Managing Advanced Progressive Supranuclear Palsy and Corticobasal Degeneration in a Palliative Care Unit: Admission Triggers and Outcomes

Background: Progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) are characterized by rapid deterioration and a fatal outcome. Objectives: Admission triggers, treatment efficacy, and care patterns. Methods: Retrospective analysis of patients with PSP/CBD admitted to an inpatient specialized palliative care service. Results: In 38 patients, there were 63 admissions for swallowing difficulties, falls, pain, impaired communication, cognitive/mood disturbances, respiratory symptoms, and infection. Mean length of stay was 11.6 days. Treatment response was variable. In 68%, of admission episodes there was stabilization or improvement, 75% were discharged home. In case of readmission, the mean interval has been 9.7 months. Time since diagnosis and admission triggers were not associated with outcome or death. Conclusion: Patients showed high symptom load contrasting with discharge rates and subsequent health care utilization. Brief multidisciplinary interventions might be helpful to preserve autonomy

Modelling Ser129 Phosphorylation Inhibits Membrane Binding of Pore-Forming Alpha-Synuclein Oligomers

Background: In several neurodegenerative diseases, hyperphosphorylation at position Ser129 is found in fibrillar deposits of alpha-synuclein (asyn), implying a pathophysiological role of asyn phosphorylation in neurodegeneration. However, recent animal models applying asyn phosphorylation mimics demonstrated a protective effect of phosphorylation. Since metal-ion induced asyn oligomers were identified as a potential neurotoxic aggregate species with membrane pore-forming abilities, the current study was undertaken to determine effects of asyn phosphorylation on oligomer membrane binding. Methods: We investigated the influence of S129 phosphorylation on interactions of metal-ion induced asyn oligomers with small unilamellar lipid vesicles (SUV) composed of POPC and DPPC applying the phosphorylation mimic asyn129E. Confocal single-particle fluorescence techniques were used to monitor membrane binding at the single-particle level. Results: Binding of asyn129E monomers to gel-state membranes (DPPC-SUV) is slightly reduced compared to wild-type asyn, while no interactions with membranes in the liquid-crystalline state (POPC-SUV) are seen for both asyn and asyn129E. Conversely, metal-ion induced oligomer formation is markedly increased in asyn129E. Surprisingly, membrane binding to POPC-SUV is nearly absent in Fe3+ induced asyn129E oligomers and markedly reduced in Al3+ induced oligomers. Conclusion: The protective effect of pseudophosphorylation seen in animal models may be due to impeded oligomer membrane binding. Phosphorylation at Ser129 may thus have a protective effect against neurotoxic asyn oligomers by preventing oligomer membrane binding and disruption of the cellular electrophysiological equilibrium. Importantly, these findings put a new complexion on experimental pharmaceutical interventions against POLO-2 kinase

Potential sources of interference with the highly sensitive detection and quantification of alpha‐synuclein seeds by qRT‐QuIC

Parkinson’s disease (PD) is a progressive neurodegenerative disease which is histologically characterized by loss of dopaminergic neurons in the substantia nigra and deposition of aggregated alpha‐synuclein (aSyn) in the brain. The detection of aSyn in well accessible fluids has been one of the central approaches in the development of biomarkers for PD. Recently, real‐time quaking‐induced conversion (RT‐QuIC) has been successfully adapted for use with aSyn seeds. Here, we systematically analysed parameters potentially impacting the reliability of this assay by using quantitative real‐time quaking‐induced conversion (qRT‐QuIC) with in vitro‐formed aSyn seeds. Seeds diluted in cerebrospinal fluid (CSF) accelerated the seeding reaction and slightly increased the sensitivity without affecting specificity. Repeated freeze–thaw cycles decreased the apparent lag times of seeds diluted in ddH2O but did not alter the seeding activity of seeds diluted in CSF. High levels of artificial contamination with blood resulted in prolonged apparent lag times, while sensitivity and specificity were unaffected. Altogether, qRT‐QuIC with aSyn seems to be robust concerning sensitivity and specificity in our model system, but quantitative interpretation might be limited under certain conditions

Multimodal brain age estimates relate to Alzheimer disease biomarkers and cognition in early stages: a cross-sectional observational study

BACKGROUND: Estimates of 'brain-predicted age' quantify apparent brain age compared to normative trajectories of neuroimaging features. The brain age gap (BAG) between predicted and chronological age is elevated in symptomatic Alzheimer disease (AD) but has not been well explored in presymptomatic AD. Prior studies have typically modeled BAG with structural MRI, but more recently other modalities, including functional connectivity (FC) and multimodal MRI, have been explored. METHODS: We trained three models to predict age from FC, structural (S), or multimodal MRI (S+FC) in 390 amyloid-negative cognitively normal (CN/A-) participants (18-89 years old). In independent samples of 144 CN/A-, 154 CN/A+, and 154 cognitively impaired (CI; CDR > 0) participants, we tested relationships between BAG and AD biomarkers of amyloid and tau, as well as a global cognitive composite. RESULTS: All models predicted age in the control training set, with the multimodal model outperforming the unimodal models. All three BAG estimates were significantly elevated in CI compared to controls. FC-BAG was significantly reduced in CN/A+ participants compared to CN/A-. In CI participants only, elevated S-BAG and S+FC BAG were associated with more advanced AD pathology and lower cognitive performance. CONCLUSIONS: Both FC-BAG and S-BAG are elevated in CI participants. However, FC and structural MRI also capture complementary signals. Specifically, FC-BAG may capture a unique biphasic response to presymptomatic AD pathology, while S-BAG may capture pathological progression and cognitive decline in the symptomatic stage. A multimodal age-prediction model improves sensitivity to healthy age differences. FUNDING: This work was supported by the National Institutes of Health (P01-AG026276, P01- AG03991, P30-AG066444, 5-R01-AG052550, 5-R01-AG057680, 1-R01-AG067505, 1S10RR022984-01A1, and U19-AG032438), the BrightFocus Foundation (A2022014F), and the Alzheimer's Association (SG-20-690363-DIAN)

A unified classification approach rating clinical utility of protein biomarkers across neurologic diseases

A major evolution from purely clinical diagnoses to biomarker supported clinical diagnosing has been occurring over the past years in neurology. High-throughput methods, such as next-generation sequencing and mass spectrometry-based proteomics along with improved neuroimaging methods, are accelerating this development. This calls for a consensus framework that is broadly applicable and provides a spot-on overview of the clinical validity of novel biomarkers. We propose a harmonized terminology and a uniform concept that stratifies biomarkers according to clinical context of use and evidence levels, adapted from existing frameworks in oncology with a strong focus on (epi)genetic markers and treatment context. We demonstrate that this framework allows for a consistent assessment of clinical validity across disease entities and that sufficient evidence for many clinical applications of protein biomarkers is lacking. Our framework may help to identify promising biomarker candidates and classify their applications by clinical context, aiming for routine clinical use of (protein) biomarkers in neurology

Klinische und pathophysiologische Aspekte neurodegenerativer Tauopathien

Ungeachtet des enormen Wissenszuwachses speziell in den vergangenen zwei Jahrzehnten stellen uns neurodegenerative Erkrankungen weiterhin in vielen Bereichen – von der Pathophysiologie bis zur medizinischen Versorgungsstruktur – vor enorme Herausforderungen. Wenngleich gerade die Pathophysiologie dieser Erkrankungen immer präziser und umfassender charakterisiert wird, verdeutlicht das Fehlen verlaufsmodifizierender Therapien für Tauopathien und Synukleinopathien, dass das komplexe Zusammenspiel der zahlreichen potenziell krankheitsrelevanten Einflussfaktoren weiterhin unzureichend verstanden ist. Insbesondere der im Rahmen dieser Arbeit dargestellte differenzielle Effekt der Phosphorylierung auf die Aggregationsneigung und Membranaffinität der Proteine Tau und αSyn kann hierzu einen Beitrag leisten. Die Beobachtung, dass durch Phosphorylierung und limitierte Proteolyse die Aggregationsneigung in Gegenwart dreiwertiger Metallionen bei beiden Proteinen deutlich gesteigert ist, schafft eine Verbindung zwischen früher Oligomer-Bildung und dem vielfach mit Neurodegeneration in Zusammenhang gebrachten oxidativen Stress. Der differentielle Effekt der Phosphorylierung auf die Membranbindung dieser Oligomere mit erhöhter Membranaffinität des Tau-Proteins und verminderter Affinität für αSyn kann auf unterschiedliche toxische Wirkungen dieser Oligomere hinweisen. Insgesamt unterstreichen diese Beobachtungen, dass Metallionen-induzierte Oligomere eine lohnende Zielstruktur der experimentell-pharmakologischen Entwicklung darstellen. Für die klinische Versorgung von Menschen mit einer Progressiven Supranukleären Blickparese leistet die Arbeit einen Beitrag zur Differentialdiagnostik und regt Verbesserungen in der psychosozialen Versorgung von Menschen mit atypischen Parkinson-Syndromen an. Die Mitwirkung an Projekten zur Evaluation von FDG-PET und Ganganalyse in der Differentialdiagnose der PSP liefert weitere diagnostische Optionen im klinischen Versorgungsalltag. Eine Verbesserung der pharmakologischen Therapie konnte mit der PROSPERA-Studie zur Erprobung von Rasagilin bei PSP aufgrund des fehlenden Wirknachweises zwar nicht erbracht werden; jedoch liefert die Studie wertvolle Daten zur Planung zukünftiger pharmakologischer Studien, sowie erste Sicherheitsdaten zur Anwendung dopaminerger Substanzen bei PSP. Die Beobachtung eines hohen Anteils atypischer Parkinson-Syndrome bei assistierten Suiziden, und insbesondere die hier festgestellte frühe Antragsstellung meist im ersten Jahr nach Diagnosestellung, mahnt eine ausführlichere Untersuchung psychosozialer Belastungsfaktoren bei atypischen Parkinson-Syndromen im Umfeld der Diagnosestellung sowie eine aktive Exploration von Suizidalität in diesen Situationen an. Ebenfalls auf eine Verbesserung der Patientenversorgung ausgerichtet sind die Untersuchungen zur Alzheimer-Demenz bei Menschen mit einem Down-Syndrom. Die Etablierung der ersten neurologisch geführten Ambulanz speziell für dieses Krankheitsbild erforderte klinische Grundlagenarbeit wie die Etablierung eines zuverlässigen Diagnose-Algorithmus für die Alzheimer-Demenz bei Trisomie 21. Um Menschen mit einem Down-Syndrom Zugang zu internationaler Forschungsentwicklung zu ermöglichen, war zudem die Verfügbarmachung international etablierter Skalen wie der CAMDEX-DS notwendig. Aufbauend auf diese Vorarbeiten gelang ein erster wichtiger Beitrag zur Charakterisierung diagnostischer und prognostischer Biomarker, speziell der Neurofilament-Leichtkette im Blutplasma, im Rahmen einer internationalen Kollaboration. Insgesamt leistet die hier vorgestellte Arbeit einen Beitrag zum Verständnis neurodegenerativer Erkrankungen, speziell der Tauopathien, sowohl auf der Ebene der molekularen Pathophysiologie als auch hinsichtlich des Versorgungsbedarfs und -von Therapieoptionen im klinischen Alltag