Up to 13% of patients with LGI1 Abs develop cognitive impairment without criteria of encephalitis. After immunotherapy, only 35% of patients return to their baseline cognitive function. Serum LGI1 Abs may remain detectable after full clinical recovery.
IgG NMDAR antibodies are highly specific for anti-NMDAR encephalitis and cause a decrease of the levels of NMDAR. In contrast, IgA or IgM antibodies occur infrequently and nonspecifically in other diseases and do not alter the receptor levels.
ObjectiveTo report the presenting syndromes and to determine whether pretreatment criteria of Hashimoto encephalopathy (HE) predict response to steroids.MethodsWe assessed symptoms and steroid responsiveness in 24 patients with pretreatment criteria of HE, including (1) subacute onset of cognitive impairment, psychiatric symptoms, or seizures; (2) euthyroid status or mild hypothyroidism; (3) serum thyroid peroxidase antibodies (TPOAb) >200 IU/mL; (4) absent neuronal antibodies in serum/CSF; and (5) no other etiologies. Additional studies included determination of TPOAb (>200 IU/mL) in 74 patients with criteria of possible autoimmune encephalitis (AE) without neuronal antibodies and 205 patients with different neuroimmunologic diseases, psychosis, or new-onset refractory status epilepticus (NORSE). Serum antibodies to the amino (ΝΗ2)-terminal of α-enolase (NH2-α-enolaseAb) were examined in the indicated 24 patients and 13 controls.ResultsThe 24 patients (14 women) with suspected HE had a median age of 48 years (range 8–79 years). Four syndromes were identified: psychiatric (7, 29%), encephalopathy (7, 29%), NORSE-like (6, 25%), and limbic encephalitis (4, 17%). Only 6 of 19 (31.6%) patients completely responded to steroids. The frequency of TPOAb in the 74 patients with possible AE (6 of 74, 8.1%) was similar to that of the 205 controls (17 of 205, 8.2%; p = 0.84). NH2-α-enolaseAb were identified in 1 of 24 suspected HE cases and 1 of 13 controls.ConclusionCurrent pretreatment criteria of HE do not predict steroid responsiveness. The detection of TPOAb across all control groups reveals their poor disease-specificity. NH2-α-enolaseAb did not help in the diagnosis of HE. These findings imply a redefinition of HE that requires a systematic exclusion of antibody-mediated encephalitis.
DPPX antibodies are predominantly IgG1 and IgG4 and associate with cognitive-mental deficits and symptoms of CNS hyperexcitability that are usually preceded by diarrhea, other gastrointestinal symptoms, and weight loss. The disorder is responsive to immunotherapy, and this is supported by the reversibility of the antibody effects in cultured neurons.
SUMMARY
Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is a severe neuropsychiatric disorder mediated by autoantibodies against the GluN1 subunit of the NMDAR. Patients’ antibodies cause crosslinking and internalization of NMDAR, but the synaptic events leading to depletion of NMDAR are poorly understood. Using super-resolution microscopy, we studied the effects of the autoantibodies on the nanoscale distribution of NMDAR in cultured neurons. Our findings show that, under control conditions, NMDARs form nanosized objects and patients’ antibodies increase the clustering of synaptic and extrasynaptic receptors inside the nano-objects. This clustering is subunit specific and predominantly affects GluN2B-NMDARs. Following internalization, the remaining surface NMDARs return to control clustering levels but are preferentially retained at the synapse. Monte Carlo simulations using a model in which antibodies induce NMDAR cross-linking and disruption of interactions with other proteins recapitulated these results. Finally, activation of EphB2 receptor partially antagonized the antibody-mediated disorganization of the nanoscale surface distribution of NMDARs.
Double immunofluorolabeling for 3-repeat (3R) and 4-repeat (4R) tau was performed with two monoclonal antibodies, RD3 and RD4, after an additional pretreatment with potassium permanganate and oxalic acid to eliminate nonspecific 3R tau cytoplasmic staining. This method involves hyperdilution of one of the primary monoclonal antibodies (≥100-fold), making it undetectable by usual secondary antibodies. The hyperdiluted primary antibody can then only be detected after tyramide amplification. Subsequent application of the other monoclonal antibody at its usual concentration allows double immunofluorolabeling without cross-reaction. This novel method revealed that tau immunoreactivity (IR) in the hippocampal pyramidal neurons of Alzheimer's disease (AD) brains is heterogeneous in that pretangle neurons exhibit 4R-selective (3R-/4R+) IR, ghost tangles exhibit 3R-selective (3R+/4R-) IR, and neurofibrillary tangles exhibit both 3R and 4R (3R+/4R+) IR. Some nigral neurons exhibited RD3 IR in both AD and corticobasal degeneration/progressive supranuclear palsy (CBD/PSP) brains. However, in CBD/PSP cases, 3R IR was always superimposed on 4R IR, while 3R-selective neurons were present in AD cases. These differential isoform profiles may provide a pivotal molecular reference, closely related to the morphological evolution of tau-positive neurons, which may be variable according to disease (CBD/PSP vs. AD), lesion site (cerebral cortex and substantia nigra), or the stage of evolution (from pretangles to ghost tangles). These findings should provide a more comprehensive understanding of the histological differentiation of various tau deposits in human neurodegenerative disease.
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