Revisiting the Molecular Mechanism of Neurological Manifestations in Antiphospholipid Syndrome: Beyond Vascular Damage

Antiphospholipid syndrome (APS) is a multiorgan disease often affecting the central nervous system (CNS). Typically, neurological manifestations of APS include thrombosis of cerebral vessels leading to stroke and requiring prompt initiation of treatment with antiplatelet drugs or anticoagulant therapy. In these cases, alterations of the coagulation system at various levels caused by multiple effects of antiphospholipid antibodies (aPL) have been postulated to explain the vascular damage to the CNS in APS. However, several nonvascular neurological manifestations of APS have progressively emerged over the past years. Nonthrombotic, immune-mediated mechanisms altering physiological basal ganglia function have been recently suggested to play a central role in the pathogenesis of these manifestations that include, among others, movement disorders such as chorea and behavioral and cognitive alterations. Similar clinical manifestations have been described in other autoimmune CNS diseases such as anti-NMDAR and anti-VGCK encephalitis, suggesting that the spectrum of immune-mediated basal ganglia disorders is expanding, possibly sharing some pathophysiological mechanisms. In this review, we will focus on thrombotic and nonthrombotic neurological manifestations of APS with particular attention to immune-mediated actions of aPL on the vascular system and the basal ganglia

Immunity and inflammation in neurodegenerative diseases.

Immune reactions inside the central nervous system are finely regulated, thanks to the presence of several checkpoints that have the fundamental purpose to preserve this fragile tissue form harmful events. The current knowledge on the role of neuroinflammation and neuro-immune interactions in the fields of multiple sclerosis, Alzheimer's disease and Parkinson's disease is reviewed. Moreover, a focus on the potential role of both active and passive immunotherapy is provided. Finally, we propose a common perspective, which implies that, under pathological conditions, inflammation may exert both detrimental and protective functions, depending on local factors and the timing of immune activation and shutting-off systems

Peripheral nervous system involvement in Parkinson's disease: Evidence and controversies

n/

ANO3 as a Cause of Early‐Onset Chorea Combined with Dystonia: Illustration of Phenotypic Evolution

Here, we signpost a case of a childhood-onset chorea-dominant phenotype later evolved into a dystonia-dominant phenotype during adulthood, in a subject carrying a missense pathogenic variant (c.1528 G > A; p.Glu510Lys)1 in the anoctamin 3 protein-coding gene (ANO3, DYT24, OMIM 610110).

Evidence of pre-synaptic dopaminergic deficit in a patient with a novel progranulin mutation presenting with atypical parkinsonism

Parkinsonism can be the presenting feature of frontotemporal dementia due to Progranulin (GRN) mutations or develop over the course of the disease, mimicking idiopathic Parkinson's disease or atypical parkinsonism. Here we report on a patient carrying a novel GRN mutation who presented with asymmetric parkinsonism and developed cognitive decline and language alterations two years later. Brain MRI showed mild asymmetric fronto-parietal atrophy. Single-photon emission computed tomography with I123 ioflupane (DAT-Scan) demonstrated reduced tracer uptake in the left putamen. Larger studies are needed to clarify whether presynaptic dopaminergic deficit is present in all GRN mutation carriers or only in those with parkinsonism

Identification of novel CSF biomarkers for neurodegeneration and their validation by a high-throughput multiplexed targeted proteomic assay

BACKGROUND: Currently there are no effective treatments for many neurodegenerative diseases. Reliable biomarkers for identifying and stratifying these diseases will be important in the development of future novel therapies. Lewy Body Dementia (LBD) is considered an under diagnosed form of dementia for which markers are needed to discriminate LBD from other forms of dementia such as Alzheimer's Disease (AD). This work describes a Label-Free proteomic profiling analysis of cerebral spinal fluid (CSF) from non-neurodegenerative controls and patients with LBD. Using this technology we identified several potential novel markers for LBD. These were then combined with other biomarkers from previously published studies, to create a 10 min multiplexed targeted and translational MRM-LC-MS/MS assay. This test was used to validate our new assay in a larger cohort of samples including controls and the other neurodegenerative conditions of Alzheimer's and Parkinson's disease (PD). RESULTS: Thirty eight proteins showed significantly (p < 0.05) altered expression in LBD CSF by proteomic profiling. The targeted MRM-LC-MS/MS assay revealed 4 proteins that were specific for the identification of AD from LBD: ectonucleotide pyrophosphatase/phosphodiesterase 2 (p < 0.0001), lysosome-associated membrane protein 1 (p < 0.0001), pro-orexin (p < 0.0017) and transthyretin (p < 0.0001). Nineteen proteins were elevated significantly in both AD and LBD versus the control group of which 4 proteins are novel (malate dehydrogenase 1, serum amyloid A4, GM2-activator protein, and prosaposin). Protein-DJ1 was only elevated significantly in the PD group and not in either LBD or AD samples. Correlations with Alzheimer-associated amyloid β-42 levels, determined by ELISA, were observed for transthyretin, GM2 activator protein and IGF2 in the AD disease group (r(2) ≥ 0.39, p ≤ 0.012). Cystatin C, ubiquitin and osteopontin showed a strong significant linear relationship (r(2) ≥ 0.4, p ≤ 0.03) with phosphorylated-tau levels in all groups, whilst malate dehydrogenase and apolipoprotein E demonstrated a linear relationship with phosphorylated-tau and total-tau levels in only AD and LBD disease groups. CONCLUSIONS: Using proteomics we have identified several potential and novel markers of neurodegeneration and subsequently validated them using a rapid, multiplexed mass spectral test. This targeted proteomic platform can measure common markers of neurodegeneration that correlate with existing diagnostic makers as well as some that have potential to show changes between AD from LBD

The CACNA1B R1389H variant is not associated with myoclonus-dystonia in a large European multicentric cohort.

Myoclonus-dystonia (M-D) is a very rare movement disorder, caused in ∼30-50% of cases by mutations in SGCE. The CACNA1B variant c.4166G>A; (p.R1389H) was recently reported as the likely causative mutation in a single 3-generation Dutch pedigree with five subjects affected by a unique dominant M-D syndrome and cardiac arrhythmias. In an attempt to replicate this finding, we assessed by direct sequencing the frequency of CACNA1B c.4166G>A; (p.R1389H) in a cohort of 520 M-D cases, in which SGCE mutations had been previously excluded. A total of 146 cases (28%) had a positive family history of M-D. The frequency of the variant was also assessed in 489 neurologically healthy controls and in publicly available data sets of genetic variation (1000 Genomes, Exome Variant Server and Exome Aggregation Consortium). The variant was detected in a single sporadic case with M-D, but in none of the 146 probands with familial M-D. Overall, the variant was present at comparable frequencies in M-D cases (1 out of 520; 0.19%) and healthy controls (1 out of 489; 0.2%). A similar frequency of the variant was also reported in all publicly available databases. These results do not support a causal association between the CACNA1B c.4166G>A; (p.R1389H) variant and M-D

Partial loss-of-function of sodium channel SCN8A in familial isolated myoclonus.

Variants in the neuronal sodium channel gene SCN8A have been implicated in several neurological disorders. Early infantile epileptic encephalopathy type 13 results from de novo gain-of-function mutations that alter the biophysical properties of the channel. Complete loss-of-function variants of SCN8A have been identified in cases of isolated intellectual disability. We now report a novel heterozygous SCN8A variant, p.Pro1719Arg, in a small pedigree with five family members affected with autosomal dominant upper limb isolated myoclonus without seizures or cognitive impairment. Functional analysis of the p.Pro1719Arg variant in transfected neuron-derived cells demonstrated greatly reduced Nav 1.6 channel activity without altered gating properties. Hypomorphic alleles of Scn8a in the mouse are known to result in similar movement disorders. This study expands the phenotypic and functional spectrum of SCN8A variants to include inherited nonepileptic isolated myoclonus. SCN8A can be considered as a candidate gene for isolated movement disorders without seizures