Progressive supranuclear palsy (PSP) is a movement disorder with prominent tau neuropathology. Brain diseases with abnormal tau deposits are called tauopathies, the most common being Alzheimer’s disease. Environmental causes of tauopathies include repetitive head trauma associated with some sports. To identify common genetic variation contributing to risk for tauopathies, we carried out a genome-wide association study of 1,114 PSP cases and 3,247 controls (Stage 1) followed up by a second stage where 1,051 cases and 3,560 controls were genotyped for Stage 1 SNPs that yielded P ≤ 10−3. We found significant novel signals (P < 5 × 10−8) associated with PSP risk at STX6, EIF2AK3, and MOBP. We confirmed two independent variants in MAPT affecting risk for PSP, one of which influences MAPT brain expression. The genes implicated encode proteins for vesicle-membrane fusion at the Golgi-endosomal interface, for the endoplasmic reticulum unfolded protein response, and for a myelin structural component.
Survival is reduced in GBA carriers compared to noncarriers; this seems to be partially independent from the increased risk for early dementia. The risk for dementia is strongly modulated by type of mutation. In the clinical continuum between PD and DLB, patients with GBA mutations seem to localize midway, with carriers of severe mutations closer to DLB than to idiopathic PD. Ann Neurol 2016;80:662-673.
We studied the frequency and clinical correlates of different IgM specificities in 75 patients with neuropathy associated with IgM monoclonal gammopathy. Patients were tested for IgM reactivity with the myelin-associated glycoprotein, P0, neurofilaments, and tubulin by immunoblot; with GM1, asialo-GM1, GM2, GD1a, GD1b, sulfatide, and chondroitin sulfate C by enzyme-linked immunosorbent assay; and with brain and nerve glycolipids by overlay high-performance thin-layer chromatography. Forty-two patients (56%) had high titers of IgM antibodies to MAG; 4 (5%), to sulfatide (1 also to myelin-associated glycoprotein); 4 (5%), to the 200-kd neurofilament (2 also to myelin-associated protein); and 1 each, to GD1b and chondroitin sulfate C. No reactivity was found in 26 patients (35%). More patients with anti-myelin-associated glycoprotein IgM (62%) than with unknown IgM reactivity (31%) had a predominantly sensory neuropathy (p < 0.025). Nerve conduction findings were consistent with a demyelinating neuropathy in 77% of patients reactive to myelin-associated glycoprotein and 24% with unknown reactivity (p < 0.0001) and the mean conduction velocity of peroneal nerve was lower in the former group (22.9 m/sec) than in the latter group (39.6 m/sec) (p < 0.000001). Patients with anti-sulfatide IgM had a sensorimotor neuropathy with morphological evidence of demyelination while anti-neurofilament IgM was not associated with homogeneous findings. Patients with anti-GD1b or anti-chondroitin sulfate C IgM had a predominantly motor impairment. The frequent occurrence of anti-neural IgM antibodies in neuropathy associated with IgM gammopathy, and their frequent, though not constant association with similar neuropathy features, support their possible pathogenetic role in the neuropathy.
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