Monoaminergic Degeneration and Ocular Motor Abnormalities in De Novo Parkinson's Disease.

BACKGROUND: Evaluating eye movements in Parkinson's disease (PD) provides valuable insights into the underlying pathophysiological changes. OBJECTIVE: The aim was to investigate the relationship between monoaminergic degeneration and ocular motor abnormalities in de novo PD. METHODS: Drug-naive PD patients who underwent N-(3-[18 F]fluoropropyl)-2-carbomethoxy-3-(4-iodophenyl) nortropane positron emission tomography scans and video-oculography at diagnosis were eligible. Measurements of saccadic accuracy, latency, and smooth pursuit gain and square wave jerk frequency were collected. Patients underwent Movement Disorders Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) and detailed cognitive tests. We investigated the associations between ocular motor measurements and specific tracer uptake ratios (SUR) in the caudate nucleus, anterior and posterior putamen, thalamus, and dorsal raphe nuclei, along with motor and cognitive symptoms. RESULTS: One-hundred twenty-four subjects were included in this study. Saccadic accuracy was positively associated with parkinsonian motor severity expressed as Hoehn and Yahr stages, MDS-UPDRS Part III scores, and subscores for bradykinesia and rigidity but not with tremor scores (PFDR < 0.05). Saccadic accuracy correlated with poor performances in the Rey-Complex-Figure copy, and latency with the Digit Symbol Coding and the Montreal Cognitive Assessment scores (PFDR < 0.05). Prolonged saccadic latency correlated with reduced thalamic SUR, whereas decreased saccadic accuracy correlated with reduced SUR in the anterior and posterior putamen (PFDR < 0.05). Reduced smooth pursuit gain showed associations with reduced SUR in the dorsal raphe, a serotonin-predominant region, but did not correlate with parkinsonism severity scores. CONCLUSION: Defective dopaminergic and nondopaminergic neural systems may discretely influence ocular motor function in de novo PD patients. © 2023 International Parkinson and Movement Disorder Society.

Brain olfactory-related atrophy in isolated rapid eye movement sleep behavior disorder.

OBJECTIVE: To investigate structural and functional connectivity changes in brain olfactory-related structures in a longitudinal prospective cohort of isolated REM sleep behavior disorder (iRBD) and their clinical correlations, longitudinal evolution, and predictive values for phenoconversion to overt synucleinopathies, especially Lewy body diseases. METHODS: The cohort included polysomnography-confirmed iRBD patients and controls. Participants underwent baseline assessments including olfactory tests, neuropsychological evaluations, the Movement Disorders Society-Unified Parkinson's Disease Rating Scale, 3T brain MRI, and 18 F-FP-CIT PET scans. Voxel-based morphometry (VBM) was performed to identify regions of atrophy in iRBD, and volumes of relevant olfactory-related regions of interest (ROI) were estimated. Subgroups of patients underwent repeated volumetric MRI and resting-state functional MRI (fMRI) scans after four years. RESULTS: A total of 51 iRBD patients were included, with 20 of them converting to synucleinopathy (mean time to conversion 3.08 years). Baseline VBM analysis revealed atrophy in the right olfactory cortex and gyrus rectus in iRBD. Subsequent ROI comparisons with controls showed atrophy in the amygdala. These olfactory-related atrophies tended to be associated with worse depression, anxiety, and urinary problems in iRBD. Amygdala 18 F-FP-CIT uptake tended to be reduced in iRBD patients with hyposmia (nonsignificant after multiple comparison correction) and correlated with urinary problems. Resting-state fMRI of 23 patients and 32 controls revealed multiple clusters with aberrant olfactory-related functional connectivity. Hypoconnectivity between the putamen and olfactory cortex was associated with mild parkinsonian signs in iRBD. Longitudinal analysis of volumetric volumetric MRI in 22 iRBD patients demonstrated four-year progression of olfactory-related atrophy. Cox regression analysis revealed that this atrophy significantly predicted phenoconversion. INTERPRETATION: Progressive atrophy of central olfactory structures may be a potential indicator of Lewy body disease progression in iRBD.

Validation of the REM behaviour disorder phenoconversion-related pattern in an independent cohort.

BACKGROUND: A brain glucose metabolism pattern related to phenoconversion in patients with idiopathic/isolated REM sleep behaviour disorder (iRBDconvRP) was recently identified. However, the validation of the iRBDconvRP in an external, independent group of iRBD patients is needed to verify the reproducibility of such pattern, so to increase its importance in clinical and research settings. The aim of this work was to validate the iRBDconvRP in an independent group of iRBD patients. METHODS: Forty iRBD patients (70 ± 5.59 years, 19 females) underwent brain [18F]FDG-PET in Seoul National University. Thirteen patients phenoconverted at follow-up (7 Parkinson disease, 5 Dementia with Lewy bodies, 1 Multiple system atrophy; follow-up time 35 ± 20.56 months) and 27 patients were still free from parkinsonism/dementia after 62 ± 29.49 months from baseline. We applied the previously identified iRBDconvRP to validate its phenoconversion prediction power. RESULTS: The iRBDconvRP significantly discriminated converters from non-converters iRBD patients (p = 0.016; Area under the Curve 0.74, Sensitivity 0.69, Specificity 0.78), and it significantly predicted phenoconversion (Hazard ratio 4.26, C.I.95%: 1.18-15.39). CONCLUSIONS: The iRBDconvRP confirmed its robustness in predicting phenoconversion in an independent group of iRBD patients, suggesting its potential role as a stratification biomarker for disease-modifying trials.

Longitudinal evolution of cortical thickness signature reflecting Lewy body dementia in isolated REM sleep behavior disorder: a prospective cohort study.

BACKGROUND: The isolated rapid-eye-movement sleep behavior disorder (iRBD) is a prodromal condition of Lewy body disease including Parkinson's disease and dementia with Lewy bodies (DLB). We aim to investigate the longitudinal evolution of DLB-related cortical thickness signature in a prospective iRBD cohort and evaluate the possible predictive value of the cortical signature index in predicting dementia-first phenoconversion in individuals with iRBD. METHODS: We enrolled 22 DLB patients, 44 healthy controls, and 50 video polysomnography-proven iRBD patients. Participants underwent 3-T magnetic resonance imaging (MRI) and clinical/neuropsychological evaluations. We characterized DLB-related whole-brain cortical thickness spatial covariance pattern (DLB-pattern) using scaled subprofile model of principal components analysis that best differentiated DLB patients from age-matched controls. We analyzed clinical and neuropsychological correlates of the DLB-pattern expression scores and the mean values of the whole-brain cortical thickness in DLB and iRBD patients. With repeated MRI data during the follow-up in our prospective iRBD cohort, we investigated the longitudinal evolution of the cortical thickness signature toward Lewy body dementia. Finally, we analyzed the potential predictive value of cortical thickness signature as a biomarker of phenoconversion in iRBD cohort. RESULTS: The DLB-pattern was characterized by thinning of the temporal, orbitofrontal, and insular cortices and relative preservation of the precentral and inferior parietal cortices. The DLB-pattern expression scores correlated with attentional and frontal executive dysfunction (Trail Making Test-A and B: R = - 0.55, P = 0.024 and R = - 0.56, P = 0.036, respectively) as well as visuospatial impairment (Rey-figure copy test: R = - 0.54, P = 0.0047). The longitudinal trajectory of DLB-pattern revealed an increasing pattern above the cut-off in the dementia-first phenoconverters (Pearson's correlation, R = 0.74, P = 6.8 × 10-4) but no significant change in parkinsonism-first phenoconverters (R = 0.0063, P = 0.98). The mean value of the whole-brain cortical thickness predicted phenoconversion in iRBD patients with hazard ratio of 9.33 [1.16-74.12]. The increase in DLB-pattern expression score discriminated dementia-first from parkinsonism-first phenoconversions with 88.2% accuracy. CONCLUSION: Cortical thickness signature can effectively reflect the longitudinal evolution of Lewy body dementia in the iRBD population. Replication studies would further validate the utility of this imaging marker in iRBD.

Brain Metabolic Correlates of Dopaminergic Denervation in Prodromal and Early Parkinson's Disease.

BACKGROUND: It remains unclear how brain metabolic activities transform in response to dopamine deficiency in the prodromal and early phases of Parkinson's disease (PD). OBJECTIVE: To investigate the relationship between nigrostriatal dopaminergic denervation and brain glucose metabolism in patients with isolated rapid eye movement sleep behavior disorder (iRBD) and early PD. METHODS: This cohort study included 28 patients with polysomnography-confirmed iRBD, 24 patients with de novo PD with probable rapid eye movement sleep behavior disorder (denovo PD), and 28 healthy controls (HCs) who underwent two positron emission tomography scans with 18 F-fluorodeoxyglucose (all participants) and 18 F-N-3-fluoropropyl-2ß-carboxymethoxy-3ß-(4-iodophenyl)-nortropane (except for one denovo PD patient and 15 HCs). We analyzed striatal and voxel-wise whole-brain glucose metabolism in relation to nigrostriatal dopaminergic integrity and comparatively investigated the whole-brain metabolic connectivity among the groups. We also assessed longitudinal metabolic changes against progressive dopaminergic denervation over 4 years in the iRBD group. RESULTS: From HCs to iRBD and finally to the denovo PD, dopaminergic integrity positively correlated with metabolic activity in the caudate, whereas a negative correlation was observed in the posterior putamen. In the iRBD group, there was a metabolic increase in the inferior orbitofrontal cortex against putaminal dopaminergic denervation at baseline, but negative correlations were newly observed in the superior orbitofrontal cortex and superior frontal gyrus at the 4-year follow-up. The denovo PD group showed negative correlations in the cerebellum and fusiform gyrus. Intra- and inter-regional metabolic connectivities in the parieto-occipital cortices were enhanced in the iRBD group compared with the denovo PD and HC groups. In the iRBD group, overall metabolic connectivity was strengthened along with enhanced basal ganglia-frontal connection by advancing dopaminergic denervation. CONCLUSIONS: Our findings suggest diverse trajectories of metabolic responses associated with dopaminergic denervation between individual brain areas in the prodromal and early PD stages. © 2022 International Parkinson and Movement Disorder Society.

Brain Metabolism Related to Mild Cognitive Impairment and Phenoconversion in Patients With Isolated REM Sleep Behavior Disorder.

BACKGROUND AND OBJECTIVES: Mild cognitive impairment (MCI) in isolated REM sleep behavior disorder (iRBD) is a risk factor for subsequent neurodegeneration. We aimed to identify brain metabolism and functional connectivity changes related to MCI in patients with iRBD and the neuroimaging markers' predictive value for phenoconversion. METHODS: This is a prospective cohort study of patients with iRBD with a mean follow-up of 4.2 ± 2.6 years. At baseline, patients with iRBD and age- and sex-matched healthy controls (HCs) underwent 18F-fluorodeoxyglucose (FDG)-PET and resting-state fMRI scans and a comprehensive neuropsychological test battery. Voxel-wise group comparisons for FDG-PET data were performed using a general linear model. Seed-based connectivity maps were computed using brain regions showing significant hypometabolism associated with MCI in patients with iRBD and compared between groups. A Cox regression analysis was applied to investigate the association between brain metabolism and risk of phenoconversion. RESULTS: Forty patients with iRBD, including 21 with MCI (iRBD-MCI) and 19 with normal cognition (iRBD-NC), and 24 HCs were included in the study. The iRBD-MCI group revealed relative hypometabolism in the inferior parietal lobule, lateral and medial occipital, and middle and inferior temporal cortex bilaterally compared with HC and the iRBD-NC group. In seed-based connectivity analyses, the iRBD-MCI group exhibited decreased functional connectivity of the left angular gyrus with the occipital cortex. Of 40 patients with iRBD, 12 patients converted to Parkinson disease (PD) or dementia with Lewy bodies (DLB). Hypometabolism of the occipital pole (hazard ratio [95% CI] 6.652 [1.387-31.987]), medial occipital (4.450 [1.143-17.327]), and precuneus (3.635 [1.009-13.093]) was associated with higher phenoconversion rate to PD/DLB. DISCUSSION: MCI in iRBD is related to functional and metabolic changes in broad brain areas, particularly the occipital and parietal areas. Moreover, hypometabolism in these brain regions was a predictor of phenoconversion to PD or DLB. Evaluation of cognitive function and neuroimaging characteristics could be useful for risk stratification in patients with iRBD.

Mild behavioral impairment linked to progression to Alzheimer's disease and cortical thinning in amnestic mild cognitive impairment.

Background: Mild behavioral impairment (MBI) is a neurobehavioral syndrome characterized by later life emergence of sustained neuropsychiatric symptoms, as an at-risk state for dementia. However, the associations between MBI and a risk of progression to Alzheimer's disease (AD) and its neuroanatomical correlates in mild cognitive impairment (MCI) are still unclear. Method: A total 1,184 older adults with amnestic MCI was followed for a mean of 3.1 ± 2.0 years. MBI was approximated using a transformation algorithm for the Neuropsychiatric Inventory at baseline. A two-step cluster analysis was used to identify subgroups of individuals with amnestic MCI based on profiles of 5 MBI domain symptoms (decreased motivation, affective dysregulation, impulse dyscontrol, social inappropriateness, abnormal perception/thought content). A Cox regression analysis was applied to investigate differences in the risk of progression to AD between subgroups. A subset of participants (n = 202) underwent 3D T1-weighted MRI scans at baseline and cortical thickness was compared between the subgroups of amnestic MCI patients. Result: The cluster analysis classified the patients into 3 groups: (1) patients without any MBI domain symptoms (47.4%, asymptomatic group); (2) those with only affective dysregulation (29.4%, affective dysregulation group); (3) those with multiple MBI domain symptoms, particularly affective dysregulation, decreased motivation and impulse dyscontrol (23.2%, complex group). Compared to the asymptomatic group, the complex group was associated with a higher risk of progression to AD (hazard ratio = 2.541 [1.904-3.392], p < 0.001), but the affective dysregulation group was not (1.214 [0.883-1.670], p = 0.232). In cortical thickness analysis, the complex group revealed cortical thinning bilaterally in the inferior parietal, lateral occipital, lateral superior temporal, and frontopolar regions compared with the affective dysregulation group. Conclusion: The multiple co-occuring MBI domains in individuals with amnestic MCI are associated with a higher risk of progression to AD and cortical thinning in temporal, parietal and frontal areas. These results suggest that evaluation of MBI could be useful for risk stratification for AD and appropriate intervention in MCI individuals.

Mild cognitive impairment and abnormal brain metabolic expression in idiopathic REM sleep behavior disorder.

BACKGROUND: Mild cognitive impairment (MCI) is a common feature of isolated rapid-eye-movement sleep behavior disorder (iRBD). Here, we assessed cognitive functions and MCI in a prospective iRBD cohort and investigated their association with disease-specific brain metabolic patterns. METHODS: Forty-four patients with polysomnography-confirmed iRBD performed a standardized battery of neuropsychological examinations every two years. We used previously established spatial covariance patterns from de novo drug-naïve Parkinson's disease with concomitant RBD (denovoPDRBD-RP) and iRBD (iRBD-RP) using 18F-fluorodeoxyglucose PET scan. We compared those expressions between iRBD with normal cognition (iRBD-NC) and with mild cognitive impairment (iRBD-MCI), and evaluated whether they predict progressive cognitive deterioration. RESULTS: Twenty iRBD patients (45 %) had MCI at baseline and 12 patients (27 %, about 7 % per year) had clinically significant cognitive deterioration after 4 years. The iRBD-MCI and iRBD-NC groups showed similar rates of cognitive change, but iRBD-MCI consistently performed worse in the domains of verbal memory and executive function. Elevated denovoPDRBD-RP expression predicted cognitive deterioration (hazard ratio = 5.98 [1.70-21.06]), whereas iRBD-RP did not. CONCLUSIONS: Increased disease-specific brain metabolic patterns are associated with iRBD-MCI and impending cognitive deterioration with the risk of progression to Lewy body dementia.

Parkinson Disease-Related Brain Metabolic Patterns and Neurodegeneration in Isolated REM Sleep Behavior Disorder.

OBJECTIVE: To elucidate the role of Parkinson disease (PD)-related brain metabolic patterns as a biomarker in isolated REM sleep behavior disorder (iRBD) for future disease conversion. METHODS: This is a prospective cohort study consisting of 30 patients with iRBD, 25 patients with de novo PD with a premorbid history of RBD, 21 patients with longstanding PD on stable treatment, and 24 healthy controls. The iRBD group was longitudinally followed up. All participants underwent 18F-fluorodeoxyglucose (FDG) PET and were evaluated with olfaction, cognition, and the Movement Disorders Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) at baseline. From FDG-PET scans, we derived metabolic patterns from the longstanding PD group (PD-RP) and de novo PD group with RBD (dnPDRBD-RP). Subsequently, we calculated the PD-RP and dnPDRBD-RP scores in patients with iRBD. We validated the metabolic patterns in each PD group and separate iRBD cohort (n = 14). RESULTS: The 2 patterns significantly correlated with each other and were spatially overlapping yet distinct. The MDS-UPDRS motor scores significantly correlated with PD-RP (p = 0.013) but not with dnPDRBD-RP (p = 0.076). In contrast, dnPDRBD-RP correlated with olfaction in butanol threshold test (p = 0.018) in patients with iRBD, but PD-RP did not (p = 0.21). High dnPDRBD-RP in patients with iRBD predicted future phenoconversion with all cutoff ranges from 1.5 to 3 SD of the control value, whereas predictability of PD-RP was only significant in a partial range of cutoff. CONCLUSION: The dnPDRBD-RP is an efficient neuroimaging biomarker that reflects prodromal features of PD and predicts phenoconversion in iRBD that can be applied individually. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that a de novo PD pattern on FDG-PET predicts future conversion to neurodegenerative disease in patients with iRBD.

Probable REM sleep behavior disorder is associated with longitudinal cortical thinning in Parkinson's disease.

REM sleep behavior disorder (RBD) has a poor prognostic implication in both motor and non-motor functions in Parkinson's disease (PD) patients. However, to the best of our knowledge no study to date investigated the longitudinal cerebral changes underlying RBD symptoms in PD. We performed the longitudinal study to investigate the association between probable RBD and cortical and subcortical changes in early, de novo PD patients. We studied 78 participants from the Parkinson's Progression Marker Initiative who underwent structural MRI at baseline and after 2 years. The presence of probable RBD (pRBD) was evaluated using the RBD screening questionnaire. We compared the cross-sectional and longitudinal cortical thickness and subcortical volume changes, between PD patients with and without pRBD. At baseline, we found bilateral inferior temporal cortex thinning in the PD-pRBD group compared with the PD-noRBD group. Longitudinally, the PD-pRBD group revealed a significant increase in the rate of thinning in the left insula compared with the PD-noRBD group, and the increased thinning correlated with decreased cognitive performance. In subcortical volume analyses, the presence of pRBD was linked with volume decrease over time in the left caudate nucleus, pallidum and amygdala. The volume changes in the left caudate nucleus revealed correlations with global cognition. These results support the idea that RBD is an important marker of rapid progression in PD motor and non-motor symptoms and suggest that the atrophy in the left insula and caudate nucleus might be the underlying neurobiological mechanisms of the poorer prognosis in PD patients with RBD.

Longitudinal Changes in Isolated Rapid Eye Movement Sleep Behavior Disorder-Related Metabolic Pattern Expression.

BACKGROUND: It remains unclear whether and how the isolated rapid eye movement (REM) sleep behavior disorder (iRBD)-related metabolic pattern (RBDRP) changes with disease progression in iRBD. OBJECTIVE: To examine longitudinal changes in RBDRP expression in iRBD patients and to explore trajectories of relative metabolic activities of individual brain regions constituting RBDRP. METHODS: In this cohort study, 25 iRBD patients (mean age [±standard deviation], 69.2 ± 5.3 years; 12 [48%] patients were men) and 24 age-matched healthy controls were included. The patients underwent at least two 18 F-fluorodeoxyglucose positron emission tomography scans at baseline and at the 2-year and/or 4-year follow-ups. We measured the RBDRP expression of the patients and controls which was validated by reproduction in a separate iRBD cohort (n = 13). RESULTS: At baseline, the RBDRP expression discriminated iRBD patients from healthy controls. However, the RBDRP expression z scores tended to decrease over time in the patients, especially with longer follow-ups, and this tendency was observed even in patients with high-risk of phenoconversion. Furthermore, the degree of RBDRP expression at baseline did not predict the disease conversion. The RBDRP breakdown was mainly provoked by the attenuation of relative hypermetabolism in the frontal cortex including premotor areas and relative hypometabolism in the occipital cortex. The putaminal metabolic activity increased steadily with the disease progression. CONCLUSIONS: The RBDRP expression in iRBD patients was altered significantly over time. Some of the brain metabolic changes seem to represent attempted functional compensation against ongoing neurodegeneration. The RBDRP expression measurement at one time point may not be a reliable biomarker for predicting disease conversion. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Mild behavioral impairment in Parkinson's disease is associated with altered corticostriatal connectivity.

BACKGROUND: Mild behavioral impairment (MBI) is a syndrome characterized by later life onset, sustained neuropsychiatric symptoms as a marker of dementia risk. In Parkinson's disease (PD), MBI has been associated with worse cognitive abilities and increased cortical atrophy. However, the circuit level correlates of MBI have not been investigated in this population. Our objective was to investigate the relationship between MBI and corticostriatal connectivity in PD patients. This emphasis on corticostriatal connectivity was due to the significant role of these circuits in neuropsychiatric and cognitive symptoms across disease conditions. METHODS: Seventy-four non-demented patients with PD were administered the MBI-checklist, and classified as having high MBI (PD-MBI; n = 21) or low MBI scores (PD-noMBI; n = 53). Corticostriatal connectivity was assessed with both an atlas and seed-based analysis. The atlas analysis consisted of calculating the average connectivity between the striatal network and the default mode (DMN), central executive (CEN), and saliency networks (SAN). Structural measurements of cortical thickness and volume were also assessed. PD-MBI and PD-noMBI patients were compared, along with a group of age matched healthy control subjects (HC; n = 28). Subsequently, a seed analysis assessed the relationship of MBI scores with the connectivity of twelve seeds within the striatum while controlling for cognitive ability. A complementary analysis assessed the relationship between striatal connectivity and cognition, while controlling for MBI-C. RESULTS: PD-MBI demonstrated decreased connectivity between the striatum and both the DMN and SAN compared to PD-noMBI and HC. The decreased connectivity between the striatum and the SAN was explained partly by increased atrophy within the SAN in PD-MBI. The seed analysis revealed a relationship between higher MBI scores and lower connectivity of the left caudate head to the dorsal anterior cingulate cortex and left middle frontal gyrus. Higher MBI-C scores were also related to decreased connectivity of the right caudate head with the anterior cingulate cortex, precuneus, and left supramarginal gyrus, as well as increased connectivity to the left hippocampus and right cerebellar hemisphere. Caudate-precuneus connectivity was independently associated with both global behavioural and cognitive scores. CONCLUSION: These results suggest PD-MBI is associated with altered corticostriatal connectivity, particularly between the head of the caudate and cortical regions associated with the DMN and SAN. In particular, caudate-precuneus connectivity is associated with both global behavioral and cognitive symptoms in PD.

Theta-Burst Stimulation for Cognitive Enhancement in Parkinson's Disease With Mild Cognitive Impairment: A Randomized, Double-Blind, Sham-Controlled Trial.

Background: Mild cognitive impairment is a common non-motor symptom of Parkinson's disease (PD-MCI) and has minimal treatment options. Objective: In this double-blind, randomized, sham-controlled trial, we assessed the effect of repeated sessions of intermittent theta-burst stimulation over the left dorsolateral prefrontal cortex on cognition and brain connectivity in subjects with PD-MCI. Methods: Forty-one subjects were randomized to receive real (n = 21) or sham stimulation (n = 20). All subjects underwent neuropsychological assessments before, 1 day, and 1 month after stimulation. Subjects also underwent resting-state functional magnetic resonance imaging before and 48 h after stimulation. The primary outcome was the change in the cognitive domain (executive function, attention, memory, language, and visuospatial abilities) z-scores across time. Results: There was an insignificant effect on cognitive domain z-scores across time when comparing real with sham stimulation and correcting for multiple comparisons across cognitive domains (p > 0.05 Bonferroni correction). However, the real stimulation group demonstrated a trend toward improved executive functioning scores at the 1-month follow-up compared with sham (p < 0.05 uncorrected). After real stimulation, the connectivity of the stimulation site showed decreased connectivity to the left caudate head. There was no change in connectivity within or between the stimulation network (a network of cortical regions connected to the stimulation site) and the striatal network. However, higher baseline connectivity between the stimulation network and the striatal network was associated with improved executive function scores at 1 month. Conclusions: These results suggest that intermittent theta-burst stimulation over the dorsolateral prefrontal cortex in subjects with PD-MCI has minimal effect on cognition compared with sham, although there were trends toward improved executive function. This intervention may be more effective in subjects with higher baseline connectivity between the stimulation network and the striatal network. This trial supports further investigation focusing on executive function and incorporating connectivity-based targeting. Clinical Trial Registration: www.ClinicalTrials.gov, identifier NCT03243214.

Cognitive signature of brain FDG PET based on deep learning: domain transfer from Alzheimer's disease to Parkinson's disease.

PURPOSE: Although functional brain imaging has been used for the early and objective assessment of cognitive dysfunction, there is a lack of generalized image-based biomarker which can evaluate individual's cognitive dysfunction in various disorders. To this end, we developed a deep learning-based cognitive signature of FDG brain PET adaptable for Parkinson's disease (PD) as well as Alzheimer's disease (AD). METHODS: A deep learning model for discriminating AD from normal controls (NCs) was built by a training set consisting of 636 FDG PET obtained from Alzheimer's Disease Neuroimaging Initiative database. The model was directly transferred to images of mild cognitive impairment (MCI) patients (n = 666) for identifying who would rapidly convert to AD and another independent cohort consisting of 62 PD patients to differentiate PD patients with dementia. The model accuracy was measured by area under curve (AUC) of receiver operating characteristic (ROC) analysis. The relationship between all images was visualized by two-dimensional projection of the deep learning-based features. The model was also designed to predict cognitive score of the subjects and validated in PD patients. Cognitive dysfunction-related regions were visualized by feature maps of the deep CNN model. RESULTS: AUC of ROC for differentiating AD from NC was 0.94 (95% CI 0.89-0.98). The transfer of the model could differentiate MCI patients who would convert to AD (AUC = 0.82) and PD with dementia (AUC = 0.81). The two-dimensional projection mapping visualized the degree of cognitive dysfunction compared with normal brains regardless of different disease cohorts. Predicted cognitive score, an output of the model, was highly correlated with the mini-mental status exam scores. Individual cognitive dysfunction-related regions included cingulate and high frontoparietal cortices, while they showed individual variability. CONCLUSION: The deep learning-based cognitive function evaluation model could be successfully transferred to multiple disease domains. We suggest that this approach might be extended to an objective cognitive signature that provides quantitative biomarker for cognitive dysfunction across various neurodegenerative disorders.

Macular ganglion-cell-complex layer thinning and optic nerve integrity in drug-naïve Parkinson's disease.

To reveal the macular inner retinal change linked to axonal degeneration in Parkinson's disease (PD), we performed macular optical coherence tomography scan and diffusion tensor imaging of the retrobulbar optic nerve on both eyes of 36 drug-naïve PD patients. Thicknesses of inner retinal layers were automatically measured, and correlation analysis was conducted between the retinal thickness and diffusion parameters of the optic nerve. PD patients showed thinning of the inner retinal layers compared to control data. Thicknesses of the ganglion cell and inner plexiform layers were both correlated positively with fractional anisotropy and negatively with diffusivity indices of ipsilateral optic nerve (FDR-adjusted p < 0.05). This study revealed a novel in vivo connection between macular parafoveal ganglion cell change and integrity in the retrobulbar optic nerve in drug-naïve PD.

Mild behavioral impairment is linked to worse cognition and brain atrophy in Parkinson disease.

OBJECTIVE: To evaluate the associations of mild behavioral impairment (MBI) with cognitive deficits and patterns of gray matter changes in Parkinson disease (PD). METHODS: Sixty patients with PD without dementia and 29 healthy controls underwent a cognitive neuropsychological evaluation and structural MRI scan. MBI was evaluated with the MBI Checklist (MBI-C), a rating scale designed to elicit emergent neuropsychiatric symptoms in accordance with MBI criteria. We divided the patients with PD into 2 groups: 1 group with high MBI-C scores (PD-MBI) and the other with low MBI-C scores (PD-noMBI). RESULTS: Among 60 patients with PD, 20 were categorized as having PD-MBI (33.33%). In healthy controls, no participants met the MBI cut-point threshold. The PD-MBI group had significantly lower Montreal Cognitive Assessment and z scores in all 5 domains and the global score compared to healthy controls and those with PD-noMBI. In addition, all cognitive domains except language and global cognition negatively correlated with the MBI-C total score in all patients with PD. For cortical structures, the PD-MBI group revealed middle temporal cortex thinning and decreased volume compared with the PD-noMBI group, and decreased volume in this area negatively correlated with the MBI-C total score. CONCLUSIONS: The impaired cognitive function over all domains and atrophy in the temporal area in the PD-MBI group are in line with posterior cortical circuit deficits in PD, which have been associated with a faster rate of progression to dementia. These initial results suggest that MBI might be an early and important marker for incident cognitive decline and dementia in patients with PD.

Nonmotor and Dopamine Transporter Change in REM Sleep Behavior Disorder by Olfactory Impairment.

OBJECTIVE: It is unclear whether the decline in dopamine transporters (DAT) differs among idiopathic rapid eye movement sleep behavior disorder (iRBD) patients with different levels of olfactory impairment. This study aimed to characterize DAT changes in relation to nonmotor features in iRBD patients by olfactory loss. METHODS: This prospective cohort study consisted of three age-matched groups: 30 polysomnography-confirmed iRBD patients, 30 drug-naïve Parkinson's disease patients, and 19 healthy controls without olfactory impairment. The iRBD group was divided into two groups based on olfactory testing results. Participants were evaluated for reported prodromal markers and then underwent 18F-FP-CIT positron emission tomography and 3T MRI. Tracer uptakes were analyzed in the caudate, anterior and posterior putamen, substantia nigra, and raphe nuclei. RESULTS: Olfactory impairment was defined in 38.5% of iRBD patients. Mild parkinsonian signs and cognitive functions were not different between the two iRBD subgroups; however, additional prodromal features, constipation, and urinary and sexual dysfunctions were found in iRBD patients with olfactory impairment but not in those without. Tracer uptake showed significant group differences in all brain regions, except the raphe nuclei. The iRBD patients with olfactory impairment had uptake reductions in the anterior and posterior putamen, caudate, and substantia nigra (p < 0.016 in all, adjusted for age), which ranged from 0.6 to 0.8 of age-normative values. In contrast, those without olfactory impairment had insignificant changes in all regions ranging above 0.8. CONCLUSION: There was a clear distinction in DAT loss and nonmotor profiles by olfactory status in iRBD.

A New Metabolic Network Correlated with Olfactory and Executive Dysfunctions in Idiopathic Rapid Eye Movement Sleep Behavior Disorder.

BACKGROUND AND PURPOSE: To identify a metabolic network reflecting neurodegeneration in patients with idiopathic rapid eye movement (REM) sleep behavior disorder (iRBD). METHODS: We recruited a prospective cohort comprising patients with de novo Parkinson's disease (PD) with probable REM sleep behavior disorder (PDRBD, n=21), polysomnography-confirmed iRBD patients (n=28), and age-matched healthy controls (HC) (n=24). PDRBD-related spatial covariance pattern (PDRBD-RP) were determined from ¹8F-fluorodeoxyglucose PET images of the PDRBD group and validated by reproduction in a separate PD cohort with polysomnography-confirmed REM sleep behavior disorder (n=11). We also confirmed via ¹8F-N-3-fluoropropyl-2ß-carboxymethoxy-3ß-(4-iodophenyl)-nortropane PET that none of our iRBD patients had any loss of dopamine transporters (DATs) suggestive of PD. Differences in the PDRBD-RP across groups were compared, and the clinical significance of these metabolic patterns in iRBD patients was further evaluated based on relationships with olfactory and cognitive functions, and striatal DAT densities. RESULTS: The PDRBD-RP reflected the previously reported PD-related covariance pattern and additionally showed relative metabolic increases in the hippocampus and premotor cortex. The PDRBD-RP gradually increased from the HC to iRBD patients and to the de novo and validation PDRBD groups. In iRBD patients, the PDRBD-RP was negatively correlated with olfactory and frontal executive functions (age-controlled p<0.01 for both), and tended to be negatively correlated with the striatal DAT density, although this was insignificant after age adjustment. During the mean follow-up period of 3.5 years, 5 of 11 iRBD patients with PDRBD-RP elevation had developed Lewy body diseases, whereas those without PDRBD-RP elevation had not. CONCLUSIONS: Our results suggest that PDRBD-RP is an effective biomarker for monitoring the progression to neurodegenerative disease in iRBD patients.

Efficacy of Cilostazol Administration in Alzheimer's Disease Patients with White Matter Lesions: A Positron-Emission Tomography Study.

This study tested the efficacy of the phosphodiesterase type III inhibitor cilostazol in Alzheimer's disease patients with white matter lesions treated with donepezil in comparison with donepezil monotherapy using fluorodeoxyglucose (18F) positron-emission tomography (FDG PET). A 24-week, randomized, double-blind, placebo-controlled, parallel-group study was conducted. Thirty-six Alzheimer's disease patients with white matter lesions who received donepezil (n = 18 each in the cilostazol and placebo groups) were enrolled. Participants underwent pre and post FDG PET imaging scans and three rounds of clinical and neuropsychological tests. The cilostazol group did not show a significant decrease of regional glucose metabolism; however, regional glucose metabolism was significantly decreased in the parietal and frontal lobes of the placebo group. The repeated measures ANOVA measuring differences in uptake change revealed that regional glucose metabolism in the left inferior frontal gyrus was significantly more preserved in the cilostazol group than that in the placebo group (p < 0.005). Mean changes from baseline on the Mini-Mental State Exam, Alzheimer's Disease Assessment Scale-cognitive subscale, Alzheimer's Disease Cooperative Study-Activities of Daily Living Inventory, and the Clinical Dementia Rating Sum of Boxes did not differ between the two groups. In the cilostazol group, the increase of glucose metabolism correlated with the improvment of the Alzheimer's Disease Assessment Scale-cognitive score. We conclude that cilostazol treatment added to donepezil may delay the decline in regional cerebral metabolism in Alzheimer's disease with white matter lesions compared with donepezil monotherapy. In additon, our results verified the efficacy of cilostazol in improving or protecting cognitive function in Alzheimer's disease through increased glucose metabolism. However, the long-term effect of cilostazol on cognitive function and Alzheimer's disease modification must be tested in further studies with larger sample size and longer study period. Trial registration: http://clinicaltrials.gov : NCT01409564.

Retinal thinning associates with nigral dopaminergic loss in de novo Parkinson disease.

OBJECTIVE: To analyze the relationship between retinal thinning and nigral dopaminergic loss in de novo Parkinson disease (PD). METHODS: Forty-nine patients with PD and 54 age-matched controls were analyzed. Ophthalmologic examination and macula optical coherence tomography scans were performed with additional microperimetry, N-(3-[18F]fluoropropyl)-2-carbomethoxy-3-(4-iodophenyl) nortropane PET, and 3T MRI scans were done in patients with PD only. Retinal layer thickness and volume were measured in subfields of the 1-, 2.22-, and 3.45-mm Early Treatment of Diabetic Retinopathy Study circle and compared in patients with PD and controls. Correlation of inner retinal layer thinning with microperimetric response was examined in patients with PD, and the relationships between retinal layer thickness and dopamine transporter densities in the ipsilateral caudate, anterior and posterior putamen, and substantia nigra were analyzed. RESULTS: Retinal layer thinning was observed in the temporal and inferior 2.22-mm sectors (false discovery rate-adjusted p < 0.05) of drug-naive patients with PD, particularly the inner plexiform and ganglion cell layers. The thickness of these layers in the inferior 2.22-mm sector showed a negative correlation with the Hoehn and Yahr stage (p = 0.032 and 0.014, respectively). There was positive correlation between macular sensitivity and retinal layer thickness in all 3.45-mm sectors, the superior 2.22-mm sector, and 1-mm circle (p < 0.05 for all). There was an association between retinal thinning and dopaminergic loss in the left substantia nigra (false discovery rate-adjusted p < 0.001). CONCLUSION: Retinal thinning is present in the early stages of PD, correlates with disease severity, and may be linked to nigral dopaminergic degeneration. Retinal imaging may be useful for detection of pathologic changes occurring in early PD.