Peter Körtvelyessy

High prevalence of NMDA receptor IgA/IgM antibodies in different dementia types

To retrospectively determine the frequency of N‐Methyl‐D‐Aspartate (NMDA) receptor (NMDAR) autoantibodies in patients with different forms of dementia.

Complement-associated neuronal loss in a patient with CASPR2 antibody-associated encephalitis.

Recently, CASPR2 antibody–associated encephalitis was presented as a subentity of encephalitis with antibodies against the voltage-gated potassium channel (VGKC) complex. Besides limbic encephalitis, CASPR2 antibodies are also found in Isaac syndrome and Morvan syndrome.1,2 The specific underlying pathogenic mechanisms in limbic encephalitis are unknown. Our data suggest an antibody- and complement-mediated pathology in CASPR2 antibody–associated encephalitis.

ADEM-like presentation, anti-MOG antibodies, and MS pathology: TWO case reports

Acute disseminated encephalomyelitis (ADEM) mostly occurs in children and can be triggered by infections and vaccinations. Recently, 40% of patients with ADEM were found to be seropositive for myelin oligodendrocyte glycoprotein antibodies (MOG-abs).1 Furthermore, a subgroup of adult patients negative for aquaporin-4 antibody fulfilling diagnostic clinical and radiologic criteria for neuromyelitis optica spectrum disorder (NMOSD) harbor high-titer serum MOG-abs.2 We present clinical, serologic, and histopathologic features of 2 adult patients with a clinical diagnosis of ADEM according to the diagnostic criteria3 associated with intrathecal MOG-abs synthesis. MOG-abs were determined by live-cell immunofluorescence on HEK293T cells expressing full-length human MOG-enhanced green fluorescent protein at a starting dilution of 1:20 in serum and 1:2 in CSF using an epifluorescence microscope and end-point titration as previously described.2

Progranulin and Amyloid-β Levels: Relationship to Neuropsychology in Frontotemporal and Alzheimer’s Disease

BACKGROUND Analysis of cerebrospinal fluid (CSF) has improved over the last few years; thus specific markers for different diseases have emerged, e.g., amyloid-β (Aβ) for Alzheimers disease (AD) and progranulin for frontotemporal dementia (FTD). OBJECTIVE Evaluation of correlation between biomarkers in CSF and cognitive performance in populations with AD and FTD. METHODS 27 patients with AD and 16 with FTD were included. CSF tau, P-tau(181P), Aβ₄₂, and progranulin (PGRN) were measured and a standardized neuropsychological test battery applied. Olfactory testing was additionally included where available. RESULTS For all patients across both groups, an association between PGRN and categoric (p = 0.016) and letter fluency (p = 0.029), naming (p = 0.003), and overall cognition (Mini-Mental State Examination: p = 0.04) was observed. Aβ42 was strongly associated with memory function (learning: p = 0.001; recall: p = 0.002). A correlation between Aβ₄₂ and memory performance was moreover found for each group separately, while PGRN also showed a correlation with recognition memory (p = 0.04) in AD. Furthermore, an association between reduced PGRN and olfactory dysfunction was revealed (p = 0.01). CONCLUSIONS CSF-levels of PGRN and Aβ₄₂ levels express deficits in cognition differentially, with PGRN being predominantly associated with frontal and Aβ₄₂ with temporal dysfunction. This mirrors the cerebral occurrence of these proteins. These associations appear to be consistent across both disease groups. The relationship between PGRN and olfaction further underpins the association between PRGN and frontal dysfunction.

Hereditary diffuse leukoencephalopathy with spheroids (HDLS) with a novel CSF1R mutation and spinal cord involvement

Abstract We report a 53year old male who presented with rapidly progressive dementia and hemiparesis. He had been noted to have a cervical myelopathy twelve months earlier but decompressive surgery had offered no improvement. Cerebral MRI revealed asymmetrical frontal white matter lesions, biopsy of which found periodic acid Schiff positive (PAS) and amyloid precursor protein (APP) positive spheroids suggestive of hereditary diffuse leukoencephalopathy with spheroids (HDLS). Sequencing of the CSF1R gene identified a novel mutation at c.2699G>A; p.R900K. Aside from the novel mutation, this is a molecularly confirmed case of HDLS with a myelopathy. This case of HDLS further extends the phenotypic variability of this rare disease to include cord involvement.

CSF Biomarkers of Neurodegeneration in Progressive Non-fluent Aphasia and Other Forms of Frontotemporal Dementia: Clues for Pathomechanisms?

Frontotemporal Dementia (FTD) encompasses distinct pathophysiologically heterogenous disorders with different genetic and cellular disease mechanisms. The objective of this study is to compare the constellation of biomarkers of neurodegeneration in the cerebrospinal fluid (CSF) to the FTD type categorized by clinical symptoms. We investigated the levels of Phospho181-tau, Total-tau, Beta-amyloid1−42, Neurofilament light chain, and Progranulin in the CSF of n = 99 FTD patients regarding to the different subtypes of FTD, including semantic dementia (SD), progressive non-fluent aphasia (PNFA), behavioral variant FTD (bvFTD). We compared these groups to patients without neurodegenerative disorders and another cohort encompassing tauopathies with distinct clinical syndromes (Cortico basal syndrome and progressive supranuclear palsy) and logopenic PNFA (lPPA) as another disorder with predominant speech disturbance. CSF-Progranulin levels were significantly lower in FTD type patients with semantic dementia and behavioral variant FTD mainly attributed to the Tar-DNA-Binding-Protein (TDP) 43 compared to predominantly Tau-mediated PNFA (p < 0.05). Also, neurofilament light chain was significantly higher (p < 0.036) in all FTD patients especially in SD patients (p < 0.01). CSF-Nfl levels also distinguished SD patients from logopenic Alzheimers patients (p < 0.05). In sum, CSF-Neurofilament light chain and CSF-Progranulin seem to be promising biomarkers for FTD, the latter predominantly for assumed TDP43-mediated FTD.

Peripheral nerve atrophy together with higher cerebrospinal fluid progranulin indicate axonal damage in amyotrophic lateral sclerosis

We aimed to investigate whether sonographic peripheral cross‐sectional nerve area (CSA) and progranulin (PGRN), a neuritic growth factor, are related to each other and whether they interact to predict clinical and paraclinical measures in amyotrophic lateral sclerosis (ALS).

Peripheral nerve atrophy together with higher cerebrospinal fluid progranulin indicate axonal damage in amyotrophic lateral sclerosis: Nerve Atrophy and CSF PGRN in ALS

We aimed to investigate whether sonographic peripheral cross‐sectional nerve area (CSA) and progranulin (PGRN), a neuritic growth factor, are related to each other and whether they interact to predict clinical and paraclinical measures in amyotrophic lateral sclerosis (ALS).

Biomarkers of Neurodegeneration in Autoimmune-Mediated Encephalitis

Progranulin (PGRN), Total-Tau (t-tau), and Neurofilament light chain (NfL) are well known biomarkers of neurodegeneration. The objective of the present study was to investigate whether these parameters represent also biomarkers in autoimmune-mediated Encephalitis (AE) and may give us insights into the pathomechanisms of AE. We retrospectively examined the concentration of PGRN in the cerebrospinal fluid (CSF) and serum of 38 patients suffering from AE in acute phase and/or under treatment. This AE cohort comprises patients with autoantibodies against: NMDAR (n = 18 patients), Caspr2 (n = 8), Lgi-1 (n = 10), GABAB(R) (n = 1), and AMPAR (n = 1). Additionally, the concentrations of NfL (n = 25) and t-tau (n = 13) in CSF were measured when possible. Follow up data including MRI were available in 13 patients. Several age-matched cohorts with neurological diseases besides neuroinflammation or neurodegeneration served as control groups. We observed that PGRN was significantly elevated in the CSF of patients with NMDAR-AE in the acute phase, but normalized at follow up under treatment (p < 0.01). In the CSF of other patients with AE PGRN was in the range of the CSF levels of control groups. T-tau was highly elevated in the CSF of patients with temporal FLAIR-signal in the MRI and in patients developing a hippocampal sclerosis. NfL was exceptionally high initially in Patients with AE with a paraneoplastic or parainfectious cause and also normalized under treatment. The normalizations of all biomarkers were mirrored in an improvement on the modified Rankin scale. The data suggest that the concentration of PGRN in CSF might be a biomarker for acute NMDAR-AE. Pathological high t-tau levels may indicate a risk for hippocampal sclerosis. The biomarker properties of NfL remain unclear since the levels decrease under treatment, but it could not predict severity of disease in this small cohort. According to our results, we recommend to measure in clinical practice PGRN and t-tau in the CSF of patients with AE.

Peripheral nerve atrophy together with higher CSF progranulin indicate axonal damage in ALS

We aimed to investigate whether sonographic peripheral cross‐sectional nerve area (CSA) and progranulin (PGRN), a neuritic growth factor, are related to each other and whether they interact to predict clinical and paraclinical measures in amyotrophic lateral sclerosis (ALS).