Microglial Activation and Progression of Nigrostriatal Dysfunction in Isolated REM Sleep Behavior Disorder.

BACKGROUND: Using 11 C-(R)-PK11195-PET, we found increased microglia activation in isolated REM sleep behavior disorder (iRBD) patients. Their role remains to be clarified. OBJECTIVES: The objective is to assess relationships between activated microglia and progression of nigrostriatal dysfunction in iRBD. METHODS: Fifteen iRBD patients previously scanned with 11 C-(R)-PK11195 and 18 F-DOPA-PET underwent repeat 18 F-DOPA-PET after 3 years. 18 F-DOPA Ki changes from baseline were evaluated with volumes-of-interest and voxel-based analyses. RESULTS: Significant 18 F-DOPA Ki reductions were found in putamen and caudate. Reductions were larger and more widespread in patients with increased nigral microglia activation at baseline. Left nigral 11 C-(R)-PK11195 binding at baseline was a predictor of 18 F-DOPA Ki reduction in left caudate (coef = -0.0426, P = 0.016). CONCLUSIONS: Subjects with increased baseline 11 C-(R)-PK11195 binding have greater changes in nigrostriatal function, suggesting a detrimental rather than protective effect of microglial activation. Alternatively, both phenomena occur in patients with prominent nigrostriatal dysfunction without a causative link. The clinical and therapeutic implications of these findings need further elucidation. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Progression of brain cholinergic dysfunction in patients with isolated rapid eye movement sleep behavior disorder.

BACKGROUND: Reduced cortical acetylcholinesterase activity, as measured by 11 C-donepezil positron emission tomography (PET), has been reported in patients with isolated rapid eye movement (REM) sleep behavior disorder (iRBD). However, its progression and clinical implications have not been fully investigated. Here, we explored the relationship between longitudinal changes in brain acetylcholinesterase activity and cognitive function in iRBD. METHODS: Twelve iRBD patients underwent 11 C-donepezil PET at baseline and after 3 years. PET images were interrogated with statistical parametric mapping (SPM) and a regions of interest (ROI) approach. Clinical progression was assessed with the Movement Disorder Society-Unified Parkinson's Disease Rating Scale-Part III (MDS-UPDRS-III). Cognitive function was rated using the Mini-Mental State Examination (MMSE) and the Montreal Cognitive Assessment (MoCA). RESULTS: From baseline to follow-up, the mean 11 C-donepezil distribution volume ratio (DVR) decreased in the cortex (p = 0.006), thalamus (p = 0.013), and caudate (p = 0.013) ROI. Despite no significant changes in the group mean MMSE or MoCA scores being observed, individually, seven patients showed a decline in their scores on these cognitive tests. Subgroup analysis showed that only the subgroup of patients with a decline in cognitive scores had a significant reduction in mean cortical 11 C-donepezil DVR. CONCLUSIONS: Our results show that severity of brain cholinergic dysfunction in iRBD patients increases significantly over 3 years, and those changes are more severe in those with a decline in cognitive test scores.

Blocking IL-6 signaling prevents astrocyte-induced neurodegeneration in an iPSC-based model of Parkinson's disease.

Parkinson's disease (PD) is a neurodegenerative disease associated with progressive death of midbrain dopamine (DAn) neurons in the substantia nigra (SN). Since it has been proposed that patients with PD exhibit an overall proinflammatory state, and since astrocytes are key mediators of the inflammation response in the brain, here we sought to address whether astrocyte-mediated inflammatory signaling could contribute to PD neuropathology. For this purpose, we generated astrocytes from induced pluripotent stem cells (iPSCs) representing patients with PD and healthy controls. Transcriptomic analyses identified a unique inflammatory gene expression signature in PD astrocytes compared with controls. In particular, the proinflammatory cytokine IL-6 was found to be highly expressed and released by PD astrocytes and was found to induce toxicity in DAn. Mechanistically, neuronal cell death was mediated by IL-6 receptor (IL-6R) expressed in human PD neurons, leading to downstream activation of STAT3. Blockage of IL-6R by the addition of the FDA-approved anti-IL-6R antibody, Tocilizumab, prevented PD neuronal death. SN neurons overexpressing IL-6R and reactive astrocytes expressing IL-6 were detected in postmortem brain tissue of patients at early stages of PD. Our findings highlight the potential role of astrocyte-mediated inflammatory signaling in neuronal loss in PD and pave the way for the design of future therapeutics.

A biological definition of neuronal α-synuclein disease: towards an integrated staging system for research.

Parkinson's disease and dementia with Lewy bodies are currently defined by their clinical features, with α-synuclein pathology as the gold standard to establish the definitive diagnosis. We propose that, given biomarker advances enabling accurate detection of pathological α-synuclein (ie, misfolded and aggregated) in CSF using the seed amplification assay, it is time to redefine Parkinson's disease and dementia with Lewy bodies as neuronal α-synuclein disease rather than as clinical syndromes. This major shift from a clinical to a biological definition of Parkinson's disease and dementia with Lewy bodies takes advantage of the availability of tools to assess the gold standard for diagnosis of neuronal α-synuclein (n-αsyn) in human beings during life. Neuronal α-synuclein disease is defined by the presence of pathological n-αsyn species detected in vivo (S; the first biological anchor) regardless of the presence of any specific clinical syndrome. On the basis of this definition, we propose that individuals with pathological n-αsyn aggregates are at risk for dopaminergic neuronal dysfunction (D; the second biological anchor). Our biological definition establishes a staging system, the neuronal α-synuclein disease integrated staging system (NSD-ISS), rooted in the biological anchors (S and D) and the degree of functional impairment caused by clinical signs or symptoms. Stages 0-1 occur without signs or symptoms and are defined by the presence of pathogenic variants in the SNCA gene (stage 0), S alone (stage 1A), or S and D (stage 1B). The presence of clinical manifestations marks the transition to stage 2 and beyond. Stage 2 is characterised by subtle signs or symptoms but without functional impairment. Stages 2B-6 require both S and D and stage-specific increases in functional impairment. A biological definition of neuronal α-synuclein disease and an NSD-ISS research framework are essential to enable interventional trials at early disease stages. The NSD-ISS will evolve to include the incorporation of data-driven definitions of stage-specific functional anchors and additional biomarkers as they emerge and are validated. Presently, the NSD-ISS is intended for research use only; its application in the clinical setting is premature and inappropriate.

Eficacia y seguridad de la palidotomía posteroventral en el tratamiento de la enfermedad de Parkinson avanzada / Efficacy and safety of posteroventral pallidotomy for the treatment of advanced Parkinson's disease

Fundamento: Analizar la efectividad y seguridad de la palidotomía unilateral guiada por microrregistro en el tratamiento de la enfermedad de Parkinson (EP) avanzada después de 3 meses y al año de la intervención. Pacientes y métodos: Se intervinieron 23 pacientes con EP avanzada (edad media, 58,9 años; duración media de la enfermedad, 14,4 años). La evaluación clínica, a los 3 meses (n = 23) y al año (n = 16) de la intervención, se efectuó por la mañana 12 h después de la última dosis de medicación (off) y tras la administración de un 100-150 por ciento de la dosis habitual (on). En cada una de las evaluaciones se administraron escalas para valoración de las actividades de la vida diaria, evaluación motora y discinesias, así como pruebas cronometradas de la actividad motora. Resultados: Las discinesias contralaterales al hemisferio intervenido se redujeron un 92 por ciento a los 3 meses y un 89 por ciento al año. Los síntomas motores de la enfermedad mejoraron un 36,5 por ciento a los 3 meses y un 26,7 por ciento al año de la intervención. En el análisis anual apareció una mejoría en el temblor contralateral del 48 por ciento, en la rigidez del 36,2 por ciento y en la bradicinesia del 37,4 por ciento Todos los cambios observados fueron estadísticamente significativos (p < 0,01). Los efectos adversos fueron leves o transitorios. La dosis de medicación antiparkinsoniana no se modificó durante el tiempo de seguimiento. Conclusiones: La palidotomía unilateral guiada por microrregistro es un método seguro y eficaz para mejorar los síntomas de la EP contralaterales, siendo especialmente eficaz en el tratamiento de las discinesias inducidas por L-dopa. (AU)

Enfermedad de parkinson esporádica y familiar: estudio comparativo / Sporadic and familial Parkinson's disease: comparative study

FUNDAMENTO: Diversos estudios han constatado que entre el 13 y el 33 por ciento de los pacientes con enfermedad de Parkinson (EP) presentan antecedentes familiares de la enfermedad. Los objetivos de este trabajo fueron identificar casos de EP familiar y analizar la existencia de rasgos distintivos entre los casos esporádicos y familiares. PACIENTES Y MÉTODO: Se evaluó prospectivamente a 402 pacientes con EP controlados en el Hospital Clínic i Universitari de Barcelona. Se realizó un examen clínico a 169 pacientes utilizando diversas escalas. La EP se subclasificó como predominantemente tremorígena, rígida o mixta en función de los síntomas que predominaban. RESULTADOS: La frecuencia de EP familiar fue del 13 por ciento. La edad de inicio no fue diferente en los casos familiares y esporádicos, pero fue significativamente mayor en las mujeres (57,4 [13] años) que en los varones (54,8 [11,4] años) (p < 0,05). La forma tremorígena de EP fue más frecuente en los casos familiares (35,5 por ciento; p < 0,05). En los casos de EP familiar, la edad de inicio fue menor en los hijos (53 [13] años) que en los padres (68 [7,8] años) (p = 0,001). CONCLUSIONES: Los factores genéticos pueden desempeñar un papel importante en el desarrollo de la EP, y pueden existir factores ligados al sexo que modulen la edad de inicio de la enfermedad. Los casos familiares sólo se diferencian de los esporádicos en una mayor frecuencia de las formas predominantemente tremorígenas. La menor edad de inicio en los hijos que en los padres apunta a la existencia de un fenómeno de anticipación genética en la EP familiar (AU)