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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: The relationship between menopausal hormone therapy (MHT) and risk of Parkinson's disease (PD) remains controversial. Objective: This nationwide population-based cohort study investigated the association between MHT and PD development. Methods: Data from the National Health Insurance System of South Korea from 2007 to 2020 were used. The MHT group included women who underwent MHT for the first time between 2011–2014, while the non-MHT group included women who visited a healthcare provider for menopause during the same period but never received hormonal therapy. We used propensity score matching (1 : 1) to adjust for potential confounders, and Cox regression models to assess the association between MHT and PD. Results: We selected 303,260 female participants (n = 151,630 per MHT and non-MHT groups). The median age of the participants was 50 (48–54) years, and the follow-up period lasted 7.9 (6.9–8.9) years. Cox regression analysis revealed an increased risk of PD with MHT (hazard ratio [HR] 1.377, 95% confidence interval [CI] 1.184–1.602), particularly with tibolone (HR 1.554, 95% CI 1.297–1.861) and estrogen alone (HR 1.465, 95% CI 1.054–2.036). Tibolone and estrogen alone were linked to PD within three years; however, no association was observed after three years. In contrast, the use of combined estrogen-progesterone was linked to a higher risk of PD, which increased with the duration of MHT (HR 1.885, 95% CI 1.218–2.918 for over five years). Conclusions: This study demonstrated that the MHT is closely associated with the risk of PD in a regimen- and duration-specific manner. [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]

Background: Dihydropyridines (DHPs) may have neuroprotective effects against Parkinson's disease (PD). Objective: This study investigated the effects of DHPs on nigrostriatal dopaminergic denervation and longitudinal motor and cognitive outcomes in PD. Methods: We classified 476 patients with drug‐naive PD who had undergone dopamine transporter imaging into three groups. They were selected according to a prior diagnosis of hypertension and use of DHPs and were matched using propensity scores: patients without hypertension (HTN−; n = 50) and patients with hypertension treated without DHP (HTN+/DHP−; n = 50) or with DHP (HTN+/DHP+; n = 50). Multiple linear regression and linear mixed model analyses were performed to determine intergroup differences in baseline dopamine transporter availability and longitudinal changes in the levodopa‐equivalent dose, respectively. Using Kaplan–Meier analyses, we compared the risks of levodopa‐induced dyskinesia, wearing off, and dementia‐free survival during the 5.06 years of the mean follow‐up period. The Cox regression model determined the independent effects of DHPs on dementia conversion. Results: Dopamine transporter availability in all striatal subregions was comparable between the HTN−, HTN+/DHP−, and HTN+/DHP+ groups. The risks of levodopa‐induced dyskinesia and wearing off, as well as longitudinal changes in the levodopa‐equivalent dose, did not differ between the groups. The HTN+/DHP+ group had a lower risk of developing dementia than the HTN+/DHP− (Bonferroni‐corrected Plog‐rank = 0.036) group. The use of DHP was independently associated with a lower risk of dementia conversion after controlling for other antihypertensive drugs and confounding factors (hazard ratio, 0.242; 95% confidence interval, 0.087–0.668; P = 0.006). Conclusions: DHPs may be associated with better long‐term cognitive outcomes in hypertensive patients with PD. © 2023 International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Background and purpose: Cholesterol is vital in neuronal function; however, the influence of cholesterol levels on parkinsonism is unclear. This study investigated the relationship between baseline total cholesterol (TC) levels, dopamine loss, and motor symptoms in drug‐naïve Parkinson disease (PD). Methods: This cross‐sectional study enrolled 447 drug‐naïve patients with PD who underwent dopamine transporter (DAT) imaging. Multivariate linear regression was used to investigate the effect of cholesterol levels on Unified Parkinson's Disease Rating Scale Part III (UPDRS‐III) total score and each subscore after adjusting for the covariates. An interaction analysis was performed to examine the interaction between TC levels and statin use on the UPDRS‐III scores. Results: No significant correlation was found between TC levels and DAT availability after adjusting for potential confounders. Multivariate linear regression showed that TC levels were significantly and negatively associated with the UPDRS‐III total score (β = −0.116, p = 0.013) and bradykinesia subscore (β = −0.145, p = 0.011). Dichotomized analysis according to TC levels showed that TC levels were significantly associated with UPDRS‐III total score, and rigidity, bradykinesia, and axial subscores only in the low TC group. There was an interaction effect between TC levels and statin use for the axial subscores (β = −0.523, p = 0.025). Subgroup analysis showed that TC levels were significantly and negatively associated with the axial subscore in statin users; however, no association was found in statin nonusers. Conclusions: This study suggests that TC levels affect parkinsonian motor symptoms, especially in subjects with low cholesterol status, whereas the severity of axial motor symptoms is negatively associated with TC levels only in statin users. [ABSTRACT FROM AUTHOR]

Introduction: A bundle of evidence indicates that biological sex is an important factor for clinical phenotypes as well as prognosis in Parkinson's disease (PD). We investigated the effect of nigrostriatal dopaminergic degeneration on longitudinal outcomes according to sex in patients with PD.Methods: We recruited 571 consecutive drug-naïve PD patients (279 men and 292 women) who were followed up for ≥2 years after their first visit to the clinic with baseline dopamine transporter (DAT) imaging. A Cox proportional hazard model was used to compare the risk of developing levodopa-induced dyskinesia (LID), wearing-off, freezing of gait (FOG), or PD dementia (PDD) between male and female PD patients. A mediation analysis was used to determine the relationship between biological sex, striatal dopamine deficiency, and longitudinal outcomes.Results: Female PD patients exhibited less severely decreased DAT availability in all striatal subregions than male PD patients. The future development of wearing-off and FOG did not differ according to sex. LID developed more frequently in female PD patients than in male PD patients, while the risk of PDD conversion was higher in male PD patients than in female PD patients. In the mediation analyses, the direct effect of biological sex on the development of LID or PDD was major, while the mediating effect through the striatal DAT availability was minimal.Conclusion: Differences in longitudinal outcomes according to biological sex may be ascribed to a non-dopaminergic basis. This study suggests that therapeutic strategies targeting the extra-nigrostriatal pathway should be considered in future trials. [ABSTRACT FROM AUTHOR]

Introduction: This study investigated the relationship between white matter hyperintensities (WMHs), nigrostriatal dopamine deficits, and cognitive decline in patients with drug-naïve early-stage Parkinson's disease (PD).Method: This cross-sectional study enrolled 309 non-demented patients with de novo PD who underwent [18F] N-(3-fluoropropyl)-2β-carbonethoxy-3β-(4-iodophenyl) nortropane positron emission tomography, brain magnetic resonance imaging, and a detailed neuropsychological test at baseline. We quantified dopamine transporter (DAT) availability in each striatal sub-region and applied the Scheltens scale to assess the severity of periventricular and deep WMHs. The relationships between WMHs, DAT availability, and cognition in PD were assessed using multivariate linear regression and mediation analyses while adjusting for age at parkinsonian symptom onset, sex, disease duration, and vascular risk factors.Results: The severities of periventricular and frontal WMHs were associated with striatal DAT availability. Periventricular WMHs affected the level of cognitive performance in all cognitive domains, while frontal WMHs affected the attention/working memory and frontal/executive function domains. The effects of WMHs on attention/working memory and frontal/executive dysfunction were mostly direct with minimal mediating effects through striatal DAT availability. Meanwhile, striatal DAT availability fully mediated the association between WMHs and cognitive impairment in the visuospatial and memory function domains.Conclusion: This study demonstrated the different effects of WMHs on cognitive impairment depending on the cognitive domains in PD. These findings suggest a close link between comorbid WMHs, striatal dopamine depletion, and cognition in patients with PD. [ABSTRACT FROM AUTHOR]

Background: Premorbid educational attainment is a well-known proxy of reserve, not only with regard to cognition, but also to motor symptoms. Objective: In the present study, we investigated the relationship between educational attainment and long-term motor prognosis in patients with Parkinson's disease (PD). Methods: We analyzed 466 patients with de novo PD without dementia who underwent dopamine transporter (DAT) scans and were followed up more than 2 years. Patients were divided into three groups: low education (years-of-education ≤6, n = 125), intermediate education (6

Background: Neuropsychiatric symptoms (NPS) are the most common non-motor symptom in Parkinson's disease (PD). Objective: To investigate the association between the burden of NPS and motor prognosis in patients with PD. Methods: We enrolled 329 drug-naïve patients with PD, who was non-demented and followed-up≥2 years after their first visit to the clinic with baseline dopamine transporter (DAT) imaging and neuropsychiatric inventory (NPI) scores. We performed a survival analysis and a linear mixed model analysis to assess longitudinal motor outcomes according to the NPI total score. Results: The Kaplan-Meier analysis showed no difference in the development of levodopa-induced dyskinesia and wearing-off according to the NPI total score. However, higher burden of NPI total score was associated with earlier freezing of gait (FOG) development in the time-dependent Cox regression models after adjusting for age at symptom onset, sex, disease duration, Unified PD Rating Scale motor score, baseline Mini-Mental State Examination score, DAT activity in the posterior putamen and levodopa-equivalent daily dose (LEDD) (Hazard ratio 1.047, p = 0.002). A linear mixed model analysis revealed that patients with a higher NPI total score had a more rapid LEDD increment (NPI×time, p = 0.003). Among 52 patients with PD who eventually developed FOG during the follow-up period, there was a significant correlation between the NPI total score and time with FOG development (γ= –0.472; p = 0.001) after adjusting for confounding factors. Conclusion: The present study demonstrated that the severity of NPS is a predictor of early freezing and motor progression in patients with PD. [ABSTRACT FROM AUTHOR]

Statins are more widely used not only for the primary and secondary prevention of cardiovascular disease by blocking cholesterol biosynthesis but also for the potential neuroprotective agents during neurological disorders due to their pleiotropic effects. In this study, we investigate whether the previous use of statins affect baseline nigrostriatal dopamine loss at the time of diagnosis and longitudinal motor and cognitive outcomes in patients with Parkinson's disease. Five hundred drug-naïve patients with Parkinson's disease who underwent dopamine transporter imaging were classified into two groups according to the prior use of statins: patients with and without statin use. Multivariate linear regression was used to determine intergroup differences in dopamine transporter availability. We evaluated the longitudinal changes in levodopa-equivalent dose and dementia conversion between the groups using a linear mixed model and survival analysis, respectively. In addition, mediation analysis was applied to examine the effect of total cholesterol. Patients with Parkinson's disease treated with statins had a lower baseline dopamine transporter availability in the anterior (2.13 ± 0.55 versus 2.37 ± 0.67; P = 0.002), posterior (1.31 ± 0.43 versus 1.49 ± 0.54; P = 0.003) and ventral putamina (1.40 ± 0.39 versus 1.56 ± 0.47; P = 0.002) than that in matched patients with Parkinson's disease without statins. After adjusting for age at symptom onset, sex, disease duration and vascular risk factors, linear regression models showed that a previous treatment with statins remained significantly and independently associated with more severely decreased dopamine transporter availability in the anterior putamen (Beta = -0.140, P = 0.004), posterior putamen (Beta = -0.162, P = 0.001) and ventral putamen (Beta = -0.140, P = 0.004). A linear mixed model revealed that patients with Parkinson's disease being treated with statins had a faster longitudinal increase in levodopa-equivalent dose than those without. A survival analysis showed that the rate of dementia conversion was significantly higher in patients with Parkinson's disease with statins (hazard ratio, 2.019; 95% confidence interval, 1.108-3.678; P = 0.022) than those without. Mediation analyses revealed that the effect of statin treatment on baseline dopamine transporter availability and longitudinal outcome was not mediated by total cholesterol levels. This study suggests that statin use may have a detrimental effect on baseline nigrostriatal dopamine degeneration and long-term outcomes in patients with Parkinson's disease. [ABSTRACT FROM AUTHOR]

Background: Olfactory or autonomic dysfunction is one of the earliest prodromal symptoms of Parkinson's disease (PD). It has not been investigated whether PD patients have different phenotypes depending on the presence of these prodromal symptoms. Objective: To investigate whether hyposmia-dominant and dysautonomia-dominant patients with early PD have different clinical manifestations and nigrostriatal degeneration. Methods: This cross-sectional study recruited 168 drug-naive PD patients and 34 control subjects. PD patients were classified as patients without hyposmia and dysautonomia (PD–H–D–, n = 51), hyposmia-dominant patients (PD–H+D–, n = 36), dysautonomia-dominant patients (PD–H–D+, n = 33), and patients with hyposmia and dysautonomia (PD–H+D+, n = 48). We then compared the baseline clinical characteristics, striatal specific to non-specific binding ratio (SNBR), neuropsychological performance, and neuropsychiatric symptoms among the groups. Results: The PD–H+D–group had a lower SNBR in the ventral striatum (p = 0.013), a greater asymmetric index of striatal SNBRs, and higher prevalence of apathy (p = 0.021) than the PD–H–D+ group. The PD–H–D+ group had older age at onset (p = 0.043) and a higher prevalence of REM sleep behavior disorder (p = 0.041) than the PD–H+D–group. The PD–H+D+ group had higher motor deficits, lower cognitive function, and lower SNBRs in all striatal subregions than the PD–H–D–group. Decreased SNBRs in the anterior caudate, posterior caudate, and ventral striatum were associated with the presence of apathy. Conclusion: The present study suggests that hyposmia-dominant and dysautonomia-dominant PD have different clinical characteristics and patterns of striatal dopamine depletion. [ABSTRACT FROM AUTHOR]

Background: White matter hyperintensities, prevalent in patients with Parkinson's disease (PD), significantly affect parkinsonian motor symptoms. The objective of this study was to investigate the relationship between white matter hyperintensities and nigrostriatal dopamine depletion and their interaction or mediating effects on motor symptoms in patients with drug‐naive early‐stage PD. Methods: This cross‐sectional study enrolled 501 patients with de novo PD who initially underwent [18F] N‐(3‐fluoropropyl)‐2β‐carbonethoxy‐3β‐(4‐iodophenyl) nortropane positron emission tomography and brain magnetic resonance imaging scans between April 2009 and September 2015 in a tertiary‐care university hospital. We quantified dopamine transporter availability in each striatal subregion and assessed the severity of periventricular and lobar white matter hyperintensities using the Scheltens scale. The relationship between white matter hyperintensities, dopamine transporter availability in the posterior putamen, and Unified Parkinson's Disease Rating Scale (UPDRS) motor scores was assessed using multivariate linear regression and mediation analyses. Results: Periventricular and frontal white matter hyperintensities were generally associated with dopamine transporter availability in striatal subregions after adjusting for age at symptom onset, sex, disease duration, and vascular risk factors. There was an interaction effect between periventricular white matter hyperintensities and dopamine transporter availability in the posterior putamen for the axial motor score. The effect of white matter hyperintensities on UPDRS total score and bradykinesia subscore was indirectly mediated by dopamine transporter availability in the posterior putamen, whereas the axial sub‐score was directly affected by white matter hyperintensities. Conclusions: This study suggests that the detrimental effect of white matter hyperintensities on parkinsonian motor symptoms is more relevant and independent for axial motor impairments in the status of mildly decreased striatal dopamine transporter availability. © 2021 International Parkinson and Movement Disorder Society [ABSTRACT FROM AUTHOR]

Dipeptidyl peptidase 4 (DPP4) inhibitors are widely used hypoglycaemic agents and improve glucose metabolism by enhancing the bioavailability of active glucagon-like peptide-1. In this study, we hypothesized that treatment with DPP4 inhibitors may have beneficial effects on nigrostriatal dopamine and longitudinal motor performance in diabetic patients with Parkinson's disease. We classified 697 drug naive patients with de novo Parkinson's disease who had undergone dopamine transporter imaging into three groups according to a prior diagnosis of diabetes and use of DPP4 inhibitors: diabetic patients with Parkinson's disease being treated with (n = 54) or without DPP4 inhibitors (n = 85), and non-diabetic patients with Parkinson's disease (n = 558). Diabetic patients with Parkinson's disease being treated with DPP4 inhibitors had a higher baseline dopamine transporter availability in the anterior (2.56 ± 0.74 versus 2.10 ± 0.50; P = 0.016), posterior (1.83 ± 0.69 versus 1.40 ± 0.50; P < 0.001), and ventral putamina (1.72 ± 0.58 versus 1.35 ± 0.37; P = 0.001) than that in diabetic patients with Parkinson's disease without DPP4 inhibitors. Additionally, diabetic patients with Parkinson's disease being treated with DPP4 inhibitors had higher dopamine transporter availability in the posterior putamen than that in non-diabetic patients with Parkinson's disease (1.83 ± 0.69 versus 1.43 ± 0.59; P < 0.001). After adjusting for age, sex, disease duration, and vascular risk factors, linear regression models showed that a prior treatment of DPP4 inhibitors remained independently and significantly associated with dopamine transporter availability in the anterior (β = -0.186, P = 0.012; β = -0.207, P = 0.003), posterior (β = -0.336, P < 0.001; β = -0.286, P < 0.001), and ventral putamina (β = -0.204, P = 0.005; β = -0.250, P < 0.001). A linear mixed model revealed that the diabetic group with Parkinson's disease being treated with DPP4 inhibitors had a slower longitudinal increase in levodopa-equivalent dose than the other groups (P = 0.003). Survival analyses showed that the rate of levodopa-induced dyskinesia was significantly lower in the diabetic group with a prior treatment with DPP4 inhibitors than the diabetic group without DPP4 inhibitors (hazard ratio = 0.194, P = 0.037). These findings suggest that DPP4 inhibitors may confer beneficial effects on the baseline nigrostriatal dopamine degeneration and long-term motor outcomes in diabetic patients with Parkinson's disease and may extend its role into non-diabetic patients with Parkinson's disease. [ABSTRACT FROM AUTHOR]

Background and purpose Methods Results Conclusions The co‐occurrence of amyloid‐β pathology in Parkinson's disease (PD) is common; however, the role of amyloid‐β deposition in motor prognosis remains elusive. This study aimed to investigate the association between striatal amyloid deposition, motor complications and motor prognosis in patients with PD.Ninety‐six patients with PD who underwent 18F florbetaben (FBB) positron emission tomography were retrospectively assessed. The ratio of the striatum to global (STG) FBB uptake was obtained for each individual, and patients were allotted into low and high STG groups according to the median value. The effect of STG group on regional amyloid deposition, the occurrence of motor complications and longitudinal change in levodopa equivalent dose (LED) requirement were investigated after controlling for age, sex, LED and disease duration at FBB scan.The high STG group was associated with lower cortical FBB uptake in the parietal, occipital and posterior cingulate cortices and higher striatal FBB uptake compared to the low STG group. Patients in the high STG group had a higher risk of developing wearing off and levodopa‐induced dyskinesia than those in the low STG group, whereas the risk for freezing of gait was comparable between the two groups. The high STG group showed a more rapid increase in LED requirements over time than the low STG group.These findings suggest that relatively high striatal amyloid deposition is associated with poor motor outcomes in patients with PD. [ABSTRACT FROM AUTHOR]