Search

Parkinson's disease (PD) is the second most common neurodegenerative disease, with two main pathological features: misfolded α-synuclein protein accumulation and neurodegeneration. Inflammation has recently been identified as a contributor to a cascade of events that may aggravate PD pathology. Inflammasomes, a group of intracellular protein complexes, play an important role in innate immune responses to various diseases, including infection. In PD research, accumulating evidence suggests that α-synuclein aggregations may activate inflammasomes, particularly the nucleotide-binding oligomerization domain-leucine-rich repeat-pyrin domain-containing 3 (NLRP3) type, which exacerbates inflammation in the central nervous system by secreting proinflammatory cytokines like interleukin (IL)-18 and IL-1β. Afterward, activated NLRP3 triggers local microglia and astrocytes to release additional IL-1β. In turn, the activated inflammatory process may contribute to additional α-synuclein aggregation and cell loss. This review summarizes current research evidence on how the NLRP3 inflammasome contributes to PD pathogenesis, as well as potential therapeutic strategies targeting the NLRP3 inflammasome in PD. [ABSTRACT FROM AUTHOR]

Increased burdens of rare coding variants in genes related to lysosomal storage disease or mitochondrial pathways were reported to be associated with idiopathic Parkinson's disease. Under a hypothesis that the burden of damaging rare coding variants is increased in causative genes for hereditary parkinsonism, we analyzed the burdens of rare coding variants with a case-control design. Two cohorts of whole-exome sequencing data and a cohort of genome-wide genotyping data of clinically validated idiopathic Parkinson's disease cases and controls, which were open to the public, were used. The sequence kernel association test–optimal was used to analyze the burden of rare variants in the hereditary parkinsonism gene set, which was constructed from the Online Mendelian Inheritance in Man database through manual curation. The hereditary parkinsonism gene set consisted of 17 genes with a locus symbol prefix for familial Parkinson's disease and 75 hereditary atypical parkinsonism genes. We detected a significant association of enriched burdens of predicted damaging rare coding variants in hereditary parkinsonism genes in all three datasets. Meta-analyses of the rare variant burden test in a subgroup of gene sets revealed an association between burdens of rare damaging variants with PD in a hereditary atypical parkinsonism gene set, but not in a subgroup gene set with a locus symbol prefix for familial Parkinson's disease. Our results highlight the roles of rare damaging variants in causative genes for hereditary atypical parkinsonian disorders. We propose that Mendelian genes associated with hereditary disorders accompanying parkinsonism are involved in Parkinson's disease-related genetic networks. • Manual curation of OMIM identified 92 Mendelian genes for hereditary parkinsonism. • Hereditary parkinsonism genes consist of 17 PARK genes and 75 non-PARK genes. • The burden of rare damaging variants in PARK and non-PARK genes was increased in Parkinson's disease. • A meta-analysis revealed the enrichment of rare damaging variants in non-PARK genes in Parkinson's disease. [ABSTRACT FROM AUTHOR]

We investigated olfactory function and its relation to cardiac 123I-metaiodobenzylguanidine (MIBG) uptake in 15 patients with drug induced parkinsonism (DIP). The mean Cross Cultural Smell Identification (CCSI) score was significantly greater in patients with DIP than in those with Parkinson's disease (PD: 6.9 (1.6) vs 4.4 (2.2); p<0.001); however, the mean CCSI score in patients with DIP was not significantly different from controls. One patient with DIP, whose CCSI score was significantly reduced, also exhibited decreased cardiac MIBG uptake. DIP patients with CCSI scores within the normal range had normal cardiac MIBG uptake. Our study suggests that an olfactory function test may be a useful tool for detecting DIP unrelated to PD and for identifying patients with DIP who have subclinical PD. [ABSTRACT FROM AUTHOR]

We investigated olfactory function and its relation to cardiac 123I-Metaiodobenzylguanidine (MIBG) uptake in 15 patients with drug induced parkinsonism (DIP). The mean Cross Cultural Smell Identification (CCSI) score was significantly greater in patients with DIP than in those with Parkinson's disease (PD: 6.9 (1.6) vs 4.4 (2.2); p<0.00); however, the mean CCSI score in patients with DIP was not significantly different from controls. One patient with DIP, whose CCSI score was significantly reduced, also exhibited decreased cardiac MIBG uptake. DIP patients with CCSI scores within the normal range had normal cardiac MIBG uptake. Our study suggests that an olfactory function test may be a useful tool for detecting DIP unrelated to PD and for identifying patients with DIP who have subclinical. [ABSTRACT FROM AUTHOR]

Objective: We investigated whether hippocampal perfusion changes are associated with cognitive decline, motor deficits, and the risk of dementia conversion in patients with Parkinson disease (PD). Methods: We recruited patients with newly diagnosed and nonmedicated PD and healthy participants who underwent dual phase 18F‐N‐(3‐fluoropropyl)‐2β‐carboxymethoxy‐3β‐(4‐iodophenyl) nortropane positron emission tomography scans. Patients were classified into 3 groups according to hippocampal perfusion measured by standard uptake value ratios (SUVRs): (1) PD hippocampal hypoperfusion group (1 standard deviation [SD] below the mean hippocampal SUVR of healthy controls; PD‐hippo‐hypo), (2) PD hippocampal hyperperfusion group (1 SD above the mean; PD‐hippo‐hyper), and (3) the remaining patients (PD‐hippo‐normal). We compared the baseline cognitive performance, severity of motor deficits, hippocampal volume, striatal dopamine transporter (DAT) availability, and risk of dementia conversion among the groups. Results: We included 235 patients (PD‐hippo‐hypo, n = 21; PD‐hippo‐normal, n = 157; PD‐hippo‐hyper, n = 57) and 48 healthy participants. Patients in the PD‐hippo‐hypo group were older and had smaller hippocampal volumes than those in the other PD groups. The PD‐hippo‐hypo group showed less severely decreased DAT availability in the putamen than the other groups despite similar severities of motor deficit. The PD‐hippo‐hypo group had a higher risk of dementia conversion compared to the PD‐hippo‐normal (hazard ratio = 2.59, p = 0.013) and PD‐hippo‐hyper (hazard ratio = 3.73, p = 0.006) groups, despite similar cognitive performance at initial assessment between groups. Interpretation: Hippocampal hypoperfusion may indicate a reduced capacity to cope with neurodegenerative processes in terms of the development of motor deficits and cognitive decline in patients with PD. ANN NEUROL 2024;95:388–399 [ABSTRACT FROM AUTHOR]

Background: To investigate whether the cingulate island sign (CIS) ratio (i.e., the ratio of regional uptake in the posterior cingulate cortex relative to the precuneus and cuneus on cerebral perfusion scans) is associated with early dementia conversion in Parkinson's disease (PD). Methods: We enrolled 226 patients with newly diagnosed PD and 48 healthy controls who underwent dual‐phase 18F‐FP‐CIT PET scans. Patients with PD were classified into three groups according to the CIS ratio on early‐phase 18F‐FP‐CIT PET images: a PD group with CIS or high CIS ratios (PD‐CIS; n = 96), a PD group with inverse CIS or low CIS ratios (PD‐iCIS; n = 40), and a PD group consisting of the remaining patients with normal CIS ratios (PD‐nCIS; n = 90). We compared the risk of dementia conversion within a 5‐year time point between the groups. Results: There were no significant differences in age, sex, education, or baseline cognitive function between the PD groups. The PD‐CIS group had higher Unified Parkinson's Disease Rating Scale (UPDRS) motor scores and more severely decreased dopamine transporter availability in the putamen. The PD‐iCIS group had a smaller hippocampal volume compared with the other groups. The risk of dementia conversion in the PD‐CIS group did not differ from that in the PD‐iCIS and PD‐nCIS groups. Meanwhile, the PD‐iCIS group had a higher risk of dementia conversion than the PD‐nCIS group. Conclusion: The results of this study suggest that inverse CIS, rather than CIS, is relevant to early dementia conversion in patients with PD. [ABSTRACT FROM AUTHOR]

Background: Patients with Parkinson's disease (PD) exhibit widespread brain perfusion changes. Objective: This study investigated whether cerebral regions with hypoperfusion and hyperperfusion have differential effects on motor and cognitive symptoms in PD using early‐phase 18F‐N‐(3‐fluoropropyl)‐2β‐carboxymethoxy‐3β‐(4‐iodophenyl) nortropane (18F‐FP‐CIT) positron emission tomography (PET) scans. Methods: We enrolled 394 patients with newly diagnosed PD who underwent dual‐phase 18F‐FP‐CIT PET scans. Indices reflecting associated changes in regional cerebral hypoperfusion and hyperperfusion on early‐phase 18F‐FP‐CIT PET scans were calculated as PD[hypo] and PD[hyper], respectively. The associations of PD[hypo] and PD[hyper] on motor and cognitive symptoms at baseline were assessed using multivariate linear regression. Also, Cox regression and linear mixed models were performed to investigate the effects of baseline PD[hypo] and PD[hyper] on longitudinal outcomes. Results: There was a weak correlation between PD[hypo] and PD[hyper] (γ = −0.19, P < 0.001). PD[hypo] was associated with baseline Unified Parkinson's Disease Rating Scale Part III scores (β = −1.02, P = 0.045), rapid increases in dopaminergic medications (β = −18.02, P < 0.001), and a higher risk for developing freezing of gait (hazard ratio [HR] = 0.67, P = 0.019), whereas PD[hyper] was not associated. Regarding cognitive function, PD[hypo] was more relevant to the baseline cognitive performance levels of visuospatial, memory, and frontal/executive function than PD[hyper]. However, greater PD[hyper] was associated with future dementia conversion (HR = 1.43, P = 0.004), whereas PD[hypo] was not associated. Conclusions: These findings suggest that PD[hypo] and PD[hyper] may differentially affect motor and cognitive functions in patients with PD. © 2023 International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Background and purpose: The choroid plexus (CP) clears harmful metabolites from the central nervous system as part of the glymphatic system. We investigated the association of CP volume (CPV) with baseline and longitudinal cognitive decline in patients with Parkinson disease (PD). Methods: We retrospectively reviewed the medical records of 240 patients with newly diagnosed PD who had undergone detailed neuropsychological tests and high‐resolution T1‐weighted structural magnetic resonance imaging during the initial assessment. The CPV of each patient was automatically segmented, and the intracranial volume ratio was used in subsequent analyses. The relationship between CPV and baseline composite scores of each cognitive domain was assessed using multivariate linear regression analyses. A Cox proportional hazards model was used to compare the risk of dementia conversion with CPV. Results: CPV negatively correlated with composite scores of the frontal/executive function domain (β = −0.375, p = 0.002) after adjusting for age, sex, years of education, and parkinsonian symptom duration. The Cox regression model revealed that a larger CPV was associated with a higher risk of dementia conversion (hazard ratio [HR] = 1.509, p = 0.038), which was no longer significant after adjusting for the composite scores of the frontal/executive function domain. A mediation analysis demonstrated that the effect of CPV on the risk of dementia conversion was completely mediated by frontal/executive function (direct effect: HR = 1.203, p = 0.396; indirect effect: HR = 1.400, p = 0.015). Conclusions: Baseline CPV is associated with baseline frontal/executive function, which subsequently influences dementia conversion risk in patients with PD. [ABSTRACT FROM AUTHOR]