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Background The clinical diagnosis of Parkinson's disease (PD) requires the presence of parkinsonism and supportive criteria that include a clear and dramatic beneficial response to dopaminergic therapy. Our aim was to test the diagnostic criterion of dopaminergic response by evaluating its association with pathologically confirmed diagnoses in a large population of parkinsonian patients. Methods We reviewed clinical data maintained in an electronic medical record from all patients with autopsy data who had been seen in the Movement Disorders Center at Washington University, St. Louis, between 1996 and 2018. All patients with parkinsonism who underwent postmortem neuropathologic examination were included in this analysis. Results There were 257 unique parkinsonian patients with autopsy-based diagnoses who had received dopaminergic therapy. Marked or moderate response to dopaminergic therapy occurred in 91.2% (166/182) of those with autopsy-confirmed PD, 52.0% (13/25) of those with autopsy-confirmed multiple systems atrophy, 44.4% (8/18) of those with autopsy-confirmed progressive supranuclear palsy, and 1 (1/8) with autopsy-confirmed corticobasal degeneration. Other diagnoses were responsible for the remaining 24 individuals, 9 of whom had a moderate response to dopaminergic therapy. Conclusion A substantial response to dopaminergic therapy is frequent but not universal in PD. An absent response does not exclude PD. In other neurodegenerative disorders associated with parkinsonism, a prominent response may also be evident, but this occurs less frequently than in PD. © 2020 International Parkinson and Movement Disorder Society.

Background Gait impairments are common in Parkinson's Disease (PD) and are likely caused by degeneration in multiple brain circuits, including the basal ganglia, thalamus and mesencephalic locomotion centers (MLC). Diffusion tensor imaging (DTI) assesses fractional anisotropy (FA) and mean diffusivity (MD) that reflect the integrity of neuronal microstructure. We hypothesized that DTI changes in motor circuits correlate with gait changes in PD. Objective We aimed to identify microstructural changes of brain locomotion control centers in PD via DTI and their correlations with clinical and quantitative measures of gait. Methods Twenty-one PD patients reporting gait impairment and 15 controls were recruited. Quantitative gait and clinical tests were recorded in PD subjects’ medication ON and OFF states. Region of Interest (ROI) analysis of the thalamus, basal ganglia and MLC was performed using ExploreDTI. Correlations between FA/MD with clinical gait parameters were examined. Results Microstructural changes were seen in the thalamus, caudate and MLC in the PD compared to the control group. Thalamic microstructural changes significantly correlated with gait parameters in the pace domain including the Timed Up and Go in the ON state. Caudate changes correlated with cadence and stride time in the OFF state. Conclusions Our pilot study suggests that PD is associated with a characteristic regional pattern of microstructural degradation in the thalamus, caudate and MLC. The DTI changes may represent subcortical locomotion network failure. Overall, DTI ROI analyses might provide a useful tool for assessing PD for functional status and specific motor domains, such as gait, and potentially could serve as an imaging marker.

Magnetic resonance imaging of subcortical gray matter structures, which mediate behavior, cognition and the pathophysiology of several diseases, is crucial for establishing typical maturation patterns across the human lifespan. This single site study examines T1-weighted MPRAGE images of 3 healthy cohorts: (i) a cross-sectional cohort of 406 subjects aged 5-83 years; (ii) a longitudinal neurodevelopment cohort of 84 subjects scanned twice approximately 4 years apart, aged 5-27 years at first scan; and (iii) a longitudinal aging cohort of 55 subjects scanned twice approximately 3 years apart, aged 46-83 years at first scan. First scans from longitudinal subjects were included in the cross-sectional analysis. Age-dependent changes in thalamus, caudate, putamen, globus pallidus, nucleus accumbens, hippocampus, and amygdala volumes were tested with Poisson, quadratic, and linear models in the cross-sectional cohort, and quadratic and linear models in the longitudinal cohorts. Most deep gray matter structures best fit to Poisson regressions in the cross-sectional cohort and quadratic curves in the young longitudinal cohort, whereas the volume of all structures except the caudate and globus pallidus decreased linearly in the longitudinal aging cohort. Males had larger volumes than females for all subcortical structures, but sex differences in trajectories of change with age were not significant. Within subject analysis showed that 65%-80% of 13-17 year olds underwent a longitudinal decrease in volume between scans (∼4 years apart) for the putamen, globus pallidus, and hippocampus, suggesting unique developmental processes during adolescence. This lifespan study of healthy participants will form a basis for comparison to neurological and psychiatric disorders. Hum Brain Mapp 38:3771-3790, 2017. © 2017 Wiley Periodicals, Inc.

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.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.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.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.

OBJECTIVE: The huntingtin gene is critical for the formation and differentiation of the CNS, which raises questions about the neurodevelopmental effect of CAG expansion mutations within this gene (mHTT) that cause Huntington disease (HD). We sought to test the hypothesis that child and adolescent carriers of mHTT exhibit different brain growth compared to peers without the mutation by conducting structural MRI in youth who are at risk for HD. We also explored whether the length of CAG expansion affects brain development. METHODS: Children and adolescents (age 6–18) with a parent or grandparent diagnosed with HD underwent MRI and blinded genetic testing to confirm the presence or absence of mHTT. Seventy-five individuals were gene-expanded (GE) and 97 individuals were gene-nonexpanded (GNE). The GE group was estimated to be on average 35 years from clinical onset. Following an accelerated longitudinal design, age-related changes in brain regions were estimated. RESULTS: Age-related striatal volume changes differed significantly between the GE and GNE groups, with initial hypertrophy and more rapid volume decline in GE. This pattern was exaggerated with CAG expansion length for CAG > 50. A similar age-dependent group difference was observed for the globus pallidus, but not in other major regions. CONCLUSION: Our results suggest that pathogenesis of HD begins with abnormal brain development. An understanding of potential neurodevelopmental features associated with mHTT may be needed for optimized implementation of preventative gene silencing therapies, such that normal aspects of neurodevelopment are preserved as neurodegeneration is forestalled.

Purpose Freezing of gait is a major source of disability associated with the progression of Parkinson's disease (PD). Our objective was to determine whether evolving changes in nigral iron content in association with declining motor function in early PD differentiates subjects who develop freezing from those who do not. Methods A cohort of previously untreated individuals with early PD (n = 19) was followed for 36 months clinically and with MRI. The cohort was divided into two groups based on the development of freezing during follow-up. A multiple gradient echo MRI sequence provided an index of basal ganglia iron content. Results There were significant baseline differences between those who developed freezing (n = 7) and those who did not (n = 12) in Unified Parkinson's Disease Rating Scale motor scores, time to complete a 14 m walk and timed up and go. There was a significant correlation between the measured change in transverse relaxation in the lateral substantia nigra pars compacta and the change in motor score from baseline to 36 months (p = 0.002). The freezing group showed a greater change in motor score and iron content than did the non-freezing group. Conclusions Individuals destined to develop freezing early in PD have more motor impairment at baseline, more rapid deterioration in motor function, and pars compacta changes suggestive of increased iron content in comparison to those who do not.

Huntington disease (HD) is a neurodegenerative condition with prominent motor (including oculomotor), cognitive, and psychiatric effects. While neuropsychological deficits are present in HD, motor impairments may impact performance on neuropsychological measures, especially those requiring a speeded response, as has been demonstrated in multiple sclerosis and schizophrenia. The current study is the first to explore associations between oculomotor functions and neuropsychological performance in HD. Participants with impaired oculomotor functioning performed worse than those with normal oculomotor functioning on cognitive tasks requiring oculomotor involvement, particularly on psychomotor speed tasks, controlling for covariates. Consideration of oculomotor dysfunction on neuropsychological performance is critical, particularly for populations with motor deficits.

Background: Parkinson disease (PD) presents with motor and non-motor symptoms (NMS). The NMS often precede the onset of motor symptoms, but may progress throughout the disease course. Tremor dominant, postural instability gait difficulty (PIGD), and indeterminate phenotypes can be distinguished using Unified PD Rating scales (UPDRS-III). We hypothesized that the PIGD phenotype would be more likely to develop NMS, and that the non-dopamine–responsive axial signs would correlate with NMS severity. Methods: We conducted a retrospective cross-sectional chart review to assess the relationship between NMS and PD motor phenotypes. PD patients were administered the NMS Questionnaire, the UPDRS-III, and the Mini-Mental State Examination score. The relationship between NMS burden and PD subtypes was examined using linear regression models. The prevalence of each NMS among difference PD motor subtypes was analyzed using chi-square test. Results: PD patients with more advanced disease based on their UPDRS-III had higher NMS Questionnaire scores. The axial component of UPDRS-III correlated with higher NMS. There was no correlation between NMS and tremor scores. There was a significant correlation between PIGD score and higher NMS burden. PIGD group had higher prevalence in most NMS domains when compared with tremor dominant and indeterminate groups independent of disease duration and severity. Conclusions: NMS profile and severity vary according to motor phenotype. We conclude that in the PD population, patients with a PIGD phenotype who have more axial involvement, associated with advanced disease and poor motor response, have a higher risk for a higher NMS burden.

Objective To determine whether, in patients with early Parkinson's disease (PD), longitudinal changes in midbrain iron content are associated with declining motor function over a period of three years. Methods Nineteen untreated subjects with early PD and 13 age- and sex-matched controls were followed clinically for 36 months. MRI with a 3 T magnet was performed at baseline, 18 months and 36 months with a multiple gradient echo sequence designed for rapid single-scan mapping of the proton transverse relaxation rate R 2 *. R 2 * was calculated for midbrain and forebrain basal ganglia regions. Results A difference in R 2 * between patients and controls was observed at baseline ( p = 0.035) but not at 18 or 36 months in the lateral substantia nigra pars compacta (SNc). Linear regression indicated significant correlations between the change in R 2 * in the lateral SNc and the change score in UPDRS III ( p = 0.008) and the PDQ-39 -mobility sub-score ( p = 0.03) from baseline to 36 months. R 2 * tended to increase in those with more advanced disease and to decrease in those with milder disease. Conclusions High field MRI demonstrates lateral SNc abnormalities that progress over 3 years in early PD consistent with increased iron content in those with more advanced disease, corresponding to the known distribution of neuronal loss occurring in this disorder, and correlating with motor symptomatology. Larger and longer investigations with more precise mapping of iron-containing midbrain structures are needed to fully evaluate the potential of R 2 * as a biomarker of disease progression in PD.

Background Accurate diagnosis of Parkinson disease (PD) and other degenerative parkinsonian syndromes is important for management and prognostic purposes. Diagnosis can be challenging in early disease and in atypical cases. Methods We reviewed the literature on the application of dopamine transporter single-photon emission computed tomography (DAT-SPECT) in degenerative parkinsonism and related disorders as a diagnostic tool. Results The use of DAT-SPECT shows some utility in the early diagnosis of PD and differentiation from other non-degenerative parkinsonian disorders (i.e. essential tremor, dystonic tremor, drug-induced and in most cases of psychogenic parkinsonism), since it can accurately detect the presynaptic dopaminergic deficit. The test has been shown to have high sensitivity/specificity by multiple studies. DAT imaging may also have some prognostic value for disease progression. However, it has limited value in differentiating among degenerative causes of parkinsonism. DAT imaging has some limitations. In most studies, true test accuracy is unknown since the gold standard is clinical diagnosis by a movement disorders neurologist. Therefore, the sensitivity of the test cannot exceed that of the clinical diagnosis. In addition, false negative scans occur and highlight the need for clinical follow-up. Conclusion Clinical assessment remains the most important aspect in evaluating these patients. DAT-SPECT is a sensitive modality to detect nigrostriatal degeneration. In spite of increasing data using this technique, however, more long-term clinical studies are required to determine how DAT-SPECT scan can guide decision-making.

Huntington disease (HD) is a neurodegenerative disorder that involves preferential atrophy in the striatal complex and related subcortical nuclei. In this article, which is based on a dataset extracted from the PREDICT-HD study, we use statistical shape analysis with deformation markers obtained through "Large Deformation Diffeomorphic Metric Mapping" of cortical surfaces to highlight specific atrophy patterns in the caudate, putamen, and globus pallidus, at different prodromal stages of the disease. On the basis of the relation to cortico-basal ganglia circuitry, we propose that statistical shape analysis, along with other structural and functional imaging studies, may help expand our understanding of the brain circuitry affected and other aspects of the neurobiology of HD, and also guide the most effective strategies for intervention.

Background Parkinson's disease (PD), characterized by motor dysfunction and cognitive decline, may demonstrate specific patterns of brain atrophy. Although cross-sectional magnetic resonance imaging (MRI) studies show correlation between regional brain volume loss and cognitive impairment, there is only scarce evidence from longitudinal studies validating the link between cognition and brain anatomy in PD. Objective To test the relationship between magnitude and spatial extent of atrophy in PD patients with progressive, significant cognitive decline and dementia (PDD). Methods We followed thirty-three initially non-demented patients with prevalent PD for three years while monitoring cognitive function and brain atrophy. Longitudinally acquired T1-weighted magnetic resonance images were analyzed in the voxel-based morphometry framework of SPM. Results Groups did not differ significantly with respect to age or gender. More males developed PDD (7 males, 3 females) compared to those remaining intact (12 males, 11 females). Clusters of lower grey matter volume were found in PDD compared to PD in left uncus at baseline and an expanded region that included the left hippocampus and parahippocampal gyrus at 36 months. The cognitive status by scan interaction showed differential changes between groups in the right insula. At a more liberal statistical threshold we observed changes in the right insula and bilateral hippocampi as well as the right cuneus additional to the lower brain stem. Conclusions Region specific atrophy, consistent with the pattern of cortical Lewy body deposition seen in autopsy studies, can be detected with MRI in PD patients with significant cognitive decline. MRI may be useful for tracking cognitive decline in PD.

Identifying measures that are associated with the cytosine-adenine-guanine (CAG) expansion in individuals before diagnosis of Huntington disease (HD) has implications for designing clinical trials.To identify the earliest features associated with the motor diagnosis of HD in the Prospective Huntington at Risk Observational Study (PHAROS).A prospective, multicenter, longitudinal cohort study was conducted at 43 US and Canadian Huntington Study Group research sites from July 9, 1999, through December 17, 2009. Participants included 983 unaffected adults at risk for HD who had chosen to remain unaware of their mutation status. Baseline comparability between CAG expansion (≥37 repeats) and nonexpansion (37 repeats) groups was assessed. All participants and investigators were blinded to individual CAG analysis. A repeated-measures analysis adjusting for age and sex was used to assess the divergence of the linear trend between the expanded and nonexpanded groups. Data were analyzed from April 27, 2010, to September 3, 2013.Huntington disease mutation status in individuals with CAG expansion vs without CAG expansion.Unified Huntington's Disease Rating Scale motor (score range, 0-124; higher scores indicate greater impairment), cognitive (symbol digits modality is the total number of correct responses in 90 seconds; lower scores indicate greater impairment), behavioral (score range, 0-176; higher scores indicate greater behavioral symptoms), and functional (Total Functional Capacity score range, 0-13; lower scores indicate reduced functional ability) domains were assessed at baseline and every 9 months up to a maximum of 10 years.Among the 983 research participants at risk for HD in the longitudinal cohort, 345 (35.1%) carried the CAG expansion and 638 (64.9%) did not. The mean (SD) duration of follow-up was 5.8 (3.0) years. At baseline, participants with expansions had more impaired motor (3.0 [4.2] vs 1.9 [2.8]; P .001), cognitive (P .05 for all measures except Verbal Fluency, P = .52), and behavioral domain scores (9.4 [11.4] vs 6.5 [8.5]; P .001) but not significantly different measures of functional capacity (12.9 [0.3] vs 13.0 [0.2]; P = .23). With findings reported as mean slope (95% CI), in the longitudinal analyses, participants with CAG expansions showed significant worsening in motor (0.84 [0.73 to 0.95] vs 0.03 [-0.05 to 0.11]), cognitive (-0.54 [-0.67 to -0.40] vs 0.22 [0.12 to 0.32]), and functional (-0.08 [-0.09 to -0.06] vs -0.01 [-0.02 to 0]) measures compared with those without expansion (P .001 for all); behavioral domain scores did not diverge significantly between groups.Using these prospectively accrued clinical data, relatively large treatment effects would be required to mount a randomized, placebo-controlled clinical trial involving premanifest HD individuals who carry the CAG expansion.

Age-related ventricular enlargement is accelerated in Alzheimer's disease, but its relationship to cognitive decline in Parkinson's disease is less clear, even though dementia is common in Parkinson's disease. Our goals were to determine if greater enlargement of the ventricles and gray or white matter atrophy occurred in Parkinson's disease patients developing cognitive decline. Older nondemented patients with Parkinson's disease (33) and age- and sex-matched controls (39) were recruited and prospectively assessed for the development of significant cognitive decline over 36 months. Magnetic resonance imaging was obtained every 18 months, and ventricular volume and total brain gray and white matter volumes were measured using reliable segmentation of T1-weighted volumetric scans. Subjects with incidental intracranial abnormalities, an atypical course, and stroke as well as dropouts were excluded from a cohort of 52 patients and 50 controls. Among 33 patients and 39 controls, 10 patients and 3 controls developed significant cognitive impairment or dementia. Ventricular change and Parkinson's disease status were significantly associated with dementia. Ventricular change was significantly correlated with change in Mini-Mental Status Examination in the Parkinson's disease with dementia group (r = 0.87, P = .001). Gray matter atrophy was greater in Parkinson's disease with dementia, with similar change over time in both Parkinson's disease and Parkinson's disease with dementia. White matter volumes were not significantly different between Parkinson's disease and Parkinson's disease with dementia; however, the decrease over time might be greater in Parkinson's disease with dementia. Ventricular dilatation occurs early in the course of significant cognitive decline in patients with Parkinson's disease, possibly reflecting both cortical gray and white matter loss. © 2011 Movement Disorder Society

Biochemical studies have reported increased iron content in the substantia nigra pars compacta (SNc) in Parkinson disease (PD), with changes most marked in severe disease, suggesting that measurement of regional iron content in the nigra may provide an indication of the pathologic severity of the disease. Although basal ganglia structures, including the substantia nigra, are readily visualized with MRI, in part because of their high iron content, conventional imaging techniques have failed to show definitive abnormalities in individuals with PD. We have developed MRI-based methodology to estimate regional iron content utilizing a 1.5 tesla system and have shown a correlation between age and striatal iron, as well as a significant increase in putaminal and pallidal iron in PD that correlated with the severity of clinical symptomatology. Several investigators have utilized novel MR techniques implemented on 3 tesla magnets and have suggested the presence of increased nigral iron content in treated patients with PD, in addition to a correlation between nigral iron and simple reaction time. We have applied a modification of our original method to determine whether SNc changes evident at 3 tesla corresponded anatomically to the distribution of neuropathologic changes reported previously. Our results indicate the presence of lateral SNc abnormalities in untreated patients with early PD, consistent with increased iron content and corresponding to the known distribution of neuronal loss occurring in this disorder. We suggest that this may ultimately provide an imaging marker for disease progression in PD, although longitudinal studies are required.

The purpose of this study was to determine if focal cortical abnormalities may occur in early Parkinson's disease (PD). We studied 26 untreated patients with early PD and 14 healthy control subjects, with cognitive screening and magnetic resonance imaging (MRI). Voxel-based morphometry was used to assess for the presence of localized cortical grey matter (GM) and/or subcortical white matter (WM) changes. Patient and control groups showed no differences in age or gender distribution. Females had a greater GM% than males (P = 0.001). Comparison of patients and controls revealed no difference in local GM volumes. In PD, however, there was decreased WM volume in the anterior right fusiform gyrus and superior temporal gyrus. There were no correlations between the California Verbal Learning Test long delay free recall, Judgment of Line Orientation, Trail Making A or B and either the GM or WM localized volumes. These results suggest that right anterior temporal lobe changes occur in untreated patients with PD. The earliest changes may occur in subcortical white matter rather than temporal cortex.

Although motor symptoms of Parkinson's disease (PD) are initially responsive to dopamine replacement therapy, nonresponsive features develop over time, suggesting that impaired dopaminergic function alone may not be wholly responsible for all the motor features of the disease. Previous studies suggest impaired function in the presupplementary motor area (pre-SMA) in PD. Our objective was to determine whether pre-SMA abnormalities are present in untreated patients with early disease. We measured N-acetyl aspartate (NAA)/creatine (Cr) and choline (Cho)/Cr ratios in pre-SMA in 26 untreated patients with early PD (disease duration 3.0 ± 2.0 yr) and 15 control subjects with single voxel magnetic resonance spectroscopy. Neither NAA/Cr nor Cho/Cr ratios differed significantly between groups. These observations suggest that, although pre-SMA function is impaired in moderately advanced PD, it is relatively spared in early disease. We suggest that pre-SMA dysfunction is in part responsible for the dopamine nonresponsive features associated with disease progression. © 2008 Movement Disorder Society

While Parkinson's disease (PD) is associated with motor slowing, less attention has been paid to variability in performance on motor and cognitive tasks. To examine reaction time latencies and intraindividual variability in untreated patients with PD compared to healthy controls. Twenty-nine (19 men/10 women) patients with untreated PD and 16 controls (8 men/8 women) were examined using measures of simple reaction time (SRT) and choice reaction time (CRT) in addition to cognitive measures of executive function (Trail Making Test; adaptive digit ordering). Latencies and intraindividual variability were compared between groups. Partial correlation coefficients, adjusting for age, sex and education were used to examine the relationship between RT measures and motor or cognitive measures. Patients and controls did not differ with respect to age or sex distribution. Education and cognitive status differed between groups, but no subject was demented or clinically depressed. After adjusting for age, sex and education, significant group differences were found in latencies (2-choice RT and 8-choice RT) and intraindividual variability scores (all CRT conditions). Latencies did not differ significantly after adjusting for finger tapping rate. In the PD group neither the motor nor the executive measures correlated significantly with any of the reaction time measures. We conclude that CRT intraindividual variability and latencies are increased in untreated PD.

Objective To determine the sensitivity of positron emission tomography with11C-labeled dihydrotetrabenazine (DTBZ) to the nigrostriatal changes associated with early, untreated Parkinson's disease (PD), and to determine the correlation between any regionally reduced DTBZ binding and the major motor features of PD. Methods Untreated patients with early PD (n = 27) and age-matched control subjects (n = 33) underwent DTBZ/positron emission tomography scanning to measure binding to the presynaptic type 2 vesicular monoamine transporter site in dopaminergic neurons in basal ganglia regions. Clinical symptoms were rated with the Unified Parkinson's Disease Rating Scale. Results Mean striatal DTBZ binding values in the patient group were decreased as compared with control subjects (p < 0.001) in all regions examined. The difference between patients and control subjects was most marked in the midputamen, where only one patient had DTBZ binding within 3 standard deviations of the control mean. Bradykinesia and rigidity scores correlated with DTBZ binding in the contralateral midputamen region, particularly for the clinically least affected limbs. Tremor scores showed no significant correlation. Interpretation Reduced striatal binding of DTBZ is associated with early PD. Tremor appears to be only partially related to presynaptic dopaminergic function and may have a mechanism differing from that of symptoms such as bradykinesia. The method appears to be most sensitive in mildly affected individuals with a possible “floor” effect that may limit the degree of additional change occurring once more severe clinical symptoms are evident. Ann Neurol 2008

Objective: Subtle signs and symptoms of Huntington disease (HD) are often present before impairments reach a point where the neurologic disease is manifest and a diagnosis must be considered. The objective is to examine the prognostic significance of these early clinical signs and symptoms regarding time until unequivocal clinical HD diagnosis. Methods: We analyzed longitudinal data from 218 at-risk but healthy participants in the Huntington Study Group database who had either normal motor examination results or minimal soft motor signs at first observation. This group was followed periodically in HD clinics for up to 4.5 years. We used survival analysis to examine predictors of time until HD diagnosis. Results: Diagnostic prediction was significantly improved using specific, nonredundant items from the Unified Huntington9s Disease Rating Scale. When a movement disorder specialist initially had a global impression of “soft signs” present, cumulative relative risk of diagnosis was 4.68 times greater at 1.5 years of follow-up and 3.58 at 3 years. A neuropsychological test pattern with psychomotor speed 1 SD worse than a semantic knowledge measure increased cumulative risk by 1.99 times at 1.5 years and 1.81 at 3 years. Finally, reports of various subjective HD symptoms increased 3-year relative risk by 2.6 to 3.4. Conclusions: Findings demonstrate that neuropsychological performance and both the clinician rating and the patient subjective perception of motor difficulties contribute nonredundantly to a prediction of Huntington disease diagnosis. These findings may have implications for prognostic assessment of persons at risk and eventually assist with early interventions.

Objective: To determine if future studies of coenzyme Q10 and GPI-1485 in Parkinson disease (PD) may be warranted. Methods: We conducted a randomized, double-blind, calibrated futility clinical trial of coenzyme Q10 and GPI-1485 in early untreated PD using placebo data from the DATATOP study to establish the futility threshold. Results: The primary outcome measure (change in total Unified Parkinson's Disease Rating Scale scores over 1 year) did not meet the prespecified criteria for futility for either agent. Secondary analyses using calibration controls and other more recent placebo data question the appropriateness of the predetermined definition of futility, and suggest that a more restrictive threshold may be needed. Conclusions: Coenzyme Q10 and GPI-1485 may warrant further study in Parkinson disease, although the data are inconsistent. Additional factors (cost, availability of other agents, more recent data on placebo outcomes, other ongoing trials) should also be considered in the selection of agents for Phase III studies. NEUROLOGY 2007;68:20-28

The objective of this study was to compare basal ganglia activation in patients with Parkinson's disease to that of healthy controls, using functional MRI (fMRI). Six mildly-affected patients, off antiparkinsonian medications for at least 12h, and seven age-matched controls performed a unilateral motor switching task during fMRI data acquisition. Clear differences in basal ganglia activation were seen, with control subjects showing greater activation during both the left and right movement sessions. We observed activation of right sided basal ganglia structures in both groups, particularly with right sided movements, with caudate activation noted most frequently. This observation is consistent with right caudate involvement in the learning of new tasks and in association with externally paced movements.

The serum concentration of the copper protein ceruloplasmin has been an important diagnostic indicator of Wilson's disease (WD). It is widely quoted that 95% of people with WD have low serum ceruloplasmin concentrations. Current evidence suggests that a normal serum ceruloplasmin concentration is more common in patients with WD, particularly those with liver disease, perhaps in part because of the routine use of an immunologic assay. This assay might indicate a normal level of ceruloplasmin when the enzymatic activity is lower. Enzymatic activity is the biologically relevant parameter. We compared the immunologic measurement with the enzymatic assessment of oxidase activity in patients with liver or neurologic symptoms of unknown origin in whom WD was considered in the differential diagnosis. Although a strong correlation of ceruloplasmin protein concentration with oxidase activity was observed in controls, this was not the case for these patients. Twelve patients, presenting with various types of hepatic disease, demonstrated a weak correlation between ceruloplasmin protein concentration and oxidase activity. Ten percent of patients with neurologic symptoms ( n = 41) had low ceruloplasmin concentrations and oxidase activity, and another 8% had normal ceruloplasmin concentrations associated with low oxidase activity. Although the enzymatic method is preferred for its biologic relevance, ceruloplasmin analysis is not a reliable diagnostic parameter for the diagnosis of WD in patients with liver disease. An important use of the ceruloplasmin oxidase assay is in the follow-up of patients with WD. Ceruloplasmin oxidase activity was undetectable in sera from patients with WD who were undergoing long-term chelation therapy, suggesting an early sign of copper depletion and a need for subsequent monitoring for symptoms of copper deficiency.

Parkinson's disease (PD) is a common neurodegenerative disorder in humans with wide variability in the age of disease onset. Although the disease has been thought previously to occur sporadically in most patients, there is increasing evidence of a genetic contribution to the disorder. Recently, a polymorphic variant within intron 6 of the Nurr1 gene was reported to be associated with sporadic and familial PD. In an effort to identify susceptibility genes for PD, we have collected 783 PD patients from 372 families and 397 healthy controls from 217 families. PD patients and healthy controls were genotyped for the intron 6 insertion polymorphism by BseRI restriction endonuclease digestion. No significant difference in either homozygosity or heterozygosity for the 7048G7049 (IVS6 1361 +16insG) polymorphism was detected in the PD patient cohort as compared with the panel of healthy controls. Moreover, direct sequencing of exon 1 of the Nurr1 gene in PD patients failed to detect either of the two recently reported Nurr1 mutations identified in a small subset of a PD patient cohort. Taken together, these data suggest that genetic alteration at the Nurr1 locus is not a significant risk factor for the development of Parkinson's disease in our large sample of familial PD patients.

Parkinson disease (PD) is the second most common neurodegenerative disorder. We studied 754 affected individuals, comprising 425 sibling pairs, to identify PD susceptibility genes. Screening of the parkin gene was performed in a subset of the sample having earlier age of PD onset or a positive LOD score with a marker in the parkin gene. All subjects were evaluated using a rigorous neurological assessment. Two diagnostic models were considered for genome-wide, non-parametric linkage analyses. Model I included only those individuals with a more stringent diagnosis of verified PD (216 sibling pairs) and resulted in a maximum LOD score of 3.4 on chromosome 2. Model II included all affected individuals (425 sibling pairs) and yielded a LOD score of 3.1 on the X chromosome. Our large sample was then employed to test for gene-by-gene (epistatic) interactions. A genome screen using the 23 families with PD patients having a mutation in only one allele of the parkin gene detected evidence of linkage to chromosome 10 (LOD=2.3). The 85 families with a very strong family history of PD were employed in a genome screen and, in addition to strong evidence of linkage to chromosome 2 (LOD = 4.9), also produced a LOD of 2.4 on chromosome 14. A genome screen performed in the 277 families without a strong family history of PD detected linkage to chromosomes 10 (LOD = 2.4) and X (LOD = 3.2). These findings demonstrate consistent evidence of linkage to chromosomes 2 and X and also support the hypothesis that gene-by-gene interactions are important in PD susceptibility.

Parkinson's disease is a progressive neurodegenerative disorder that demands a holistic approach to treatment. Both pharmacologic and nonpharmacologic interventions play an important role in the comprehensive management of this disorder. While levodopa remains the single most effective medication for symptomatic treatment, dopamine agonists are playing an increasingly important role. Motor complications of dopaminergic therapy are a significant issue, particularly in patients with more advanced disease who have been on levodopa for several years. All therapeutic interventions must be tailored to the individual and modified as the disease progresses, with the goal of minimizing significant functional disability as much as possible.

A multiple-gradient-echo sequence is proposed for accurately mapping R in the presence of in-slice macroscopic susceptibility gradients. In-slice signal loss caused by background macroscopic susceptibility gradients is mitigated by combining three successive gradient-echo images whose slice refocus gradients are successively incremented. The optimum incrementation of slice-refocusing gradients was determined by numerical simulation. By repeating further cycles of three images in the same sequence, artifact-compensated data spanning a range of echo times (TEs) was acquired leading to single-scan, R maps that are quantitatively reflective of microscopic field inhomogeneities. The performance of the sequence was demonstrated at 3.0T, first with a doped aqueous phantom, and then on the head of a normal volunteer. That performance is compared quantitatively with previously published work. Magn Reson Med 48:867–876, 2002. © 2002 Wiley-Liss, Inc.

We studied daytime sleepiness in 160 patients with Parkinson's disease and 40 normal subjects. We compared the prevalence of daytime sleepiness in patients who were taking levodopa alone, levodopa with bromocriptine, levodopa with ropinirole, and levodopa with pramipexole. We found that (1) all these anti-Parkinson drugs can cause daytime sleepiness; (2) 'dozing off' correlated highly with 'falling asleep without warning'; (3) after statistical adjustment for confounding variables there was no significant difference among the risks for any of these anti-Parkinson drugs causing daytime somnolence.

Background Preclinical studies suggest that glutamate antagonists help ameliorate motor fluctuations in patients with PD treated with levodopa. Methods In a multicenter, randomized, double-blind, placebo-controlled, parallel-group, dose-ranging study, the authors assessed the safety, tolerability, and efficacy of the glutamate receptor blocker remacemide hydrochloride in 279 patients with motor fluctuations treated with levodopa. The primary objective was to assess the short-term tolerability and safety of four dosage levels of remacemide during 7 weeks of treatment. Patients were also monitored with home diaries and the Unified PD Rating Scale (UPDRS) to collect preliminary data on treatment efficacy. Results Remacemide was well tolerated up to a dosage of 300 mg/d on a twice daily schedule and 600 mg/d on a four times daily schedule. The most common dosage-related adverse events were dizziness and nausea, as observed in previous studies of remacemide. The percent "on" time and motor UPDRS scores showed trends toward improvement in the patients treated with 150 and 300 mg/d remacemide compared with placebo-treated patients, although these improvements were not significant. Conclusion Remacemide is a safe and tolerable adjunct to dopaminergic therapy for patients with PD and motor fluctuations. Although this study had limited power to detect therapeutic effects, the observed improvement is consistent with studies of non-human primates with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced parkinsonian signs and symptoms. Additional studies are warranted to confirm these results over an extended period of observation, and to explore the potential neuroprotective effects of remacemide in slowing the progression of PD.

Mutations in LRRK2 were first reported as causing Parkinson's disease (PD) in late 2004. Since then, approximately a dozen LRRK2 substitutions have been identified that are believed to be pathogenic mutations. The substitution of adenine for guanine at nucleotide 4541 (4541G>A) in LRRK2 was recently reported. This substitution resulted in the replacement of an arginine at position 1514 with a glutamine (R1514Q). Although this substitution was not found in a large cohort of controls, its pathogenicity could not be verified. We have now genotyped the R1514Q substitution in a sample of 954 PD patients from 429 multiplex PD families. This substitution was identified in 1.8% of the PD patients; however, the majority of the PD sibships segregating this substitution were discordant for this putative mutation. In addition, the R1514Q substitution was detected in 1.4% of neurologically evaluated, control individuals. These data suggest that the R1514Q variant is not a pathogenic LRRK2 mutation. We believe it is imperative that the causative nature of any newly identified genetic variant be determined before it is included in any panel for diagnostic testing.

Free-radical-mediated mechanisms may contribute to neuronal damage in Parkinson's disease (PD), other neurodegenerative conditions also associated with aging, and the aging process itself. Cytotoxic free radicals are generated in the brain by oxidation/reduction reactions that are catalyzed by transition metals such as iron. Any regional increase in brain iron concentration may increase the potential for local freeradical formation. The purpose of this study was to determine the relationship between age and basal ganglia iron content in 20 normal individuals ranging from 24 to 79 years of age. We used an in vivo magnetic resonance method to quantify the effects of paramagnetic centers sequestered inside cellular membranes, thereby enabling the determination of a quantitative index of local brain iron content. We observed a strong direct relationship between age and regional iron content in the putamen (r = 0.76, p < 0.0001) and caudate (r = 0.69, p < 0.001), but not in the globus pallidus (r = 0.32, p = 0.17) or thalamus (r = 0.13, p = 0.58). In conclusion, striatal iron content increases with advancing age. This increase may increase the probability of free-radical formation in the striatum, therefore representing a risk factor for the development of neurodegenerative disorders such as PD in which nigrostriatal neurons may be affected by increased oxidant stress.

Background: A 61-year-old woman with Parkinson's disease, receiving pergolide 1.75 mg four times daily, was admitted with progressive dyspnea. Methods: Investigations revealed mitral and aortic regurgitation. She underwent surgical mitral replacement and aortic repair, but had a postoperative course characterized by repeated bouts of congestive heart failure. Results: Severe tricuspid valve (TV) regurgitation developed within one month after the TV was reported on echocardiography to be relatively normal. Subsequent discontinuation of pergolide was associated with symptomatic improvement. Conclusions: This case illustrates the severity and rapidity with which cardiac valvular abnormalities can develop in patients receiving pergolide.

Freezing of gait (FOG) is common in patients with Parkinson disease (PD) and responds poorly to medical treatment. Botulinum toxin A (BTX-A) injections into calf muscles decreased FOG in previous open-label studies. The authors conducted a randomized double-blind placebo-controlled crossover study of BTX-A vs placebo in 12 subjects with PD and FOG. No significant improvement with BTX-A was found using subjective and objective measures.

To validate their correlation with tissue iron concentration, proton transverse relaxation measurements have been made at 2.35 T (100 MHz) in 25 samples of excised, frozen, but unfixed human gray matter tissue obtained from the globus pallidus, putamen, caudate, thalamus, and cortex of five postmortem brains free of neurological disease. The iron concentration was independently measured, using atomic absorption spectroscopy. The proton transverse relaxation measurements exploited the interecho time dependence of the apparent transverse relaxation rate, R2app, obtained from a Carr-Purcell-Meiboom-Gill (CPMG) sequence. An empirical semilogarithmic relationship between R2app and the interecho time provided a measure of the relaxation enhancement due to iron, namely, a slope p, which demonstrated a significant correlation (r = 0.78, P < 0.001) with tissue iron concentration. Moreover, a simple rate difference, δR2app, determined between interecho time values of 6 and 60 ms, was also found to correlate significantly with iron concentration (r = 0.81, P < 0.001). Both of the foregoing correlations were better than that of R2app itself. When the tissue samples were subdivided into brain structure groups, the intergroup differences in p reflected their known differences in iron accumulation and correlated with those of the mean group iron content, determined by atomic absorption spectrometry.

Summary Advances in imaging have made it possible to detect functional and, increasingly, structural changes in Parkinson's disease. Although imaging is not yet routinely used for diagnosis, such an application is becoming increasingly feasible. Of potentially greater interest, however, is the use of imaging as a biomarker to detect premotor disease and disease progression. Imaging also provides insights into complications of Parkinson's disease and its long-term treatment, and the role of dopamine in the normal brain. Furthermore, these techniques can be applied to animal models, to help validate these models and allow their use in the study of potential disease-modifying therapies.

Diffusion tensor imaging (DTI) has been used widely to show structural brain changes during both development and aging. Lifespan studies are valuable because they connect these two processes, yet few DTI studies have been conducted that include both children and elderly subjects. This study used DTI tractography to investigate 12 major white matter connections in 403 healthy subjects aged 5-83 years. Poisson fits were used to model changes of fractional anisotropy (FA) and mean diffusivity (MD) across the age span, and were highly significant for all tracts. FA increased during childhood and adolescence, reached a peak between 20 and 42 years of age, and then decreased. MD showed an opposite trend, decreasing first, reaching a minimum at 18-41 years, and then increasing later in life. These trajectories demonstrate rates and timing of development and degradation that vary regionally in the brain. The corpus callosum and fornix showed early reversals of development trends, while frontal-temporal connections (cingulum, uncinate, superior longitudinal) showed more prolonged maturation and delayed declines. FA changes were driven by perpendicular diffusivity, suggesting changes of myelination and/or axonal density. Tract volume changed significantly with age for most tracts, but did not greatly influence the FA and MD trajectories. This study demonstrates clear age-related microstructural changes throughout the brain white matter, and provides normative data that will be useful for studying white matter development in a variety of diseases and abnormal conditions.

Objective To estimate the age-specific incidence of Parkinson’s disease (PD) in elderly persons in the Canadian province of British Columbia (BC). All-cause and injury mortalities and relative risk of death for those persons with PD were also examined. Methods A historical cohort study was conducted using 5 provincial administrative databases from 1991/92 to 2000/2001. A series of algorithms based on the databases were created for case ascertainment of PD for persons 65 years or older. Crude and age-specific incidence and mortality rates were calculated using person-years of follow-up as the denominator. The impact of PD on all-cause and injury mortalities was examined using multivariate Cox regression models to provide adjusted hazard ratios. Results 10,910 incidence cases over 6,051,682 person-years of follow-up were identified. The crude annual incidence rate was 252 per 100,000 person-years. Over the nine year period, age standardized incidence for males ranged from 207 to 396 per 100,000 person-years and 127 to 259 per 100,000 person-years for females. Persons with PD were at a 43% greater risk of all-cause mortality and specifically, 51% greater risk of injury mortality. Conclusions Incidence of PD is substantially higher in advanced age with age adjusted increases for both all-cause and injury mortalities. These findings also highlight falls as a primary factor for injury mortality in PD.

Resting-state fMRI (RS-fMRI) is a noninvasive imaging technique that identifies brain regions exhibiting correlated patterns of spontaneously occurring, slow changes in brain activity that are present at rest.1 This resting brain activity is observed with MRI through changes in blood flow referred to as a blood oxygen level–dependent (BOLD) signal. RS-fMRI research has revealed a number of networks consistently present in healthy persons and representing specific patterns of synchronous activity.2 One such resting-state network, labeled the basal ganglia network (BGN), is identified in the basal ganglia and thalamus, including the pallidum, putamen, subthalamic nucleus, and substantia nigra, with a projection also to the supplementary motor area.3 The characterization of the BGN opens a potential means to investigate motor-related neuropathologies, in particular Parkinson disease (PD).

We performed sequential positron emission tomography scans with 6-[18F]fluoro-L-dopa in 9 patients with idiopathic parkinsonism and 7 age-matched normal control subjects to compare changes in the nigrostriatal dopaminergic pathway over time. The mean interval between the scans was 3.3 years for the group with idiopathic parkinsonism and 3.9 years for the control subjects. The scans were analyzed by calculating the ratio of striatal to background radioactivity. Both groups showed statistically significant reductions of striatal uptake over the interval. The rate of decrease was almost identical in each group (p = 0.6). We infer that the usual rate of loss of integrity of the dopaminergic nigrostriatal pathway in patients with idiopathic parkinsonism is slow and the rate of change between the two groups was comparable.