New knowledge on anti-IgLON5 disease.

PURPOSE OF REVIEW: Anti-IgLON5 disease is characterized by a distinctive sleep disorder, associated with a heterogeneous spectrum of neurological symptoms. Initial autopsies showed a novel neuronal tauopathy predominantly located in the tegmentum of the brainstem. Recently, new diagnostic red flags, biomarkers predictors of response to immunotherapy, and novel insights into the autoimmune pathogenesis of the disease have been reported. RECENT FINDINGS: Patients with diagnosis of neurodegenerative dementia, progressive supranuclear palsy (PSP) or with motor-neuron disease (MND)-like syndrome have been reported to have IgLON5 antibodies, which are the hallmark of anti-IgLON5 disease. Second, low levels of neurofilament light chain in serum and cerebrospinal fluid of patients at disease onset could be a predictor of immunotherapy response. Recent neuropathological studies indicate that the neuronal tau deposits occur late in the course of the disease. Moreover, IgLON5 antibodies induce cytoskeletal changes in cultured hippocampal neurons suggesting that the tauopathy could be secondary of the IgLON5 antibody effects. SUMMARY: Anti-IgLON5 disease can mimic and should be considered in atypical presentations of MND, neurodegenerative dementia and PSP. Neurofilament light chain levels seem promising biomarker for disease prognosis. Finally, the neuropathological and in vitro experimental studies strengthen the autoimmune hypothesis of the disease.

Ocular Motor Abnormalities in Anti-IgLON5 Disease.

Objective: Anti-IgLON5 disease forms an interface between neuroinflammation and neurodegeneration and includes clinical phenotypes that are often similar to those of neurodegenerative diseases. An early diagnosis of patients with anti-IgLON5 disease and differentiation from neurodegenerative diseases is necessary and may have therapeutic implications. Methods: In our small sample size study we investigated oculomotor function as a differentiating factor between anti-IgLON5 disease and neurodegenerative disorders. We examined ocular motor and vestibular function in four patients suffering from anti-IgLON5 disease using video-oculography (VOG) and a computer-controlled rotational chair system (sampling rate 60 Hz) and compared the data with those from ten age-matched patients suffering from progressive supranuclear palsy (PSP) and healthy controls (CON). Results: Patients suffering from anti-IgLON5 disease differed from PSP most strikingly in terms of saccade velocity and accuracy, the presence of square wave jerks (SWJ) (anti-IgLON5 0/4 vs. PSP 9/10) and the clinical finding of supranuclear gaze palsy (anti-IgLON5 1/4). The presence of nystagmus, analysis of smooth pursuit eye movements, VOR and VOR suppression was reliable to differentiate between the two disease entities. Clear differences in all parameters, although not always significant, were found between all patients and CON. Discussion: We conclude that the use of VOG as a tool for clinical neurophysiological assessment can be helpful in differentiating between patients with PSP and patients with anti-IgLON5 disease. VOG could have particular value in patients with suspected PSP and lack of typical Parkinson's characteristics. future trials are indispensable to assess the potential of oculomotor function as a biomarker in anti-IgLON5 disease.

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.

A walk through tau therapeutic strategies.

Tau neuronal and glial pathologies drive the clinical presentation of Alzheimer's disease and related human tauopathies. There is a growing body of evidence indicating that pathological tau species can travel from cell to cell and spread the pathology through the brain. Throughout the last decade, physiological and pathological tau have become attractive targets for AD therapies. Several therapeutic approaches have been proposed, including the inhibition of protein kinases or protein-3-O-(N-acetyl-beta-D-glucosaminyl)-L-serine/threonine Nacetylglucosaminyl hydrolase, the inhibition of tau aggregation, active and passive immunotherapies, and tau silencing by antisense oligonucleotides. New tau therapeutics, across the board, have demonstrated the ability to prevent or reduce tau lesions and improve either cognitive or motor impairment in a variety of animal models developing neurofibrillary pathology. The most advanced strategy for the treatment of human tauopathies remains immunotherapy, which has already reached the clinical stage of drug development. Tau vaccines or humanised antibodies target a variety of tau species either in the intracellular or extracellular spaces. Some of them recognise the amino-terminus or carboxy-terminus, while others display binding abilities to the proline-rich area or microtubule binding domains. The main therapeutic foci in existing clinical trials are on Alzheimer's disease, progressive supranuclear palsy and non-fluent primary progressive aphasia. Tau therapy offers a new hope for the treatment of many fatal brain disorders. First efficacy data from clinical trials will be available by the end of this decade.

Chronic meningoencephalitis with mixed pathology mimics progressive supranuclear palsy.

We report a case of a progressive supranuclear palsy-like phenotype with rapidly progressive dementia and prominent language and executive dysfunction. Pathological examination revealed no midbrain or white matter tauopathy, but rather chronic meningoencephalitis and other mixed pathology. The cerebrospinal fluid (CSF) in this case showed a novel antibody against central nervous system and renal tissue.

Cytokine expression and microglial activation in progressive supranuclear palsy.

Although little is known about the etiology of progressive supranuclear palsy (PSP), genetic and epigenetic factors, oxidative injury and inflammation are thought to contribute to its development and/or progression. Evidence for activated glia involvement in PSP has raised the possibility that neuroinflammation may contribute to its pathogenesis. To investigate the correlation between neuroinflammation and PSP, a comparative study was conducted on the patterns of cytokine expression in different regions of the brains of PSP, Alzheimer's disease (AD) patients and normal controls. Our results show different patterns of cytokine expression in each disease, with the expression of IL-1ß transcripts being significantly higher in the substantia nigra of PSP than in AD and controls, while AD brains had significantly higher IL-1ß expression in the parietal cortex compared to PSP and controls. In addition, expression of TGFß was significantly higher in the cortical areas (particularly frontal and parietal lobes) of AD compared to PSP and controls. These results show a disease-specific topographical relationship among the expression of certain cytokines (IL-1ß and TGFß), microglial activation and neurodegenerative changes, suggesting that these cytokines may contribute to the pathologic process. If so, the use of cytokine-inhibitors and/or other anti-inflammatory agents may be able to slow disease progression in PSP.

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.

Tau epitope display in progressive supranuclear palsy and corticobasal degeneration.

Filamentous aggregates of the protein tau are a prominent feature of Alzheimer's disease (AD), progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). However, the extent to which the molecular structure of the tau in these aggregates is similar or differs between these diseases is unclear. We approached this question by examining these disorders with a panel of antibodies that represent different structural, conformational, and cleavage-specific tau epitopes. Although each of these antibodies reveals AD pathology, they resolved into three classes with respect to PSP and CBD: AD2 and Tau-46.1 stained the most tau pathology in all cases; Tau-1, 2, 5, and 12 exhibited variable reactivity; and Tau-66 and MN423 did not reveal any tau pathology. In addition, hippocampal neurofibrillary tangles in these cases showed a predominantly PSP/CBD-like, rather than AD-like, staining pattern. These results indicate that the patterns of the tau epitopes represented by this panel that reside in the pathological aggregates of PSP and CBD are similar to each other but distinct from that of AD.

Progressive supranuclear palsy and tau hyperphosphorylation in a patient with a C212Y parkin mutation.

Autosomal recessive-juvenile parkinsonism (AR-JP) is one of the most common forms of familial Parkinson's disease (PD) and is related to mutations in the Park-2 gene, encoding for a protein ligase of ubiquitin, parkin. Different mutations located along the parkin gene have been observed in different AR-JP affected families, possibly interfering with the normal function of parkin and the proteasome system. Two cases of patients with AR-JP have been recently described presenting different homo- and heterozygous parkin mutations and limited tau pathology. We report here the case of a patient with clinical and pathological findings compatible with progressive supranuclear palsy (PSP), carrier of a single, heterozygous mutation of the parkin gene, and homozygous for the H1/H1 haplotype in the tau gene. Abnormal tau hyperphosphorylation has been observed in our patient brain samples, suggesting that a partial deficit of parkin, a protein with ubiquitin-ligase function, may trigger tau pathology in individuals with molecular genetic risk factors.

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.

Increased concentration of C4d complement protein in the cerebrospinal fluids in progressive supranuclear palsy.

Plasma and CSF levels of C4d and the circulating immune complex (CIC) to C1q were measured in 27 patients with progressive supranuclear palsy (PSP), Parkinson's disease (PD) and cervical spondylosis (CS). There was no significant difference among groups in plasma C4d or in plasma or CSF CIC to C1q. However, the PSP group had significantly higher CSF levels of C4d than the PD and CS groups. Higher CSF C4d index in the PSP group was also shown compared with PD and CS groups. These results suggest that augmented complement activation in the wide areas of the central nervous system occurs in PSP. CSF levels of C4d or C4d index may serve as a basis for differentiating PSP from PD.

Progressive supranuclear palsy: loss of choline-acetyltransferase-like immunoreactive neurons in the pontine reticular formation.

We performed a quantitative immunocytochemical study using a polyclonal antibody directed against choline acetyltransferase (ChAT) in the lower pontine reticular formation in four control subjects and three patients with progressive supranuclear palsy (PSP). In the normal brains, there was detectable ChAT-like immunoreactivity in the nucleus papillioformis, a precerebellar reticular nucleus, and in the nucleus pontis centralis caudalis. In PSP patients, the mean estimated total number of ChAT-like immunoreactive cells was 54% of controls in nucleus papillioformis and 40% of controls in nucleus pontis centralis caudalis. The demonstration of ChAT-like immunoreactivity in nucleus papillioformis is consistent with studies suggesting an extrinsic cholinergic innervation of the cerebellar cortex. Loss of cholinergic cells in nucleus pontis centralis caudalis that corresponds largely to the paramedian pontine reticular formation may be related to disturbances of horizontal saccades in PSP patients.

Formic acid treatment exposes hidden neurofilament and tau epitopes in abnormal cytoskeletal filaments from patients with progressive supranuclear palsy and Alzheimer's disease.

In cases of progressive supranuclear palsy (PSP) and Alzheimer's disease (AD) the treatment of tissue sections with formic acid (FA) disclosed a neurofilament epitope in subcortical straight (SF) and paired helical (PHF) filaments. The same treatment produced a two-fold increase of tau-reactive neuropil threads and plaque-related neurites in AD cortical tissue. These findings indicate that epitopes of cytoskeletal proteins are hidden by the beta-pleated conformation of SF and PHF components. FA treatment should be used in immunohistochemical detection of intraneuronal abnormal cytoskeletal filaments.

Antigenic characteristics of neurofibrillary tangles in progressive supranuclear palsy.

The antigenic components of neurofibrillary tangles in the basal forebrain and brainstem were studied in 4 cases of progressive supranuclear palsy (PSP) at the light and electron microscopic levels, using antibodies to neurofilaments (in the phosphorylated and non-phosphorylated forms); the high, middle and low molecular weight neurofilament subunits; ubiquitin; the microtubule associated proteins MAP1, MAP2 and tau; isolated Alzheimer paired helical filaments and to tubulin, in the tyrosinated and detyrosinated forms. Although PSP neurofibrillary tangles appear to have most antigenic sites in common with those of Alzheimer disease, PSP tangles share epitopes with tyrosinated and detyrosinated tubulin, which has not been demonstrated in Alzheimer neurofibrillary tangles.

Influence of neuronal location on antigenic properties of neurofibrillary tangles.

We quantitatively assessed the antigenic properties of the neurofibrillary tangles (NFT) located in neurons of the tegmental nuclei of the pontine raphe in progressive supranuclear palsy (PSP) and Alzheimer's disease (AD). These properties were then compared with those of NFT of AD located in hippocampal neurons. Antibodies known to react with cortical NFT of AD were used to stain sections from PSP, AD, and control cases. The reaction with the straight filaments of NFT of PSP and with the paired helical filaments of pontine NFT of AD was ascertained by immunoelectron microscopy. The results show that, despite the ultrastructural difference, straight filaments in NFT of PSP and paired helical filaments in NFT of AD share antigenic properties when they are located in the same neuronal population. In contrast, paired helical filaments located in the cerebral cortex are antigenically different from those in pontine nuclei. Location, more than structure, may play a role as determinant of antigenic properties in straight filaments of PSP and paired helical filaments of AD.

Reductions in corticotropin releasing factor-like immunoreactivity in cerebral cortex in Alzheimer's disease, Parkinson's disease, and progressive supranuclear palsy.

Dementias occurring in Alzheimer's disease, Parkinson's disease, and progressive supranuclear palsy are associated with dysfunction and death of neurons in a variety of cell populations, including cholinergic, monoaminergic, and peptidergic systems. In the present investigation of these three disorders, we demonstrated decreased levels of corticotropin releasing factor (CRF)-like immunoreactivity in the frontal, temporal, and occipital poles of the neocortex. Moreover, reductions in peptidergic immunoreactivity correlated with reductions in the activity of choline acetyltransferase, the enzyme that catalyzes the formation of acetylcholine. The reduction in cortical CRF levels may be due to abnormalities of intrinsic cortical neurons or to dysfunction in neurons that contain CRF and innervate cortex.