Posterior Putamen Research Articles

Dissecting Motor and Cognitive Component Processes of a Finger-Tapping Task With Hybrid Dopamine Positron Emission Tomography and Functional Magnetic Resonance Imaging.

Striatal dopamine is involved in facilitation of motor action as well as various cognitive and emotional functions. Positron emission tomography (PET) is the primary imaging method used to investigate dopamine function in humans. Previous PET studies have shown striatal dopamine release during simple finger tapping in both the putamen and the caudate. It is likely that dopamine release in the putamen is related to motor processes while dopamine release in the caudate could signal sustained cognitive component processes of the task, but the poor temporal resolution of PET has hindered firm conclusions. In this study we simultaneously collected [11C]Raclopride PET and functional Magnetic Resonance Imaging (fMRI) data while participants performed finger tapping, with fMRI being able to isolate activations related to individual tapping events. The results revealed fMRI-PET overlap in the bilateral putamen, which is consistent with a motor component process. Selective PET responses in the caudate, ventral striatum, and right posterior putamen, were also observed but did not overlap with fMRI responses to tapping events, suggesting that these reflect non-motor component processes of finger tapping. Our findings suggest an interplay between motor and non-motor-related dopamine release during simple finger tapping and illustrate the potential of hybrid PET-fMRI in revealing distinct component processes of cognitive functions.

Microglial Correlates of Late Life Physical Activity: Relationship with Synaptic and Cognitive Aging in Older Adults.

Physical activity relates to reduced dementia risk, but the cellular and molecular mechanisms are unknown. We translated animal and in vitro studies demonstrating a causal link between physical activity and microglial homeostasis into humans. Decedents from Rush Memory and Aging Project completed actigraphy monitoring (average daily activity) and cognitive evaluation in life, and neuropathological examination at autopsy. Brain tissue was analyzed for microglial activation via immunohistochemistry (anti-human HLA-DP-DQ-DR) and morphology (% Stage I, II, or III), and synaptic protein levels (SNAP-25, synaptophysin, complexin-I, VAMP, syntaxin, synaptotagmin-1). Proportion of morphologically activated microglia (PAM) was estimated in ventromedial caudate, posterior putamen, inferior temporal (IT), and middle frontal gyrus. The 167 decedents averaged 90 years at death, two-thirds were nondemented, and 60% evidenced pathologic Alzheimer's disease (AD). Adjusting for age, sex, education, and motor performances, greater physical activity associated with lower PAM in the ventromedial caudate and IT. Relationships between physical activity and PAM in the ventromedial caudate or IT were particularly prominent in adults evidencing microinfarcts or AD pathology, respectively. Mediational analyses indicated that PAM IT mediated ∼30% of the relationships between (1) physical activity and synaptic protein in IT, and (2) physical activity and global cognition, in separate models. However, the size of the mediation depended on AD pathology ranging from >40% in adults with high AD burden, but <10% in adults with low AD burden. Lower microglial activation may be a pathway linking physical activity to age-related brain health in humans. Physical activity may promote AD-related synaptic and cognitive resilience through reduction of pro-inflammatory microglial states.SIGNIFICANCE STATEMENT Physical activity relates to better cognitive aging and reduced risk of neurodegenerative disease, yet the cellular and molecular pathways linking behavior-to-brain in humans are unknown. Animal studies indicate that increasing physical activity leads to decreased microglial activation and corresponding increases in synaptogenesis and neurogenesis. We objectively monitored physical activity (accelerometer-based actigraphy) and cognitive performances in life, and quantified microglial activation and synaptic markers in brain tissue at death in older adults. These are the first data supporting microglial activation as a physiological pathway by which physical activity relates to brain heath in humans. Although more interventional work is needed, we suggest that physical activity may be a modifiable behavior leveraged to reduce pro-inflammatory microglial states in humans.

Decreased putamen activation in balancing goal-directed and habitual behavior in binge eating disorder

Acute stress is associated with a shift from goal-directed to habitual behavior. This stress-induced preference for habitual behavior has been suggested as a potential mechanism by which binge eating disorder (BED) patients succumb to eating large amounts of high-caloric foods in an uncontrolled manner (i.e., binge episodes). While in healthy subjects the balance between goal-directed and habitual behavior is subserved by the anterior cingulate cortex (ACC), insular cortex, orbitofrontal cortex (OFC), anterior caudate nucleus, and posterior putamen, the brain mechanism that underlies this (possibly amplified) stress-induced behavioral shift in BED patients is currently unknown. In the current study, 76 participants (38 BED, 38 healthy controls (HCs)) learned six stimulus-response-outcome associations in a well-established instrumental learning task. Subsequently, three outcomes were selectively devalued, after which participants underwent either a stress induction procedure (Maastricht Acute Stress Test; MAST) or a no-stress control procedure. Next, the balance between goal-directed and habitual behavior was assessed during functional magnetic resonance imaging. Findings show that the balance between goal-directed and habitual behavior was associated with activity in the ACC, insula, and OFC in no-stress HCs. Although stress and BED did not modulate the balance between goal-directed and habitual behavior, BED participants displayed a smaller difference in putamen activation between trials probing goal-directed and habitual behavior compared with HCs when using a ROI approach. We conclude that putamen activity differences between BED and HC could reflect changes in monitoring of response accuracy or reward value, albeit perhaps not sufficiently to induce a measurable shift from goal-directed to habitual behavior. Future research could clarify potential boundary conditions of stress-induced shifts in instrumental behavior in BED patients.

Aberrant default mode connectivity in adolescents with early-onset psychosis: A resting state fMRI study

Abnormal default mode network (DMN) connectivity has been found in schizophrenia and other psychotic disorders. However, there are limited studies on early onset psychosis (EOP), and their results show lack of agreement. Here, we investigated within-network DMN connectivity in EOP compared to healthy controls (HC), and its relationship to clinical characteristics.A sample of 68 adolescent patients with EOP (mean age 16.53 ± 1.12 [SD] years, females 66%) and 95 HC (mean age 16.24 ± 1.50 [SD], females 60%) from two Scandinavian cohorts underwent resting state functional magnetic resonance imaging (rsfMRI). A group independent component analysis (ICA) was performed to identify the DMN across all participants. Dual regression was used to estimate spatial maps reflecting each participant’s DMN network, which were compared between EOP and HC using voxel-wise general linear models and permutation-based analyses. Subgroup analyses were performed within the patient group, to explore associations between diagnostic subcategories and current use of psychotropic medication in relation to connectivity strength.The analysis revealed significantly reduced DMN connectivity in EOP compared to HC in the posterior cingulate cortex, precuneus, fusiform cortex, putamen, pallidum, amygdala, and insula. The subgroup analysis in the EOP group showed strongest deviations for affective psychosis, followed by other psychotic disorders and schizophrenia. There was no association between DMN connectivity strength and the current use of psychotropic medication.In conclusion, the findings demonstrate weaker DMN connectivity in adolescent patients with EOP compared to healthy peers, and differential effects across diagnostic subcategories, which may inform our understanding of underlying disease mechanisms in EOP.

Altered Functional Segregated Sensorimotor, Associative, and Limbic Cortical-Striatal Connections in Parkinson's Disease: An fMRI Investigation.

Multiple studies have identified segregated functional territories in the basal ganglia for the control of goal-directed and habitual actions. It has been suggested that in PD, preferential loss of dopamine in the posterior putamen may cause a major deficit in habitual control (mediated by the sensorimotor cortical-striatal loop), and the patients may therefore be forced into a progressive reliance on the goal-directed behavior (regulated by the associative cortical-striatal loop). Functional evidence supporting this point is scarce at present. This study aims to verify the functional connectivity changes within the sensorimotor, associative, and limbic cortical-striatal loops in PD. Resting-state fMRI of 70 PD patients and 30 controls were collected. Bilateral tripartite functional territories of basal ganglia and their associated cortical structures were chosen as regions of interest, including ventral striatum and ventromedial prefrontal cortex for limbic loop; dorsomedial striatum and dorsolateral prefrontal cortex for associative loop; dorsolateral striatum and sensorimotor cortex for sensorimotor loop. Pearson's correlation coefficients for each seed pair were calculated to obtain the functional connectivity. The relationships between functional connectivity and disease severity were further investigated. Functional connectivity between dorsolateral striatum and sensorimotor cortex is decreased in PD patients, and negatively correlated with disease duration; whereas functional connectivity between dorsomedial striatum and dorsolateral prefrontal cortex is also decreased but postitively correlated with disease duration. The functional connectivity within the sensorimotor loop is pathologically decreased in PD, while the altered connectivity within the associative loop may indicate a failed attempt to compensate for the loss of connectivity within the sensorimotor loop.

Neuropsychiatric Burden Is a Predictor of Early Freezing and Motor Progression in Drug-Naïve Parkinson's Disease.

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

Altered White-Matter Functional Networks in Patients With Conduct Disorder

Drooling is a common symptom in Parkinson’s disease (PD). This study used resting-state functional MRI (fMRI) to evaluate the brain connectivity of cortico-striatal circuits in PD patients with drooling.We enrolled 30 early-stage drug-naïve PD patients and 30 matched normal controls. Among the PD patients, 15 patients were classified as “droolers” with the presence of drooling and 15 patients as “non-droolers” with the absence of drooling. All participants underwent resting-state fMRI scans on a 3-T MR system, focusing on the functional connectivity of striatum subregions.Compared with PD patients without drooling, PD patients with drooling showed the significantly reduced functional connectivity of putamen within bilateral sensorimotor cortices, superior and inferior parietal lobules and areas in the right occipital and temporal lobes. No increased functional connectivity was found between the two PD subgroups. In addition, compared with healthy controls, both PD subgroups showed the functional connectivity alterations in cortico-striatal loops. The decreased functional connectivity was prominent in the most affected posterior putamen, and the increased functional connectivity was evident only in the relatively unaffected anterior striatum and caudate.By studying a cohort of early-stage drug-naïve PD patients, we eliminated the potential confounding effects of antiparkinson medication on the functional integration of neural networks. We demonstrated decreased connectivity within cortico-striatal networks in PD patients with drooling. These findings might be helpful for promoting the further understanding of neural system effects underlying drooling in PD. Our result is preliminary and further investigation is needed.

Effects of statins on dopamine loss and prognosis in Parkinson's disease.

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.

Contralateral Posterior Putaminal 18F-Fluorodopa Uptake in Mild Stage Parkinson's Disease: A PET/CT Study.

Previous studies revealed that 18F-FDOPA uptake was significantly decreased in the subregions of striatum contralateral to the side with predominant symptoms and was helpful for improving the early diagnostic accuracy of PD. However, in these studies, more than half of the PD patients already have bilateral motor symptoms (mH&Y stage≥2). This study was aimed to extend previous findings to a milder disease stage. Sixteen PD patients with only mild and unilateral motor symptoms (mH&Y stage=1 and disease duration≤2 years) and 22 healthy controls were involved. Striatal 18F-FDOPA uptake was analyzed using a ratio approach. The SORs in the subregions of the contralateral striatum, including caudate, anterior putamen and posterior putamen were significantly decreased in the mild stage PD patients. The SOR for the contralateral posterior putamen had the largest area under the receiver operating characteristic curve (0.963) and separated mild stage PD patients from healthy controls with a sensitivity of 93.75% and a specificity of 95.45% when the cut-off value of <2.160 was selected. These data indicate that contralateral posterior putaminal 18F-FDOPA uptake may represent a potential marker for early diagnosis of PD, especially in patients with only mild and unilateral motor symptoms.

Implication of metabolic and dopamine transporter PET in dementia with Lewy bodies

To evaluate the implication of 18F-fluorodeoxyglucose (FDG)- and dopamine transporter (DAT)-positron emission tomography (PET) in the diagnosis and clinical symptoms of dementia with Lewy bodies (DLB), 55 DLB patients and 49 controls underwent neuropsychological evaluation and FDG-, DAT-, and 18F-Florbetaben (FBB) PET. DAT- and FDG-uptake and FDG/DAT ratio were measured in the anterior and posterior striatum. The first principal component (PC1) of FDG subject residual profiles was identified for each subject. Receiver operating characteristic curve analyses for the diagnosis of DLB were performed using FDG- and DAT-PET biomarkers as predictors, and general linear models for motor severity and cognitive scores were performed adding FBB standardized uptake value ratio as a predictor. Increased metabolism in the bilateral putamen, vermis, and somato-motor cortices, which characterized PC1, was observed in the DLB group, compared to the control group. A combination of posterior putamen FDG/DAT ratio and PC1 showed the highest diagnostic accuracy (91.8% sensitivity and 96.4% specificity), which was significantly greater than that obtained by DAT uptake alone. Striatal DAT uptake and PC1 independently contributed to motor severity and language, memory, frontal/executive, and general cognitive dysfunction in DLB patients, while only PC1 contributed to attention and visuospatial dysfunction.

Parkinson\u2019s disease multimodal imaging: F-DOPA PET, neuromelanin-sensitive and quantitative iron-sensitive MRI

Parkinson’s disease (PD) is a neurodegenerative synucleinopathy characterized by the degeneration of neuromelanin (NM)-containing dopaminergic neurons and deposition of iron in the substantia nigra (SN). How regional NM loss and iron accumulation within specific areas of SN relate to nigro-striatal dysfunction needs to be clarified. We measured dopaminergic function in pre- and postcommissural putamen by [18F]DOPA PET in 23 Parkinson’s disease patients and 23 healthy control (HC) participants in whom NM content and iron load were assessed in medial and lateral SN, respectively, by NM-sensitive and quantitative R2* MRI. Data analysis consisted of voxelwise regressions testing the group effect and its interaction with NM or iron signals. In PD patients, R2* was selectively increased in left lateral SN as compared to healthy participants, suggesting a local accumulation of iron in Parkinson’s disease. By contrast, NM signal differed between PD and HC, without specific regional specificity within SN. Dopaminergic function in posterior putamen decreased as R2* increased in lateral SN, indicating that dopaminergic function impairment progresses with iron accumulation in the SN. Dopaminergic function was also positively correlated with NM signal in lateral SN, indicating that dopaminergic function impairment progresses with depigmentation in the SN. A complex relationship was detected between R2* in the lateral SN and NM signal in the medial SN. In conclusion, multimodal imaging reveals regionally specific relationships between iron accumulation and depigmentation within the SN of Parkinson’s disease and provides in vivo insights in its neuropathology.

Linking Stage-Specific Plasma Biomarkers to Gray Matter Atrophy in Parkinson Disease.

The shortcomings of synucleinopathy-based Parkinson disease staging highlight the need for systematic clinicopathologic elucidation and biomarkers. In this study, we investigated associations of proteinopathy and inflammation markers with changes in gray matter volume that accompany Parkinson disease progression. We prospectively enrolled 42 patients with idiopathic Parkinson disease, subdivided into early-/late-stage groups and 27 healthy controls. Parkinson disease severity and participants' functional and cognitive performance were evaluated. Peripheral plasma α-synuclein, β-amyloid42, and tau were quantified with immunomagnetic reduction assays, and nuclear DNA by polymerase chain reaction, and regional gray matter volumes were determined by MR imaging. Statistical tests identified stage-specific biomarkers and gray matter volume patterns in the early-stage Parkinson disease, late-stage Parkinson disease, and control groups. Correlations between gray matter volume atrophy, plasma biomarkers, Parkinson disease severity, and cognitive performance were analyzed. Patients with Parkinson disease had significantly elevated α-synuclein, tau, and β-amyloid42 levels compared with controls; nuclear DNA levels were similar in early-stage Parkinson disease and controls, but higher in late-stage Parkinson disease (all P < .01). We identified 3 stage-specific gray matter volume atrophy patterns: 1) control > early-stage Parkinson disease = late-stage Parkinson disease: right midfrontal, left lingual, and fusiform gyri, left hippocampus, and cerebellum; 2) control > early-stage Parkinson disease > late-stage Parkinson disease: precentral, postcentral, parahippocampal, left superior-temporal, right temporal, right superior-frontal, and left cingulate gyri, occipital lobe, and bilateral parts of the cerebellum; 3) control = early-stage Parkinson disease > late-stage Parkinson disease: left midfrontal, superior-frontal and temporal, amygdala, and posterior cingulate gyri, caudate nucleus, and putamen. We discovered stage-specific correlations among proteinopathy, inflammation makers, topographic gray matter volume patterns, and cognitive performance that accompanied Parkinson disease progression. Identifying associations linking peripheral plasma biomarkers, gray matter volume, and clinical status in Parkinson disease may facilitate earlier diagnosis and improve prognostic accuracy.

A subcortical network for implicit visuo-spatial attention: Implications for Parkinson's Disease

Recent studies in humans and animal models suggest a primary role of the basal ganglia in the extraction of stimulus-value regularities, then exploited to orient attentional shift and build up sensorimotor memories. The tail of the caudate and the posterior putamen both receive early visual input from the superficial layers of the superior colliculus, thus forming a closed-loop. We portend that the functional value of this circuit is to manage the selection of visual stimuli in a rapid and automatic way, once sensory–motor associations are formed and stored in the posterior striatum. In Parkinson's Disease, the nigrostriatal dopamine depletion starts and tends to be more pronounced in the posterior putamen. Thus, at least some aspect of the visuospatial attention deficits observed since the early stages of the disease could be the behavioral consequences of a cognitive system that has lost the ability to translate high-level processing in stable sensorimotor memories.

Alterations of Subcortical Brain Structures in Paradoxical and Psychophysiological Insomnia Disorder

Insomnia disorder (ID) is a common illness associated with mood and cognitive impairments. Subtyping ID is an ongoing debate in sleep medicine, but the underlying mechanisms of each subtype is poorly understood. Growing evidence suggests that subcortical brain structures play the key roles in pathophysiology of ID and its subtypes. Here, we aimed to investigate structural alteration of subcortical regions in patients with two common ID subtypes i.e., paradoxical and psychophysiological insomnia. Fifty-five patients and 49 healthy controls were recruited for this study and T1-weighted images and subjective and objective sleep parameters (i.e., Pittsburgh Sleep Quality Index and polysomnography) were collected from participants. Subcortical structures including the hippocampus, amygdala, caudate, putamen, globus pallidus, nucleus accumbens, and thalamus were automatically segmented in FSL. Volume and shape (using surface vertices) of each structure were compared between the groups, controlled for covariates, and corrected for multiple comparisons. In addition, correlations of sleep parameters and surface vertices or volumes were calculated. The caudate's volume was smaller in patients than controls. Compared with controls, we found regional shrinkage in the caudate, nucleus accumbens, posterior putamen, hippocampus, thalamus, and amygdala in paradoxical insomnia and shrinkage in the amygdala, caudate, hippocampus, and putamen in psychophysiological insomnia. Interestingly, comparing two patients groups, shape alteration in the caudate, putamen, and nucleus accumbens in paradoxical insomnia and shrinkage in the thalamus, amygdala, and hippocampus in psychophysiological insomnia were observed. Both subjective and objective sleep parameters were associated with these regional shape alterations in patients. Our results support the differential role of subcortical brain structures in pathophysiology of paradoxical and psychophysiological insomnia.

Beneficial effects of dipeptidyl peptidase-4 inhibitors in diabetic Parkinson's disease.

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

Face pareidolia is associated with right striatal dysfunction in drug-naïve patients with Parkinson's disease.

Some patients with Parkinson's disease (PD) present with pareidolia, an illusion of a meaningless stimulus as a familiar object known to the observer. Since the striatum is associated with processing of visual information, we investigated correlations of pareidolia with motor symptoms and striatal dopaminergic function. A noise pareidolia test, assessment of motor symptoms using MDS-UPDRS and 123I-Ioflupane SPECT were performed in 58 drug-naïve PD patients. A number of images in which a participant noticed an illusory face (number of illusory responses) were compared with motor assessment scores and uptake of 123I-ioflupane in the striatum. Of the 58 participants, 22 had at least one illusory response. Mean scores for MDS-UPDRS part III (p<0.05), rigidity (p<0.05), and rigidity on the left side of the body (p<0.01) in patients with pareidolia were significantly higher than those in patients without pareidolia. Uptake of 123I-ioflupane in the right caudate nucleus (p<0.05), anterior putamen (p<0.01), and posterior putamen (p<0.01) in patients with pareidolia was significantly lower than in patients without pareidolia. In the 22 patients with pareidolia, the number of illusory responses was significantly correlated with total scores for MDS-UPDRS part III (r=0.443, p<0.05) and subscores for bradykinesia (r=0.440, p<0.05) and bradykinesia on the left side of the body (r=0.564, p<0.01). The prevalence of pareidolia in left-dominant parkinsonism (16/30 patients) was higher than that in right-dominant parkinsonism (6/28 patients) (p<0.05 by chi-square test). Pareidolia in PD patients is associated with dysfunction in the right striatum.

Co-registration Analysis of Fluorodopa and Fluorodeoxyglucose Positron Emission Tomography for Differentiating Multiple System Atrophy Parkinsonism Type From Parkinson's Disease.

It is difficult to differentiate between Parkinson's disease and multiple system atrophy parkinsonian subtype (MSA-P) because of the overlap of their signs and symptoms. Enormous efforts have been made to develop positron emission tomography (PET) imaging to differentiate these diseases. This study aimed to investigate the co-registration analysis of 18F-fluorodopa and 18F-flurodeoxyglucose PET images to visualize the difference between Parkinson's disease and MSA-P. We enrolled 29 Parkinson's disease patients, 28 MSA-P patients, and 10 healthy controls, who underwent both 18F-fluorodopa and 18F-flurodeoxyglucose PET scans. Patients with Parkinson's disease and MSA-P exhibited reduced bilateral striatal 18F-fluorodopa uptake (p < 0.05, vs. healthy controls). Both regional specific uptake ratio analysis and statistical parametric mapping analysis of 18F-flurodeoxyglucose PET revealed hypometabolism in the bilateral putamen of MSA-P patients and hypermetabolism in the bilateral putamen of Parkinson's disease patients. There was a significant positive correlation between 18F-flurodeoxyglucose uptake and 18F-fluorodopa uptake in the contralateral posterior putamen of MSA-P patients (rs = 0.558, p = 0.002). Both 18F-flurodeoxyglucose and 18F-fluorodopa PET images showed that the striatum was rabbit-shaped in the healthy control group segmentation analysis. A defective rabbit-shaped striatum was observed in the 18F-fluorodopa PET image of patients with Parkinson's disease and MSA-P. In the segmentation analysis of 18F-flurodeoxyglucose PET image, an intact rabbit-shaped striatum was observed in Parkinson's disease patients, whereas a defective rabbit-shaped striatum was observed in MSA-P patients. These findings suggest that there were significant differences in the co-registration analysis of 18F-flurodeoxyglucose and 18F-fluorodopa PET images, which could be used in the individual analysis to differentiate Parkinson's disease from MSA-P.

A pilot study of oxidative pathways in MS fatigue: randomized trial of N-acetyl cysteine.

ObjectiveTo assess feasibility, tolerability, and safety of N‐acetyl cysteine (NAC) for fatigue in progressive MS. Secondary objectives evaluated changes in fatigue and oxidative pathway biomarkers on NAC versus placebo.MethodsIndividuals with progressive MS with Modified Fatigue Impact Scale (MFIS) > t38 were randomized 2:1 to NAC 1250mg TID or placebo for 4 weeks. The primary outcome was tolerability and safety. The secondary outcome to evaluate efficacy was MFIS change from baseline to week 4 between groups. Exploratory biomarker outcomes included change in blood GSH/GSSG ratio (reduced‐to‐oxidized glutathione (GSH)) and in vivo relative GSH using 7T MR spectroscopy (MRS) between groups. Fisher exact test was used for categorical and rank sum for continuous outcomes.ResultsFifiteen were randomized (10 NAC, 5 placebo; mean age 56.1 years, 80% female, median EDSS 6.0). At least one adverse event (AE) occurred in 60% on NAC versus 80% on placebo (p = 0.75). There were two AEs attributed to NAC in one patient (abdominal pain and constipation), with 94% adherence to NAC. MFIS decreased in both groups at week 4, with the mean improvement of 11‐points on NAC versus 18‐points on placebo (p = 0.33). GSH/GSSG ratio decreased on placebo (−0.6) and NAC (−0.1) (p = 0.18). Change in GSH levels to total creatine in anterior and posterior cingulate cortex, insula, caudate, putamen, and thalamus did not differ between groups.InterpretationNAC was well‐tolerated in progressive MS, although reduction in fatigue on NAC was similar to placebo. Antioxidant blood and MRS biomarkers were not significantly altered by NAC, which could be due to dose, route of administration, time of sample collection, short half‐life, or lack of effect.Registeredclinicaltrials.gov NCT02804594.

41224 REDUCED FRONTOSTRIATAL FUNCTIONAL CONNECTIVITY IN 41- TO 70-YEAR-OLD ADULTS WITH HIV

ABSTRACT IMPACT: The knowledge acquired from my research can inform the development of early diagnostic methods for HIV-associated neurocognitive disorders. OBJECTIVES/GOALS: In the era of combination antiretroviral therapy (cART), the prevalence of HIV-associated neurocognitive disorders (HAND) remains high but the neural mechanisms are unclear. We examined whether older people with HIV (PWH) with minimal cognitive impairment have reduced functional connectivity in frontostriatal circuits compared to controls. METHODS/STUDY POPULATION: 99 PWH (mean age 56.6 years, 75% male, 62% Black, mean duration of HIV-infection 26.2 years ±9.3, 90% viral load &lt;50 copies, 98% on stable cART) and 38 demographically-comparable controls (mean age 54.5 years, 71% male, 58% Black) participated in a cross-sectional study. A 7-domain neuropsychological battery and an Activities of Daily Living index were used to determine HAND diagnoses: 32 PWH met criteria for asymptomatic to mild HAND. Motor skill was assessed using the Grooved Pegboard Test by measuring performance speed. Structural MRI and resting-state functional MRI were collected. Seed-to-voxel analyses were conducted using 4 distinct regions in the striatum as seed regions. We used a voxel threshold of p&lt;0.001 and cluster threshold of p&lt;0.05 (FDR-corrected) after controlling for demographic variables. RESULTS/ANTICIPATED RESULTS: Compared to controls, PWH had lower resting state functional connectivity between the default mode region of the striatum (i.e., medial caudate) and bilateral superior frontal gyrus, supplementary motor cortex and paracingulate gyrus (p&lt;0.05; cluster size: 567 voxels). Also, compared to controls, PWH had reduced resting state functional connectivity between the motor division of the striatum (i.e., posterior putamen) and anterior cingulate cortex and left supplementary motor cortex (p&lt;0.05, cluster size: 405 voxels). Performance speed on the Grooved Pegboard motor test negatively correlated with functional connectivity between the motor region of the striatum and supplementary motor frontal regions in all participants (Spearman’s rho=-0.18, p=0.04). DISCUSSION/SIGNIFICANCE OF FINDINGS: Our results support the hypothesis that frontostriatal abnormalities are widely present in PWH and might play a key role in HAND development. Our data suggest that dysfunction within the frontostriatal circuits may be involved in motor impairment in PWH, and ongoing inflammation may contribute to motor impairment and frontostriatal injury.

Striatal and cerebellar vesicular acetylcholine transporter expression is disrupted in human DYT1 dystonia.

Early-onset torsion dystonia (TOR1A/DYT1) is a devastating hereditary motor disorder whose pathophysiology remains unclear. Studies in transgenic mice suggested abnormal cholinergic transmission in the putamen, but this has not yet been demonstrated in humans. The role of the cerebellum in the pathophysiology of the disease has also been highlighted but the involvement of the intrinsic cerebellar cholinergic system is unknown. In this study, cholinergic neurons were imaged using PET with 18F-fluoroethoxybenzovesamicol, a radioligand of the vesicular acetylcholine transporter (VAChT). Here, we found an age-related decrease in VAChT expression in the posterior putamen and caudate nucleus of DYT1 patients versus matched controls, with low expression in young but not in older patients. In the cerebellar vermis, VAChT expression was also significantly decreased in patients versus controls, but independently of age. Functional connectivity within the motor network studied in MRI and the interregional correlation of VAChT expression studied in PET were also altered in patients. These results show that the cholinergic system is disrupted in the brain of DYT1 patients and is modulated over time through plasticity or compensatory mechanisms.