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ObjectiveTo determine changes in clinical features and striatal dopamine reuptake transporter (DAT) density after shunt surgery in patients with idiopathic normal pressure hydrocephalus (iNPH).MethodsParticipants with probable iNPH were assessed at baseline by means of clinical rating scales, brain MRI, and SPECT with [123I]-N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl)nortropane (FP-CIT). Levodopa responsiveness was also evaluated. Patients who did or did not undergo lumboperitoneal shunt were clinically followed up and repeated SPECT after 2 years.ResultsWe enrolled 115 patients with iNPH. Of 102 patients without significant levodopa response and no signs of atypical parkinsonism, 92 underwent FP-CIT SPECT (58 also at follow-up) and 59 underwent surgery. We identified a disequilibrium subtype (phenotype 1) and a locomotor subtype (phenotype 2) of higher-level gait disorder. Gait impairment correlated with caudate DAT density in both phenotypes, whereas parkinsonian signs correlated with putamen and caudate DAT binding in patients with phenotype 2, who showed more severe symptoms and lower striatal DAT density. Gait and caudate DAT binding improved in both phenotypes after surgery (p < 0.01). Parkinsonism and putamen DAT density improved in shunted patients with phenotype 2 (p < 0.001). Conversely, gait, parkinsonian signs, and striatal DAT binding worsened in patients who declined surgery (p < 0.01).ConclusionsThis prospective interventional study highlights the pathophysiologic relevance of striatal dopaminergic dysfunction in the motor phenotypic expression of iNPH. Absence of levodopa responsiveness, shunt-responsive parkinsonism, and postsurgery improvement of striatal DAT density are findings that corroborate the notion of a reversible striatal dysfunction in a subset of patients with iNPH.

ObjectiveTo validate the role of the dopamine transporter (DAT) imaging as a biomarker in multiple system atrophy (MSA), we analyzed the association between spatial patterns of [18F]fluoro-propyl-carbomethoxy-iodophenyl-tropane ([18F]FP-CIT) PET and the clinical characteristics of MSA.MethodsSixty-five patients with MSA who underwent [18F]FP-CIT PET between 2009 and 2018 were retrospectively enrolled. To identify spatial patterns of [18F]FP-CIT PET, principal component (PC) analysis was used and correlated with the clinical presentation.ResultsOf the 65 patients, 42 presented with parkinsonian subtype of MSA, and 23 presented with cerebellar subtype of MSA (mean age 63.7 ± 9.3 years; disease duration, 1.8 ± 1.8 years). Each PC represents a specific pattern of degeneration: PC1 and PC2 were associated with the DAT binding of the entire putamen and the posterior putamen, respectively. PC3 was associated with increased [18F]FP-CIT uptake of the caudate and decreased uptake of the dorsal pons. PC2 was significantly correlated with the presence of parkinsonism (p = 5.34 × 10−5) and a positive levodopa response (p = 0.044), with age as a cofactor. PC3 was correlated with the presence of urinary incontinence (p = 0.036). Onset age was significantly correlated with both PC2 (R = 0.48, p = 5.0 × 10−5) and PC3 (R = −0.39, p = 0.0013).ConclusionsThe spatial pattern of DAT binding can reflect distinct clinical features of MSA and provides insight into the underlying pathophysiology of a broad spectrum of clinical features in MSA.

ObjectiveTo quantify the percent volume of dilated perivascular spaces (PVS) in the subcortical forebrain in patients with early Huntington's disease (HD) and to explore the relationship between PVS and disease severity.MethodsMRI scans were performed on 25 HD patients and 23 healthy age-matched controls at Massachusetts General Hospital. The imaging data were analyzed using a novel algorithm to determine regional PVS volume. A fractional logistic regression analysis was used to quantify the association between regional percent PVS volume and (1) disease designation (HD or Control) and (2) disease severity as assessed by normalized caudate volume.ResultsHD patients had the greatest percent volume of dilated PVS in the putamen (left putamen: odds ratio 2.06 [95% CI: 1.62–2.62], HD 3.27% [95% CI: 2.83–3.78] vs Controls 1.62% [1.32–1.97], pfdr < 0.001; right putamen odds ratio 1.66 [95% CI: 1.33–2.08], HD 3.43% [95% CI: 2.94–4.01] vs Controls 2.09% [95% CI: 1.79–2.45] pfdr < 0.001) and several subcortical white matter regions, as compared to controls. Dilated PVS increased with disease severity.ConclusionsThe objective quantification of dilated PVS suggests that PVS burden is high, associated with disease severity and may impact the distribution and success of treatments administered either intrathecally, such as antisense oligonucleotides (ASOs) or by intraparenchymal administration, such as cell and gene therapies. Classification of Evidence Review: This study provides Class II evidence that increased dilated PVS is associated with worse Huntington's disease severity. The study is rated Class II because of the cross-sectional design.

ObjectiveTo determine the clinical phenotypes associated with the β-amyloid PET and dopamine transporter imaging (123I-FP-CIT SPECT) findings in mild cognitive impairment (MCI) with the core clinical features of dementia with Lewy bodies (DLB; MCI-LB).MethodsPatients with MCI who had at least 1 core clinical feature of DLB (n = 34) were grouped into β-amyloid A+ or A− and 123I-FP-CIT SPECT D+ or D− groups based on previously established abnormality cut points for A+ with Pittsburgh compound B PET standardized uptake value ratio (PiB SUVR) ≥1.48 and D+ with putamen z score with DaTQUANT 123I-FP-CIT SPECT. Individual patients with MCI-LB fell into 1 of 4 groups: A+D+, A+D−, A−D+, or A−D−. Log-transformed PiB SUVR and putamen z score were tested for associations with patient characteristics.ResultsThe A−D+ biomarker profile was most common (38.2%), followed by A+D+ (26.5%) and A−D− (26.5%). The least common was the A+D- biomarker profile (8.8%). The A+ group was older, had a higher frequency of APOE ε4 carriers, and had a lower Mini-Mental State Examination score than the A− group. The D+ group was more likely to have probable REM sleep behavior disorder. Lower putamen DaTQUANT z scores and lower PiB SUVRs were independently associated with higher Unified Parkinson’s Disease Rating Scale-III scores.ConclusionsA majority of patients with MCI-LB are characterized by low β-amyloid deposition and reduced dopaminergic activity. β-Amyloid PET and 123I-FP-CIT SPECT are complementary in characterizing clinical phenotypes of patients with MCI-LB.

ObjectiveTo test the hypothesis that there is shared regional or global functional connectivity dysfunction in a large cohort of patients with isolated focal dystonia affecting different body regions compared to control participants. In this case-control study, we obtained resting-state MRI scans (three or four 7.3-minute runs) with eyes closed in participants with focal dystonia (cranial [17], cervical [13], laryngeal [18], or limb [10]) and age- and sex-matched controls.MethodsRigorous preprocessing for all analyses was performed to minimize effect of head motion during scan acquisition (dystonia n = 58, control n = 47 analyzed). We assessed regional functional connectivity by computing a seed-correlation map between putamen, pallidum, and sensorimotor cortex and all brain voxels. We assessed significant group differences on a cluster-wise basis. In a separate analysis, we applied 300 seed regions across the cortex, cerebellum, basal ganglia, and thalamus to comprehensively sample the whole brain. We obtained participant whole-brain correlation matrices by computing the correlation between seed average time courses for each seed pair. Weighted object-oriented data analysis assessed group-level whole-brain differences.ResultsParticipants with focal dystonia had decreased functional connectivity at the regional level, within the striatum and between lateral primary sensorimotor cortex and ventral intraparietal area, whereas whole-brain correlation matrices did not differ between focal dystonia and control groups. Rigorous quality control measures eliminated spurious large-scale functional connectivity differences between groups.ConclusionRegional functional connectivity differences, not global network level dysfunction, contributes to common pathophysiologic mechanisms in isolated focal dystonia. Rigorous quality control eliminated spurious large-scale network differences between patients with focal dystonia and control participants.

Background and ObjectivesSynaptic damage has been proposed to play a major role in the pathophysiology of Huntington disease (HD), but in vivo evidence in humans is lacking. We performed a PET imaging study to assess synaptic damage and its clinical correlates in early HD in vivo.MethodsIn this cross-sectional study, premanifest and early manifest (Shoulson-Fahn stage 1 and 2) HD mutation carriers and age- and sex-matched healthy controls underwent clinical assessment of motor and nonmotor manifestations and time-of-flight PET with 11C-UCB-J, a radioligand targeting the ubiquitous presynaptic terminal marker synaptic vesicle protein 2A (SV2A). We also performed 18F-fluorodeoxyglucose (18F-FDG)-PET in all participants because regional cerebral glucose consumption is thought to largely reflect synaptic activity. Volumes of interest were delineated on the basis of individual 3-dimensional T1 MRI. Standardized uptake value ratio-1 images were calculated for 11C-UCB-J with the centrum semiovale as reference region. 18F-FDG-PET activity was normalized to the pons. All PET data were corrected for partial volume effects. Volume of interest– and voxel-based analyses were performed. Correlations between clinical scores and 11C-UCB-J PET data were calculated.ResultsEighteen HD mutation carriers (age 51.4 ± 11.6 years; 6 female; 7 premanifest, 11 early manifest) and 15 healthy controls (age 52.3 ± 3.5 years; 4 female) were included. In the HD group, significant loss of SV2A binding was found in putamen, caudate, pallidum, cerebellum, parietal, and temporal and frontal cortex, whereas reduced 18F-FDG uptake was restricted to caudate and putamen. In the premanifest subgroup, 11C-UCB-J and 18F-FDG-PET showed significant reductions in putamen and caudate only. In the total HD group, SV2A loss in the putamen correlated with motor impairment.DiscussionOur data reveal loss of presynaptic terminal integrity in early HD, which begins in the striatum in the premanifest phase, spreads extensively to extrastriatal regions in the early manifest phase, and correlates with motor impairment. 11C-UCB-J PET is more sensitive than 18F-FDG-PET for detection of extrastriatal changes in early HD.Classification of EvidenceThis study provides Class III evidence that 11C-UCB-J PET accurately discriminates individuals HD from normal controls.

ObjectiveTo investigate the effect of polygenic load on the progression of striatal dopaminergic dysfunction in patients with Parkinson disease (PD).MethodsUsing data from 335 patients with PD in the Parkinson's Progression Markers Initiative (PPMI) database, we investigated the longitudinal association of PD-associated polygenic load with changes in striatal dopaminergic activity as measured by 123I-N-3-fluoropropyl-2-β-carboxymethoxy-3β-(4-iodophenyl) nortropane (123I-FP-CIT) SPECT over 4 years. PD-associated polygenic load was estimated by calculating weighted genetic risk scores (GRS) using 1) all available 27 PD-risk single nucleotide polymorphisms (SNPs) in the PPMI database (GRS1) and 2) 23 SNPs with minor allele frequency >0.05 (GRS2).ResultsGRS1 and GRS2 were correlated with younger age at onset in patients with PD (GRS1, Spearman ρ = −0.128, p = 0.019; GRS2, Spearman ρ = −0.109, p = 0.047). Although GRS1 did not show an association with changes in striatal 123I-FP-CIT availability, GRS2 was associated with a slower decline of striatal dopaminergic activity (interactions with disease duration in linear mixed model; caudate nucleus, estimate = 0.399, SE = 0.165, p = 0.028; putamen, estimate = 0.396, SE = 0.137, p = 0.016).ConclusionsOur results suggest that genetic factors for PD risk may have heterogeneous effects on striatal dopaminergic degeneration, and some factors may be associated with a slower decline of dopaminergic activity. Composition of PD progression–specific GRS may be useful in predicting disease progression in patients.

ObjectivesTo determine the directionality of regional interactions and influences of one region on another within the functionally abnormal sensorimotor network in isolated focal dystonia.MethodsA total of 40 patients with spasmodic dysphonia with and without dystonic tremor of voice and 35 healthy controls participated in the study. Independent component analysis (ICA) of resting-state fMRI was used to identify 4 abnormally coupled brain regions within the functional sensorimotor network in all patients compared to controls. Follow-up spectral dynamic causal modeling (DCM) estimated regional effective connectivity between patients and controls and between patients with spasmodic dysphonia with and without dystonic tremor of voice to expand the understanding of symptomatologic variability associated with this disorder.ResultsICA found abnormally reduced functional connectivity of the left inferior parietal cortex, putamen, and bilateral premotor cortex in all patients compared to controls, pointing to a largely overlapping pathophysiology of focal dystonia and dystonic tremor. DCM determined that the disruption of the sensorimotor network was both top-down, involving hyperexcitable parieto-putaminal influence, and interhemispheric, involving right-to-left hyperexcitable premotor coupling in all patients compared to controls. These regional alterations were associated with their abnormal self-inhibitory function when comparing patients with spasmodic dysphonia patients with and without dystonic tremor of voice.ConclusionsAbnormal hyperexcitability of premotor-parietal-putaminal circuitry may be explained by altered information transfer between these regions due to underlying deficient connectivity. Identification of brain regions involved in processing of sensorimotor information in preparation for movement execution suggests that complex network disruption is staged well before the dystonic behavior is produced by the primary motor cortex.

ObjectiveTo assess brain morphometry in a sample of patients with juvenile-onset Huntington disease (JOHD) and several mouse models of Huntington disease (HD) that likely represent the human JOHD phenotype.MethodsDespite sharing the mutation in the Huntingtin gene, adult-onset HD characteristically presents as a hyperkinetic motor disorder, while JOHD typically presents as a hypokinetic motor disease. The University of Iowa Kids-JHD program enrolls individuals 5 to 25 years of age who have already received the clinical diagnosis. A total of 19 children with juvenile HD (JHD) (mean CAG = 72) were studied. Patients with JHD were compared to healthy controls (n = 234) using a cross-sectional study design. Volumetric data from structural MRI was compared between groups. In addition, we used the same procedure to evaluate brain morphology of R6/2, zQ175, HdhQ250 HD mice models.ResultsParticipants with JHD had substantially reduced intracranial volumes. After controlling for the small intracranial volume size, the volumes of subcortical regions (caudate, putamen, globus pallidus, and thalamus) and of cortical white matter were significantly decreased in patients with JHD. However, the cerebellum was proportionately enlarged in the JHD sample. The cerebral cortex was largely unaffected. Likewise, HD mice had a lower volume of striatum and a higher volume of cerebellum, mirroring the human MRI results.ConclusionsThe primary pathology of JOHD extends beyond changes in the striatal volume. Brain morphology in both mice and human patients with JHD shows proportional cerebellar enlargement. This pattern of brain changes may explain the unique picture of hypokinetic motor symptoms in JHD, which is not seen in the hyperkinetic chorea-like phenotype of adult-onset HD.

The claustrum is a thin, sheet-like structure located between the insular cortex and the putamen and is characterized by its reciprocal connections with all neocortical areas.1–6 This remarkable connectivity led to the proposal that the claustrum may be a nodal structure for conscious perceptual experience.1 The cortical inputs to the claustrum have both anterior–posterior and dorsal–ventral organization, with reciprocal claustral projections back to the cortex.2 The claustrum communicates most densely with medial frontal cortical regions and receives prominent inputs from the amygdala, hippocampus, and mediodorsal nucleus of the thalamus.7 Functions attributed to the claustrum include top-down control of attention by segregating attention between modalities,2,8,9 salience processing,10 allocation of attention to reward-related contextual cues,11 executive control,12 and regulation of impulsivity.13 The claustrum primarily exerts a feedforward inhibitory control over the cortex7,14 and may also orchestrate and integrate cortical activity by boosting synchronized oscillations between cortical areas.13,15 However, the functions of the claustrum remain poorly understood. Experimental studies suggest that the claustrum may be involved in focal seizures associated with altered awareness.16 The claustrum shows reversible MRI changes in disorders associated with severe seizures in the setting of encephalitis17–20 and may potentially be involved in motor and cognitive disorders. The claustrum may thus have a potential role and constitute a therapeutic target in disorders associated with disturbances of cognition, behavior, and cortical excitability.

ObjectiveTo report a case of a patient infected with severe acute respiratory syndrome coronavirus 2 (SARS–CoV-2) who acutely developed a hypokinetic-rigid syndrome.MethodsPatient data were obtained from medical records from the Hospital Universitario 12 de Octubre in Madrid, Spain. [123I]-ioflupane dopamine transporter (DaT) SPECT images were acquired 4 hours after a single dose of 185 MBq of 123I-FP-CIT. Quantitative analysis was performed with DaTQUANT software providing the specific binding ratio and z score values of the striatum.ResultsWe report a previously healthy 58-year-old man who developed hyposmia, generalized myoclonus, fluctuating and transient changes in level of consciousness, opsoclonus, and an asymmetric hypokinetic-rigid syndrome with ocular abnormalities after a severe SARS–CoV-2 infection. DaT-SPECT confirmed a bilateral decrease in presynaptic dopamine uptake asymmetrically involving both putamina. Significant improvement in the parkinsonian symptoms was observed without any specific treatment.ConclusionThis case study provides clinical and functional neuroimaging evidence to support that SARS–CoV-2 can gain access to the CNS, affecting midbrain structures and leading to neurologic signs and symptoms.

ObjectiveTo test whether symptoms of autonomic dysfunction in Parkinson disease (PD) are associated with alterations in intrinsic hypothalamic functional connectivity, given the regulatory role of the hypothalamus (HTH) in the autonomic nervous system.MethodsResting-state fMRI scans from patients with PD were analyzed, comparing patients with the highest (n = 24) and lowest (n = 28) quartile scores in a questionnaire assessing autonomic dysfunction in PD (Scales for Outcomes in Parkinson's Disease–Autonomic [SCOPA-AUT]), obtained from a larger pool of patients (n = 93). Higher scores on the SCOPA-AUT indicate more severe symptoms. Seed-based functional connectivity maps, based on a seed region in the left and right HTH, were computed for each patient and compared by use of a general linear model, with false discovery rate correction for multiple comparisons. Partial correlation tests were additionally performed to test whether the associations between SCOPA-AUT scores and hypothalamic functional connectivity were independent of motor dysfunction, disease duration, cognitive function, and age.ResultsRelative to patients with PD with lower SCOPA-AUT scores, patients with higher scores displayed significantly reduced functional connectivity between the HTH and the striatum (caudate, putamen) and thalamus. The significant association between striato-thalamo-hypothalamic functional connectivity and SCOPA-AUT scores was retained after controlling for each patient's corresponding Movement Disorder Society Unified Parkinson's Disease Rating Scale scores, age, disease duration, and cognitive function.ConclusionsPatients with PD with symptoms of autonomic dysfunction show disrupted thalamo-striato-hypothalamic functional connectivity independently of overall motor dysfunction, disease duration, age and cognitive function. These findings suggest that symptoms of autonomic dysfunction in PD are accompanied by central deficits in the neural circuits that regulate autonomic function and their interaction with the basal ganglia.

ObjectiveTo determine whether Parkinson disease (PD) affects cross-modal function of vision and olfaction because it is known that PD impairs various cognitive functions, including olfaction.MethodsWe conducted behavioral experiments to identify the influence of PD on cross-modal function by contrasting patient performance with age-matched normal controls (NCs). We showed visual effects on the strength and preference of odor by manipulating semantic connections between picture/odorant pairs. In addition, we used brain imaging to identify the role of striatal presynaptic dopamine transporter (DaT) deficits.ResultsWe found that odor evaluation in participants with PD was unaffected by visual information, while NCs overestimated smell when sniffing odorless liquid while viewing pleasant/unpleasant visual cues. Furthermore, DaT deficit in striatum, for the posterior putamen in particular, correlated to few visual effects in participants with PD.ConclusionsThese findings suggest that PD impairs cross-modal function of vision/olfaction as a result of posterior putamen deficit. This cross-modal dysfunction may serve as the basis of a novel precursor assessment of PD.

Objective:To investigate tau distribution in patients with corticobasal syndrome (CBS) using 18F-AV-1451 PET.Methods:Six consecutively recruited patients with CBS and 20 age-matched healthy controls underwent 2 PET scans with 18F-AV-1451 (for tau) and 18F-florbetaben (for β-amyloid). We compared standardized uptake value ratio maps of the 18F-AV-1451 PET images between the patients with CBS and controls.Results:Compared to controls, patients with CBS exhibited asymmetrically increased 18F-AV-1451 binding in the putamen, globus pallidus, and thalamus contralateral to the clinically more affected side and in the ipsilateral globus pallidus and dentate nucleus. Voxel-based comparison additionally showed asymmetrically increased 18F-AV-1451 binding in the focal regions of the precentral gray and white matter and in the midbrain, predominantly in the contralateral side. 18F-AV-1451 binding in the precentral white matter correlated with motor severity.Conclusions:18F-AV-1451 asymmetrically binds to motor-related subcortical gray and white matter structures in patients with CBS. This pattern corresponds to tau pathology distribution in postmortem studies, and motor deficit in patients with CBS may be associated with tau accumulation predominantly in the subcortical white matter underlying the motor cortex, leading to disruptions in motor-related networks.

Objective:To determine the predictive value of clinical assessment and dopamine transporter (DAT) uptake for the early development of neurodegenerative synucleinopathy diseases from idiopathic REM sleep behavior disorder (iRBD) over 5 years in a Chinese population.Methods:Forty-three patients with iRBD were administered clinical assessment tests, and 35 were examined by DAT-SPECT imaging during 2011. Cox proportional hazard and Kaplan-Meier analyses were used to evaluate the predictive value of the markers in a follow-up study over 5 years.Results:Eighteen patients (41.9%) developed neurodegenerative synucleinopathy diseases after a median of 4.1 years of prospective follow-up (median interval of 10.5 years from the estimated onset of iRBD symptoms). Patients with higher scores on the Nonmotor Symptom Questionnaire (hazard ratio [HR] 3.11, 95% confidence interval [CI] 1.15–8.40, p = 0.026) and Scale for Outcomes in Parkinson Disease–Autonomic questionnaire (HR 4.46, 95% CI 1.64–12.10, p = 0.003) were more likely to develop neurodegenerative synucleinopathy diseases. Furthermore, the population with decreased 99mTc-TRODAT-1 binding in the left striatum (HR 2.7, 95% CI 1.02–7.14, p = 0.046) and putamen (HR 3.23, 95% CI 1.16–8.33, p = 0.024) had a relatively higher risk of developing neurodegenerative synucleinopathy diseases.Conclusions:Our findings elucidate the predictive value of autonomic dysfunction and DAT uptake in identifying patients with iRBD at a high risk of progressing into neurodegenerative synucleinopathy diseases and could form a basis for future disease-prevention trials.

Objective:To examine possible associations between in vivo brain dopamine transporter SPECT imaging and substantia nigra pars compacta (SNc) neuronal survival in Parkinson disease (PD).Methods:Nigral neuron numbers were calculated for 18 patients (11 patients with neuropathologically confirmed PD) who had been examined with dopamine transporter (DAT) SPECT before death. Correlation analyses between SNc tyrosine hydroxylase (TH)–positive and neuromelanin-containing neuron counts and DAT striatal specific binding ratios (SBRs) were performed with semiquantitative region of interest–based and voxel-based analyses.Results:Mean putamen SBR did not correlate with the number of substantia nigra TH-positive (r = −0.11, p = 0.66) or neuromelanin-containing (r = −0.07, p = 0.78) neurons. Correlations remained clearly nonsignificant when the time interval between SPECT and death was used as a covariate, when the voxel-based analysis was used, and when only patients with PD were included.Conclusions:This cohort study demonstrates that postmortem SNc neuron counts are not associated with striatal DAT binding in PD. These results fit with the theory that there is no correlation between the number of substantia nigra neurons and striatal dopamine after a certain level of damage has occurred. Striatal DAT binding in PD may reflect axonal dysfunction or DAT expression rather than the number of viable neurons.

ObjectiveTo investigate whether the patterns of striatal dopamine depletion on dopamine transporter (DAT) scans could provide information on the long-term prognosis in Parkinson disease (PD).MethodsWe enrolled 205 drug-naive patients with early-stage PD, who underwent 18F-FP-CIT PET scans at initial assessment and received PD medications for 3 or more years. After quantifying the DAT availability in each striatal subregion, factor analysis was conducted to simplify the identification of striatal dopamine depletion patterns and to yield 4 striatal subregion factors. We assessed the effect of these factors on the development of levodopa-induced dyskinesia (LID), wearing-off, freezing of gait (FOG), and dementia during the follow-up period (6.84 ± 1.80 years).ResultsThe 4 factors indicated which striatal subregions were relatively preserved: factor 1 (caudate), factor 2 (more-affected sensorimotor striatum), factor 3 (less-affected sensorimotor striatum), and factor 4 (anterior putamen). Cox regression analyses using the composite scores of these striatal subregion factors as covariates demonstrated that selective dopamine depletion in the sensorimotor striatum was associated with a higher risk for developing LID. Selective dopamine loss in the putamen, particularly in the anterior putamen, was associated with early development of wearing-off. Selective involvement of the anterior putamen was associated with a higher risk for dementia conversion. However, the patterns of striatal dopamine depletion did not affect the risk of FOG.ConclusionsThese findings suggested that the patterns of striatal dopaminergic denervation, which were estimated by the equation derived from the factor analysis, have a prognostic implication in patients with early-stage PD.

ObjectiveTo assess the relationship among iron accumulation, blood–brain barrier (BBB) damage, and cognitive function in patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL).MethodsWe enrolled 21 patients with NOTCH3 mutations and 21 age-matched healthy controls in this cross-sectional study. All participants underwent global physical and cognitive assessments and brain MRI using voxel-based quantitative susceptibility mapping (QSM; iron deposition measure) and dynamic contrast-enhanced MRI (BBB permeability measure). We compared behavioral and imaging data between the groups and analyzed the correlations in each group.ResultsAmong 21 NOTCH3 mutation carriers, 10 were symptomatic and 11 asymptomatic. Montreal Cognitive Assessment scores were significantly different among the groups (symptomatic < asymptomatic < control participants). Voxel-based QSM analysis revealed that the symptomatic group had higher QSM values than did the asymptomatic group in the putamen, caudate nucleus, temporal pole, and centrum semiovale. These QSM values were positively correlated with regional BBB permeabilities (putamen: r = 0.57, p = 0.006; caudate nucleus: r = 0.51, p = 0.019; temporal pole: r = 0.48, p = 0.030; centrum semiovale: r = 0.45, p = 0.044) and negatively correlated with Montreal Cognitive Assessment scores (caudate nucleus: r = −0.53, p = 0.012; temporal pole: r = −0.56, p = 0.008).ConclusionsThis study showed that cerebral iron burden was associated with regional BBB permeability and cognitive dysfunction in patients with CADASIL, highlighting the potential of these imaging techniques as auxiliary biomarkers to monitor the course of small vessel disease.

ObjectiveTo investigate the relationship between β-amyloid (Aβ) deposition and striatal dopamine depletion, cognitive functions, and neuropsychiatric symptoms in dementia with Lewy bodies (DLB).MethodsWe consecutively recruited 51 patients with DLB who had undergone a neuropsychological test, Neuropsychiatric Inventory assessment, brain MRI,N-(3-[18F]fluoropropyl)-2β-carbon ethoxy-3β-(4-iodophenyl) PET, and18F-florbetaben PET within 6 months. The patients were divided into Aβ-negative (DLB-Aβ−, n = 20) and Aβ-positive (DLB-Aβ+, n = 31) groups according to the brain amyloid plaque load score. We performed comparative analyses of dopamine transporter (DAT) activity, neuropsychological profile, and neuropsychiatric symptoms between the 2 groups.ResultsCompared to the DLB-Aβ− group, the DLB-Aβ+ group had a younger age at diagnosis (p= 0.017), poorer performance in attention (p= 0.028) and visuospatial (p= 0.006) functions, and higher proportion of anxiety (p= 0.006) and total neuropsychiatric burden (p= 0.013). Those in the DLB-Aβ+ group also had lower DAT activity in the anterior putamen (p= 0.015) and ventral striatum (p= 0.006) regardless of age, sex, and years of education. In addition, lower DAT activity in the ventral striatum was significantly associated with anxiety and total neuropsychiatric burden in DLB.ConclusionsThis study demonstrated that Aβ deposition in DLB is associated with diagnosis at a younger age, higher cognitive and neuropsychiatric burden, and decreased DAT activity, suggesting that evaluation of clinical features and DAT activity can predict the presence of Aβ in DLB.

We thank Drs. Yuan and Hu for their comments on our article.1 We agree that CSF testing for prions, particularly the real-time quaking-induced conversion assay (RT-QuiC), which is superseding 14-3-3 as the test of choice in many centers, can be helpful in confirming the diagnosis of sporadic Creutzfeldt-Jakob disease (CJD) in suspected cases.2 We did not pursue such testing in our patient. She already met the proposed updated diagnostic criteria for probable CJD based on having rapidly progressive dementia (criterion A); myoclonus, cerebellar signs, extrapyramidal signs (3 of the B criteria, only 2 required); EEG periodic sharp discharges and MRI diffusion-weighted imaging abnormalities in caudate and putamen (2 of the C criteria, only 1 required); and no indication of an alternative diagnosis on routine investigations (criterion D; however, some may consider CSF to be an important routine investigation, though it carries safety risks in suspected prion disease). Nevertheless, to establish the diagnosis of definite CJD, as Drs. Yuan and Hu indicated, prion disease would need to be identified by standard neuropathologic or immunocytochemical techniques, or positive RT-QuiC of CSF or nasal brushings.

Objective: To explore longitudinal changes in brain activity in patients with Parkinson disease (PD), multiple system atrophy (MSA), and progressive supranuclear palsy (PSP) using task-based functional MRI (fMRI). Methods: A total of 112 individuals were scanned 1 year apart while performing a unimanual grip force task: 46 PD, 13 MSA, 19 PSP, and 34 healthy controls. The outcome measure was percent signal change in prespecified regions of interest: putamen, primary motor cortex (M1), supplementary motor area (SMA), and superior motor regions of the cerebellum (lobules V–VI). Results: Patients with PD showed a decline in functional activity over the course of 1 year in the putamen and M1 compared to controls. Changes after 1 year in MSA were exclusively extrastriatal, and included a reduction in functional activity in M1, SMA, and superior cerebellum. In PSP, all regions of interest were less active at 1 year compared to baseline. The functional activity of these regions did not change in the control group. Conclusions: We provide evidence using task-based fMRI for cortical and striatal functional deterioration in PD over a 1-year period of time. Results also describe more widespread and unique patterns of functional changes in MSA and PSP compared to PD, suggesting distinct rates of disease progression in parkinsonian disorders that may assist in future clinical studies testing the potential efficacy of disease-modifying therapies.

Objective:To determine whether neuroanatomically heterogeneous strokes causing hemichorea-hemiballismus localize to a common functional network.Methods:We identified 29 cases of lesion-induced hemichorea-hemiballismus from the literature and mapped each lesion volume onto a reference brain. Using a recently validated technique termed lesion network mapping, we tested whether these lesions belonged to the same functional network. To accomplish this, the network of brain regions functionally connected to each lesion was identified using a connectome dataset from healthy participants. Network maps were overlapped to identify any region functionally connected to our set of lesions. Specificity was evaluated using a case-control design; control cohorts included a group of similar lesions randomized to different brain locations and a second group of lesions causing a separate movement disorder, asterixis. Reproducibility was evaluated using an independent cohort of 10 additional hemichorea-hemiballismus cases.Results:Lesions showed heterogeneity in anatomical location, consistent with prior reports. However, at least 90% of these lesions showed network overlap in the posterolateral putamen. This result was specific to lesions causing hemichorea-hemiballismus and reproducible in an independent cohort. The putaminal overlap site was itself connected to a broader motor network that predicted the distribution of lesions causing hemichorea-hemiballismus.Conclusions:Strokes causing hemichorea-hemiballismus, while anatomically heterogeneous, localize to a common functional network. Specifically, lesions occur in regions functionally connected to the posterolateral putamen, a region previously implicated in hyperkinetic movement disorders. Lesion network mapping may be useful in identifying the neuroanatomical substrates of heterogeneous lesion-based disorders.

The striatum is the input component of the basal ganglia circuits. It provides a hub for the interaction among multiple afferents and local intrastriatal networks that regulate basal ganglia function. Via their distinct cortical connections, different components of the striatum are key elements for control of different aspects of behavior: the nucleus accumbens is primarily involved in reward-based action learning, the caudate nucleus in goal-based action selection, and the putamen in habit formation and action sequencing.

To investigate whether a serotonin-to-dopamine terminal ratio is related to the appearance of dyskinesias in patients with Parkinson disease (PD).Twenty-eight patients with idiopathic PD (17 with levodopa-induced dyskinesias [LIDs], 11 without dyskinesias) and 12 age-matched healthy controls were studied with PET and 5[(11)C]-3-amino-4-(2-dimethylaminomethylphenyl-sulfanyl)-benzonitrile ((11)C-DASB) and with SPECT and [(123)I]N-w-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl)nortropane ((123)I-ioflupane), which are in vivo specific markers of the serotonin and dopamine transporters' availability, respectively. We have employed a simplified reference tissue model for the quantification of (11)C-DASB, whereas a semiquantification approach was used for (123)I-ioflupane data. We calculated (11)C-DASB binding to (123)I-ioflupane uptake ratios for the caudate and the putamen.Patients with PD showed striatal decreases in (11)C-DASB binding potential (p0.01) and in (123)I-ioflupane mean uptake (p0.001) compared to controls. The mean (11)C-DASB binding to (123)I-ioflupane uptake ratio in the putamen was 0.779 (increased by 75.8% of the controls' mean) for the nondyskinetic group and 0.901 (increased by 103.4% of the controls' mean) for the patients with dyskinesias. There was a statistically significant difference (p0.001) in (11)C-DASB binding to (123)I-ioflupane uptake ratio in the putamen between the group of patients with and without dyskinesias. Higher (11)C-DASB to (123)I-ioflupane binding ratios correlated with longer disease duration for the 28 patients with PD (r = 0.52; p0.01).Serotonin-to-dopamine transporter binding ratio increases as PD progresses and patients experience LIDs. Our findings suggest that, when the dopaminergic innervation in the striatum is critically low, the serotonergic system plays an important role in development of LIDs.

Objective: To investigate the predictive value of striatal dopamine turnover in patients with de novo Parkinson disease (PD) for the onset of later motor complications. Methods: This retrospective, observer-blinded cohort study followed up 31 patients with early PD who completed quantitative 18 F-dopa PET imaging to measure striatal 18 F-dopa uptake (K occ ) and effective distribution volume ratio (EDVR) as the inverse of dopamine turnover prior to antiparkinsonian treatment. The onset of wearing-off and dyskinesias was determined based on blinded clinical assessments and patient records. The predictive value of baseline PET measures for motor complications was evaluated using Cox proportional hazard models. Results: During a mean follow-up time of 6.8 years, 18 (58.1%) patients developed wearing-off, 11 (35.5%) dyskinesia, and 20 (64.5%) any motor complication. Patients with dyskinesia and any motor complication showed lower baseline EDVR (higher dopamine turnover) in the putamen than those without dyskinesias and any motor complication, with differences most markedly present in the posterior putamen. Baseline EDVR in the whole and the posterior putamen predicted development of motor complications with an increasing risk with lower EDVR (higher dopamine turnover), whereas EDVR in other regions and K occ did not correlate with motor complications. Correspondingly, Kaplan-Meier curves showed reduced survival from motor complications in patients with lower baseline EDVR (higher dopamine turnover) in the posterior putamen with ongoing levodopa treatment and disease duration. Conclusions: Elevated putaminal dopamine turnover in de novo PD is associated with an increased risk for later motor complications and comprises a disease-intrinsic predisposing factor for their development.

ObjectiveTo examine the association of body mass index (BMI) and waist-to-hip ratio (WHR) with brain volume.MethodsWe used cross-sectional data from the UK Biobank study (n = 9,652, age 55.4 ± 7.5 years, 47.9% men). Measures included BMI, WHR, and total fat mass as ascertained from bioimpedance. Brain images were produced with structural MRI.ResultsAfter adjustment for a range of covariates, higher levels of all obesity measures were related to lower gray matter volume: BMI per 1 SD (β coefficient −4,113, 95% confidence interval [CI] −4,862 to −3,364), WHR (β coefficient −4,272, 95% CI −5,280 to −3,264), and fat mass (β coefficient −4,590, 95% CI −5,386 to −3,793). The combination of overall obesity (BMI ≥30 kg/m2) and central obesity (WHR >0.85 for women, >0.90 for men) was associated with the lowest gray matter compared with that in lean adults. In hypothesis-free testing with a Bonferroni correction, obesity was also related to various regional brain volumes, including caudate, putamen, pallidum, and nucleus accumbens. No associations between obesity and white matter were apparent.ConclusionThe combination of heightened BMI and WHR may be an important risk factor for gray matter atrophy.

We investigated longitudinal changes in iron concentration in the subcortical gray matter (caudate nucleus, globus pallidus, putamen, thalamus) of patients with clinically isolated syndrome (CIS) and definite multiple sclerosis (MS) and their relation to clinical and other morphologic variables.We followed 144 patients (76 CIS; median Expanded Disability Status Scale [EDSS] 1.0 [interquartile range (IQR) 0.0-2.0]; 68 MS; median EDSS 2.0 [IQR 1.0-3.3]) clinically and with 3T MRI over a median period of 2.9 (IQR 1.3-4.0) years. Iron concentration was determined by R2* relaxometry at baseline and last follow-up.At baseline, subcortical gray matter iron deposition was higher in MS compared to CIS. In CIS, R2* rates increased in the globus pallidus (p0.001), putamen (p0.001), and caudate nucleus (p0.001), whereas R2* rates in the thalamus decreased (p0.05). In MS, R2* rates increased in the putamen (p0.05), remained stable in the globus pallidus and caudate nucleus, and decreased in the thalamus (p0.01). Changes in R2* relaxation rates were unrelated to changes in the volume of respective structures, of T2 lesion load, and of disability.Iron accumulation in the basal ganglia is more pronounced in the early than later phases of the disease and occurs independent from other morphologic brain changes. Short-term changes in iron concentration are not associated with disease activity or changes in disability.

Objectives: To compare the striatum9s resting-state functional connectivity in patients with Parkinson disease (PD) with and without impulse control disorders (ICDs). Methods: Twenty patients with PD and ICDs, 19 patients with PD but no ICDs, and 19 healthy controls underwent fMRI in the resting state. The ventral striatum, dorsal caudate, and anterior and posterior putamen were segmented semiautomatically. For each region of interest, a seed-based connectivity analysis was performed on preprocessed fMRI data mapped on the ipsilateral cortical surface. An additional cortical thickness analysis was used to assess and compare gray matter atrophy in the 3 study subgroups. Results: The presence of an ICD in patients with PD was associated with functional disconnection between the left anterior putamen and both the left inferior temporal gyrus and the left anterior cingulate gyrus, as well as a trend toward a functional disconnection between several motor and associative striatal regions and limbic, associative, and motor cortical regions. Patients without ICDs did not differ from healthy controls in corticostriatal connectivity. The cortical thickness analysis did not reveal any significant differences among the 3 study subgroups. Conclusions: In PD, ICDs are associated with altered connectivity between an associative striatal area (the left anterior putamen) and associative and limbic cortical regions (the left inferior temporal gyrus and the left anterior cingulate gyrus).

To investigate dopamine transmission in patients with comorbid REM sleep behavior disorder (RBD) and major depressive disorder (MDD).This is a case-control study including 11 medicated patients with comorbid RBD and MDD (mean age 47.5 ± 8.2), 8 medicated patients with MDD only (mean age 47.9 ± 8.4), and 10 healthy participants (mean age 46.5 ± 10.6 years). They underwent clinical assessment, video-polysomnography, olfactory tests, and neuroimaging studies ((18)F-DOPA, (11)C-raclopride, and (18)F-FDG PET neuroimaging).Compared with the 2 control groups, patients with comorbid RBD and MDD had significantly lower (18)F-DOPA uptake at 60 minutes in the putamen and caudate after controlling for age and sex effect (p0.05). There were no significant differences for the (11)C-raclopride and (18)F-FDG-PET. The (18)F-DOPA uptake in putamens had significant inverse correlation with severity of RBD symptoms (p0.01) and REM-related tonic muscle activity (p0.01). The comorbid RBD and MDD group had more impairment in olfactory function.Patients with comorbid RBD and MDD had presynaptic dopamine dysfunction and impaired olfactory function. There is a distinct possibility that the development of RBD symptoms among patients with MDD may represent an early phase of α-synucleinopathy neurodegeneration instead of a merely antidepressant-induced condition.

ObjectiveTo analyze the relationship between retinal thinning and nigral dopaminergic loss in de novo Parkinson disease (PD).MethodsForty-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.ResultsRetinal 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).ConclusionRetinal 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.

Autosomal dominant striatal degeneration (ADSD) (MIM 609161) is a rare genetic disease caused by mutation in the PDE8B gene.1,2 The disease, with onset in the fourth to fifth decade, is characterized by slowly progressive dysarthria, mild parkinsonism but no tremor, brisk deep tendon reflexes, poor response to levodopa treatment, and distinctive brain MRI findings.1,2 Heterozygous mutations in the PDE8B gene, first identified in a German family,2 result in loss of protein cyclic nucleotide phosphodiesterase (PDE) function. PDEs are responsible for the breakdown of cyclic nucleotides, cyclic adenosine monophosphate, and cyclic guanosine monophosphate, and play a major role in striatal neuron regulation.3 The PDE superfamily consists of 11 families (PDE1–PDE11), each of which has 1 to 4 subtypes. Some neuropsychiatric and neurodegenerative diseases, including depression, schizophrenia, Parkinson disease, Alzheimer disease, and Huntington disease, have changes in phosphodiesterase expression in the brain.3 PDE8B expression is higher in specific brain regions affected by ADSD (putamen, caudate nucleus, and nucleus accumbens), producing peculiar lesions in the striatum.2,3

Objective: In an effort to account for deficiencies in axonal transport that limit the effectiveness of neurotrophic factors, this study tested the safety and feasibility, in moderately advanced Parkinson disease (PD), of bilaterally administering the gene therapy vector AAV2-neurturin (CERE-120) to the putamen plus substantia nigra (SN, a relatively small structure deep within the midbrain, in proximity to critical neuronal and vascular structures). Methods: After planning and minimizing risks of stereotactically targeting the SN, an open-label, dose-escalation safety trial was initiated in 6 subjects with PD who received bilateral stereotactic injections of CERE-120 into the SN and putamen. Results: Two-year safety data for all subjects suggest the procedures were well-tolerated, with no serious adverse events. All adverse events and complications were expected for patients with PD undergoing stereotactic brain surgery. Conclusions: Bilateral stereotactic administration of CERE-120 to the SN plus putamen in PD is feasible and this evaluation provides initial empirical support that it is safe and well-tolerated. Classification of evidence: This study provides Class IV evidence that bilateral neurturin gene delivery (CERE-120) to the SN plus putamen in patients with moderately advanced PD is feasible and safe.

Objective: To investigate the clinical, genetic, and neuroradiologic data of biotin-responsive basal ganglia disease (BBGD) and clarify the disease spectrum. Methods: We first investigated all patients attending our Division of Pediatric Neurology with a genetically proven diagnosis of BBGD between 2009 and 2011. All patients underwent a detailed medical history and clinical examination, extensive laboratory investigations including genetic tests, and brain MRI. Finally, we conducted a systematic review of the literature. Results: We enrolled 10 patients meeting the diagnostic criteria for BBGD, and analyzed the data on 14 patients from 4 previous reports. The BBGD occurred predominantly in preschool/school-aged patients in the Saudi population, but it was also observed in other ethnic groups. The typical clinical picture consisted of recurrent subacute encephalopathy leading to coma, seizures, and extrapyramidal manifestations. The brain MRI typically showed symmetric and bilateral lesions in the caudate nucleus and putamen, infra- and supratentorial brain cortex, and in the brainstem. Vasogenic edema characterized the acute crises as demonstrated by diffusion-weighted imaging/apparent diffusion coefficient MRI. Atrophy and gliosis in the affected regions were observed in patients with chronic disease. Early treatment with a combination of biotin and thiamine resulted in clinical and neuroradiologic improvement. Death and neurologic sequelae including dystonia, mental retardation, and epilepsy were observed in those who were not treated or were treated late. Conclusion: BBGD is an underdiagnosed pan-ethnic treatable condition. Clinicians caring for patients with unexplained encephalopathy and neuroimaging showing vasogenic edema in the bilateral putamen and caudate nuclei, infra- and supratentorial cortex, and brainstem should consider this disorder early in the hospital course because a therapeutic trial with biotin and thiamine can be lifesaving.

Objectives: Gray matter (GM) atrophy is common in multiple sclerosis (MS), as is cognitive dysfunction. Understanding the exact relationship between atrophy and cognition requires further investigation. The aim of this study was to investigate the relationship between subcortical GM atrophy and cognition in early relapsing onset MS. Methods: Structural MRI and neuropsychological evaluations were performed in 120 patients (80 women) and 50 controls (30 women), part of an early inception cohort, 6 years postdiagnosis. Deep GM volumes were segmented automatically. Cognition was assessed in 7 domains. Stepwise linear regression was used to predict average cognition in the patient group. Results: Most deep GM volumes were reduced in patients, with larger effects on average in men (−11%) than in women (−6.3%). Only the bilateral hippocampus, amygdala, and right nucleus accumbens in men, and right hippocampus and nucleus accumbens, bilateral amygdala, and putamen in women, showed no atrophy compared to controls. All cognitive domains except visuospatial memory were affected in men; none were significantly affected in women. In the MS group, average cognition was best predicted by thalamic volume, sex, and education (adjusted R 2 = 0.31), while lesion volume was not a significant predictor in the model. Conclusions: Six years postdiagnosis, almost all subcortical structures were affected by MS, especially in men. Cognition was most severely affected in male patients. Thalamic volume, sex, and education best predicted average cognition. These results underline the relevance of specific subcortical structures to cognition, as well as the relevance of (sex-specific) atrophy in MS.

Whole brain and regional volume measurement methods were used to quantify white matter, gray matter, and deep gray matter structure volumes in a population of patients with pediatric-onset multiple sclerosis (MS).Subjects included 38 patients (mean age 15.2 ± 2.4 years) and 33 age- and sex-matched healthy control (HC) participants. MRI measures included intracranial volume, normalized brain volume, normalized white and gray matter volume, and volumes of the thalamus, globus pallidus, putamen, and caudate. Because these volumes vary across age and sex in children, we normalized the volume measurements for MS and control groups by computing z scores using normative values obtained from healthy children enrolled in the MRI Study of Normal Brain Development.The intracranial volume z score was significantly lower in the patients with MS (-0.45 ± 1.16; mean ± SD) compared with the HC participants (+0.25 ± 0.98; p = 0.01). Patients with MS also demonstrated significant decreases in normalized brain volume z scores (-1.09 ± 1.49 vs -0.05 ± 1.22; p = 0.002). After correction for global brain volume, thalamic volumes in the MS population remained lower than those of HCs (-0.68 ± 1.72 vs 0.15 ± 1.35; p = 0.02), indicating an even greater loss of thalamic tissue relative to more global brain measures. Moderate correlations were found between T2-weighted lesion load and normalized thalamic volumes (r = -0.44, p0.01) and normalized brain volume (r = -0.47, p0.01) and between disease duration and normalized thalamic volume (r = -0.58, p0.001) and normalized brain volume (r = -0.46, p0.01).When compared with age- and sex-matched control subjects, the onset of MS during childhood is associated with a smaller overall head size, brain volume, and an even smaller thalamic volume.

Objective: To elucidate possible mechanisms leading to neurodegeneration in patients with glucocerebrosidase ( GBA )–associated Parkinson disease (PD) using combined proton ( 1 H) and phosphorus ( 31 P) magnetic resonance spectroscopic imaging (MRSI) in vivo. Methods: 1 H and 1 H-decoupled 31 P MRSI was performed in 13 patients with PD with heterozygous GBA mutations (GBA-PD) and 19 age- and sex-matched healthy controls to investigate metabolite concentrations in the mesostriatal target regions of PD pathology. NAA as marker of neuronal integrity, choline and ethanolamine containing compounds as markers of membrane phospholipid metabolism, and energy metabolites (notably high-energy phosphates) were quantified. Results: Compared to controls, NAA was significantly reduced in the putamen ( p = 0.012) and in the midbrain of GBA-PD ( p = 0.05). The choline concentration obtained from 1 H MRSI was significantly decreased in the midbrain of GBA-PD ( p = 0.010). The phospholipid degradation product glycerophosphoethalonamine was increased in the putamen of GBA-PD ( p = 0.05). Changes of energy metabolism were not detected in any region of interest. Conclusion: The pattern of neurodegeneration in GBA -associated PD is more pronounced in the putamen than in the midbrain. Our MRSI findings suggest that the neurodegenerative process in GBA-PD is associated with alterations of membrane phospholipid metabolism which might be also involved in abnormal α-synuclein aggregation.

Background: Welding exposes workers to manganese (Mn) fumes, but it is unclear if this exposure damages dopaminergic neurons in the basal ganglia and predisposes individuals to develop parkinsonism. PET imaging with 6-[ 18 F]fluoro-l-dopa (FDOPA) is a noninvasive measure of nigrostriatal dopaminergic neuron integrity. The purpose of this study is to determine whether welding exposure is associated with damage to nigrostriatal neurons in asymptomatic workers. Methods: We imaged 20 asymptomatic welders exposed to Mn fumes, 20 subjects with idiopathic Parkinson disease (IPD), and 20 normal controls using FDOPA PET. All subjects were examined by a movement disorders specialist. Basal ganglia volumes of interest were identified for each subject. The specific uptake of FDOPA, K i , was generated for each region using graphical analysis method. Results: Repeated measures general linear model (GLM) analysis demonstrated a strong interaction between diagnostic group and region ( F 4,112 = 15.36, p i s were lower in asymptomatic welders (0.0098 + 0.0013 minutes −1 ) compared to control subjects (0.0111 + 0.0012 minutes −1 , p = 0.002). The regional pattern of uptake in welders was most affected in the caudate > anterior putamen > posterior putamen. This uptake pattern was anatomically reversed from the pattern found in subjects with IPD. Conclusions: Active, asymptomatic welders with Mn exposure demonstrate reduced FDOPA PET uptake indicating dysfunction in the nigrostriatal dopamine system. The caudate K i reduction in welders may represent an early (asymptomatic) marker of Mn neurotoxicity and appears to be distinct from the pattern of dysfunction found in symptomatic IPD.

Objective: Dyskinesias are common in Parkinson disease (PD). Prior investigations suggest that dopamine (DA) terminals compensate for abnormal DA transmission. We verified whether similar adaptations could be related to the development of treatment-related complications. Methods: Thirty-six patients with PD with motor fluctuations were assessed with PET using [ 11 C]- d-threo -methylphenidate (MP) and [ 11 C]-(±) dihydrotetrabenazine (DTBZ). The expression of DA transporter relative to DA nerve terminal density was estimated by determining the MP/DTBZ ratio. Age, treatment, and disease severity were also taken into account in the evaluation of our data. Results: Twenty-seven of the 36 patients had dyskinesias. Nine individuals had motor fluctuations without dyskinesia. The two patient groups were comparable in terms of age, disease duration and severity, medication, and striatal MP and DTBZ binding potentials. The MP/DTBZ ratio in the caudate was not different between groups (nondyskinesia 1.54 ± 0.36, dyskinesia 1.39 ± 0.28; mean ± SD, p = 0.23). Putaminal MP/DTBZ was decreased in individuals with dyskinesia (1.18 ± 0.24), compared to those who had motor fluctuations without dyskinesia (1.52 ± 0.24, p = 0.019). The relationship between putaminal MP/DTBZ ratio and the presence of dyskinesias was not altered after correcting for age, treatment, and measures of disease severity. Conclusions: This investigation supports the role of presynaptic alterations in the appearance of dyskinesias. Dopamine (DA) transporter downregulation may minimize symptoms by contributing to increased synaptic DA levels in early Parkinson disease, but at the expense of leading to increased extracellular DA catabolism and oscillating levels of DA. Such oscillations might ultimately facilitate the appearance of dyskinesias. BP = binding potential; COMTi = catechol-O-methyl transferase inhibitors; CR = controlled release; DA = dopamine; DAT = DA transporter; DTBZ = [ 11 C]-(±) dihydrotetrabenazine; DVR = distribution volume; MF = motor fluctuation; MP = [ 11 C]- d-threo -methylphenidate; PD = Parkinson disease; ROI = region of interest; UPDRS = Unified Parkinson’s Disease Rating Scale.

Background: Behavioral and cognitive problems are frequently encountered in juvenile myoclonic epilepsy (JME). The underlying mechanisms are unknown. Based on previous data showing that the dopamine system is involved in motor as well as cognitive functions, we tested whether JME may be associated with changes in this system, and if such changes are linked to interictal dysfunctions in these patients. Method: PET and [ 11 C]PE2I was used to investigate the regional binding potential to the dopamine transporter (DAT) in 12 patients with JME and 12 healthy controls. Binding potential was calculated in the midbrain, substantia nigra, caudate, and putamen. We also tested possible correlations between the respective measures and performance in several neuropsychological tests. Results: Patients had a reduced binding potential in the substantia nigra and midbrain ( p = 0.009 and 0.007), and normal values in the caudate and putamen. They also exhibited impaired psychomotor speed and motor function, which in some tests correlated with DAT binding potential in the midbrain. Conclusion: Dopamine signaling seems impaired in the target regions for dopaminergic neurons (the striatum and frontal lobe), and related to several interictal dysfunctions in JME. The findings add a new aspect to the pathophysiology of JME.

Background: In a primate model of Parkinson disease (PD), intrastriatal infusion of an adeno-associated viral (AAV) vector containing the human aromatic l-amino acid decarboxylase ( hAADC ) gene results in robust gene expression. After gene transfer, low doses of systemically administered l-dopa are converted to dopamine in the transduced striatal neurons, resulting in behavioral improvement without the side effects typically associated with higher doses of l-dopa. These studies led to the initiation of a phase I safety trial. Here we report the findings for the first cohort of five patients. Methods: Patients with moderate to advanced PD received bilateral infusion of a low dose of the AAV-hAADC vector into the putamen. PET scans using the AADC tracer, 6-[18F]fluoro-l-m-tyrosine (FMT), were performed at baseline and at 1 and 6 months after infusion as an in vivo measure of gene expression. Results: PET results showed an average 30% increase in FMT uptake (K i c ) in the putamen after gene transfer. Preliminary analysis of clinical data indicates a modest improvement, but absence of a control and the nonblinded analyses make interpretation difficult. Conclusions: Thus far, this gene therapy approach has been well tolerated and shows PET evidence of sustained gene expression. These initial findings demonstrate the safety of the therapy; higher doses of adeno-associated viral vector containing the human aromatic l-amino acid decarboxylase gene in the next cohort of patients may further increase dopamine production in the putamen and provide more profound clinical benefit. GLOSSARY: AADC = aromatic l-amino acid decarboxylase; AAV = adeno-associated viral; DA = dopamine; FMT =6-[18F]fluoro-l-m-tyrosine; hAADC = human aromatic l-amino acid decarboxylase; l-dopa = levodopa; PD = Parkinson disease; ROI = region of interest; UPDRS = Unified Parkinson’s Disease Rating Scale.

Background: Patients with Parkinson disease (PD) may be akinetic/rigid, be tremor dominant, or have comparable severity of these motor symptoms (classic). The pathophysiologic basis of different PD phenotypes is unknown. This study assessed pallidal and striatal dopamine level patterns in different motor subgroups of PD and normal control brains. Methods: Globus pallidus and striatum dopamine (DA) levels were measured with high performance liquid chromatography in eight autopsy confirmed PD and five control frozen brains. Results: DA levels in the external globus pallidus (GPe) of normal brains were nearly six times greater than in the internal pallidum (GPi). In PD, the mean loss of DA was marked (−82%) in GPe and moderate (−51%) in GPi. DA loss of variable degree was seen in different subdivisions of GPe and GPi in PD; however, DA levels were near normal in the ventral (rostral and caudal) GPi of PD cases with prominent tremor. There was marked loss of DA (−89%) in the caudate and severe loss (−98.4%) in the putamen in PD. The pattern of pallidal DA loss did not match the putaminal DA loss. Conclusion: There is sufficient loss of dopamine (DA) in external globus pallidus and the internal globus pallidum (GPi) as may contribute to the motor manifestations of Parkinson disease (PD). The possible functional disequilibrium between GABAergic and DAergic influences in favor of DA in the caudoventral parts of the GPi may contribute to resting tremor in tremor dominant and classic PD cases. GLOSSARY: CN = caudate nucleus; DA = dopamine; GPe = external globus pallidus; GPi = internal globus pallidum; LB = Lewy body; MDCS = Movement Disorder Clinic in Saskatoon; PD = Parkinson disease; PUT = putamen; VTA = ventral tegmental area.

BACKGROUND: Patients with Parkinson disease (PD) often have cardiac sympathetic denervation and failure of neurocirculatory regulation by baroreflexes. Familial PD caused by mutation of the gene encoding alpha-synuclein or by alpha-synuclein gene triplication also features cardiac sympathetic denervation and baroreflex failure. METHODS: Here we report results of cardiac sympathetic neuroimaging by 6-[(18)F]fluorodopamine PET, baroreflex testing based on beat-to-beat hemodynamic responses to the Valsalva maneuver, and nigrostriatal neuroimaging using 6-[(18)F] fluorodopa PET in a proband with mutation of the gene encoding leucine-rich repeat kinase 2 (LRRK2), the most common genetic abnormality identified so far in familial PD. RESULTS: The patient had no detectable 6-[(18)F] fluorodopamine-derived radioactivity in the left ventricular myocardium, a progressive fall in blood pressure during the Valsalva maneuver and no pressure overshoot after release of the maneuver, and decreased 6-[(18)F] fluorodopa-derived radioactivity bilaterally in the putamen and substantia nigra. CONCLUSION: This patient with Parkinson disease (PD) caused by LRRK2 mutation had evidence of cardiac sympathetic denervation, baroreflex-sympathoneural and baroreflex-cardiovagal failure, and nigrostriatal dopamine deficiency, a pattern resembling that in the sporadic disease. The results fit with the concept that in LRRK2 PD, parkinsonism, cardiac sympathetic denervation, and baroreflex failure can result from a common pathogenetic process.

Background and objective: Hypomyelination with atrophy of the basal ganglia and cerebellum is a recently defined disorder. Only a few patients have been described. We report on 11 additional patients and new MRI findings and provide histopathologic confirmation of the MRI interpretation. Methods: We reviewed the patients9 clinical history and present findings. We scored the MRI abnormalities. The histopathology of one patient was re-examined. Results: The patients9 early psychomotor development was normal or delayed, followed by increasing extrapyramidal movement abnormalities, ataxia, and spasticity. Mental capacities were variably affected. MRI showed hypomyelination with, on follow-up, evidence of further myelin loss and variable white matter atrophy. The putamen was small or, more often, absent; the head of the caudate nucleus was decreased in size. In contrast, the thalamus and globus pallidus remained normal. Cerebellar atrophy was invariably present. Histopathology confirmed the myelin deficiency, probably related to both lack of deposition and low-grade further loss. The degeneration of putamen was subtotal. The cerebellar cortex was affected, particularly the granular layer. Conclusion: Hypomyelination with atrophy of the basal ganglia and cerebellum is a syndrome diagnosed by distinctive MRI findings. Histopathology confirms hypomyelination, low-grade further myelin loss, subtotal degeneration of the putamen, and cerebellar cortical atrophy. All known patients are sporadic, and the mode of inheritance is unclear.

The midbrain dopaminergic (DA) system is composed primarily of neurons in the substantia nigra pars compacta (SNc, area A10) and ventral tegmental area (VTA, area A9). These include at least 5 neuron subpopulations with distinct patterns of gene expression, electrophysiologic properties, projections to the striatum and cerebral cortex, and response to environmental stimuli. They are involved in several key brain functions, including action selection, motor performance, motivation and reward-based learning, working memory, and cognition. Midbrain DA neurons are activated by alerting signals involved in rapid detection of potentially relevant sensory cues. Most increase their activity in response to reward stimuli and are inhibited by aversive stimuli, thereby coding motivational value for learning reward-oriented behavior. Others are activated by aversive stimuli and code motivational salience of the stimulus. These different types of midbrain DA neurons are anatomically segregated and have specific afferent and efferent connections supporting specific aspects of behavior. Neurons encoding motivational value are located in the VTA and medial SNc and project primarily to the nucleus accumbens (NAc) and ventromedial prefrontal cortex and support Pavlovian learning of actions leading to successful outcomes. Neurons encoding motivational salience are located in the dorsolateral SNc and project to the dorsomedial striatum (primarily the caudate) and dorsolateral prefrontal cortex and modulate goal-oriented behavior. Neurons in the ventral tier of the SNc project to the dorsolateral striatum (putamen) and regulate habit formation and automatic motor behavior. Several features of ventral tier SNc neurons render them susceptible to oxidative stress and the subsequent neurodegeneration underlying Parkinson disease (PD). Involvement of other SNc and VTA neurons may contribute to nonmotor aspects of PD, such as depression, cognitive dysfunction, and impulse dyscontrol, in response to DA agonists. All these topics have been extensively discussed in several reviews.1–18

l-3,4-Dihydroxyphenylalanine (l-dopa)-induced dyskinesia affects virtually every patient with Parkinson disease (PD) after chronic administration.1 The pathophysiology of dyskinesia is complex, and several nondopaminergic systems are involved.2 The serotonin (5-HT) system has received much attention over the past years as a critical player underlying dyskinesia and as a potentially efficacious therapeutic target. 5-HT neurons contain the required enzymes to synthesize dopamine from l-dopa3 but without the regulatory mechanisms required for dopaminergic transmission, resulting in dysregulated, nonphysiologic dopamine release, which underlies the dyskinetic state.4 However, if this aberrant dopamine release by 5-HT fibers is the culprit in dyskinesia, it is also responsible, at least partly, for the antiparkinsonian action of l-dopa.5 As a result, it has proven difficult to achieve an antidyskinetic benefit with agonists of the 5-HT1A receptors, which act by dampening this aberrant dopamine release by 5-HT terminals, without hindering the therapeutic effect of l-dopa in both preclinical and clinical settings.6,7

A 64-year-old patient developed shuffling gait and postural instability over 8 months, in parallel to risperidone intake. Examination showed symmetric parkinsonian syndrome and mild left hemiparesis with spasticity, related to right middle cerebral artery stroke 10 years before. Within 1 month of risperdone withdrawal, parkinsonism disappeared, confirming drug-induced etiology. While degenerative parkinsonism is associated with reduction in striatal dopamine transporters binding in absence of structural lesions to basal ganglia, binding in drug-induced parkinsonism is normal.1 In our case, SPECT anomaly was incidental, related to the ischemic sequela (figure).2 This case highlights the importance of brain structural integrity for SPECT interpretation.

Objective: To determine whether automated and observer-independent volumetric MRI analysis is able to discriminate among patients with Parkinson disease (PD), multiple system atrophy (MSA), and progressive supranuclear palsy (PSP) in early to moderately advanced stages of disease. Methods: T1-weighted volumetric MRI from patients with clinically probable PD (n = 40), MSA (n = 40), and PSP (n = 30) and a mean disease duration of 2.8 ± 1.7 y were examined using automated volume measures of 22 subcortical regions. The clinical follow-up period was 2.5 ± 1.2 years. The data were split into a training (n = 72) and a test set (n = 38). The training set was used to build a C4.5 decision tree model in order to classify patients as MSA, PSP, or PD. The classification algorithm was examined by the test set using the final clinical diagnosis at last follow-up as diagnostic gold standard. Results: The midbrain and putaminal volume as well as the cerebellar gray matter compartment were identified as the most significant brain regions to construct a prediction model. The diagnostic accuracy for PD vs MSA or PSP was 97.4%. In contrast, diagnostic accuracy based on validated clinical consensus criteria at the time of MRI acquisition was 62.9%. Conclusions: Volume segmentation of subcortical brain areas differentiates PD from MSA and PSP and improves diagnostic accuracy in patients presenting with early to moderately advanced stage parkinsonism. Classification of evidence: This study provides Class III evidence that automated MRI analysis accurately discriminates among early-stage PD, MSA, and PSP.

A girl with carbamoyl phosphate synthetase 1 (CPS-1) deficiency, symptomatic since the newborn period, underwent liver transplantation at 7 months. She later developed ataxia and truncal dystonia. MRI brain at age 2 years showed hyperintensities in proton density and fluid-attenuated inversion recovery images involving the insular cortices, deep frontal gyri (figure 1, A and B), caudate nucleus, and putamen (figure 2, A and B). These findings are characteristic of proximal urea cycle disorders, namely CPS-1 deficiency,1, 2 and are unlikely due to myelinolysis, pontine or extrapontine. The above findings on an MRI in an encephalopathic child give a clue to the diagnosis of a hyperammonemic disorder.

Objective: To investigate the regional cerebral perfusion in patients with idiopathic REM behavior disorder (RBD) in order to establish the topography of networks involved. Methods: We performed cerebral blood flow evaluation using 99m Tc-Ethylene Cysteinate Dimer (ECD) SPECT on eight patients with polysomnographically confirmed RBD and nine age-matched controls. Comparisons were made using SPM2. Results: We found increased perfusion in the pons and putamen bilaterally and in the right hippocampus. In addition, we observed a decreased perfusion in frontal (Brodmann area [BA] 4, 6, 10, 43, 44, 47 bilaterally and left BA 9, 46) and temporo-parietal (BA 13, 22, 43 bilaterally and left BA 7, 19, 20, 21, 39, 40, 41, 42) cortices. Conclusion: Perfusional abnormalities in patients with REM behavior disorder were located in the brainstem, striatum, and cortex. These abnormalities are consistent with the anatomic metabolic profile of Parkinson disease.