Peter Körtvelyessy

Functional neuroimaging studies suggested a biphasic trajectory of neuronal activity in Alzheimer’s disease (AD), with early hyperactivity followed by later hypoactivity. However, the underlying neurochemical mechanisms in humans remain unclear. Animal studies suggested that amyloid-beta (Aβ) causes intrasynaptic glutamate increases through impaired astrocytic clearance. This study aimed to build a mechanistic bridge between findings from human neuroimaging studies and preclinical models by providing in vivo measurements of glutamate, GABA, and glutamine across the AD continuum using 7T magnetic resonance spectroscopy (MRS). We acquired longitudinal data from cognitively normal (CN) individuals with and without Aβ pathology (CN Aβ-n=43, CN Aβ+ n=17), individuals with mild cognitive impairment (MCI Aβ+, n=20) or AD dementia (AD Aβ+, n=24). Over the course of up to 5 years, glutamate levels increased in the CN Aβ+ and MCI Aβ+ groups but decreased in the AD Aβ+ group. Consistent with a transient homeostatic response to glutamatergic hyperexcitation, GABA levels showed modest increases in both CN Aβ+ and MCI Aβ+ groups. Elevated plasma GFAP was associated with reduced glutamine, suggesting astrocytic dysfunction and impaired glutamate–glutamine cycling as contributors to early hyperexcitability. Together, our results provide the first direct demonstration in patients with AD that glutamate alterations underlie the biphasic trajectory of neuronal activity and that astrocytic glutamate regulation might be a potential therapeutic target.

BACKGROUND: Associations between longitudinal changes of plasma biomarkers and cerebral magnetic resonance (MR)‐derived measurements in Alzheimer's disease (AD) remain unclear.METHODS: In a study population (n = 127) of healthy older adults and patients within the AD continuum, we examined associations between longitudinal plasma amyloid beta 42/40 ratio, tau phosphorylated at threonine 181 (p‐tau181), glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL), and 7T structural and functional MR imaging and spectroscopy using linear mixed models.RESULTS: Increases in both p‐tau181 and GFAP showed the strongest associations to 7T MR‐derived measurements, particularly with decreasing parietal cortical thickness, decreasing connectivity of the salience network, and increasing neuroinflammation as determined by MR spectroscopy (MRS) myo‐inositol.DISCUSSION: Both plasma p‐tau181 and GFAP appear to reflect disease progression, as indicated by 7T MR‐derived brain changes which are not limited to areas known to be affected by tau pathology and neuroinflammation measured by MRS myo‐inositol, respectively.Highlights: This study leverages high‐resolution 7T magnetic resonance (MR) imaging and MR spectroscopy (MRS) for Alzheimer's disease (AD) plasma biomarker insights. Tau phosphorylated at threonine 181 (p‐tau181) and glial fibrillary acidic protein (GFAP) showed the largest changes over time, particularly in the AD group. p‐tau181 and GFAP are robust in reflecting 7T MR‐based changes in AD. The strongest associations were for frontal/parietal MR changes and MRS neuroinflammation.

Objective: Remote self-assessment of the revised amyotrophic lateral sclerosis functional rating scale (ALSFRS-R) using digital data capture was investigated for its feasibility as an add-on to ALSFRS-R assessments during multidisciplinary clinic visits. Methods: From August 2017 to December 2021, at 12 ALS centers in Germany, an observational study on remote assessment of the ALSFRS-R was performed. In addition to the assessment of ALSFRS-R during clinic visits, patients were offered a digital self-assessment of the ALSFRS-R – either on a computer or on a mobile application (“ALS-App”). Results: An estimated multicenter cohort of 4,670 ALS patients received care at participating ALS centers. Of these patients, 971 remotely submitted the ALSFRS-R, representing 21% of the multicenter cohort. Of those who opted for remote assessment, 53.7% (n = 521) completed a minimum of 4 ALSFRS-R per year with a mean number of 10.9 assessments per year. Different assessment frequencies were found for patients using a computer (7.9 per year, n = 857) and mobile app (14.6 per year, n = 234). Patients doing remote assessments were more likely to be male and less functionally impaired but many patients with severe disability managed to complete it themselves or with a caregiver (35% of remote ALSFRS-R cohort in King’s Stage 4). Conclusions: In a dedicated ALS center setting remote digital self-assessment of ALSFRS-R can provide substantial data which is complementary and potentially an alternative to clinic assessments and could be used for research purposes and person-level patient management. Addressing barriers relating to patient uptake and adherence are key to its success.

Objective To determine whether IgG subclasses of antiparanodal autoantibodies are related to disease course and treatment response in acute- to subacute-onset neuropathies, we retrospectively screened 161 baseline serum/CSF samples and 66 follow-up serum/CSF samples. Methods We used ELISA and immunofluorescence assays to detect antiparanodal IgG and their subclasses and titers in serum/CSF of patients with Guillain-Barré syndrome (GBS), recurrent GBS (R-GBS), Miller-Fisher syndrome, and acute- to subacute-onset chronic inflammatory demyelinating polyradiculoneuropathy (A-CIDP). We evaluated clinical data retrospectively. Results We detected antiparanodal autoantibodies with a prevalence of 4.3% (7/161), more often in A-CIDP (4/23, 17.4%) compared with GBS (3/114, 2.6%). Longitudinal subclass analysis in the patients with GBS revealed IgG2/3 autoantibodies against Caspr-1 and against anti–contactin-1/Caspr-1, which disappeared at remission. At disease onset, patients with A-CIDP had IgG2/3 anti–Caspr-1 and anti–contactin-1/Caspr-1 or IgG4 anti–contactin-1 antibodies, IgG3 being associated with good response to IV immunoglobulins (IVIg). In the chronic phase of disease, IgG subclass of one patient with A-CIDP switched from IgG3 to IgG4. Conclusion Our data (1) confirm and extend previous observations that antiparanodal IgG2/3 but not IgG4 antibodies can occur in acute-onset neuropathies manifesting as monophasic GBS, (2) suggest association of IgG3 to a favorable response to IVIg, and (3) lend support to the hypothesis that in some patients, an IgG subclass switch from IgG3 to IgG4 may be the correlate of a secondary progressive or relapsing course following a GBS-like onset.

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.

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.

The current knowledge about neuroprotective mechanisms in humans after status epilepticus is scarce. One reason is the difficulty to measure possible mediators of these neuroprotective mechanisms. The dawn of microRNA detection in the cerebrospinal fluid (CSF) and the recent advancements in measuring proteins in the CSF such as progranulin, which is, e.g., responsible for neurite outgrowth and limiting exceeding neuroinflammatory responses, have given us new insights into putative neuroprotective mechanisms following status epilepticus. This should complement the animal data. In this review, we cover what is known about the role of progranulin as well as the links between microRNA changes and the progranulin pathway following status epilepticus in humans and animals hypothesizing neuroprotective and neurorehabilitative effects. Progranulin has also been found to feature prominently in the neuroprotective processes under hypoxic conditions and initiating neurorehabilitative processes. These properties may be used therapeutically, e.g., through drugs that raise the progranulin levels and therefore the cerebral progranulin levels as well with the goal of improving the outcome after status epilepticus.