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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 18 F-N-(3-fluoropropyl)-2ß-carboxymethoxy-3ß-(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.
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Demência , Doença de Parkinson , Humanos , Doença de Parkinson/complicações , Doença de Parkinson/diagnóstico por imagem , Tomografia por Emissão de Pósitrons/métodos , Tropanos , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Cognição , Hipocampo/diagnóstico por imagem , Hipocampo/metabolismo , Demência/complicações , Perfusão , Tomografia Computadorizada de Emissão de Fóton Único/métodosRESUMO
BACKGROUND: Minor hallucinations (mHs) and well-structured major hallucinations (MHs) are common symptoms of Parkinson's disease (PD) psychosis. OBJECTIVES: To investigate the resting-state networks (RSNs) in patients with PD without hallucinations (PD-nH), with mH (PD-mH), and with MH (PD-MH). METHODS: A total of 73 patients with PD were enrolled (27 PD-nH, 23 PD-mH, and 23 PD-MH). Using seed-based functional connectivity analyses, we investigated the RSNs supposedly related to hallucinations in PD: the default mode network (DMN), executive control network (ECN), dorsal attention network (DAN), ventral attention network (VAN), and visual network (VN). We compared the cognitive function and RSN connectivity among the three groups. In addition, we performed a seed-to-seed analysis to examine the inter-network connectivity within each group using the corresponding RSN seeds. RESULTS: PD-MH group had lower test scores for attention and visuospatial functions compared with those in the other groups. The connectivity of the right intracalcarine cortex within the DAN was lower in the PD-MH group than in the others. The PD-mH and PD-MH groups showed higher connectivity in the left orbitofrontal cortex within DMN compared with the PD-nH group, whereas the connectivity was lower in the right middle frontal gyrus (MFG) within ECN, precuneus cortex within VAN, right middle temporal gyrus and precuneus cortex within DAN, and left MFG within VN. The PD-mH and PD-MH groups showed different inter-network connectivity between the five RSNs, especially regarding DAN connectivity. CONCLUSIONS: DAN dysfunction may be a key factor in the progression from mH to MH in patients with PD. © 2023 International Parkinson and Movement Disorder Society.
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Doença de Parkinson , Humanos , Doença de Parkinson/complicações , Doença de Parkinson/diagnóstico por imagem , Mapeamento Encefálico , Imageamento por Ressonância Magnética , Rede Nervosa/diagnóstico por imagem , Encéfalo/diagnóstico por imagem , Alucinações/diagnóstico por imagem , Alucinações/etiologiaRESUMO
BACKGROUND AND PURPOSE: The co-occurrence of amyloid-ß pathology in Parkinson's disease (PD) is common; however, the role of amyloid-ß 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: These findings suggest that relatively high striatal amyloid deposition is associated with poor motor outcomes in patients with PD.
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BACKGROUND: There is growing evidence that sex and onset age are important factors of clinical features in Parkinson's disease. AIM: The study aimed to identify nonmotor symptoms based on sex and onset age in people with Parkinson's disease. DESIGN: This is a cross-sectional descriptive study. METHODS: A total of 210 participants were recruited from the university hospital and the Parkinson's disease association. This study measured the Korean version of the nonmotor symptoms questionnaire which includes gastrointestinal, urinary, apathy/attention/memory, hallucination/delusions, depression/anxiety, sexual function, cardiovascular, sleep disorder, and miscellaneous domains. RESULTS: All participants reported at least one nonmotor symptom. The most commonly reported symptoms were nocturia (65.7%) and constipation (61.9%). The male participants reported more dribbling of saliva, constipation, and impaired sexual function, whereas the female reported more weight change. Young-onset people with Parkinson's disease reported more depression than late-onset people with Parkinson's disease. CONCLUSION: This study contributes to the understanding of symptom experience beyond motor-related symptomatology for those with Parkinson's disease and adds to the current literature. Individualized symptom assessment and management should be provided by prioritizing prevalent sex or onset age-specific symptoms, rather than addressing with all nonmotor symptoms.
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Doença de Parkinson , Transtornos do Sono-Vigília , Humanos , Masculino , Feminino , Doença de Parkinson/complicações , Doença de Parkinson/diagnóstico , Idade de Início , Estudos Transversais , Constipação Intestinal/etiologia , Constipação Intestinal/complicaçõesRESUMO
BACKGROUND: Concomitant amyloid pathology contributes to the clinical heterogeneity of Lewy body diseases (LBDs). OBJECTIVE: The objective of this study was to investigate the pattern and effect of amyloid accumulation on cognitive dysfunction in Parkinson's disease (PD) and dementia with Lewy bodies (DLB). METHODS: We retrospectively assessed 205 patients with LBD (91 with DLB and 114 with PD) who underwent 18 F-florbetaben positron emission tomography and divided them into amyloid-positive and amyloid-negative groups depending on global standardized uptake value ratios (SUVRs). We investigated the effect of group on the regional and global SUVRs using general linear models (GLMs) after controlling for age, sex, cognitive status, and score on the Korean version of the Mini-Mental State Examination. Moreover, the effect of amyloid on cognitive function, depending on the type of LBD, was evaluated using GLMs with interaction analysis. RESULTS: In all evaluated regions including the striatum, the DLB group showed a higher SUVR than the PD group. Among amyloid-positive patients, the DLB group had a higher regional SUVR than the PD group in the frontal and parietal cortices. There was a significant interaction effect between amyloid and disease groups in language and memory function. In patients with PD, global amyloid load was negatively associated with language (B = -2.03; P = 0.010) and memory functions (B = -1.96; P < 0.001). However, amyloid load was not significantly associated with cognitive performance in the DLB group. CONCLUSIONS: Although the burden of amyloid was higher in the DLB group, amyloid accumulation was negatively associated with the memory and language functions in the PD group only. © 2022 International Parkinson and Movement Disorder Society.
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Doença de Alzheimer , Doença por Corpos de Lewy , Doença de Parkinson , Humanos , Doença de Parkinson/complicações , Doença por Corpos de Lewy/patologia , Corpos de Lewy/patologia , Estudos Retrospectivos , Amiloide , Cognição , Doença de Alzheimer/complicaçõesRESUMO
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.
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Di-Hidropiridinas , Discinesias , Hipertensão , Doença de Parkinson , Humanos , Doença de Parkinson/complicações , Doença de Parkinson/tratamento farmacológico , Levodopa/efeitos adversos , Antiparkinsonianos/efeitos adversos , Proteínas da Membrana Plasmática de Transporte de Dopamina , Di-Hidropiridinas/uso terapêutico , Discinesias/tratamento farmacológico , Hipertensão/tratamento farmacológico , CogniçãoRESUMO
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 18 F-N-(3-fluoropropyl)-2ß-carboxymethoxy-3ß-(4-iodophenyl) nortropane (18 F-FP-CIT) positron emission tomography (PET) scans. METHODS: We enrolled 394 patients with newly diagnosed PD who underwent dual-phase 18 F-FP-CIT PET scans. Indices reflecting associated changes in regional cerebral hypoperfusion and hyperperfusion on early-phase 18 F-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 (ß = -1.02, P = 0.045), rapid increases in dopaminergic medications (ß = -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.
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Transtornos Neurológicos da Marcha , Doença de Parkinson , Humanos , Doença de Parkinson/complicações , Doença de Parkinson/diagnóstico por imagem , Transtornos Neurológicos da Marcha/complicações , Tropanos , Tomografia por Emissão de Pósitrons , Proteínas da Membrana Plasmática de Transporte de Dopamina , Tomografia Computadorizada de Emissão de Fóton Único/métodosRESUMO
The background of this study is to investigate whether striatal dopamine depletion patterns (selective involvement in the sensorimotor striatum or asymmetry) are associated with motor deficits in Parkinson's disease (PD). We enrolled 404 drug-naïve patients with early stage PD who underwent dopamine transporter (DAT) imaging. After quantifying DAT availability in each striatal sub-region, principal component (PC) analysis was conducted to yield PCs representing the spatial patterns of striatal dopamine depletion. Subsequently, multivariate linear regression analysis was conducted to investigate the relationship between striatal dopamine depletion patterns and motor deficits assessed using the Unified PD Rating Scale Part III (UPDRS-III). Mediation analyses were used to evaluate whether dopamine deficiency in the posterior putamen mediated the association between striatal dopamine depletion patterns and parkinsonian motor deficits. Three PCs indicated patterns of striatal dopamine depletion: PC1 (overall striatal dopamine deficiency), PC2 (selective dopamine loss in the sensorimotor striatum), and PC3 (symmetric dopamine loss in the striatum). Multivariate linear regression analysis revealed that PC1 (ß = - 1.605, p < 0.001) and PC2 (ß = 3.201, p < 0.001) were associated with motor deficits (i.e., higher UPDRS-III scores in subjects with severe dopamine depletion throughout the whole striatum or more selective dopamine loss in the sensorimotor striatum), whereas PC3 was not (ß = - 0.016, p = 0.992). Mediation analyses demonstrated that the effects of PC1 and PC2 on UPDRS-III scores were indirectly mediated by DAT availability in the posterior putamen, with a non-significant direct effect. Dopamine deficiency in the posterior putamen was most relevant to the severity of motor deficits in patients with PD, while the spatial patterns of striatal dopamine depletion were not a key determinant.
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Doença de Parkinson , Humanos , Doença de Parkinson/complicações , Doença de Parkinson/diagnóstico por imagem , Dopamina , Tomografia por Emissão de Pósitrons , Corpo Estriado/diagnóstico por imagem , Corpo Estriado/metabolismo , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Putamen/diagnóstico por imagem , Putamen/metabolismoRESUMO
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 18 F-FP-CIT PET scans. Patients with PD were classified into three groups according to the CIS ratio on early-phase 18 F-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.
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Demência , Doença de Parkinson , Humanos , Doença de Parkinson/complicações , Doença de Parkinson/diagnóstico por imagem , Tropanos , Tomografia por Emissão de Pósitrons , Demência/diagnóstico por imagem , Demência/etiologiaRESUMO
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 (ß = -0.116, p = 0.013) and bradykinesia subscore (ß = -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 (ß = -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.
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Inibidores de Hidroximetilglutaril-CoA Redutases , Doença de Parkinson , Humanos , Doença de Parkinson/complicações , Doença de Parkinson/diagnóstico por imagem , Dopamina , Hipocinesia , Estudos Transversais , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêuticoRESUMO
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 (ß = -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.
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Disfunção Cognitiva , Demência , Doença de Parkinson , Humanos , Doença de Parkinson/complicações , Doença de Parkinson/diagnóstico por imagem , Doença de Parkinson/psicologia , Demência/etiologia , Demência/complicações , Estudos Retrospectivos , Plexo Corióideo/diagnóstico por imagem , Cognição/fisiologia , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/complicações , Testes Neuropsicológicos , Imageamento por Ressonância Magnética/métodosRESUMO
Dementia with Lewy bodies (DLB), the second most common neurodegenerative dementia, is characterized by cognitive decline, fluctuation of cognition and alertness, visual hallucinations, rapid eye movement sleep behaviour disorder and parkinsonism. Imaging biomarkers are of great importance in diagnosing patients with DLB and associated with characteristic clinical features including cognitive decline. In this study, we investigate interrelation between nigrostriatal dopamine depletion, brain metabolism and cognition in DLB. We enrolled 55 patients with probable DLB (15 with prodromal DLB and 40 with DLB) and 13 healthy controls. All subjects underwent N-(3-[18F]fluoropropyl)-2ß-carbomethoxy-3ß-(4-iodophenyl) nortropane PET/CT, 18F-fluorodeoxyglucose PET/CT, 18F-florbetaben PET/CT and detailed neuropsychological testing. The relationship between striatal dopamine transporter availability and regional brain metabolism was assessed using general linear models, and the effect of striatal dopamine transporter availability and brain metabolism on specific cognitive function was evaluated by multivariate linear regression analysis. Path analyses were used to evaluate the relationship between striatal dopamine transporter availability, fluorodeoxyglucose uptake and cognitive function scores. Additionally, a linear mixed model was used to investigate the association between baseline dopamine transporter availability or brain metabolism and longitudinal cognitive decline. Independent of amyloid deposition, caudate and putamen dopamine transporter availabilities were positively correlated with brain metabolism in the DLB-specific hypometabolic regions, most prominently in the occipital and lateral parietal cortices. Both reduced caudate dopamine and brain hypometabolism were associated with low z-scores of Rey-Osterrieth Complex Figure Test copy, Seoul Verbal Learning Test immediate recall and Controlled Oral Word Association Test (COWAT)-animal. Path analyses showed that the effect of reduced caudate dopamine on the Rey-Osterrieth Complex Figure Test copy z-score was completely mediated by brain hypometabolism, whereas it affected the Seoul Verbal Learning Test immediate recall z-score both directly and via the mediation of brain hypometabolism. Caudate dopamine depletion was directly associated with the COWAT-animal z-score, not mediated by brain hypometabolism. Both baseline caudate dopamine transporter availability and brain hypometabolism were associated with longitudinal cognitive decline, with brain hypometabolism being more relevant. Our findings suggest that in DLB, striatal dopaminergic depletion and brain hypometabolism are closely related, and they differentially affect cognitive dysfunction in an item-specific manner. Additionally, brain hypometabolism would be more relevant to longitudinal cognitive outcomes than striatal dopaminergic degeneration.
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Proteínas da Membrana Plasmática de Transporte de Dopamina , Doença por Corpos de Lewy , Humanos , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Doença por Corpos de Lewy/metabolismo , Dopamina/metabolismo , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Cognição , Encéfalo/metabolismo , Fluordesoxiglucose F18/metabolismoRESUMO
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 (ß = -0.186, P = 0.012; ß = -0.207, P = 0.003), posterior (ß = -0.336, P < 0.001; ß = -0.286, P < 0.001), and ventral putamina (ß = -0.204, P = 0.005; ß = -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.
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Encéfalo/efeitos dos fármacos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Hipoglicemiantes/uso terapêutico , Doença de Parkinson , Idoso , Antiparkinsonianos/efeitos adversos , Encéfalo/metabolismo , Diabetes Mellitus Tipo 2/complicações , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Discinesia Induzida por Medicamentos/epidemiologia , Feminino , Humanos , Levodopa/efeitos adversos , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/complicações , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/patologia , Estudos RetrospectivosRESUMO
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.
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Corpo Estriado/metabolismo , Dopamina/metabolismo , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/metabolismo , Idoso , Corpo Estriado/diagnóstico por imagem , Corpo Estriado/efeitos dos fármacos , Feminino , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/diagnóstico por imagem , Prognóstico , Estudos RetrospectivosRESUMO
The pons is one of the earliest affected regions in patients with synucleinopathies. We aimed to investigate the diagnostic value of measuring pontine damage using diffusion tensor imaging (DTI) in these patients. We enrolled 49 patients with Parkinson's disease (PD), 16 patients with idiopathic rapid eye movement sleep behavior disorder (iRBD), 23 patients with multiple system atrophy (MSA), and 39 healthy controls in this study. All the participants underwent high-resolution T1-weighted imaging and DTI. Mean diffusivity (MD) and fraction anisotropy (FA) values in the pons were calculated to characterize structural damage. The discriminatory power of pontine MD and FA values to differentiate patients with synucleinopathies from healthy controls was examined using receiver operating characteristics (ROC) analyses. Compared to healthy controls, patients with PD, iRBD, and MSA had increased MD values and decreased FA values in the pons, although no correlation was observed between these DTI measures and disease severity. The ROC analyses showed that MD values in the pons had a fair discriminatory power to differentiate healthy controls from patients with PD (area under the curve [AUC], 0.813), iRBD (AUC, 0.779), and MSA (AUC, 0.951). The AUC for pontine FA values was smaller than that for pontine MD values when differentiating healthy controls from patients with PD (AUC, 0.713; p = 0.054) and iRBD (AUC, 0.686; p = 0.045). Our results suggest that MD values in the pons may be a useful marker of brain stem neurodegeneration in patients with synucleinopathies.
Assuntos
Transtorno do Comportamento do Sono REM , Sinucleinopatias , Anisotropia , Imagem de Tensor de Difusão/métodos , Humanos , Ponte/diagnóstico por imagem , Transtorno do Comportamento do Sono REM/diagnóstico por imagem , Sinucleinopatias/diagnóstico por imagemRESUMO
OBJECTIVE: We aimed to determine the association between striatal dopaminergic depletion, cerebral ß-amyloid deposition, and cognitive dysfunction in Lewy body disease (LBD). METHODS: This cross-sectional study recruited 48 LBD patients (30 with dementia, 18 with mild cognitive impairment) and 15 control subjects from a university-based hospital. We measured the striatal dopamine transporter (DAT) activity and regional ß-amyloid burden using N-(3-[18 F]fluoropropyl)-2ß-carbon ethoxy-3ß-(4-iodophenyl) nortropane (FP-CIT) positron emission tomography (PET) and 18 F-florbetaben (FBB) PET, respectively. The relationship between striatal FP-CIT uptake, regional cortical FBB uptake, and cognitive function scores was evaluated using path analyses. We also investigated the effects of striatal FP-CIT uptake and cortical FBB uptake on the interval between motor symptom and dementia onset. RESULTS: Reduced striatal FP-CIT uptake was associated with increased FBB uptake in the posterior cortical regions, most prominently in the occipital cortices. Reduced FP-CIT uptake in the anterior putamen was associated with visuospatial dysfunction with mediation of increased occipital FBB uptake. Reduced FP-CIT uptake in the posterior putamen and an increased parietal FBB uptake were independently associated with memory dysfunction. Reduced striatal FP-CIT uptake was associated with attention, language, and frontal/executive dysfunction, independent of amyloid deposition. Increased FBB uptake, especially in the parietal cortex, was associated with earlier onset of dementia. INTERPRETATION: Our results suggest that occipital ß-amyloid deposition may contribute to the association between striatal dopaminergic depletion and visuospatial dysfunction in LBD patients. Although the effects of reduced DAT activity are more prominent than those of ß-amyloid burden on cognitive dysfunction, the latter affects the onset of cognitive dysfunction. ANN NEUROL 2020;87:739-750.
Assuntos
Peptídeos beta-Amiloides/metabolismo , Disfunção Cognitiva/etiologia , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Doença por Corpos de Lewy/metabolismo , Doença por Corpos de Lewy/patologia , Idoso , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Encéfalo/patologia , Cognição/fisiologia , Estudos Transversais , Feminino , Humanos , Doença por Corpos de Lewy/complicações , Masculino , Tomografia por Emissão de PósitronsRESUMO
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 [18 F] N-(3-fluoropropyl)-2ß-carbonethoxy-3ß-(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.
Assuntos
Doença de Parkinson , Substância Branca , Corpo Estriado/metabolismo , Estudos Transversais , Dopamina , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Humanos , Doença de Parkinson/diagnóstico por imagem , Substância Branca/diagnóstico por imagemRESUMO
BACKGROUND AND PURPOSE: The aim was to investigate the neural correlates of impaired self-awareness of cognitive deficits (IACd) in non-demented patients with Parkinson's disease (PD). METHODS: This cross-sectional study enrolled 153 drug-naïve and non-demented PD patients who underwent brain magnetic resonance imaging, dopamine transporter (DAT) positron emission tomography, detailed neuropsychological testing, and the Cognitive Complaints Interview at baseline. Based on the presence of mild cognitive impairment and subjective cognitive complaints, patients were grouped into those with IACd (PD-IACd+, n = 33) and those with normal recognition of cognitive function (n = 82) or underestimation of cognitive function (n = 38). Cortical thickness, white matter (WM) integrity, DAT availability and cognitive function were compared between the groups. RESULTS: The prevalence of IACd was 21.6% in drug-naïve patients with PD. The PD-IACd+ group had a lower z-score in the Stroop color reading test than the other groups. Patients in the PD-IACd+ group had WM disintegrity, especially in the genu of the corpus callosum and anterior limb of the internal capsule, compared to those without IACd, whilst cortical thickness or striatal DAT availability was comparable regardless of the presence of IACd. Amongst patients with mild cognitive impairment, those with IACd had more severe WM disintegrity than those without IACd. CONCLUSION: Structural connectivity between and from the frontal lobes is closely associated with self-awareness of cognitive deficits in PD. Evaluating frontal structural connectivity from the early stages of PD will be important in assessing the actual cognitive and daily life performance of patients with PD.
Assuntos
Disfunção Cognitiva , Doença de Parkinson , Cognição , Disfunção Cognitiva/complicações , Disfunção Cognitiva/etiologia , Estudos Transversais , Humanos , Imageamento por Ressonância Magnética , Testes Neuropsicológicos , Doença de Parkinson/complicações , Doença de Parkinson/diagnóstico por imagem , Doença de Parkinson/patologiaRESUMO
BACKGROUND: The severity of motor symptoms in Parkinson's disease (PD) does not always correlate with the degree of nigral dopaminergic neuronal loss. Individuals with greater motor reserve may have milder motor signs than their striatal dopamine loss. In this study, we explored the functional brain network associated with motor reserve in early-stage PD. METHODS: We analyzed 134 patients with de novo PD who underwent dopamine transporter scans and resting-state functional magnetic resonance imaging. We estimated individual motor reserve based on initial motor deficits and striatal dopamine depletion using a residual model. We applied network-based statistic analysis to identify the functional brain network associated with the measure of motor reserve (ie, motor reserve network). We also assessed the effect of motor reserve network connectivity strength on the longitudinal increase in levodopa-equivalent dose during the 2-year follow-up period. RESULTS: Network-based statistic analysis identified the motor reserve network composed of the basal ganglia, inferior frontal cortex, insula, and cerebellar vermis at a primary threshold of P value 0.001. Patients with an increased degree of functional connectivity within the motor reserve network had greater motor reserve. There was a significant interaction between the motor reserve network strength and time in the linear mixed model, indicating that higher motor reserve network strength was associated with slower longitudinal increase in levodopa-equivalent dose. CONCLUSIONS: The present study revealed the functional brain network associated with motor reserve in patients with early-stage PD. Functional connections within the motor reserve network are associated with the individual's capacity to cope with PD-related pathologies. © 2020 International Parkinson and Movement Disorder Society.
Assuntos
Doença de Parkinson , Encéfalo/diagnóstico por imagem , Dopamina , Humanos , Levodopa , Imageamento por Ressonância Magnética , Vias Neurais/diagnóstico por imagem , Doença de Parkinson/diagnóstico por imagemRESUMO
OBJECTIVE: To investigate the role of motor cerebellar connectivity in future development of freezing of gait, because it is a complex network disorder in Parkinson's disease (PD). METHODS: We recruited 26 de novo patients with PD who experienced freezing of gait within 5 years from magnetic resonance imaging acquisition (vulnerable PD group), 61 patients with PD who had not experienced freezing of gait within 5 years (resistant PD group), and 27 healthy control subjects. We compared the resting state functional connectivity between the motor cerebellum and the whole brain between the groups. In addition, we evaluated the relationship between motor cerebellar connectivity and freezing of gait latency. RESULTS: The vulnerable PD group had increased functional connectivity between the motor cerebellum and parieto-occipito-temporal association cortices compared with the control group or the resistant PD group. Connectivity between lobule VI and the right superior parietal lobule, right fusiform gyrus, and left inferior temporal gyrus; between lobule VIIb and the right superior parietal lobule, right hippocampus, and right middle temporal gyrus; and between lobule VIIIb and the bilateral fusiform gyri, right middle occipital gyrus, and bilateral parietal lobes was inversely proportional to freezing of gait latency. The freezing of gait latency-related cortical functional connectivity from the motor cerebellum was also significantly higher in the vulnerable PD group compared with the control group, as well as the resistant PD group. CONCLUSIONS: The data suggest that the motor cerebellar functional connectivity with the posterior cortical areas play an important role in future development of freezing of gait in PD. © 2020 International Parkinson and Movement Disorder Society.