Predictors associated with the rate of progression of nigrostriatal degeneration in Parkinson's disease.

BACKGROUND: Parkinson's disease (PD) manifests as a wide variety of clinical phenotypes and its progression varies greatly. However, the factors associated with different disease progression remain largely unknown. METHODS: In this retrospective cohort study, we enrolled 113 patients who underwent 18F-FP-CIT PET scan twice. Given the negative exponential progression pattern of dopamine loss in PD, we applied the natural logarithm to the specific binding ratio (SBR) of two consecutive 18F-FP-CIT PET scans and conducted linear mixed model to calculate individual slope to define the progression rate of nigrostriatal degeneration. We investigated the clinical and dopamine transporter (DAT) availability patterns associated with the progression rate of dopamine depletion in each striatal sub-region. RESULTS: More symmetric parkinsonism, the presence of dyslipidemia, lower K-MMSE total score, and lower anteroposterior gradient of the mean putaminal SBR were associated with faster progression rate of dopamine depletion in the caudate nucleus. More symmetric parkinsonism and lower anteroposterior gradient of the mean putaminal SBR were associated with faster depletion of dopamine in the anterior putamen. Older age at onset, more symmetric parkinsonism, the presence of dyslipidemia, and lower anteroposterior gradient of the mean putaminal SBR were associated with faster progression rate of dopamine depletion in the posterior putamen. Lower striatal mean SBR predicted the development of LID, while lower mean SBR in the caudate nuclei predicted the development of dementia. DISCUSSION: Our results suggest that the evaluation of baseline clinical features and patterns of DAT availability can predict the progression of PD and its prognosis.

Association of Basal Forebrain Volume with Amyloid, Tau, and Cognition in Alzheimer's Disease.

Background: Degeneration of cholinergic basal forebrain (BF) neurons characterizes Alzheimer's disease (AD). However, what role the BF plays in the dynamics of AD pathophysiology has not been investigated precisely. Objective: To investigate the baseline and longitudinal roles of BF along with core neuropathologies in AD. Methods: In this retrospective cohort study, we enrolled 113 subjects (38 amyloid [Aß]-negative cognitively unimpaired, 6 Aß-positive cognitively unimpaired, 39 with prodromal AD, and 30 with AD dementia) who performed brain MRI for BF volume and cortical thickness, 18F-florbetaben PET for Aß, 18F-flortaucipir PET for tau, and detailed cognitive testing longitudinally. We investigated the baseline and longitudinal association of BF volume with Aß and tau standardized uptake value ratio and cognition. Results: Cross-sectionally, lower BF volume was not independently associated with higher cortical Aß, but it was associated with tau burden. Tau burden in the orbitofrontal, insular, lateral temporal, inferior temporo-occipital, and anterior cingulate cortices were associated with progressive BF atrophy. Lower BF volume was associated with faster Aß accumulation, mainly in the prefrontal, anterior temporal, cingulate, and medial occipital cortices. BF volume was associated with progressive decline in language and memory functions regardless of baseline Aß and tau burden. Conclusions: Tau deposition affected progressive BF atrophy, which in turn accelerated amyloid deposition, leading to a vicious cycle. Also, lower baseline BF volume independently predicted deterioration in cognitive function.

Different effect of hypo- and hypermetabolism on cognition in dementia with Lewy bodies: are they coupled or independent?

Patients with dementia with Lewy bodies (DLB) show widespread brain metabolic changes. This study investigated whether brain hypo- and hypermetabolism in DLB have differential effects on cognition. We enrolled 55 patients with DLB (15 prodromal DLB [MCI-LB] and 40 probable DLB) and 13 healthy controls who underwent 18F-fluorodeoxyglucose positron emission tomography and detailed neuropsychological tests. Metabolic indices reflecting associated changes in regional cerebral glucose metabolism were calculated as follows: index(-) for hypometabolism [DLB-hypo] and index(+) for hypermetabolism [DLB-hyper]. The effects of DLB-hypo or DLB-hyper on cognitive function were assessed using a multivariate linear regression model. Additionally, a linear mixed model was used to investigate the association between each index and the longitudinal cognitive decline. There was no correlation between DLB-hypo and DLB-hyper in the disease group. The multivariate linear regression model showed that DLB-hypo was associated with language, visuospatial, visual memory, and frontal/executive functions; whereas DLB-hyper was responsible for attention and verbal memory. There was significant interaction between DLB-hypo and DLB-hyper for verbal and visual memory, which was substantially affected by DLB-hyper in relatively preserved DLB-hypo status. A linear mixed model showed that DLB-hypo was associated with longitudinal cognitive outcomes, regardless of cognitive status, and DLB-hyper contributed to cognitive decline only in the MCI-LB group. The present study suggests that DLB-hypo and DLB-hyper may be independent of each other and differentially affect the baseline and longitudinal cognitive function in patients with DLB.

Differential effects of cholesterol levels on cognition according to body mass index in Parkinson's disease.

BACKGROUND: Cholesterol is an essential component of the neuronal cell membrane and is crucial for neuronal function; however, the role of cholesterol levels in Parkinson's disease (PD) is debatable. This study investigated the complex relationship between total cholesterol (TC) levels, body mass index (BMI), and cognition in patients with PD. METHODS: This study included 321 drug-naïve patients with PD who underwent dopamine transporter (DAT) imaging and baseline neuropsychological tests. Multivariate linear regression and Cox regression models were used to investigate the effect of TC levels on the composite score of each cognitive domain and dementia conversion after adjusting for covariates, respectively. Interaction analyses were performed to examine the interaction effect between TC levels and BMI on baseline cognition and dementia conversion. RESULTS: TC levels and cognition showed no significant relationship after adjusting for potential confounders. A significant interaction effect between TC levels and BMI was observed in frontal/executive function and dementia conversion. Further analyses showed that TC levels were positively associated with frontal/executive function in the under-/normal weight group (ß = 0.205, p = 0.013), whereas a negative relationship existed between TC levels and frontal/executive function in the obese group (ß = - 0.213, p = 0.017). Cox regression analyses also showed the differential effects of TC levels on dementia conversion according to BMI (under-/normal weight group: hazard ratio [HR] = 0.550, p = 0.013; obese group: HR = 2.085, p = 0.014). CONCLUSIONS: This study suggests a cross-over interaction between TC levels and BMI on cognitive symptoms in PD.

Association of Sleep Disturbances With Brain Amyloid and Tau Burden, Cortical Atrophy, and Cognitive Dysfunction Across the AD Continuum.

BACKGROUND AND OBJECTIVES: Patients with Alzheimer disease (AD) frequently suffer from various sleep disturbances. However, how sleep disturbance is associated with AD and its progression remains poorly investigated. We investigated the association of total sleep time with brain amyloid and tau burden, cortical atrophy, cognitive dysfunction, and their longitudinal changes in the AD spectrum. METHODS: In this retrospective cohort study, we enrolled participants on the AD spectrum who were positive on 18F-florbetaben (FBB) PET. All participants underwent the Pittsburgh Sleep Quality Index, brain MRI, FBB PET, 18F-flortaucipir (FTP) PET, and detailed neuropsychological testing. In addition, a subset of participants completed follow-up assessments. We analyzed the association of total sleep time with the baseline and longitudinal FBB-standardized uptake value ratio (SUVR), FTP-SUVR, cortical thickness, and cognitive domain composite scores. RESULTS: We examined 138 participants on the AD spectrum (15 with preclinical AD, 62 with prodromal AD, and 61 with AD dementia; mean age 73.4 ± 8.0 years; female 58.7%). Total sleep time was longer in the AD dementia group (7.4 ± 1.6 hours) compared with the preclinical (6.5 ± 1.4 hours; p = 0.026) and prodromal groups (6.6 ± 1.4 hours; p = 0.001), whereas other sleep parameters did not differ between groups. Longer total sleep time was not associated with amyloid accumulation but rather with tau accumulation, especially in the amygdala, hippocampus, basal forebrain, insular, cingulate, occipital, inferior temporal cortices, and precuneus. Longer total sleep time predicted faster tau accumulation in Braak regions V-VI (ß = 0.016, p = 0.007) and disease progression to mild cognitive impairment or dementia (hazard ratio = 1.554, p = 0.024). Longer total sleep time was also associated with memory deficit (ß = -0.19, p = 0.008). DISCUSSION: Prolonged total sleep time was associated with tau accumulation in sleep-related cortical and subcortical areas as well as memory dysfunction. It also predicted faster disease progression with tau accumulation. Our study highlights the clinical importance of assessing total sleep time as a marker for disease severity and prognosis in the AD spectrum.

A selective ER-phagy exerts neuroprotective effects via modulation of α-synuclein clearance in parkinsonian models.

The endoplasmic reticulum (ER) is selectively degraded by ER-phagy to maintain cell homeostasis. α-synuclein accumulates in the ER, causing ER stress that contributes to neurodegeneration in Parkinson's disease (PD), but the role of ER-phagy in α-synuclein modulation is largely unknown. Here, we investigated the mechanisms by which ER-phagy selectively recognizes α-synuclein for degradation in the ER. We found that ER-phagy played an important role in the degradation of α-synuclein and recovery of ER function through interaction with FAM134B, where calnexin is required for the selective FAM134B-mediated α-synuclein clearance via ER-phagy. Overexpression of α-synuclein in the ER of the substantia nigra (SN) resulted in marked loss of dopaminergic neurons and motor deficits, mimicking PD characteristics. However, enhancement of ER-phagy using FAM134B overexpression in the SN exerted neuroprotective effects on dopaminergic neurons and recovered motor performance. These data suggest that ER-phagy represents a specific ER clearance mechanism for the degradation of α-synuclein.

Distinct amyloid-dependent patterns of nigra dopamine depletion in Lewy body diseases.

Introduction: Concomitant amyloid pathology is not uncommon and contributes to the clinical characteristics of Lewy body disease (LBD). We investigated the effect of amyloid on striatal18F-FP-CIT uptake patterns in LBD, including Parkinson's disease (PD) and dementia with Lewy bodies. Methods: We enrolled 125 patients with LBD who underwent18F-florbetaben positron emission tomography (PET) and18F-FP-CIT PET. Patients were divided into amyloid-positive and amyloid-negative groups. We investigated the effect of amyloid on striatal dopamine transporter (DAT) availability, depending on the type of LBD, using general linear models with interaction analysis after controlling for age, sex, education, deep white matter hyperintensity (WMH), periventricular WMH, and cognitive status. Results: There was a significant interaction effect between the disease group and the presence of amyloid on DAT availability in the anterior putamen, posterior putamen, caudate, and ventral striatum. In the presence of amyloid, only the PD group exhibited decreased DAT availability in the anterior and posterior putamen. In both groups, the presence of amyloid was not associated with DAT availability in the caudate and ventral striatum. The presence of amyloid was not directly related to the worse parkinsonian motor symptoms in both groups. However, there was a significant indirect effect of amyloid on parkinsonian motor symptoms, which was mediated by anterior and posterior putaminal DAT availability in the PD group alone. Discussion: This study demonstrates different amyloid-dependent or amyloid-independent18F-FP-CIT PET patterns in patients with LBD, suggesting distinctive interactions between α-synuclein and amyloid pathology based on the type of LBD.

Nigrosome 1 visibility and its association with nigrostriatal dopaminergic loss in Parkinson's disease.

BACKGROUND: Nigrosome 1 (NG1), a small cluster of dopaminergic cells in the substantia nigra and visible in the susceptibility map-weighted magnetic resonance image (SMwI), is severely affected in Parkinson's disease (PD). However, the degree of nigrostriatal degeneration according to the visibility of NG1 has not yet been well elucidated. METHODS: We consecutively recruited 138 PD and 78 non-neurodegenerative disease (non-ND) patients, who underwent both 18 F-FP-CIT positron emission tomography (PET) and SMwI. Three neurologists and one radiologist evaluated the visibility of NG1 in SMwI. The participants were thereby grouped into visible, intermediate, and non-visible groups. Nigrostriatal dopaminergic input was calculated using the specific binding ratio (SBR) of the 18 F-FP-CIT PET. We determined the threshold of regional SBR for discriminating NG1 visibility and the probability for NG1 visibility according to regional SBR. RESULTS: Visual rating of NG1 showed excellent interobserver agreements as well as high sensitivity and specificity to differentiate the PD group from the non-ND group. NG1 was visible in seven patients (5.1%) in the PD group, who had relatively short disease duration or less severe loss of striatal dopamine. The threshold of putaminal SBR reduction on the more affected side for the disappearance of NG1 was 45.5%, and the probability for NG1 visibility dropped to 50% after the reduction of putaminal SBR to 41% from the normal mean. CONCLUSIONS: Almost half loss of nigrostriatal dopaminergic input is required to dissipate the hyperintensity of NG1 on SMwI, suggesting its utility in diagnosing PD only after the onset of the motor symptoms.

Effects of Dihydropyridines on the Motor and Cognitive Outcomes of Patients with Parkinson's Disease.

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.

Cortical Thickness and Brain Glucose Metabolism in Healthy Aging.

BACKGROUND AND PURPOSE: We aimed to determine the effect of demographic factors on cortical thickness and brain glucose metabolism in healthy aging subjects. METHODS: The following tests were performed on 71 subjects with normal cognition: neurological examination, 3-tesla magnetic resonance imaging, 18F-fluorodeoxyglucose positron-emission tomography, and neuropsychological tests. Cortical thickness and brain metabolism were measured using vertex- and voxelwise analyses, respectively. General linear models (GLMs) were used to determine the effects of age, sex, and education on cortical thickness and brain glucose metabolism. The effects of mean lobar cortical thickness and mean lobar metabolism on neuropsychological test scores were evaluated using GLMs after controlling for age, sex, and education. The intracranial volume (ICV) was further included as a predictor or covariate for the cortical thickness analyses. RESULTS: Age was negatively correlated with the mean cortical thickness in all lobes (frontal and parietal lobes, p=0.001; temporal and occipital lobes, p<0.001) and with the mean temporal metabolism (p=0.005). Education was not associated with cortical thickness or brain metabolism in any lobe. Male subjects had a lower mean parietal metabolism than did female subjects (p<0.001), while their mean cortical thicknesses were comparable. ICV was positively correlated with mean cortical thickness in the frontal (p=0.016), temporal (p=0.009), and occipital (p=0.007) lobes. The mean lobar cortical thickness was not associated with cognition scores, while the mean temporal metabolism was positively correlated with verbal memory test scores. CONCLUSIONS: Age and sex affect cortical thickness and brain glucose metabolism in different ways. Demographic factors must therefore be considered in analyses of cortical thickness and brain metabolism.

Association of cholesterol level with dopamine loss and motor deficits in Parkinson disease: A cross-sectional study.

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.

Implication of EEG theta/alpha and theta/beta ratio in Alzheimer's and Lewy body disease.

We evaluated the patterns of quantitative electroencephalography (EEG) in patients with Alzheimer's disease (AD), Lewy body disease (LBD), and mixed disease. Sixteen patients with AD, 38 with LBD, 20 with mixed disease, and 17 control participants were recruited and underwent EEG. The theta/alpha ratio and theta/beta ratio were measured. The relationship of the log-transformed theta/alpha ratio (TAR) and theta/beta ratio (TBR) with the disease group, the presence of AD and LBD, and clinical symptoms were evaluated. Participants in the LBD and mixed disease groups had higher TBR in all lobes except for occipital lobe than those in the control group. The presence of LBD was independently associated with higher TBR in all lobes and higher central and parietal TAR, while the presence of AD was not. Among cognitively impaired patients, higher TAR was associated with the language, memory, and visuospatial dysfunction, while higher TBR was associated with the memory and frontal/executive dysfunction. Increased TBR in all lobar regions and temporal TAR were associated with the hallucinations, while cognitive fluctuations and the severity of Parkinsonism were not. Increased TBR could be a biomarker for LBD, independent of AD, while the presence of mixed disease could be reflected as increased TAR.

Temporal trajectory model for dopaminergic input to the striatal subregions in Parkinson's disease.

INTRODUCTION: Almost half of the nigral neurons are already lost during the preclinical period of Parkinson's disease (PD), and then the speed of neuronal loss is slowly attenuated during the subsequent progression. We sought to establish long-term temporal trajectory models for the dopaminergic input to the striatal subregions and a 4D-temporal trajectory model for the dopamine transporter positron emission tomography (PET). METHODS: We selected 83 patients in PD spectrum who underwent dopamine transporter PET scan twice and 71 age-matched healthy controls. We created temporal trajectories of specific binding ratios of the striatal subregions by integrating function between baseline values and their annual change rates and also created 4D-temporal trajectory model by applying the same method for each striatal voxel. Using the PET data of additional 100 PD patients, we estimated an individual time point in the 4D-temporal trajectory model for the validation. RESULTS: Degenerative loss of striatal dopaminergic input first appeared in the posterior dorsal putamen in the more affected side at 14.4 years before the clinical onset, and subsequently in the posterior ventral and anterior putamen, and finally in the caudate. The time delay between the initiation of dopaminergic loss in the more and less affected posterior dorsal putamen was 6.1 years. The estimated individual time points within the entire disease course were correlated with the motor severity. CONCLUSION: Our temporal trajectory model demonstrated a sequential loss of dopaminergic input in the striatal subregions in PD and may be beneficial for the evaluation of individual status of disease progression.

Contracted thalamic shape is associated with early development of levodopa-induced dyskinesia in Parkinson's disease.

Levodopa-induced dyskinesia (LID), a long-term motor complication in Parkinson's disease (PD), is attributable to both presynaptic and postsynaptic mechanisms. However, no studies have evaluated the baseline structural changes associated with LID at a subcortical level in PD. A total of 116 right-handed PD patients were recruited and based on the LID latency of 5 years, we classified patients into those vulnerable to LID (PD-vLID, n = 49) and those resistant to LID (PD-rLID, n = 67). After adjusting for covariates including dopamine transporter (DAT) availability of the posterior putamen, we compared the subcortical shape between the groups and investigated its association with the onset of LID. The PD-vLID group had lower DAT availability in the posterior putamen, higher parkinsonian motor deficits, and faster increment in levodopa equivalent dose than the PD-rLID group. The PD-vLID group had significant inward deformation in the right thalamus compared to the PD-rLID group. Inward deformation in the thalamus was associated with an earlier onset of LID at baseline. This study suggests that independent of presynaptic dopamine depletion, the thalamus is a major neural substrate for LID and that a contracted thalamic shape at baseline is closely associated with an early development of LID.

Uric Acid Enhances Neurogenesis in a Parkinsonian Model by Remodeling Mitochondria.

Background: Adult neurogenesis is the process of generating new neurons to enter neural circuits and differentiate into functional neurons. However, it is significantly reduced in Parkinson's disease (PD). Uric acid (UA), a natural antioxidant, has neuroprotective properties in patients with PD. This study aimed to investigate whether UA would enhance neurogenesis in PD. Methods: We evaluated whether elevating serum UA levels in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced parkinsonian mouse model would restore neurogenesis in the subventricular zone (SVZ). For a cellular model, we primary cultured neural precursor cells (NPCs) from post-natal day 1 rat and evaluated whether UA treatment promoted cell proliferation against 1-methyl-4-phenylpyridinium (MPP+). Results: Uric acid enhanced neurogenesis in both in vivo and in vitro parkinsonian model. UA-elevating therapy significantly increased the number of bromodeoxyuridine (BrdU)-positive cells in the SVZ of PD animals as compared to PD mice with normal UA levels. In a cellular model, UA treatment increased the expression of Ki-67. In the process of modulating neurogenesis, UA elevation up-regulated the expression of mitochondrial fusion markers. Conclusion: In MPTP-induced parkinsonian model, UA probably enhanced neurogenesis via regulating mitochondrial dynamics, promoting fusion machinery, and inhibiting fission process.

Interrelation of striatal dopamine, brain metabolism and cognition in dementia with Lewy bodies.

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.

White matter connectivity networks predict levodopa-induced dyskinesia in Parkinson's disease.

BACKGROUND: Although levodopa-induced dyskinesia-relevant white matter change has been evaluated, it is uncertain whether these changes may reflect the underlying predisposing conditions leading to the development of levodopa-induced dyskinesia. OBJECTIVE: To elucidate the role of white matter connectivity networks in the development of levodopa-induced dyskinesia in drug-naïve Parkinson's disease. METHODS: We recruited 30 patients who developed levodopa-induced dyskinesia within 5 years from MRI acquisition (vulnerable-group), 47 patients who had not developed levodopa-induced dyskinesia within 5 years (resistant-group), and 28 controls. We performed comparative analyses of whole-brain white matter integrity and connectivity using tract-based spatial and network- and degree-based statistics. We evaluated the predictability of levodopa-induced dyskinesia development and relationship with its latency, using the average connectivity strength as a predictor in Cox- and linear-regression, respectively. RESULTS: Mean-diffusivity was lower mainly at the left frontal region in the vulnerable-group compared to the resistant-group. Network-based statistics identified a subnetwork consisting of the bilateral fronto-striato-pallido-thalamic and lateral parietal regions (subnetwork A) and degree-based statistics identified four subnetworks (hub-subnetwork) consisting of edges centered on the left superior frontal gyrus, left putamen, left insular, or left precentral gyrus, where the vulnerable-group had stronger connectivity compared to the resistant-group. Stronger connectivity within the subnetwork A and hub-subnetwork centered on the left superior frontal gyrus was a predictor of levodopa-induced dyskinesia development independent of known risk factors and had an inverse relationship with its latency. CONCLUSIONS: Our data suggest that white matter connectivity subnetworks within corticostriatal regions play a pivotal role in the development of levodopa-induced dyskinesia.

Association of ß-Amyloid and Basal Forebrain With Cortical Thickness and Cognition in Alzheimer and Lewy Body Disease Spectra.

OBJECTIVE: Cholinergic degeneration and ß-amyloid contribute to brain atrophy and cognitive dysfunction in Alzheimer disease (AD) and Lewy body disease (LBD), but their relationship has not been comparatively evaluated. METHODS: In this cross-sectional study, we recruited 28 normal controls (NC), 55 patients with AD mild cognitive impairment (MCI), 34 patients with AD dementia, 28 patients with LBD MCI, and 51 patients with LBD dementia. Participants underwent cognitive evaluation, brain MRI to measure the basal forebrain (BF) volume and global cortical thickness (CTh), and 18F-florbetaben (FBB) PET to measure the standardized uptake value ratio (SUVR). Using general linear models and path analyses, we evaluated the association of FBB-SUVR and BF volume with CTh or cognitive dysfunction in the AD spectrum (AD and NC) and LBD spectrum (LBD and NC), respectively. Covariates included age, sex, education, deep and periventricular white matter hyperintensities, intracranial volume, hypertension, diabetes, and hyperlipidemia. RESULTS: BF volume mediated the association between FBB-SUVR and CTh in both the AD and LBD spectra, while FBB-SUVR was associated with CTh independently of BF volume only in the LBD spectrum. Significant correlation between voxel-wise FBB-SUVR and CTh was observed only in the LBD group. FBB-SUVR was independently associated with widespread cognitive dysfunction in both the AD and LBD spectra, especially in the memory domain (standardized beta [B] for AD spectrum = -0.60, B for LBD spectrum = -0.33). In the AD spectrum, BF volume was associated with memory dysfunction (B = 0.18), and CTh was associated with language (B = 0.21) and executive (B = 0.23) dysfunction. In the LBD spectrum, however, BF volume and CTh were independently associated with widespread cognitive dysfunction. CONCLUSIONS: There is a common ß-amyloid-related degenerative mechanism with or without the mediation of BF in the AD and LBD spectra, while the association of BF atrophy with cognitive dysfunction is more profound and there is localized ß-amyloid-cortical atrophy interaction in the LBD spectrum.

Differentially targeted seeding reveals unique pathological alpha-synuclein propagation patterns.

Parkinson's disease is a progressive neurodegenerative disorder characterized by the intracellular accumulation of insoluble alpha-synuclein aggregates into Lewy bodies and neurites. Increasing evidence indicates that Parkinson's disease progression results from the spread of pathologic alpha-synuclein through neuronal networks. However, the exact mechanisms underlying the propagation of abnormal proteins in the brain are only partially understood. The objective of this study was first to describe the long-term spatiotemporal distributions of Lewy-related pathology in mice injected with alpha-synuclein preformed fibrils and then to recreate these patterns using a computational model that simulates in silico the spread of pathologic alpha-synuclein. In this study, 87 2-3-month-old non-transgenic mice were injected with alpha-synuclein preformed fibrils to generate a comprehensive post-mortem dataset representing the long-term spatiotemporal distributions of hyperphosphorylated alpha-synuclein, an established marker of Lewy pathology, across the 426 regions of the Allen Mouse Brain Atlas. The mice were injected into either the caudoputamen, nucleus accumbens or hippocampus, and followed over 24 months with pathologic alpha-synuclein quantified at seven intermediate time points. The pathologic patterns observed at each time point in this high-resolution dataset were then compared to those generated using a Susceptible-Infected-Removed (SIR) computational model, an agent-based model that simulates the spread of pathologic alpha-synuclein for every brain region taking simultaneously into account the effect of regional brain connectivity and Snca gene expression. Our histopathological findings showed that differentially targeted seeding of pathological alpha-synuclein resulted in unique propagation patterns over 24 months and that most brain regions were permissive to pathology. We found that the SIR model recreated the observed distributions of pathology over 24 months for each injection site. Null models showed that both Snca gene expression and connectivity had a significant influence on model fit. In sum, our study demonstrates that the combination of normal alpha-synuclein concentration and brain connectomics contributes to making brain regions more vulnerable to the pathological process, providing support for a prion-like spread of pathologic alpha-synuclein. We propose that this rich dataset and the related computational model will help test new hypotheses regarding mechanisms that may alter the spread of pathologic alpha-synuclein in the brain.