome. Patients with this syndrome develop a variety of recurrent infections due to the associated immunodeficiency. We describe a patient with cytomegalovirus encephalitis associated with Good syndrome and discuss the pathologic findings present on autopsy. The possibility of a cytomegalovirus infection should be considered early in the evaluation of patients with Good syndrome if appropriate clinical symptoms are present.

Agammaglobulinemia↗

PubMed2002

Co-occurrence of Parkinson's disease with progressive supranuclear palsy.

Parkinson's disease (PD) and progressive supranuclear palsy (PSP) are distinct neurodegenerative disorders. We describe an 81-year-old woman with 3 years of progressive gait unsteadiness, frequent falls, and mild cognitive dysfunction, all considered clinically to be an early fronto-temporal neurodegenerative disorder. She died of an acute myocardial infarction. Examination of her brain revealed alpha-synuclein- and tau-positive inclusions diagnostic of PD and PSP. Immunoelectron microscopy and Western blot analysis confirmed combined PD/PSP. This case provides strategies for the reliable molecular validation of concomitant PD and PSP, and demonstrates the utility of these techniques in patients with atypical clinical presentations.

Aged↗

PubMed2002

Amyotrophic lateral sclerosis/parkinsonism dementia complex: transgenic mice provide insights into mechanisms underlying a common tauopathy in an ethnic minority on Guam.

Intracytoplasmic filamentous tau inclusions are neuropathological hallmarks of amyotrophic lateral sclerosis/parkinsonism-dementia complex (ALS/PDC) of Guam and the defining lesions of other neurodegenerative disorders known as tauopathies. Here we review current insights into the cell and molecular neuropathology of ALS/PDC, a common tauopathy in the Chamorro population on Guam. We also summarize recent advances in understanding this disorder through studies of transgenic (Tg) mouse models of this tauopathy. Briefly, overexpression of human tau isoforms in the central nervous system of Tg mice resulted in a neurodegenerative tauopathy with a phenotype similar to ALS/PDC. Specifically, argyrophilic, congophilic, and tau immunoreactive inclusions accumulated with age in cortical and brainstem neurons of these mice, but they were most abundant in spinal cord neurons, and the inclusions contained 10- to 20-nm tau-positive straight filaments. There also was extensive gliosis in spinal cord associated with axonal degeneration in the ventral roots, while remaining axons in spinal nerves showed a loss of microtubules and reduced fast axonal transport. With advancing age, these Tg mice showed increasing motor weakness, and this was accompanied by a progressive increase in the phosphorylation and insolubility of brain and spinal cord tau proteins. Thus, tau Tg mice recapitulate key phenotypic features of ALS/PDC neuropathology in an ethnic minority on Guam, and these animal models provide new opportunities to discover novel therapies for this and related tauopathies.

Amyotrophic Lateral Sclerosis↗

PubMed2002

Tau and alpha-synuclein pathology in amygdala of Parkinsonism-dementia complex patients of Guam.

Amyotrophic lateral sclerosis/parkinsonism-dementia complex (ALS/PDC) is a progressive neurodegenerative disorder of Chamorro residents of Guam and the Mariana Islands, characterized by abundant neuron loss and tau neurofibrillary pathology similar to that observed in Alzheimer's disease (AD). A variety of neurodegenerative diseases with tau pathology including ALS/PDC also have alpha-synuclein positive pathology, primarily in the amygdala. We further characterized the tau and alpha-synuclein pathology in the amygdala of a large series of 30 Chamorros using immunohistochemical and biochemical techniques. Tau pathology was readily detected in both affected and unaffected Chamorros. In contrast, alpha-synuclein pathology was detected in 37% of patients with PDC but not detected in Chamorros without PDC or AD. The alpha-synuclein aggregates often co-localized within neurons harboring neurofibrillary tangles suggesting a possible interaction between the two proteins. Tau and alpha-synuclein pathology within the amygdala is biochemically similar to that observed in AD and synucleinopathies, respectively. Thus, the amygdala may be selectively vulnerable to developing both tau and alpha-synuclein pathology or tau pathology may predispose it to synuclein aggregation. Furthermore, in PDC, tau and alpha-synuclein pathology occurs independent of beta-amyloid deposition in amygdala thereby implicating the aggregation of these molecules in the severe neurodegeneration frequently observed in this location.

Aged↗

PubMed2002

Signature tau neuropathology in gray and white matter of corticobasal degeneration.

Corticobasal degeneration (CBD) is an adult-onset progressive neurodegenerative disorder characterized by L-dopa-resistant rigidity, focal cortical deficits, and variable dementia. The neuropathological hallmark of CBD is the deposition of filamentous inclusions in neurons and glia composed of hyperphosphorylated tau with only four microtubule-binding repeats (4R-tau). To characterize the regional burden of tau pathology in CBD, we studied 12 brains with the neuropathological diagnosis of CBD using biochemical and histochemical techniques. Eleven brain regions were evaluated including gray and white matter from frontal, parietal, temporal, and occipital lobes and cerebellum as well as basal ganglia. Although the distribution of tau pathology was variable, neuropathological and biochemical data showed a similar burden of tau abnormalities in frontal, temporal, and parietal lobes and basal ganglia of both hemispheres. This included abundant, sarkosyl-insoluble 4R-tau in both gray and white matter of two or more of these cortical regions and basal ganglia, and to a lesser extent, cerebellar white matter. The insoluble tau pathology in gray and white matter showed overlapping but distinct phosphorylated epitopes suggesting cell-type and subcellular localization (ie, cell bodies versus cell processes)-specific differences in tau phosphorylation. In contrast, soluble tau was composed of normal 4R/3R-tau ratios indicating no gross abnormality in tau splicing. Thus, although clinically heterogeneous, CBD is a distinct lobar and basal ganglionic tauopathy with selective aggregation of 4R-tau.

Aged↗