Background: IgLON5 disease is an autoimmune disorder that shares neuropathological aspects with a tauopathy. Its clinical spectrum is heterogeneous, and figural memory impairment as an initial phenomenon of IgLON5 syndrome has not yet been described. The rationale of this report is to highlight symptoms related to IgLON5 disease that have not been reported to date. This case report will thereby emphasize how important it is to initiate thorough diagnostic methods including cerebrospinal fluid analysis (CSF) before starting early immunotherapy. Methods: We examined a 65-year-old Caucasian male via neuropsychological tests, magnetic resonance imaging (MRI), electroencephalography (EEG), neurography and polysomnography. He also underwent two lumbar punctures from which we determined specific autoantibodies in cerebrospinal (CSF) and peripheral blood (PB). Results: The patient presented initially complaining of memory loss, gradual dysphagia and sleeping dysfunction. Neuropsychological testing at first presentation and follow-up revealed subtle figural and working memory impairment. At onset and at his 6-month follow-up, we detected IgLON5 antibodies in CSF and PB. Furthermore, we identified in the CSF a blood-brain barrier disturbance at disease onset and follow-up, and markers of neuroaxonal damage such as mildly elevated phosphorylated Tau-181 protein with 86 pg/ ml (normal range ≤ 61 pg/ml) at onset. Three months after his initial presentation, he was suffering from axonal neuropathy and transient ataxia in the extremities. Assuming a definitive autoimmune encephalitis-associated with anti-IgLON5 antibodies, we applied high-dose steroids monthly (1g methylprednisolone i.v. for five consecutive days) and his memory complaints, ataxia of extremities and peripheral neuropathy as well as sleeping dysfunction decreased.
BackgroundNeural autoantibody-associated dementia (NABD) is an increasing phenomenon in memory clinics with a high impact on later therapy. Biomarkers are lacking that differentiate this type of dementia from neurodegenerative dementia such as Alzheimer’s dementia (AD). Our aim is to analyze neurodegeneration markers and their relationship to progressing cognitive dysfunction in NABD and AD to test for tools differentiating these two forms of dementia prior to neural autoantibody testing.MethodsIn our retrospective, observational study, we investigated 14 patients with dementia and serum and/or cerebrospinal fluid (CSF) neural autoantibodies as well as 14 patients with AD by relying on recent CSF and clinical criteria for AD. Patient files were checked for psychopathology, neuropsychological test performance, autoimmune indicators, CSF, and MRI results.ResultsOur patient groups did not differ in their psychopathology, autoimmune indicators, or MRI profile. The progression of cognitive dysfunction [as measured by the difference in Mini-Mental State Examination (MMSE) scores since disease onset, and the yearly progression rate (MMSE loss/per year)] did not vary significantly between groups. Total tau protein was significantly higher in AD patients than NABD patients revealing no signs of Alzheimer’s disease pathology in their CSF (p < 0.05). Total tau protein levels in CSF correlated with cognitive decline since disease onset (r = 0.38, p < 0.05) and yearly progression rates (r = 0.56, p < 0.005) in all patients.DiscussionOur results suggest that the progression of cognitive dysfunction as defined by MMSE does not seem to be an appropriate biomarker for distinguishing NABD from AD. However, the total tau protein level in CSF might be a relevant molecular biomarker that can indicate disease pathology and/or progression in both known AD and NABD, which is often accompanied by axonal degeneration. Total tau protein may be an additional diagnostic tool with which to differentiate anti-neural-associated dementia from AD if further research confirms these proof-of-concept findings in larger patient cohorts.
Autoimmune dementia is a novel and expanding field which subsumes neuropsychiatric disorders with predominant cognitive impairments due to an underlying autoimmune etiology. Progressive dementias with atypical clinical presentation should trigger a thorough diagnostic approach including testing for neural surface and intracellular antibodies to avoid a delay in accurate diagnosis and initiating appropriate therapy. Here, we present two emerging cases of progressive dementia with co-existing serum autoantibodies against the KCNA2 (potassium voltage-gated channel subfamily A member 2) subunit. We found various cognitive deficits with dominant impairments in the memory domain, particularly in delayed recall. One patient presented a subacute onset of then-persisting cognitive deficits, while the other patient’s cognitive impairments progressed more chronically and fluctuated. Cognitive impairments coincided with additional neuropsychiatric symptoms. Both had a potential paraneoplastic background according to their medical history and diagnostic results. We discuss the potential role of KCNA2 autoantibodies in these patients and in general by reviewing the literature. The pathogenetic role of KCNA2 antibodies in cognitive impairment is not well delineated; clinical presentations are heterogeneous, and thus a causal link between antibodies remains questionable. Current evidence indicates an intracellular rather than extracellular epitope. We strongly suggest additional prospective studies to explore KCNA2 antibodies in specifically-defined cohorts of cognitively impaired patients via a systematic assessment of clinical, neuropsychological, neuroimaging, as well as laboratory and CSF (cerebrospinal fluid) parameters, and antibody studies to (1) determine the epitope’s location (intracellular vs. extracellular), (2) the mode of action, and (3) seek co-existing, novel pathogenetic autoantibodies in sera and CSF.
Alzheimer's disease (AD) pathology precedes the onset of clinical symptoms by several decades. Thus, biomarkers are required to identify prodromal disease stages to allow for the early and effective treatment. The methoxy-X04-derivative BSC4090 is a fluorescent ligand which was designed to target neurofibrillary tangles in AD. BSC4090 staining was previously detected in post-mortem brains and olfactory mucosa derived from AD patients. We tested BSC4090 as a potential diagnostic marker of prodromal and early AD using olfactory mucosa biopsies from 12 individuals with AD, 13 with mild cognitive impairment (MCI), and 10 cognitively normal (CN) controls. Receiver-operating curve analysis revealed areas under the curve of 0.78 for AD versus CN and of 0.86 for MCI due to AD versus MCI of other causes. BSC4090 labeling correlated significantly with cerebrospinal fluid levels of tau protein phosphorylated at T181. Using NMR spectroscopy, we find that BSC4090 binds to fibrillar and pre-fibrillar but not to monomeric tau. Thus, BSC4090 may be an interesting candidate to detect AD at the early disease stages.
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