Transient dystonia correlates with parkinsonism after 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine in nonhuman primates.

Unilateral internal carotid artery 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) infusion in non-human primates produces transient contralateral hemi-dystonia followed by stable contralateral hemi-parkinsonism; the relationship between dystonia and parkinsonism remains unclear. We hypothesized that transient dystonia severity following MPTP correlates with parkinsonism severity. In male Macaca nemestrina (n = 3) and M. fascicularis (n = 17) we administered unilateral intra-carotid MPTP, then correlated validated blinded ratings of transient peak dystonia and delayed parkinsonism. We also correlated dystonia severity with post-mortem measures of residual striatal dopamine and nigral neuron counts obtained a mean 53 ± 15 days following MPTP, after resolution of dystonia but during stable parkinsonism. Median latency to dystonia onset was 1 day, and peak severity 2.5 days after MPTP; total dystonia duration was 13.5 days. Parkinsonism peaked a median of 19.5 days after MPTP, remaining nearly constant thereafter. Peak dystonia severity highly correlated with parkinsonism severity (r[18] = 0.82, p < 0.001). Residual cell counts in lesioned nigra correlated linearly with peak dystonia scores (r[18] = -0.68, p=<0.001). Dystonia was not observed in monkeys without striatal dopamine depletion (n = 2); dystonia severity correlated with striatal dopamine depletion when residual nigral cell loss was less than 50% ([11] r = -0.83, p < 0.001) but spanned a broad range with near complete striatal dopamine depletion, when nigral cell loss was greater than 50%. Our data indicate that residual striatal dopamine may not reflect dystonia severity. We speculate on mechanisms of transient dystonia followed by parkinsonism that may be studied using this particular NHP MPTP model to better understand relationships of transient dystonia to nigrostriatal injury and parkinsonism.

Treatment Efficacy Score-continuous residual cancer burden-based metric to compare neoadjuvant chemotherapy efficacy between randomized trial arms in breast cancer trials.

BACKGROUND: Difference in pathologic complete response (pCR) rate after neoadjuvant chemotherapy does not capture the impact of treatment on downstaging of residual cancer in the experimental arm. We developed a method to compare the entire distribution of residual cancer burden (RCB) values between clinical trial arms to better quantify the differences in cytotoxic efficacy of treatments. PATIENTS AND METHODS: The Treatment Efficacy Score (TES) reflects the area between the weighted cumulative distribution functions of RCB values from two trial arms. TES is based on a modified Kolmogorov-Smirnov test with added weight function to capture the importance of high RCB values and uses the area under the difference between two distribution functions as a statistical metric. The higher the TES the greater the shift to lower RCB values in the experimental arm. We developed TES from the durvalumab + olaparib arm (n = 72) and corresponding controls (n = 282) of the I-SPY2 trial. The 11 other experimental arms and control cohorts (n = 947) were used as validation sets to assess the performance of TES. We compared TES to Kolmogorov-Smirnov, Mann-Whitney, and Fisher's exact tests to identify trial arms with higher cytotoxic efficacy and assessed associations with trial arm level survival differences. Significance was assessed with a permutation test. RESULTS: In the validation set, TES identified arms with a higher pCR rate but was more accurate to identify regimens as less effective if treatment did not reduce the frequency of high RCB values, even if the pCR rate improved. The correlation between TES and survival was higher than the correlation between the pCR rate difference and survival. CONCLUSIONS: TES quantifies the difference between the entire distribution of pathologic responses observed in trial arms and could serve as a better early surrogate to predict trial arm level survival differences than pCR rate difference alone.

Predicted sensitivity to endocrine therapy for stage II-III hormone receptor-positive and HER2-negative (HR+/HER2-) breast cancer before chemo-endocrine therapy.

BACKGROUND: We proposed that a test for sensitivity to the adjuvant endocrine therapy component of treatment for patients with stage II-III breast cancer (SET2,3) should measure transcription related to estrogen and progesterone receptors (SETER/PR index) adjusted for a baseline prognostic index (BPI) combining clinical tumor and nodal stage with molecular subtype by RNA4 (ESR1, PGR, ERBB2, and AURKA). PATIENTS AND METHODS: Patients with clinically high-risk, hormone receptor-positive (HR+), human epidermal growth factor receptor 2 (HER2)-negative (HR+/HER2-) breast cancer received neoadjuvant taxane-anthracycline chemotherapy, surgery with measurement of residual cancer burden (RCB), and then adjuvant endocrine therapy. SET2,3 was measured from pre-treatment tumor biopsies, evaluated first in an MD Anderson Cancer Center (MDACC) cohort (n = 307, 11 years' follow-up, U133A microarrays), cut point was determined, and then independent, blinded evaluation was carried out in the I-SPY2 trial (n = 268, high-risk MammaPrint result, 3.8 years' follow-up, Agilent-44K microarrays, NCI Clinical Trials ID: NCT01042379). Primary outcome measure was distant relapse-free survival. Multivariate Cox regression models tested prognostic independence of SET2,3 relative to RCB and other molecular prognostic signatures, and whether other prognostic signatures could substitute for SETER/PR or RNA4 components of SET2,3. RESULTS: SET2,3 added independent prognostic information to RCB in the MDACC cohort: SET2,3 [hazard ratio (HR) 0.23, P = 0.004] and RCB (HR 1.77, P < 0.001); and the I-SPY2 trial: SET2,3 (HR 0.27, P = 0.031) and RCB (HR 1.68, P = 0.008). SET2,3 provided similar prognostic information irrespective of whether RCB-II or RCB-III after chemotherapy, and in both luminal subtypes. Conversely, RCB was most strongly prognostic in cancers with low SET2,3 status (MDACC P < 0.001, I-SPY2 P < 0.001). Other molecular signatures were not independently prognostic; they could effectively substitute for RNA4 subtype within the BPI component of SET2,3, but they could not effectively substitute for SETER/PR index. CONCLUSIONS: SET2,3 added independent prognostic information to chemotherapy response (RCB) and baseline prognostic score or subtype. Approximately 40% of patients with clinically high-risk HR+/HER2- disease had high SET2,3 and could be considered for clinical trials of neoadjuvant endocrine-based treatment.

A new measure for end of life planning, preparation, and preferences in Huntington disease: HDQLIFE end of life planning.

BACKGROUND: Huntington disease is a fatal inherited neurodegenerative disease. Because the end result of Huntington disease is death due to Huntington disease-related causes, there is a need for better understanding and caring for individuals at their end of life. AIM: The purpose of this study was to develop a new measure to evaluate end of life planning. DESIGN: We conducted qualitative focus groups, solicited expert input, and completed a literature review to develop a 16-item measure to evaluate important aspects of end of life planning for Huntington disease. Item response theory and differential item functioning analyses were utilized to examine the psychometric properties of items; exploratory factor analysis was used to establish meaningful subscales. PARTICIPANTS: Participants included 508 individuals with pre-manifest or manifest Huntington disease. RESULTS: Item response theory supported the retention of all 16 items on the huntington disease quality of life ("HDQLIFE") end of life planning measure. Exploratory factor analysis supported a four-factor structure: legal planning, financial planning, preferences for hospice care, and preferences for conditions (locations, surroundings, etc.) at the time of death. Although a handful of items exhibited some evidence of differential item functioning, these items were retained due to their relevant clinical content. The final 16-item scale includes an overall total score and four subscale scores that reflect the different end of life planning constructs. CONCLUSIONS: The 16-item HDQLIFE end of life planning measure demonstrates adequate psychometric properties; it may be a useful tool for clinicians to clarify patients' preferences about end of life care.

Pathologic correlates of supranuclear gaze palsy with parkinsonism.

INTRODUCTION: Supranuclear gaze palsy (SGP) is a classic clinical feature of progressive supranuclear palsy (PSP) but is not specific for this diagnosis and has been reported to occur in several other neurodegenerative parkinsonian conditions. Our objective was to evaluate the association between SGP and autopsy-proven diagnoses in a large population of patients with parkinsonism referred to a tertiary movement disorders clinic. METHODS: We reviewed clinical and autopsy data maintained in an electronic medical record from all patients seen in the Movement Disorders Clinic at Washington University, St. Louis between 1996 and 2015. All patients with parkinsonism from this population who had subsequent autopsy confirmation of diagnosis underwent further analysis. RESULTS: 221 unique parkinsonian patients had autopsy-proven diagnoses, 27 of whom had SGP documented at some point during their illness. Major diagnoses associated with SGP were: PSP (9 patients), Parkinson disease (PD) (10 patients), multiple system atrophy (2 patients), corticobasal degeneration (2 patients), Creutzfeld-Jakob disease (1 patient) and Huntington disease (1 patient). In none of the diagnostic groups was the age of onset or disease duration significantly different between cases with SGP and those without SGP. In the PD patients, the UPDRS motor score differed significantly between groups (p = 0.01) with the PD/SGP patients having greater motor deficit than those without SGP. CONCLUSION: Although a common feature of PSP, SGP is not diagnostic for this condition and can be associated with other neurodegenerative causes of parkinsonism including PD.

HDQLIFE: development and assessment of health-related quality of life in Huntington disease (HD).

PURPOSE: Huntington disease (HD) is a chronic, debilitating genetic disease that affects physical, emotional, cognitive, and social health. Existing patient-reported outcomes (PROs) of health-related quality of life (HRQOL) used in HD are neither comprehensive, nor do they adequately account for clinically meaningful changes in function. While new PROs examining HRQOL (i.e., Neuro-QoL-Quality of Life in Neurological Disorders and PROMIS-Patient-Reported Outcomes Measurement Information System) offer solutions to many of these shortcomings, they do not include HD-specific content, nor have they been validated in HD. HDQLIFE addresses this by validating 12 PROMIS/Neuro-QoL domains in individuals with HD and by using established PROMIS methodology to develop new, HD-specific content. METHODS: New item pools were developed using cognitive debriefing with individuals with HD, and expert, literacy, and translatability reviews. Existing item banks and new item pools were field tested in 536 individuals with prodromal, early-, or late-stage HD. RESULTS: Moderate to strong relationships between Neuro-QoL/PROMIS measures and generic self-report measures of HRQOL, and moderate relationships between Neuro-QoL/PROMIS and clinician-rated measures of similar constructs supported the validity of Neuro-QoL/PROMIS in individuals with HD. Exploratory and confirmatory factor analysis, item response theory, and differential item functioning analyses were utilized to develop new item banks for Chorea, Speech Difficulties, Swallowing Difficulties, and Concern with Death and Dying, with corresponding six-item short forms. A four-item short form was developed for Meaning and Purpose. CONCLUSIONS: HDQLIFE encompasses both validated Neuro-QoL/PROMIS measures, as well as five new scales in order to provide a comprehensive assessment of HRQOL in HD.

New measures to capture end of life concerns in Huntington disease: Meaning and Purpose and Concern with Death and Dying from HDQLIFE (a patient-reported outcomes measurement system).

PURPOSE: Huntington disease (HD) is an incurable terminal disease. Thus, end of life (EOL) concerns are common in these individuals. A quantitative measure of EOL concerns in HD would enable a better understanding of how these concerns impact health-related quality of life. Therefore, we developed new measures of EOL for use in HD. METHODS: An EOL item pool of 45 items was field tested in 507 individuals with prodromal or manifest HD. Exploratory and confirmatory factor analyses (EFA and CFA, respectively) were conducted to establish unidimensional item pools. Item response theory (IRT) and differential item functioning analyses were applied to the identified unidimensional item pools to select the final items. RESULTS: EFA and CFA supported two separate unidimensional sets of items: Concern with Death and Dying (16 items), and Meaning and Purpose (14 items). IRT and DIF supported the retention of 12 Concern with Death and Dying items and 4 Meaning and Purpose items. IRT data supported the development of both a computer adaptive test (CAT) and a 6-item, static short form for Concern with Death and Dying. CONCLUSION: The HDQLIFE Concern with Death and Dying CAT and corresponding 6-item short form, and the 4-item calibrated HDQLIFE Meaning and Purpose scale demonstrate excellent psychometric properties. These new measures have the potential to provide clinically meaningful information about end-of-life preferences and concerns to clinicians and researchers working with individuals with HD. In addition, these measures may also be relevant and useful for other terminal conditions.

HDQLIFE: the development of two new computer adaptive tests for use in Huntington disease, Speech Difficulties, and Swallowing Difficulties.

PURPOSE: Huntington disease (HD) is an autosomal dominant neurodegenerative disease which results in several progressive symptoms, including bulbar dysfunction (i.e., speech and swallowing difficulties). Although difficulties in speech and swallowing in HD have a negative impact on health-related quality of life, no patient-reported outcome measure exists to capture these difficulties that are specific to HD. Thus, we developed a new patient-reported outcome measure for use in the Huntington Disease Health-Related Quality of Life (HDQLIFE) Measurement System that focused on the impact that difficulties with speech and swallowing have on HRQOL in HD. METHODS: Five hundred and seven individuals with prodromal and/or manifest HD completed 47 newly developed items examining speech and swallowing difficulties. Unidimensional item pools were identified using exploratory factor analysis and confirmatory factor analysis (EFA and CFA, respectively). Item response theory (IRT) was used to calibrate the final measures. RESULTS: EFA and CFA identified two separate unidimensional sets of items: Speech Difficulties (27 items) and Swallowing Difficulties (16 items). Items were calibrated separately for these two measures and resulted in item banks that can be administered as computer adaptive tests (CATs) and/or 6-item, static short forms. Reliability of both of these measures was supported through high correlations between the simulated CAT scores and the full item bank. CONCLUSIONS: CATs and 6-item calibrated short forms were developed for HDQLIFE Speech Difficulties and HDQLIFE Swallowing Difficulties. These measures both demonstrate excellent psychometric properties and may have clinical utility in other populations where speech and swallowing difficulties are prevalent.

Improving evidence developed from population-level experience with targeted agents.

Off-label drug use is common in oncology, due in part to significant unmet medical need, the rarity of many cancers, and the difficulty of conducting randomized controlled trials (RCTs) to support labeling of every drug in every disease setting. As new drugs are developed for use in tumors defined by genomic aberrations, it may be scientifically reasonable to expect that a targeted anti-cancer agent with efficacy in a biomarker-defined population within one tumor type may also have activity in another tumor type expressing the same biomarker. Such expectations also fuel off-label prescribing. However, the current approach to prescribing targeted agents off-label does not capture patient outcomes, thus missing an opportunity to gather data that could validate this approach. We explore the potential for collecting such data, highlight two proposals for oncology-specific patient registries, and put forward considerations that should be addressed to move toward better evidence development around off-label use.

Regulation of dopamine D3 receptor in the striatal regions and substantia nigra in diffuse Lewy body disease.

The regulation of D3 receptor has not been well documented in diffuse Lewy body disease (DLBD). In this study, a novel D3-preferring radioligand [(3)H]WC-10 and a D2-preferring radioligand [(3)H]raclopride were used and the absolute densities of the dopamine D3 and D2 receptors were determined in the striatal regions and substantia nigra (SN) from postmortem brains from five cases of DLBD, which included dementia with Lewy bodies (DLB, n=4) and Parkinson disease dementia (PDD, n=1). The densities of the dopamine D1 receptor, vesicular monoamine transporter 2 (VMAT2), and dopamine transporter (DAT) were also measured by quantitative autoradiography using [(3)H]SCH23390, [(3)H]dihydrotetrabenazine, and [(3)H]WIN35428, respectively. The densities of these dopaminergic markers were also measured in the same brain regions in 10 age-matched control cases. Dopamine D3 receptor density was significantly increased in the striatal regions including caudate, putamen and nucleus accumbens (NAc). There were no significant changes in the dopamine D1 and D2 receptor densities in any brain regions measured. VMAT2 and DAT densities were reduced in all the brain regions measured in DLB/PDD, however, the significant reduction was found in the putamen for DAT and in the NAc and SN for VMAT2. The decrease of dopamine pre-synaptic markers implies neuronal loss in the substantia nigra pars compacta (SNpc) in these DLB/PDD cases, while the increase of D3 receptors in striatal regions could be attributed to dopaminergic medication history and psychiatric states such as hallucinations. Whether it also reflects compensatory regulation upon dopaminergic denervation warrants further confirmations on larger populations.

Cerebral blood flow responses to dorsal and ventral STN DBS correlate with gait and balance responses in Parkinson's disease.

OBJECTIVES: The effects of subthalamic nucleus (STN) deep brain stimulation (DBS) on gait and balance vary and the underlying mechanisms remain unclear. DBS location may alter motor benefit due to anatomical heterogeneity in STN. The purposes of this study were to (1) compare the effects of DBS of dorsal (D-STN) versus ventral (V-STN) regions on gait, balance and regional cerebral blood flow (rCBF) and (2) examine the relationships between changes in rCBF and changes in gait and balance induced by D-STN or V-STN DBS. METHODS: We used a validated atlas registration to locate and stimulate through electrode contacts in D-STN and V-STN regions of 37 people with Parkinson's disease. In a within-subjects, double-blind and counterbalanced design controlled for DBS settings, we measured PET rCBF responses in a priori regions of interest and quantified gait and balance during DBS Off, unilateral D-STN DBS and unilateral V-STN DBS. RESULTS: DBS of either site increased stride length without producing significant group-level changes in gait velocity, cadence or balance. Both sites increased rCBF in subcortical regions and produced variable changes in cortical and cerebellar regions. DBS-induced changes in gait velocity are related to premotor cortex rCBF changes during V-STN DBS (r=-0.40, p=0.03) and to rCBF changes in the cerebellum anterior lobe during D-STN DBS (r=-0.43, p=0.02). CONCLUSIONS: DBS-induced changes in gait corresponded to rCBF responses in selected cortical and cerebellar regions. These relationships differed during D-STN versus V-STN DBS, suggesting DBS acts through distinct neuronal pathways dependent on DBS location.

Dopamine pathway loss in nucleus accumbens and ventral tegmental area predicts apathetic behavior in MPTP-lesioned monkeys.

Apathy, primarily defined as a lack of motivation, commonly occurs in people with Parkinson disease (PD). Although dysfunction of basal ganglia pathways may contribute to apathy, the role of dopamine remains largely unknown. We investigated the role of dopaminergic pathways in the manifestation of apathetic behaviors by measuring the effects of the selective dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on monkeys' willingness to attempt goal directed behaviors, distinct from their ability to perform tasks. Fifteen macaques received variable doses of MPTP, had PET scans with [(11)C]-dihydrotetrabenazine (DTBZ), [(11)C]-2ß-3ß-4-fluorophenyltropane (CFT), and [(18)F]-fluorodopa (FD) and performed tasks to assess apathetic behaviors and motor impairment. At 8 weeks post-MPTP, primates were euthanized and stereological cell counts and dopamine measurements were done. Apathy scores were compared to motor scores, in vitro and in vivo dopaminergic measures. Apathy scores increased following MPTP and correlated with DTBZ (r(S) = -0.85), CFT (r(S) = -0.87), and FD (r(S) = -0.85) specific uptake in nucleus accumbens (NAcc,) and dopaminergic cell counts in ventral tegmental area (VTA, r(S) = -0.80). Dopaminergic cell loss in VTA provided significant predictive power for apathy scores after controlling for the influence of cell loss in SN. Additionally, forward step-wise regression analyses indicated that neuropathological changes in the VTA-NAcc pathway predict apathetic behavior better than motor impairment or neuropathological changes in the nigrostriatal network. Our findings suggest that dopaminergic dysfunction within the VTA-NAcc pathway plays a role in the manifestation of apathetic behaviors in MPTP-lesioned primates. Similar changes in people with PD may contribute to apathy.

Neurologist care in Parkinson disease: a utilization, outcomes, and survival study.

OBJECTIVE: To investigate the utilization of neurologist providers in the treatment of patients with Parkinson disease (PD) in the United States and determine whether neurologist treatment is associated with improved clinical outcomes. METHODS: This was a retrospective observational cohort study of Medicare beneficiaries with PD in the year 2002. Multilevel logistic regression was used to determine which patient characteristics predicted neurologist care between 2002 and 2005 and compare the age, race, sex, and comorbidity-adjusted annual risk of skilled nursing facility placement and hip fracture between neurologist- and primary care physician-treated patients with PD. Cox proportional hazards models were used to determine the adjusted 6-year risk of death using incident PD cases, stratified by physician specialty. RESULTS: More than 138,000 incident PD cases were identified. Only 58% of patients with PD received neurologist care between 2002 and 2005. Race and sex were significant demographic predictors of neurologist treatment: women (odds ratio [OR] 0.78, 95% confidence interval [CI] 0.76-0.80) and nonwhites (OR 0.83, 95% CI 0.79-0.87) were less likely to be treated by a neurologist. Neurologist-treated patients were less likely to be placed in a skilled nursing facility (OR 0.79, 95% CI 0.77-0.82) and had a lower risk of hip fracture (OR 0.86, 95% CI 0.80-0.92) in logistic regression models that included demographic, clinical, and socioeconomic covariates. Neurologist-treated patients also had a lower adjusted likelihood of death (hazard ratio 0.78, 95% CI 0.77-0.79). CONCLUSIONS: Women and minorities with PD obtain specialist care less often than white men. Neurologist care of patients with PD may be associated with improved selected clinical outcomes and greater survival.

Reduced uptake of [¹8F]FDOPA PET in asymptomatic welders with occupational manganese exposure.

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 < 0.001). Caudate K(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.

Effects of deep brain stimulation of dorsal versus ventral subthalamic nucleus regions on gait and balance in Parkinson's disease.

OBJECTIVE: Deep brain stimulation (DBS) of the subthalamic nucleus (STN) improves motor function, including gait and stability, in people with Parkinson's disease (PD) but differences in DBS contact locations within the STN may contribute to variability in the degree of improvement. Based on anatomical connectivity, dorsal STN may be preferentially involved in motor function and ventral STN in cognitive function. METHODS: To determine whether dorsal DBS affects gait and balance more than ventral DBS, a double blind evaluation of 23 PD patients with bilateral STN DBS was conducted. Each participant underwent gait analysis and balance testing off Parkinson's medication under three DBS conditions (unilateral DBS in the dorsal STN region, unilateral DBS in the ventral STN region and both stimulators off) on 1 day. RESULTS: Improvements were seen in Unified Parkinson's Disease Rating Scale (UPDRS)-III scores and velocity in walking trials as fast as possible (Fast gait) and preferred pace (Pref gait), as well as stride length for Fast and Pref gait, with dorsal and ventral stimulation compared with the off condition (post hoc tests, p<0.05). However, there were no differences with dorsal compared to ventral stimulation. Balance, assessed using the multi-item mini-Balance Evaluation Systems Test (mini-BESTest), was similar across conditions. CONCLUSIONS: Absence of differences in gait and balance between the dorsal and ventral conditions suggests motor connections involved in gait and balance may be more diffusely distributed in STN than previously thought, as opposed to neural connections involved in cognitive processes, such as response inhibition, which are more affected by ventral stimulation.

Novel THAP1 sequence variants in primary dystonia.

BACKGROUND: THAP1 encodes a transcription factor (THAP1) that harbors an atypical zinc finger domain and regulates cell proliferation. An exon 2 insertion/deletion frameshift mutation in THAP1 is responsible for DYT6 dystonia in Amish-Mennonites. Subsequent screening efforts in familial, mainly early-onset, primary dystonia identified additional THAP1 sequence variants in non-Amish subjects. OBJECTIVE: To examine a large cohort of subjects with mainly adult-onset primary dystonia for sequence variants in THAP1. METHODS: With high-resolution melting, all 3 THAP1 exons were screened for sequence variants in 1,114 subjects with mainly adult-onset primary dystonia, 96 with unclassified dystonia, and 600 controls (400 neurologically normal and 200 with Parkinson disease). In addition, all 3 THAP1 exons were sequenced in 200 subjects with dystonia and 200 neurologically normal controls. RESULTS: Nine unique melting curves were found in 19 subjects from 16 families with primary dystonia and 1 control. Age at dystonia onset ranged from 8 to 69 years (mean 48 years). Sequencing identified 6 novel missense mutations in conserved regions of THAP1 (G9C [cervical, masticatory, arm], D17G [cervical], F132S [laryngeal], I149T [cervical and generalized], A166T [laryngeal], and Q187K [cervical]). One subject with blepharospasm and another with laryngeal dystonia harbored a c.-42C>T variant. A c.57C>T silent variant was found in 1 subject with segmental craniocervical dystonia. An intron 1 variant (c.71+9C>A) was present in 7 subjects with dystonia (7/1,210) but only 1 control (1/600). CONCLUSIONS: A heterogeneous collection of THAP1 sequence variants is associated with varied anatomical distributions and onset ages of both familial and sporadic primary dystonia.

In vivo amyloid imaging in autopsy-confirmed Parkinson disease with dementia.

OBJECTIVE: To investigate the specificity of in vivo amyloid imaging with [(11)C]-Pittsburgh Compound B (PIB) in Parkinson disease dementia (PDD). METHODS: We performed detailed neuropathologic examination for 3 individuals with PDD who had PIB PET imaging within 15 months of death. RESULTS: We observed elevated cortical uptake of [(11)C]-PIB on in vivo PET imaging in 2 of the 3 cases. At autopsy, all 3 individuals had abundant cortical Lewy bodies (Braak PD stage 6), and were classified as low-probability Alzheimer disease (AD) based on NIA-Reagan criteria. The 2 PIB-positive individuals had abundant diffuse Abeta plaques but only sparse neuritic plaques and intermediate neurofibrillary tangle pathology. The PIB-negative individual had rare diffuse plaques, no neuritic plaques, and low neurofibrillary tangle burden. CONCLUSIONS: [(11)C]-Pittsburgh Compound B (PIB) PET is specific for fibrillar Abeta molecular pathology but not for pathologic diagnosis of comorbid Alzheimer disease in individuals with Parkinson disease dementia. The ability to specifically identify fibrillar Abeta amyloid in the setting of alpha-synucleinopathy makes [(11)C]-PIB PET a valuable tool for prospectively evaluating how the presence of Abeta amyloid influences the clinical course of dementia in patients with Lewy body disorders.

Subthalamic nucleus stimulation-induced regional blood flow responses correlate with improvement of motor signs in Parkinson disease.

Deep brain stimulation of the subthalamic nucleus (STN DBS) improves motor symptoms in idiopathic Parkinson's disease, yet the mechanism of action remains unclear. Previous studies indicate that STN DBS increases regional cerebral blood flow (rCBF) in immediate downstream targets but does not reveal which brain regions may have functional changes associated with improved motor manifestations. We studied 48 patients with STN DBS who withheld medication overnight and underwent PET scans to measure rCBF responses to bilateral STN DBS. PET scans were performed with bilateral DBS OFF and ON in a counterbalanced order followed by clinical ratings of motor manifestations using Unified Parkinson Disease Rating Scale 3 (UPDRS 3). We investigated whether improvement in UPDRS 3 scores in rigidity, bradykinesia, postural stability and gait correlate with rCBF responses in a priori determined regions. These regions were selected based on a previous study showing significant STN DBS-induced rCBF change in the thalamus, midbrain and supplementary motor area (SMA). We also chose the pedunculopontine nucleus region (PPN) due to mounting evidence of its involvement in locomotion. In the current study, bilateral STN DBS improved rigidity (62%), bradykinesia (44%), gait (49%) and postural stability (56%) (paired t-tests: P < 0.001). As expected, bilateral STN DBS also increased rCBF in the bilateral thalami, right midbrain, and decreased rCBF in the right premotor cortex (P < 0.05, corrected). There were significant correlations between improvement of rigidity and decreased rCBF in the SMA (r(s) = -0.4, P < 0.02) and between improvement in bradykinesia and increased rCBF in the thalamus (r(s) = 0.31, P < 0.05). In addition, improved postural reflexes correlated with decreased rCBF in the PPN (r(s) = -0.38, P < 0.03). These modest correlations between selective motor manifestations and rCBF in specific regions suggest possible regional selectivity for improvement of different motor signs of Parkinson's disease.

Neural correlates of STN DBS-induced cognitive variability in Parkinson disease.

BACKGROUND: Although deep brain stimulation of the subthalamic nucleus (STN DBS) in Parkinson disease (PD) improves motor function, it has variable effects on working memory (WM) and response inhibition (RI) performance. The purpose of this study was to determine the neural correlates of STN DBS-induced variability in cognitive performance. METHODS: We measured bilateral STN DBS-induced blood flow changes (PET and [(15)O]-water on one day) in the supplementary motor area (SMA), dorsolateral prefrontal cortex (DLPFC), anterior cingulate cortex (ACC), and right inferior frontal cortex (rIFC) as well as in exploratory ROIs defined by published meta-analyses. STN DBS-induced WM and RI changes (Spatial Delayed Response and Go-No-Go on the next day) were measured in 24 PD participants. On both days, participants withheld PD medications overnight and conditions (OFF vs. ON) were administered in a counterbalanced, double-blind manner. RESULTS: As predicted, STN DBS-induced DLPFC blood flow change correlated with change in WM, but not RI performance. Furthermore, ACC blood flow change correlated with change in RI but not WM performance. For both relationships, increased blood flow related to decreased cognitive performance in response to STN DBS. Of the exploratory regions, only blood flow changes in DLPFC and ACC were correlated with performance. CONCLUSIONS: These results demonstrate that variability in the effects of STN DBS on cognitive performance relates to STN DBS-induced cortical blood flow changes in DLPFC and ACC. This relationship highlights the need to further understand the factors that mediate the variability in neural and cognitive response to STN DBS.