Marguerite Wieler

Diffusion tensor imaging of white matter tract evolution over the lifespan.

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.

Midbrain iron content in early Parkinson disease A potential biomarker of disease status

Background: Parkinson disease (PD) is a progressive neurodegenerative disorder in which the major pathologic substrate is a loss of dopaminergic neurons from the lateral substantia nigra pars compacta (SNc). Our objective was to determine whether, in patients with early PD, SNc changes evident on MRI sequences sensitive to iron content corresponded anatomically to the pathologic changes reported previously, and to correlate these changes to the duration and severity of clinical manifestations of PD. Methods: Twenty-six untreated patients with early PD and 13 age- and gender-matched control subjects had MRI with a 3 tesla magnet using a multiple gradient echo sequence designed for rapid single-scan mapping of the proton transverse relaxation rate (R2*). R2* was calculated for midbrain and forebrain basal ganglia regions. Clinical features were rated with the Unified Parkinsons Disease Rating Scale. Results: A difference in measured R2* values between patients and controls was observed in the lateral SNc (p ≤ 0.005). Linear regression indicated a correlation between the lateralized motor score from the clinically most affected side and R2* values from the opposite lateral SNc (p = 0.01). Conclusions: High field strength MRI demonstrates lateral substantia nigra pars compacta abnormalities in early Parkinson disease (PD) consistent with increased iron content and corresponding to the known distribution of neuronal loss occurring in this disorder. This may ultimately provide an imaging marker for disease progression in PD, although longitudinal studies are required. GLOSSARY: AC = anterior commissure; CN = caudate nucleus; GP = globus pallidus; LantGP = left anterior GP; LantPu = left anterior Pu; LlatSNc = left lateral SNc; LlatSNr = left lateral SNr; LmedSNc = left medial SNc; LmedSNr = left medial SNr; LpostGP = left posterior GP; LpostPu = left posterior Pu; PC = posterior commissure; PD = Parkinson disease; Pu = putamen; RantGP = right anterior GP; RantPu = right anterior Pu; RlatSNc = right lateral SNc; RlatSNr = right lateral SNr; RmedSNc = right medial SNc; RmedSNr = right medial SNr; RN = red nucleus; ROI = region of interest; RpostGP = right posterior GP; RpostPu = right posterior Pu; SNc = substantia nigra compacta; SNr = substantia nigra reticulata; TE = echo times; UPDRS = Unified Parkinsons Disease Rating Scale.

Heterozygosity for a mutation in the parkin gene leads to later onset Parkinson disease

Background: The vast majority of the parkin mutations previously identified have been found in individuals with juvenile or early onset PD. Previous screening of later onset PD cohorts has not identified substantial numbers of parkin mutations. Methods: Families with at least two siblings with PD were ascertained to identify genes contributing to PD susceptibility. Screening of the parkin gene, by both quantitative PCR and exon sequencing, was performed in those families with either early onset PD (age onset ≤50 years) or positive lod score with a marker in intron 7 of the parkin gene. Results: A total of 25 different mutations in the parkin gene were identified in 103 individuals from 47 families. Mutations were found in both parkin alleles in 41 of the individuals, whereas a single mutation in only one of the two parkin alleles was observed in 62 individuals. Thirty-five of the subjects (34%) with a parkin mutation had an age at onset of 60 years or above with 30 of these 35 (86%) having a detectable mutation on only one parkin allele. Few significant clinical differences were observed among the individuals with two, one, or no mutated copies of the parkin gene. Conclusion: Mutations in the parkin gene occur among individuals with PD with an older age at onset (≥60 years) who have a positive family history of the disease. In addition, the clinical findings of parkin-positive individuals are remarkably similar to those without mutations.

Significant Linkage of Parkinson Disease to Chromosome 2q36-37

Parkinson disease (PD) is the second most common neurodegenerative disorder, surpassed in frequency only by Alzheimer disease. Elsewhere we have reported linkage to chromosome 2q in a sample of sibling pairs with PD. We have now expanded our sample to include 150 families meeting our strictest diagnostic definition of verified PD. To further delineate the chromosome 2q linkage, we have performed analyses using only those pedigrees with the strongest family history of PD. Linkage analyses in this subset of 65 pedigrees generated a LOD score of 5.1, which was obtained using an autosomal dominant model of disease transmission. This result strongly suggests that variation in a gene on chromosome 2q36-37 contributes to PD susceptibility.

Multicenter evaluation of electrical stimulation systems for walking

OBJECTIVE To test the long-term benefits of several noninvasive systems for functional electrical stimulation (FES) during walking. DESIGN Forty subjects (average years since injury, 5.4) were studied in four centers for an average time of 1 year. Gait parameters were tested for all subjects with and without FES. Thus, subjects served as their own controls, since the specific effect of using FES could be separated from improvements resulting from other factors (e.g., training). SETTING Subjects used the devices in the community, but were tested in a university or hospital setting. PATIENTS Subjects with spinal cord injury (n = 31) were compared to subjects with cerebral damage (n = 9). MAIN OUTCOME MEASURES Gait parameters (speed, cycle time, stride length). Acceptance was studied by means of a questionnaire. RESULTS Some initial improvement in walking speed (average increase of >20%) occurred, and continuing gains were seen (average total improvement, 45%). The largest relative gains were seen in the slowest walkers (speeds of <0.3 m/sec). Acceptance of the FES systems was good and improved systems have been developed using feedback from the subjects. CONCLUSIONS Based on the improvements in speed and the acceptance of these FES systems, a greatly increased role for FES in treating gait disorders is suggested.

Predictors of nursing home placement in Huntington disease

Objective: To determine whether motor, behavioral, or psychiatric symptoms in Huntington disease (HD) predict skilled nursing facility (SNF) placement. Methods: Subjects were participants in the Huntington Study Group’s Unified Huntington Disease Rating Scale Database (Rochester, NY) between January 1994 and September 1999. Specific motor, psychiatric, and behavioral variables in subjects residing at home and in SNF were analyzed using χ2 and Student’s t-tests. For a subset of subjects for whom longitudinal data existed, a Cox proportional hazards model controlling for age, sex, and disease duration was used. Results: Among 4,809 subjects enrolled, 3,070 had clinically definite HD. Of these, 228 (7.4%) resided in SNF. The SNF residents’ average age was 52 years, average disease duration was 8.6 years, and they were predominantly women (63%). The SNF residents had worse motor function (chorea, bradykinesia, gait abnormality, and imbalance, p < 0.0001); were more likely to have obsessions, compulsions, delusions, and auditory hallucinations; and had more aggressive, disruptive (p < 0.0001), and irritable behaviors (p = 0.0012). For 1,559 subjects, longitudinal data existed (average length of follow-up, 1.9 years), and 87 (5%) moved from home to SNF. In the Cox model, bradykinesia (HR 1.965, 95% CI 1.083 to 3.564), impaired gait (HR 3.004, 95% CI 1.353 to 6.668), and impaired tandem walking (HR 2.546, 95% CI 1.460 to 4.439) were predictive of SNF placement. Conclusions: Institutionalized patients with HD are more motorically, psychiatrically, and behaviorally impaired than their counterparts living at home. However, motor variables alone predicted institutionalization. Treatment strategies that delay the progression of motor dysfunction in HD may postpone the need for institutionalization.

Dihydrotetrabenazine positron emission tomography imaging in early, untreated Parkinson's disease

To determine the sensitivity of positron emission tomography with 11 C‐labeled dihydrotetrabenazine (DTBZ) to the nigrostriatal changes associated with early, untreated Parkinsons disease (PD), and to determine the correlation between any regionally reduced DTBZ binding and the major motor features of PD.

Temporal lobe changes in early, untreated Parkinson's disease.

The purpose of this study was to determine if focal cortical abnormalities may occur in early Parkinsons 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.

Early, untreated Parkinson's disease patients show reaction time variability

While Parkinsons 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.

Tracking motor impairments in the progression of Huntington's disease

The Unified Huntingtons Disease Rating Scale is used to characterize motor impairments and establish motor diagnosis. Little is known about the timing of diagnostic confidence level categories and the trajectory of motor impairments during the prodromal phase. Goals of this study were to estimate the timing of categories, model the prodromal trajectory of motor impairments, estimate the rate of motor impairment change by category, and provide required sample size estimates for a test of efficacy in clinical trials. In total, 1010 gene‐expanded participants from the Neurobiological Predictors of Huntingtons Disease (PREDICT‐HD) trial were analyzed. Accelerated failure time models were used to predict the timing of categories. Linear mixed effects regression was used to model the longitudinal motor trajectories. Age and length of gene expansion were incorporated into all models. The timing of categories varied significantly by gene expansion, with faster progression associated with greater expansion. For the median expansion, the third diagnostic confidence level category was estimated to have a first occurrence 1.5 years before diagnosis, and the second and first categories were estimated to occur 6.75 years and 19.75 years before diagnosis, respectively. Motor impairments displayed a nonlinear prodromal course. The motor impairment rate of change increased as the diagnostic confidence level increased, with added acceleration for higher progression scores. Motor items can detect changes in motor impairments before diagnosis. Given a sufficiently high progression score, there is evidence that the diagnostic confidence level can be used for prodromal staging. Implications for Huntingtons disease research and the planning of clinical trials of efficacy are discussed.