Moaning Phenomenon and Rapidly Progressive Dementia in Anti LGI-1 Associated Progressive Supranuclear Palsy Syndrome.

Background: Immunological causes of atypical parkinsonisms linked to neuronal specific antibodies have been recently reported. As these are potentially treatable disorders, it is desirable to identify which clinical features may suggest an autoimmune etiology. Case Report: A 60-year-old-man with progressive supranuclear palsy associated with anti-LGI-1 antibodies presented with rapidly progressive dementia and moaning. Treatment with steroids and immunoglobulin resulted in temporary clinical improvement and disease stabilization. Discussion: Anti-LGI-1 antibodies interfere with normal synaptic activity and maturation in the central nervous system. We suggest that an immune-mediated mechanism might be considered in atypical parkinsonisms with unusual features such as rapidly progressive dementia. Highlights: We present a case of rapidly evolving progressive supranuclear palsy-like parkinsonism associated with anti-LGI-1 antibodies, suggesting that immune-mediated mechanisms might be involved in rapid progression of some atypical parkinsonisms. This case also contributes to the expanding spectrum of moaning-associated disorders.

Narcolepsy, REM sleep behavior disorder, and supranuclear gaze palsy associated with Ma1 and Ma2 antibodies and tonsillar carcinoma.

OBJECTIVE: To describe a patient with diencephalic and mesencephalic presentation of a Ma1 and Ma2 antibody-associated paraneoplastic neurological disorder. DESIGN: Case report. SETTING: The Colorado Neurological Institute Movement Disorders Center in Englewood, Colorado, and the Mayo Clinic in Rochester, Minnesota. PATIENT: A 55-year-old man with a paraneoplastic neurological disorder characterized by rapid eye movement sleep behavior disorder, narcolepsy, and a progressive supranuclear palsy-like syndrome in the setting of tonsillar carcinoma. INTERVENTION: Immunotherapy for paraneoplastic neurological disorder, surgery and radiotherapy for cancer, and symptomatic treatment for parkinsonism and sleep disorders. MAIN OUTCOME MEASURES: Polysomnography, multiple sleep latency test, and neurological examination. RESULTS: The cancer was detected at a limited stage and treatable. After oncological therapy and immunotherapy, symptoms stabilized. Treatment with modafinil improved daytime somnolence. CONCLUSIONS: Rapid onset and progression of multifocal deficits may be a clue to paraneoplastic etiology. Early treatment of a limited stage cancer (with or without immunotherapy) may possibly slow progression of neurological symptoms. Symptomatic treatment may be beneficial.

Ki-67 immunoreactivity in Alzheimer's disease and other neurodegenerative disorders.

Cell cycle-associated nuclear proteins may have more specialized functions in the adult nervous system in addition to those directly associated with cell proliferation, as suggested by a recent study showing that neurofibrillary tangles (NFT) and dystrophic neurites in Alzheimer's disease (AD) are immunoreactive for the proliferation-associated antigen p105. To further investigate this hypothesis, we studied the expression of another proliferation-associated antigen, Ki-67, in the brains of patients with AD and other neurodegenerative disorders. Formalin-fixed, paraffin-embedded sections from autopsy cases of AD, Down's syndrome with dementia and AD pathology (DS/AD), Pick's disease (PiD), progressive supranuclear palsy (PSP), Lewy body disease (LBD), Parkinson's disease (PD), corticobasal degeneration (CBD), and young and aged normal brains, and from two surgically resected gangliogliomas were immunostained using antibodies to Ki-67 (MIB-1 clone equivalent) and tau (tau). Ki-67 staining was performed following antigen retrieval by microwave heating. Ki-67 labeled NFT that were observed in the AD, DS/AD, PiD, PSP, LBD, and PD cases, one aged normal brain, and one ganglioglioma. Ki-67 generally labeled fewer NFT compared to tau. Pick bodies, ballooned neurons (Pick cells) in CBD and PiD, and nigral corticobasal inclusions in CBD were immunoreactive for tau but not Ki-67. Neither antibody labeled cortical or subcortical Lewy bodies. Our findings suggest that Ki-67 may be involved in the pathogenesis of neurofibrillary degeneration in AD, other neurodegenerative disorders, normal aging, and neoplasms such as ganglioglioma. We postulate a possible role for Ki-67 in the production of the abnormally phosphorylated tau protein that leads to the formation of paired helical filaments within susceptible neurons.

Antigenic determinant properties of neurofibrillary tangles. Relevance to progressive supranuclear palsy.

Neuronal cytoskeleton is composed of microfilaments, neurofilaments and microtubules which show distinctive ultrastructural characteristics. Different groups of antibodies against neurofilaments and microtubule associated proteins which were grouped according to their specificity for proteins of perykarium, axons and/or dendrites have been produced. A 8.6 kD polypeptide called ubiquitin has been recognized as one of the heat shock proteins. Ubiquitin is implicated in the non-lysosomal degradation of abnormal proteins and other proteolytic intracellular mechanisms. Several immunohistological studies on Alzheimer's disease (AD)-neurofibrillary tangles (NFTs) demonstrated that antibodies for different normal cytoskeletal components bind to NFTs-bearing neurons. AD-NFTs could be also demonstrated using antibodies for the beta-amyloid protein. The production and accumulation of abnormal proteins such as those observed in AD-NFTs induce a ubiquitin-mediated degradative pathway to remove them. It has been demonstrated that ubiquitin is covalently associated with insoluble neurofibrillary material of AD-NFTs. Topographical differences in the distribution of NFTs underscore that different neuronal populations including neocortical neurones are affected in progressive supranuclear palsy (PSP) and AD. Differences in the molecular composition of PSP-NFTs highlighted by immunochemical studies induce us to speculate that different physio- and aetiopathogenetic mechanisms are operative in the production of PSP-NFTs.

Neurofibrillary tangles in Alzheimer's disease and progressive supranuclear palsy: antigenic similarities and differences. Microtubule-associated protein tau antigenicity is prominent in all types of tangles.

The antigenic profile of neurofibrillary tangles (NFT) in Alzheimer's disease (AD), senile dementia of Alzheimer type (SDAT), progressive supranuclear palsy (PSP) and in non-demented aged humans was investigated by light and electron microscopic immunocytochemistry using antisera and monoclonal antibodies to tubulin, microtubule-associated proteins (MAP1, MAP2 and tau), neurofilament proteins and determinants unique to Alzheimer paired helical filaments (PHF). Antibodies to tau proteins labeled NFT in all cases investigated (AD, SDAT, PSP and non-demented aged humans). However, one monoclonal antibody to PHF recognized numerous tangles in AD/SDAT, but only a small minority of the PSP tangles. Antibodies to tubulin, MAP1, MAP2 and neurofilament proteins did not selectively stain NFT. Whereas pretreatment of sections with phosphatase was required for the detection of tangles with Tau-1 monoclonal antibody, digestion of sections with either phosphatase or pronase had no significant effect on the staining pattern obtained with the other antibodies. Our studies show that, as previously described for AD/SDAT, phosphorylated tau polypeptides are also a major antigenic determinant of tangles in PSP, indicating that tangle formation may follow a common pathogenetic pathway in neurofibrillary degenerations. There is, however, at least one epitope in AD/SDAT tangles which seems to be absent on, or at least inaccessible in, the 15-nm straight fibrils of PSP.