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Dementia in general and Alzheimer's disease in particular is increasingly seen in association with autoimmunity being causatively or supportively involved in the pathogenesis. Besides classic autoantibodies (AABs) present in dementia patients, there is the new autoantibody class called functional autoantibodies, which is directed against G-protein coupled receptors (GPCRs; GPCR-AABs) and are seen as pathogenic players. However, less is known about dementia patients' burden with functional autoantibodies. We present here for the first time a study analyzing the prevalence of GPCR-AABs in patients with different dementia forms such as unclassified, Lewy body, vascular and Alzheimer's dementia. We identified the GPCR-AABs' specific targets on the receptors and introduced a neutralization strategy for GPCR-AABs. Patients with Alzheimer’s and vascular dementia carried GPCR-AABs targeting the second loop of the alpha1- and the first loop of the beta2-adrenergic receptors (α1-AABs; β2-AABs). The majority of patients with Lewy body dementia lacked any of the GPCR-AABs. In vitro, the function of the dementia-associated GPCR-AABs could be neutralized by the aptamer BC007. Due to the presence of GPCR-AABs in dementia patients mainly in those suffering from Alzheimer's and vascular dementia, the orchestra of immune players in these dementia forms, so far preferentially represented by the classic autoantibodies, should be supplemented by functional autoantibodies. As dementia-associated functional autoantibodies could be neutralized by the aptamer BC007, the first step was taken for a new in vivo treatment option in dementia patients who were positive for GPCR-AABs.

Objective: To validate predictive models for neural antibody positivity and immunotherapy response in epilepsy., Methods: We conducted a retrospective study of epilepsy cases at Mayo Clinic (Rochester-MN; Scottsdale-AZ, and Jacksonville-FL) in whom autoimmune encephalopathy/epilepsy/dementia autoantibody testing profiles were requested (06/30/2014-06/30/2016). An Antibody Prevalence in Epilepsy (APE) score, based on clinical characteristics, was assigned to each patient. Among patients who received immunotherapy, a Response to Immunotherapy in Epilepsy (RITE) score was assigned. Favorable seizure outcome was defined as >50% reduction of seizure frequency at the first follow-up., Results: Serum and cerebrospinal fluid (CSF) from 1,736 patients were sent to the Mayo Clinic Neuroimmunology Laboratory for neural autoantibody evaluation. Three hundred eighty-seven of these patients met the diagnostic criteria for epilepsy. Central nervous system (CNS)-specific antibodies were detected in 44 patients. Certain clinical features such as new-onset epilepsy, autonomic dysfunction, viral prodrome, faciobrachial dystonic seizures/oral dyskinesia, inflammatory CSF profile, and mesial temporal magnetic resonance imaging (MRI) abnormalities had a significant association with positive antibody results. A significantly higher proportion of antibody-positive patients had an APE score ≥4 (97.7% vs. 21.6%, p < 0.01). Sensitivity and specificity of an APE score ≥4 to predict presence of specific neural auto-antibody were 97.7% and 77.9%, respectively. In the subset of patients who received immunotherapy (77), autonomic dysfunction, faciobrachial dystonic seizures/oral dyskinesia, early initiation of immunotherapy, and presence of antibodies targeting plasma membrane proteins (cell-surface antigens) were associated with favorable seizure outcome. Sensitivity and specificity of a RITE score ≥7 to predict favorable seizure outcome were 87.5% and 83.8%, respectively., Significance: APE and RITE scores can aid diagnosis, treatment, and prognostication of autoimmune epilepsy. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here., (Wiley Periodicals, Inc. © 2017 International League Against Epilepsy.)

Paroxysmal dystonic choreoathetosis (PDC) is an episodic, non-kinesogenic, extrapyramidal movement disorder. It is postulated that PDC is an ion channel disorder. We describe a sporadic case of paroxysmal dystonic choreoathetosis occurring after streptococcal pharyngitis. The episodes were characterized by abrupt-onset dystonic posturing, choreoathetosis, visual hallucinations and behavioral disturbance. Each episode lasted between 10 minutes and 4 hours, and occurred up to 4 times per day. In between attacks, examination was normal. The episodes waxed and waned in frequency during a 6-month illness. Magnetic resonance imaging of the brain was normal. Post-streptococcal neuropsychiatric disease has a proposed autoimmune etiology, which is supported by the presence of serum antibasal ganglia antibodies. Western immunoblotting of this case's serum demonstrated antibody binding to a basal ganglia antigens of molecular weight 80 kDa and 95 kDa. Immunohistochemistry examination demonstrated specific antibody binding to large striatal neurones. We propose that autoantibodies produced in post-streptococcal neuropsychiatric disease cause alteration in neurotransmission, possibly secondary to ion channel binding., (Copyright 2002 Movement Disorder Society)

Alzheimer's disease (AD) is associated with serum antibodies directed specifically against phosphorylated epitopes highly enriched in the heavy neurofilament protein NF-H of cholinergic neurons. Prolonged immunization of rats with these molecules but not with other NF-H isoforms results in cognitive impairments. This animal model, termed experimental autoimmune dementia (EAD), supports a role for such antibodies in neurodegeneration in AD. In the present study we investigated the cellular and immunological mechanisms underlying the cognitive defects in EAD. Immunohistochemical studies revealed that IgG accumulate in the septum, hippocampus and in the entorhinal cortex of the EAD rats. This is accompanied by a marked reduction in the density of septal cholinergic neurons. An inverse correlation was observed between the level of IgG in the septum of individual EAD rats and the density of their septal cholinergic neurons. Time course studies revealed that the decrease in the density of cholinergic neurons in the septum of EAD rats and the accumulation of IgG in this brain area have the same time course and are both significant by three to four months following the initiation of immunization with cholinergic NF-H. The cognitive deficits of the EAD rats evolve more slowly and are pronounced only after six months following the initation of immunization. In vitro studies revealed that anti NF-H IgG bind to the outer surface of neurons in tissue cultures of rat forebrain and can affect neuronal viability. These AD and in vitro findings provide model systems for studying the mechanisms underlying the neuropathological effects of specific anti NF-H antibodies.

A 22-year-old woman gradually developed depression, dementia, and chorea over an 8-month period. She fulfilled the criteria for the primary antiphospholipid antibody syndrome but not those for systemic lupus erythematosus. Her chorea and neurobehavioral deficits responded favorably to a regimen of prednisone, hydroxychloroquine, and aspirin. This appears to be the first report of a patient with a lupus anticoagulant and reversible dementia. The response to immunosuppressive therapy implies an antibody-mediated condition similar to Sydenham's chorea.

Sera of Alzheimer's disease and Down's syndrome patients contain antibodies which bind specifically to the high molecular weight neurofilament protein of Torpedo cholinergic neurons. We have recently shown that prolonged immunization of rats with this antigen results in the accumulation of IgG in neurons in the septum and hippocampus of the immunized rats and in cognitive impairments. This animal model is termed experimental autoimmune dementia. In the present study we examined whether the anti-cholinergic high molecular weight neurofilament subunit immune response of the experimental autoimmune dementia rats affects forebrain cholinergic neurons. This was performed immunohistochemically utilizing a monoclonal antibody to nerve growth factor receptor, a specific marker of cholinergic neurons in the forebrain. The results obtained revealed significant decreases in the density of cholinergic neurons in the medial septal nucleus and diagonal band of the experimental autoimmune dementia rats. These decreases are specific to the anti-cholinergic high molecular weight neurofilament subunit immune response of the experimental autoimmune dementia rats and are not observed in control rats which were immunized with chemically heterogeneous high molecular weight neurofilament subunit. The decrease in density of forebrain cholinergic neurons in experimental autoimmune dementia rats may mimic pathogenic processes in Alzheimer's disease and supports a role for anti-cholinergic high molecular weight neurofilament subunit antibodies in the degeneration of cholinergic neurons in the disease.

Experimental autoimmune dementia is a rat model designed to examine the potential role of anti-cholinergic neurons antibodies in neuronal degeneration in dementia and Alzheimer's disease. We have previously shown that sera of patients with Alzheimer's disease contain antibodies which bind specifically to the high molecular weight neurofilament protein of the purely cholinergic electromotor neurons of Torpedo. Production of such antibodies in experimental autoimmune dementia rats by prolonged immunization with the Torpedo cholinergic high molecular weight neurofilament subunit results in accumulation of antibodies in the septum and hippocampus of the immunized rats, in a marked decrease in the density of forebrain cholinergic neurons, and in memory deficits. In the present study we characterized the open-field behavior of experimental autoimmune dementia rats, and examined whether, like in dementia, the spatiotemporal organization of their behavior is impaired. The results obtained revealed that experimental autoimmune dementia rats travel shorter distances; explore a smaller part of the open-field; and perform less round-trips to the key location--the home base--in reference to which their behavior is normally organized. The shrinkage of the explored space and the reduced number of round trips are independent of the amount of locomotion and represent a deterioration in the organization of behavior in time and space. These behavioral changes are specific to the anti-cholinergic immune response of experimental autoimmune dementia rats as they are not observed in rats which were immunized with chemically heterogeneous high molecular weight neurofilament subunit.(ABSTRACT TRUNCATED AT 250 WORDS)

Cognitive dysfunction may be induced in rats by immunization with cholinergic neuronal antigens and is associated with degeneration of nuclei in the septum and hippocampus and white matter tracts in the forebrain. Such rats are a putative model of Alzheimer's disease named experimental autoimmune dementia (EAD). The aim of the present study was to investigate brainstem auditory evoked potentials (BAEP) in EAD rats in order to define the extent of white matter tract involvement in this model. Clear reproducible evoked potentials were obtained and the normal range of BAEP in rats was established in adjuvant immunized controls. Measurements of inter peak latencies (IPL) I-IV in 9 EAD rats revealed that they were not significantly prolonged (3.00 +/- 0.22 ms, mean +/- S.E.M.) compared to 9 controls (2.80 +/- 0.08 ms), (P > 0.2, Student's t-test). The lack of significant change in IPL I-IV is compatible with preliminary histological findings and indicates that brainstem structures are generally unaffected in EAD.

Circulating autoantibody to a 48-kD nuclear protein in neurons and astrocytes of the human and bovine cerebrum were present in the serum of a demented patient with an autoimmune disorder. Other human visceral organs, dorsal root ganglion cells, neuroblastoma and glioblastoma cell lines, and rat cerebrum did not react with the patient's serum. No sera from age-matched controls, including those with Alzheimer's disease, reacted with the 48-kD protein. Only the mature neurons and astrocytes of humans and some mammals express the 48-kD protein. This antibody may be responsible for the patient's demented condition.

The authors observed one case of myoclonic dementia reversible with steroid therapy, associated with Grave's disease and Sjögren's syndrome. A circulating IgG fraction was demonstrated reacting specifically with cerebral micro-vessels and which evolved in parallel with the neuro-psychiatric disturbances. These results support the hypothesis of an autoimmune vasculitis causing the dementia. The persistence of abnormalities one year after clinical cure showing an alteration of the blood-brain barrier associated with the appearance of circulating antibodies against the hypophyseal cells, and in view of the predictive value of these antibodies, suggests a possibility of the eventual apparition of an Alzheimer type dementia.

Sixty-four patients suffering from senile dementia were compared with 71 age-matched controls suffering from functional psychiatric illness, in terms of their chromosome complement, tuberculin and dinitrochlorobenzene response and total immunoglobulin levels. No significant differences emerged between these groups except for slightly reduced levels of immunoglobulin G in the dement sample. We conclude that senile dementia as a whole is not related to a defect in immunological function.