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BACKGROUND: Higher nigral iron has been reported in Parkinson’s disease (PD). OBJECTIVE: To understand the dynamics of nigral iron accumulation in PD and its association with drug treatment. METHODS: Susceptibility MRI data was obtained from 79 control, 18 drug-naïve (PD(DN)), and 87 drug-treated (PD(DT)) subjects. Regional brain iron in basal ganglia and cerebellar structures was estimated using quantitative susceptibility mapping. Nigral iron was compared among PD(DN) and PD(DT) subgroups defined by disease duration [early (PDE, 6 years)]. Associations with both disease duration and types of antiparkinson drugs were explored using regression analysis. RESULTS: Compared to controls, PD(DN) had lower iron in the substantia nigra (p=0.018), caudate nucleus (p=0.038), and globus pallidus (p=0.01), but not in the putamen or red nucleus. In contrast, PD(DT) had higher iron in the nigra (p’s < 0.001), but not other regions, compared to either controls or PD(DN). Iron in the nigra increased with disease duration [ PDE > PD(DN) (p=0.001), PDM > PDE (p=0.045)] except for PDM versus PDL (p=0.226). Levodopa usage was associated with higher (p=0.013) nigral iron, whereas lower nigral iron was correlated with selegiline usage (p= 0.030). CONCLUSION: Nigral iron is lower prior to the start of dopaminergic medication, and then increases throughout the disease until it plateaus at late stages, suggesting increased iron may not be an etiological factor. Interestingly, PD medications may have differential associations with iron accumulation that are worthy of further investigation.

BACKGROUND Deep brain stimulation (DBS) of the nucleus basalis of Meynert (NBM) is an emerging target to potentially treat cognitive dysfunction. OBJECTIVES The aim of this study is to achieve feasibility and safety of globus pallidus pars interna (GPi) and NBM DBS in advanced PD with cognitive impairment. METHODS We performed a phase-II double-blind crossover pilot trial in six participants to assess safety and cognitive measures, the acute effect of NBM stimulation on attention, motor and neuropsychological data at one year, and neuroimaging biomarkers of NBM stimulation. RESULTS NBM DBS was well tolerated but did not improve cognition. GPi DBS improved dyskinesia and motor fluctuations (P = 0.04) at one year. NBM stimulation was associated with reduced right frontal and parietal glucose metabolism (P

Background 18 F-APN-1607 is a novel tau PET tracer characterized by high binding affinity for 3- and 4-repeat tau deposits. Whether 18 F-APN-1607 PET imaging is clinically useful in PSP remains unclear. Objectives The objective of this study was to investigate the clinical utility of 18 F-APN-1607 PET in the diagnosis, differential diagnosis, and assessment of disease severity in patients with PSP. Methods We enrolled 3 groups consisting of patients with PSP (n = 20), patients with α-synucleinopathies (MSA with predominant parkinsonism, n = 7; PD, n = 10), and age- and sex-matched healthy controls (n = 13). The binding patterns of 18 F-APN-1607 in PET/CT imaging were investigated. Regional standardized uptake ratios were compared across groups and examined in relation to their utility in the differential diagnosis of PSP versus α-synucleinopathies. Finally, the relationships between clinical severity scores and 18 F-APN-1607 uptake were investigated after adjustment for age, sex, and disease duration. Results Compared with healthy controls, patients with PSP showed increased 18 F-APN-1607 binding in several subcortical regions, including the striatum, putamen, globus pallidus, thalamus, subthalamic nucleus, midbrain, tegmentum, substantia nigra, pontine base, red nucleus, raphe nuclei, and locus coeruleus. We identified specific regions that were capable of distinguishing PSP from α-synucleinopathies. The severity of PSP was positively correlated with the amount of 18 F-APN-1607 uptake in the subthalamic nucleus, midbrain, substantia nigra, red nucleus, pontine base, and raphe nuclei. Conclusions 18 F-APN-1607 PET imaging holds promise for the diagnosis, differential diagnosis, and assessment of disease severity in patients with PSP. © 2021 International Parkinson and Movement Disorder Society.

Background Deep brain stimulation of the subthalamic nucleus is a widely used adjunctive therapy for motor symptoms of Parkinson's disease, but with variable motor response. Predicting motor response remains difficult, and novel approaches may improve surgical outcomes as well as the understanding of pathophysiological mechanisms. The objective of this study was to determine whether preoperative resting-state functional connectivity MRI predicts motor response from deep brain stimulation of the subthalamic nucleus. Methods We collected preoperative resting-state functional MRI from 70 participants undergoing subthalamic nucleus deep brain stimulation. For this cohort, we analyzed the strength of STN functional connectivity with seeds determined by stimulation-induced (ON/OFF) 15 O H2 O PET regional cerebral blood flow differences in a partially overlapping group (n = 42). We correlated STN-seed functional connectivity strength with postoperative motor outcomes and applied linear regression to predict motor outcomes. Results Preoperative functional connectivity between the left subthalamic nucleus and the ipsilateral internal globus pallidus correlated with postsurgical motor outcomes (r = -0.39, P = 0.0007), with stronger preoperative functional connectivity relating to greater improvement. Left pallidal-subthalamic nucleus connectivity also predicted motor response to DBS after controlling for covariates. Discussion Preoperative pallidal-subthalamic nucleus resting-state functional connectivity predicts motor benefit from deep brain stimulation, although this should be validated prospectively before clinical application. These observations suggest that integrity of pallidal-subthalamic nucleus circuits may be critical to motor benefits from deep brain stimulation. © 2020 International Parkinson and Movement Disorder Society.

Stereotactic lesioning of the bilateral globus pallidus (GPi) was one of the first surgical treatments for medication‐refractory dystonia but has largely been abandoned in clinical practice after the introduction of deep brain stimulation (DBS). However, some patients with dystonia are not eligible for DBS. Therefore, we reviewed the efficacy, safety, and sustainability of bilateral pallidotomy by conducting a systematic review of individual patient data (IPD). Guidelines of the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses and IPD were followed. In May 2020, Medline, Embase, Web of Science, and Cochrane Library were searched for studies reporting on outcome of bilateral pallidotomy for dystonia. If available, IPD were collected. In this systematic review, 100 patients from 33 articles were evaluated. Adverse events were reported in 20 patients (20%), of which 8 were permanent (8%). Pre‐and postoperative Burke‐Fahn‐Marsden Dystonia Rating Movement Scale scores were available for 53 patients. A clinically relevant improvement (>20%) of this score was found in 42 of 53 patients (79%). Twenty‐five patients with status dystonicus (SD) were described. In all but 2 the SD resolved after bilateral pallidotomy. Seven patients experienced a relapse of SD. Median‐reported follow‐up was 12 months (n = 83; range: 2–180 months). Based on the current literature, bilateral pallidotomy is an effective and relatively safe procedure for certain types of dystonia, particularly in medication‐refractory SD. Although due to publication bias the underreporting of negative outcomes is very likely, bilateral pallidotomy is a reasonable alternative to DBS in selected dystonia patients. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Background Progressive supranuclear palsy (PSP) is a neurodegenerative clinically heterogeneous disorder, formal diagnosis being based on postmortem histological brain examination. Objective We aimed to perform a precise in vivo staging of neurodegeneration in PSP using quantitative multimodal MRI. The ability of MRI biomarkers to differentiate PSP from PD was also evaluated. Methods Eleven PSP patients were compared to 26 age-matched healthy controls and 51 PD patients. Images were acquired at 3 Tesla (three-dimensional T1 -weighted, diffusion tensor, and neuromelanin-sensitive images) and 7 Tesla (three-dimensional-T2 * images). Regions of interest included the cortical areas, hippocampus, amygdala, basal ganglia, basal forebrain, brainstem nuclei, dentate nucleus, and cerebellum. Volumes, mean diffusivity, and fractional anisotropy were measured. In each region, a threshold value for group categorization was calculated, and four grades of change (0-3) were determined. Results PSP patients showed extensive volume decreases and diffusion changes in the midbrain, SN, STN, globus pallidus, basal forebrain, locus coeruleus, pedunculopontine nucleus, and dentate nucleus, in close agreement with the degrees of impairment in histological analyses. The predictive factors for the separation of PSP and healthy controls were, in descending order, the neuromelanin-based SN volume; midbrain fractional anisotropy; volumes of the midbrain, globus pallidus, and putamen; and fractional anisotropy in the locus coeruleus. The best predictors for separating PSP from PD were the neuromelanin-based volume in the SN, fractional anisotropy in the pons, volumes of the midbrain and globus pallidus, and fractional anisotropy in the basal forebrain. Conclusions These results suggest that it is possible to evaluate brain neurodegeneration in PSP noninvasively, even in small brainstem nuclei, in close agreement with previously published histological data. © 2019 International Parkinson and Movement Disorder Society.

ObjectiveThis study investigates the association between pallidal low‐frequency activity and motor sign severity in dystonia after chronic deep brain stimulation for several months.MethodsLocal field potentials were recorded in 9 dystonia patients at 5 timepoints (T1–T5) during an OFF‐stimulation period of 5 to 7 hours in parallel with clinical assessment using Burke‐Fahn‐Marsden Dystonia Rating Scale. A linear mixed effects model was used to investigate the potential association of motor signs with local field potential activity in the low frequency (3–12 Hz) and beta range (13–30 Hz).ResultsA significant association of Burke‐Fahn‐Marsden Dystonia Rating Scale scores with low‐frequency activity (3–12 Hz; b = 4.4; standard error = 1.5, degrees of freedom = 43, P = 0.006, 95% confidence interval, 1.3–7.5), but not beta activity (13–30 Hz) was revealed within participants across timepoints.ConclusionLow‐frequency activity is associated with dystonic motor sign severity, even months after chronic deep brain stimulation. Our findings corroborate the pathophysiological role of low‐frequency activity in dystonia and highlight the potential utility as a biomarker for adaptive neuromodulation. © 2019 International Parkinson and Movement Disorder Society

Background [11 C]pyridinyl-butadienyl-benzothiazole 3 is a PET imaging agent designed for capturing pathological tau aggregates in diverse neurodegenerative disorders, and would be of clinical utility for neuropathological investigations of PSP. Objectives To explore the usefulness of [11 C]pyridinyl-butadienyl-benzothiazole 3/PET in assessing characteristic distributions of tau pathologies and their association with clinical symptoms in the brains of living PSP patients. Methods We assessed 13 PSP patients and 13 age-matched healthy control subjects. Individuals negative for amyloid β PET with [11 C]Pittsburgh compound B underwent clinical scoring, MR scans, and [11 C]pyridinyl-butadienyl-benzothiazole 3/PET. Results There were significant differences in binding potential for [11 C]pyridinyl-butadienyl-benzothiazole 3 between PSP patients and healthy control subjects (P = 0.02). PSP patients exhibited greater radioligand retention than healthy control subjects in multiple brain regions, including frontoparietal white matter, parietal gray matter, globus pallidus, STN, red nucleus, and cerebellar dentate nucleus. [11 C]pyridinyl-butadienyl-benzothiazole 3 deposition in frontoparietal white matter, but not gray matter, was correlated with general severity of parkinsonian and PSP symptoms, whereas both gray matter and white matter [11 C]pyridinyl-butadienyl-benzothiazole 3 accumulations in the frontoparietal cortices were associated with nonverbal cognitive impairments. Autoradiographic and fluorescence labeling with pyridinyl-butadienyl-benzothiazole 3 was observed in gray matter and white matter of PSP motor cortex tissues. Conclusions Our findings support the in vivo detectability of tau fibrils characteristic of PSP by [11 C]pyridinyl-butadienyl-benzothiazole 3/PET, and imply distinct and synergistic contributions of gray matter and white matte tau pathologies to clinical symptoms. [11 C]pyridinyl-butadienyl-benzothiazole 3/PET potentially provides a neuroimaging-based index for the evolution of PSP tau pathologies promoting the deterioration of motor and cognitive functions. © 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Background In Parkinson's disease, the emergence of motor dysfunction is thought to be related to an imbalance between "antikinetic" and "prokinetic" patterns of oscillatory activity in the motor network. Invasive recordings from the basal ganglia and cortex in surgical patients have suggested that levodopa and therapeutic deep brain stimulation can suppress antikinetic beta band (13-30 Hz) rhythms while promoting prokinetic gamma band (60-90 Hz) rhythms. Surgical ablation of the globus pallidus internus is one of the oldest effective therapies for Parkinson's disease and produces remarkably immediate relief of rigidity and bradykinesia, but its effects on oscillatory activity in the motor network have not been studied. Objectives We characterize the effects of pallidotomy on cortical oscillatory activity in Parkinson's patients. Methods Using a temporary 6-contact lead placed over the sensorimotor cortex in the subdural space, we recorded acute changes in cortical oscillatory activities in 3 Parkinson's disease patients undergoing pallidotomy and compared the results to that of 3 essential tremor patients undergoing thalamotomy. Results In all 3 Parkinson's disease patients, we observed the emergence of a ~70-80 Hz narrowband oscillation with effective thermolesion of the pallidum. This gamma oscillatory activity was spatially localized over the primary motor cortex, was minimally affected by voluntary movements, and was not found in the motor cortex of essential tremor patients undergoing thalamotomy. Conclusions Our finding suggests that acute lesioning of the pallidum promotes cortical gamma band oscillations. This may represent an important mechanism for alleviating bradykinesia in Parkinson's disease. © 2019 International Parkinson and Movement Disorder Society.

Background Morphology builds Wilson's disease's clincal basis. Objectives To detect and quantify regional morphometric abnormalities, in terms of both volume and shape, in patients with Wilson's disease. Methods Twenty-seven Wilson's disease patients and 24 healthy controls were enrolled. Specific brain structures, including the bilateral caudate, putamen, globus pallidus, thalamus, amygdala, hippocampus, red nucleus, and substantia nigra (SN), were automatically extracted from each participant's T1 -weighted image. Volume abnormalities and correlations with the modified Young scale were investigated. Furthermore, vertex-based shape analysis was performed to explore region-specific morphometric abnormalities. Results Significant global volume atrophy and local shape abnormalities were detected and quantified in the bilateral caudate, putamen, globus pallidus, thalamus, amygdala, red nucleus, and SN. Morphometric abnormalities of the caudate, putamen, and thalamus were strong, whereas those of the globus pallidus, amygdala, red nucleus, and SN were weaker. No hippocampal abnormalities were observed. The modified Young scale was found to correlate significantly with the volumes of the bilateral putamen and the right globus pallidus. Shape analysis revealed subregion-specific atrophy of the bilateral caudate and putamen. They were concentrated in the subregions that project to the limbic and executive cortices. Significant region-specific atrophy was also detected in the bilateral thalamic subregions that project to the primary motor, sensory, and premotor cortices. Conclusions We found significant morphometric abnormalities of specific structures of interest in patients with Wilson's disease, both globally and locally. These morphometric abnormalities may serve as useful imaging biomarkers for Wilson's disease. © 2019 International Parkinson and Movement Disorder Society.

BACKGROUND Huntington's disease (HD) is caused by a CAG repeat expansion in the huntingtin gene. This mutation leads to progressive dysfunction that is largely attributable to dysfunction of the striatum. The earliest signs of striatal pathology in HD are found in indirect pathway gamma-Aminobutyric acid (GABA)-ergic spiny projection neurons that innervate the external segment of the globus pallidus (GPe). What is less clear is whether the synaptic coupling of spiny projection neurons with GPe neurons changes in HD. OBJECTIVES The principal goal of this study was to determine whether striatopallidal synaptic transmission was altered in 2 mouse models of HD. METHODS Striatopallidal synaptic transmission was studied using electrophysiological and optogenetic approaches in ex vivo brain slices from 2 HD models: Q175 heterozygous (het) and R6/2 mice. RESULTS Striatopallidal synaptic transmission increased in strength with the progression of behavioral deficits in Q175 and R6/2 mice. The alteration in synaptic transmission was evident in both prototypical and arkypallidal GPe neurons. This change did not appear attributable to an increase in the probability of GABA release but, rather, to an enhancement in the postsynaptic response to GABA released at synaptic sites. This alteration significantly increased the ability of striatopallidal axon terminals to pause ongoing GPe activity. CONCLUSIONS In 2 mouse models of HD, striatopallidal synaptic transmission increased in parallel with the progression of behavioral deficits. This adaptation could compensate in part for the concomitant deficit in the ability of corticostriatal signals to activate spiny projection neurons and pause GPe activity. © 2019 International Parkinson and Movement Disorder Society.

Background Striatal cyclic adenosine monophosphate activity modulates movement and is determined from the balance between its synthesis by adenylate cyclase 5 (ADCY5) and its degradation by phosphodiesterase 10A (PDE10A). Objective We assessed the integrity of striatocortical pathways, in vivo, in 2 genetic hyperkinetic disorders caused by ADCY5 and PDE10A mutations. Methods We studied 6 subjects with PDE10A and ADCY5 mutations using [11 C]IMA107 PET, [123 I]FP-CIT Single-photon emission computed tomography (SPECT) and multimodal MRI to investigate PDE10A and dopamine transporter availability, neuromelanin-containing neurons, and microstructural white and gray matter changes, respectively. Results We found that PDE10A and ADCY5 mutations were associated with decreased PDE10A expression in the striatum and globus pallidus, decreased dopamine transporter expression in the striatum, loss of substantia nigra neuromelanin-containing neurons, and microstructural white and gray matter changes within the substantia nigra, striatum, thalamus, and frontoparietal cortices. Conclusions Our findings indicate an association between PDE10A and ADCY5 mutations and pre/postsynaptic molecular changes, substantia nigra damage, and white and gray matter changes within the striatocortical pathways. © 2018 International Parkinson and Movement Disorder Society.

Background: Tourette syndrome is a hyperkinetic neurodevelopmental disorder characterized by tics.Objective: Assess the neuronal changes in the associative/limbic GP associated with Tourette syndrome.Methods: Neurophysiological recordings were performed from the anterior (associative/limbic) GPe and GPi of 8 awake patients during DBS electrode implantation surgeries.Results: The baseline firing rate of the neurons was low in a state-dependent manner in both segments of the GP. Tic-dependent transient rate changes were found in the activity of individual neurons of both segments around the time of the tic. Neither oscillatory activity of individual neurons nor correlations in their interactions were observed.Conclusions: The results demonstrate the involvement of the associative/limbic pathway in the underlying pathophysiology of Tourette syndrome and point to tonic and phasic modulations of basal ganglia output as a key mechanisms underlying the abnormal state of the disorder and the expression of individual tics, respectively. (C) 2017 International Parkinson and Movement Disorder Society

Background: Tourette syndrome is a hyperkinetic neurodevelopmental disorder characterized by tics. Objective: Assess the neuronal changes in the associative/limbic GP associated with Tourette syndrome. Methods: Neurophysiological recordings were performed from the anterior (associative/limbic) GPe and GPi of 8 awake patients during DBS electrode implantation surgeries. Results: The baseline firing rate of the neurons was low in a state-dependent manner in both segments of the GP. Tic-dependent transient rate changes were found in the activity of individual neurons of both segments around the time of the tic. Neither oscillatory activity of individual neurons nor correlations in their interactions were observed. Conclusions: The results demonstrate the involvement of the associative/limbic pathway in the underlying pathophysiology of Tourette syndrome and point to tonic and phasic modulations of basal ganglia output as a key mechanisms underlying the abnormal state of the disorder and the expression of individual tics, respectively. © 2017 International Parkinson and Movement Disorder Society

Objectives Mutations in RAB39B have been reported as a potential cause of X-linked Parkinson's disease (PD), a rare form of familial PD. We conducted a genetic analysis on RAB39B to evaluate whether RAB39B mutations are related to PD in the Chinese population. Methods In this study, 2 patients from an X-linked juvenile parkinsonism pedigree were clinically characterized and underwent whole-exome sequencing. A comprehensive screening for RAB39B mutations in 505 sporadic patients with PD and 510 healthy controls in a Chinese population was also performed. Results A novel mutation, c. 536dupA (p.E179fsX48), in RAB39B was identified in the juvenile parkinsonism pedigree. Brain MRI and CT scans in the 2 patients revealed calcification within the bilateral globus pallidus. No other potentially disease-causing RAB39B mutations were found in sporadic PD patients and controls. Conclusions X-linked juvenile parkinsonism could be caused by a RAB39B mutation, and basal ganglia calcification may be a novel clinical feature of RAB39B-related parkinsonism. © 2016 International Parkinson and Movement Disorder Society.

Background: Progressive supranuclear palsy (PSP) is difficult to diagnose accurately. The recently developed tau PET tracers may improve the diagnostic work-up of PSP. Methods: Regional tau accumulation was studied using 18F-AV-1451 PET in 11 patients with PSP and 11 age-matched healthy controls in the Swedish BioFinder study. Results: 18F-AV-1451 standard uptake volume ratios were significantly higher in the basal ganglia in PSP patients when compared with controls (globus pallidus 1.75 vs 1.50; putamen 1.51 vs 1.35). Retention in the basal ganglia was correlated with age in both groups (r=.43-.78, P

BackgroundThe aim of this study was to assess psychiatric and social outcome 12 months after bilateral deep brain stimulation (DBS) of the globus pallidus pars interna (GPi) and subthalamic nucleus (STN) for advanced Parkinson's disease (PD). MethodsWe randomly assigned patients to receive GPi DBS (n=65) or STN DBS (n=63). Standardized psychiatric and social questionnaires were assessed at baseline and after 12 months. ResultsNo differences were found between GPi DBS and STN DBS on psychiatric evaluation. Within-group comparisons showed small but statistically significant changes on several measures in both groups. Descriptive statistics indicated slight changes in social functioning. Marital satisfaction of patients and partners remained relatively stable after GPi and STN DBS. ConclusionsWe found neither differences in psychiatric and social outcome between GPi DBS and STN DBS nor any relevant within-group differences. The decision for GPi DBS or STN DBS cannot be based on expected psychiatric or social effects. (c) 2015 International Parkinson and Movement Disorder Society

Background We have previously defined a parkinsonism-related metabolic brain network in rhesus macaques using a high-resolution research positron emission tomography camera. This brief article reports a descriptive pilot study to assess the reproducibility of network activity and regional glucose metabolism in independent parkinsonian macaques using a clinical positron emission tomography/CT camera. Methods [18F]fluorodeoxyglucose PET scans were acquired longitudinally over 3 months in three drug-naive parkinsonian and three healthy control cynomolgus macaques. Group difference and test–retest stability in network activity and regional glucose metabolism were evaluated graphically, using all brain images from these macaques. Results Comparing the parkinsonian macaques with the controls, network activity was elevated and remained stable over 3 months. Normalized glucose metabolism increased in putamen/globus pallidus and sensorimotor regions but decreased in posterior parietal cortices. Conclusions Parkinsonism-related network activity can be reliably quantified in different macaques with a clinical positron emission tomography/CT scanner and is reproducible over a period typically employed in preclinical intervention studies. This measure can be a useful biomarker of disease process or drug effects in primate models of Parkinson's disease. ©2015 International Parkinson and Movement Disorder Society

BACKGROUND The pathophysiology of cervical dystonia is poorly understood. Increased brain iron deposition has been described in different movement disorders. Our aim was to investigate brain iron content in patients with cervical dystonia, using R2* relaxation rate, a validated MRI marker of brain iron level. METHODS Twelve female patients with primary focal cervical dystonia (mean age: 45.4 ± 8.0 years) and 12 age-matched healthy female subjects (mean age: 45.0 ± 8.0 years) underwent 3T MRI to obtain regional R2* relaxation rates of the thalamus, caudate nucleus, putamen, and globus pallidus (GP). Regions of interest were delineated automatically on T1-weighted MRIs. RESULTS R2* values in the putamen were positively correlated with age. Patients with cervical dystonia showed elevated R2* values in the GP. CONCLUSIONS This pilot study provides the first quantitative support for increased brain iron deposition in cervical dystonia. Further studies are needed to explore the implications of this finding.

Objectives The goal of this work was to investigate iron deposition in the basal ganglia and thalamus in symptomatic and asymptomatic leucine-rich repeat kinase 2 (LRRK2) and Parkin-associated Parkinson's disease (PD), using R2* relaxometry rate. Methods Twenty subjects with genetic PD (four symptomatic and two asymptomatic Parkin subjects, nine symptomatic and five asymptomatic LRRK2 subjects) were compared with 20 patients with idiopathic PD (IPD) and 20 healthy subjects. Images were obtained at 3 teslas, using multi-echo T2 and T2* sequences. R2 and R2* values were calculated in the substantia nigra (SN), the striatum, the globus pallidus, and the thalamus. Results The R2* values in the SN were increased in IPD and mutation-carrying patients as compared with controls and in mutation-carrying patients as compared with IPD. Asymptomatic mutation carriers showed higher R2* values than controls and did not differ from IPD patients. No changes were seen in the other structures or in R2 values. Conclusion These results are consistent with increased iron load in LRRK2- and Parkin-mutation carriers. The increased R2* in asymptomatic PD-mutation carriers suggests that iron deposition occurs early during the preclinical phase of the disease. R2* measurements may be used as markers for investigating nigrostriatal damage in preclinical mutation-carrying patients. © 2015 International Parkinson and Movement Disorder Society

Background Myoclonus–dystonia related to epsilon-sarcoglycan gene mutations is characterized by myoclonic jerks and mild to moderate dystonia. The role of basal ganglia dysfunction in the pathogenesis is unknown. Methods Pallidal neuronal activity was recorded in six myoclonus–dystonia and six primary generalized dystonia patients operated on for internal globus pallidus deep brain stimulation. Results In myoclonus–dystonia patients compared with primary-dystonia patients, internal pallidum neurons showed higher burst frequency, lower mean burst, and pause durations. External pallidum neurons showed higher mean pause frequency. Oscillatory activity was present in 33% and 35% of internal pallidum neurons in myoclonus–dystonia and primary-dystonia patients, respectively, predominantly in the theta frequency band (3-8 Hz). In myoclonus–dystonia patients with more severe myoclonus, internal pallidum neurons exhibited a higher bursting activity with high intraburst frequency and lower oscillatory activity frequency. Conclusions Myoclonus–dystonia appears to be related to specific changes in internal pallidum activity, leading to disruption in striato-pallido-thalamo-cortical circuits. © 2015 International Parkinson and Movement Disorder Society

Huntington’s disease (HD) is a progressive, fatal, autosomal-dominant, neurodegenerative disease with no disease-modifying treatment. The disease is caused by an abnormal trinucleotide cytosine-adenine-guanine (CAG) expansion in the huntingtin gene. Detecting pathophysiological processes underlying HD before a clinical motor diagnosis offers hope for assessment of treatments and allows for early intervention, which ultimately will result in improved outcomes.1 To evaluate treatments before a clinical motor diagnosis is given, biomarkers are needed that can be objectively measured, are an indicator of disease progression, and measure a pharmacological response. To date, there are no proven biomarkers in HD and continued evaluation of potential biomarkers is needed.2 MRI provides a number of modalities that have been studied as potential biomarkers for HD progression during the premanifest phase preceding motor diagnosis, including structural imaging, diffusion imaging, magnetization transfer imaging, spectroscopy, and functional imaging, as previously reviewed in Bohanna et al.3 Weir et al.4 and van Den Bogaard et al.5 The size of the caudate and putamen have been shown to be potential biomarkers for disease progression.6,7 Based on the PREDICT-HD study, decreased volume of the striatum and white matter (WM) are detectable years to decades before estimated motor diagnosis of HD8 and are significantly atrophied close to clinical manifestation.9 The change in volume has been found to be approximately linear during the premanifest phase of the illness. Changes in brain metabolism10,11 and function12–15 have also been reported. There has been growing interest in using quantitative parametric MRI as a biomarker for neurodegenerative disorders.16–22 Quantitative imaging has a number of advantages over existing MRI techniques, including the ability to study changes in the relaxation time without the need to normalize to a standard (e.g., volumetric normalized to intracranial volume). Quantitative measurements offer the possibility to relate these changes back to pathological processes given that they reflect tissue properties at the microscopic level, instead of the macroscopic level, such as striatal volume. Coupling of multiple quantitative parametric imaging techniques facilitates the identification of the underlying mechanisms that may be responsible for the relaxation time changes. Previous studies have employed quantitative T2 and T2* mapping to study how these relaxation times change in HD19,23–25 These studies were motivated by the findings that subjects with HD have an increased iron concentration in the striatum postmortem16,26 and the known sensitivity of these relaxation parameters to metal ion concentrations. These studies have largely found decreased T2* relaxation rates within the globus pallidus (GP) and nonsignificant changes in the striatum.19,23–25 WM T2* relaxation times have been found to increase only during the early manifest stage.23 T2 mapping has been shown to largely disassociate from iron concentrations in HD,19 suggesting that other microstructural changes are largely driving the changes in T2 relaxation times. Recently, another quantitative MR parameter, T1 relaxation in the rotating frame (T1ρ), has been used to study progressive changes in Parkinson’s and Alzheimer’s disease.21,27,28 T1ρ measures proton exchange, which is influenced by metabolism (pH and glucose)29–31 and protein concentrations.32 However, T1ρ relaxation is sensitive to a number of microscopic environmental factors, including water content, which can be measured using T2 measurements. Therefore, this study was designed to collect multiple quantitative imaging parameters to better understand the underlying microscopic changes that are occurring associated with disease progression. The aims of this study were to apply multiple quantitative MRI techniques to determine whether T1ρ can serve as a unique quantitative biomarker for disease progression and examine whether T1ρ changes occur in the absence of T2 changes in terms of regional specificity and proximity to disease onset.

In the recent past, basal ganglia circuitry was simplified as represented by the direct and indirect pathways and by hyperdirect pathways. Based on data from animal studies, we hypothesized a fourth pathway, the cortico-pallidal, pathway, that complements the hyperdirect pathway to the subthalamus. Ten normal brains were analyzed by using the high angular resolution diffusion imaging-constrained spherical deconvolution (CSD)-based technique. The study was performed with a 3T magnetic resonance imaging (MRI) scanner (Achieva, Philips Healthcare, Best, Netherlands); by using a 32-channel SENSE head coil. We showed that CSD is a powerful technique that allows a fine evaluation of both the long and small tracts between cortex and basal ganglia, including direct, indirect, and hyperdirect pathways. In addition, a pathway directly connecting the cortex to the globus pallidus was seen. Our results confirm that the CSD tractography is a valuable technique allowing a reliable reconstruction of small- and long-fiber pathways in brain regions with multiple fiber orientations, such as basal ganglia. This could open a future scenario in which CSD could be used to focally target with deep brain stimulation (DBS) the small bundles within the basal ganglia loops.

Maladaptive plasticity at corticostriatal synapses plays an important role in the development of levodopa-induced dyskinesia. Recently, it has been shown that synaptic plasticity is closely linked to morphologic changes of dendritic spines. To evaluate morphologic changes of dendritic spines of two types of striatal medium spiny neurons, which project to the internal segment of globus pallidus or the external segment of globus pallidus, in the levodopa-induced dyskinesia model, we used 6-hydroxydopamine-lesioned rats chronically treated with levodopa. Dendritic spines were decreased and became enlarged in the direct pathway neurons of the model of levodopa-induced dyskinesia. The same levodopa treatment to normal rats, in which no dyskinesia was observed, also induced enlargement of dendritic spines, but not a decrease in density of spines in the direct pathway neurons. These results suggest that a loss and enlargement of dendritic spines in the direct pathway neurons plays important roles in the development of levodopa-induced dyskinesia.