Nicholas W. Sterling

Striatal shape in Parkinson's disease

Parkinsons disease (PD) is marked pathologically by nigrostriatal dopaminergic terminal loss. Histopathological and in vivo labeling studies demonstrate that this loss occurs most extensively in the caudal putamen and caudate head. Previous structural studies have suggested reduced striatal volume and atrophy of the caudate head in PD subjects. The spatial distribution of atrophy in the putamen, however, has not been characterized. We aimed to delineate the specific locations of atrophy in both of these striatal structures. T1- and T2-weighted brain MR (3T) images were obtained from 40 PD and 40 control subjects having no dementia and similar age and gender distributions. Shape analysis was performed using doubly segmented regions of interest. Compared to controls, PD subjects had lower putamen (p = 0.0003) and caudate (p = 0.0003) volumes. Surface contraction magnitudes were greatest on the caudal putamen (p ≤ 0.005) and head and dorsal body of the caudate (p ≤ 0.005). This spatial distribution of striatal atrophy is consistent with the known pattern of dopamine depletion in PD and may reflect global consequences of known cellular remodeling phenomena.

Statins may facilitate Parkinson's disease: Insight gained from a large, national claims database

Using a large U.S. claims database (MarketScan), we investigated the controversy surrounding the role of statins in Parkinsons disease (PD).

History of smoking and olfaction in Parkinson's disease

Olfactory dysfunction is the most common pre‐motor symptom in Parkinsons disease (PD), and smoking is known to be associated with lower risk of PD. This study tested the hypothesis that smoking is associated with better olfaction in PD.

Stage-dependent loss of cortical gyrification as Parkinson disease “unfolds”

Objective: Nigrostriatal terminal losses are known to progress most rapidly in early-stage Parkinson disease (PD) and then plateau, whereas cortical pathology continues and may provide a better marker of PD progression in later stages. We investigated cortical gyrification indices in patients with different durations of PD, since cortical folding may capture complex processes involving transverse forces of neuronal sheets or underlying axonal connectivity. Methods: Longitudinal cohort structural MRI were obtained at baseline, 18 months, and 36 months from 70 patients with PD without dementia and 70 control participants. Cortical local gyrification index (LGI) was compared between controls and PD subgroups based upon duration of illness (DOI, <1 year [PDE, n = 17], 1–5 years [PDM, n = 19], >5 years [PDL, n = 24]) and adjusted using false discovery rate. Associations between LGI and clinical measurements were assessed using multiple linear regression. Areas having significantly reduced LGI also were analyzed using baseline data from a newly established cohort (PD n = 87, control n = 66) to validate our findings. Results: In the longitudinal cohort, PDL had significantly reduced overall gyrification, and bilaterally in the inferior parietal, postcentral, precentral, superior frontal, and supramarginal areas, compared to controls (p < 0.05). Longitudinally, loss of gyrification was accelerated in PDM participants, compared to controls. LGI showed robust correlations with DOI and also was correlated with PD-related clinical measurements. Similar results were obtained in the validation sample. Conclusions: Loss of cortical gyrification may be accelerated within the first few years after PD diagnosis, and become particularly prominent in later stages. Thus, it may provide a metric for monitoring progression in vivo.

Cortical Thinning and Cognitive Impairment in Parkinson's Disease without Dementia

Parkinsons disease (PD) is a progressive neurodegenerative disorder characterized clinically by motor dysfunction (bradykinesia, rigidity, tremor, and postural instability), and pathologically by the loss of dopaminergic neurons in the substantia nigra of the basal ganglia. Growing literature supports that cognitive deficits may also be present in PD, even in non-demented patients. Gray matter (GM) atrophy has been reported in PD and may be related to cognitive decline. This study investigated cortical thickness in non-demented PD subjects and elucidated its relationship to cognitive impairment using high-resolution T1-weighted brain MRI and comprehensive cognitive function scores from 71 non-demented PD and 48 control subjects matched for age, gender, and education. Cortical thickness was compared between groups using a flexible hierarchical multivariate Bayesian model, which accounts for correlations between brain regions. Correlation analyses were performed among brain areas and cognitive domains as well, which showed significant group differences in the PD population. Compared to Controls, PD subjects demonstrated significant age-adjusted cortical thinning predominantly in inferior and superior parietal areas and extended to superior frontal, superior temporal, and precuneus areas (posterior probability >0.9). Cortical thinning was also found in the left precentral and lateral occipital, and right postcentral, middle frontal, and fusiform regions (posterior probability >0.9). PD patients showed significantly reduced cognitive performance in executive function, including set shifting (p = 0.005) and spontaneous flexibility (p = 0.02), which were associated with the above cortical thinning regions (p < 0.05).

Structural Imaging and Parkinson's Disease: Moving Toward Quantitative Markers of Disease Progression

Parkinson’s disease (PD) is a progressive age-related neurodegenerative disorder. Although the pathological hallmark of PD is dopaminergic cell death in the substantia nigra pars compacta, widespread neurodegenerative changes occur throughout the brain as disease progresses. Postmortem studies, for example, have demonstrated the presence of Lewy pathology, apoptosis, and loss of neurotransmitters and interneurons in both cortical and subcortical regions of PD patients. Many in vivo structural imaging studies have attempted to gauge PD-related pathology, particularly in gray matter, with the hope of identifying an imaging biomarker. Reports of brain atrophy in PD, however, have been inconsistent, most likely due to differences in the studied populations (i.e. different disease stages and/or clinical subtypes), experimental designs (i.e. cross-sectional vs. longitudinal), and image analysis methodologies (i.e. automatic vs. manual segmentation). This review attempts to summarize the current state of gray matter structural imaging research in PD in relationship to disease progression, reconciling some of the differences in reported results, and to identify challenges and future avenues.

Dopaminergic Modulation of Arm Swing During Gait Among Parkinson's Disease Patients

BACKGROUND Reduced arm swing amplitude, symmetry, and coordination during gait have been reported in Parkinsons disease (PD), but the relationship between dopaminergic depletion and these upper limb gait changes remains unclear. OBJECTIVE We aimed to investigate the effects of dopaminergic drugs on arm swing velocity, symmetry, and coordination in PD. METHODS Forearm angular velocity was recorded in 16 PD and 17 control subjects (Controls) during free walking trials. Angular velocity amplitude of each arm, arm swing asymmetry, and maximum cross-correlation were compared between control and PD groups, and between OFF- and ON-medication states among PD subjects. RESULTS Compared to Controls, PD subjects in the OFF-medication state exhibited lower angular velocity amplitude of the slower- (p = 0.0018), but not faster- (p = 0.2801) swinging arm. In addition, PD subjects demonstrated increased arm swing asymmetry (p = 0.0046) and lower maximum cross-correlation (p = 0.0026). Following dopaminergic treatment, angular velocity amplitude increased in the slower- (p = 0.0182), but not faster- (p = 0.2312) swinging arm among PD subjects. Furthermore, arm swing asymmetry decreased (p = 0.0386), whereas maximum cross-correlation showed no change (p = 0.7436). Pre-drug angular velocity amplitude of the slower-swinging arm was correlated inversely with the change in arm swing asymmetry (R = -0.73824, p = 0.0011). CONCLUSIONS This study provides quantitative evidence that reduced arm swing and symmetry in PD can be modulated by dopaminergic replacement. The lack of modulations of bilateral arm coordination suggests that additional neurotransmitters may also be involved in arm swing changes in PD. Further studies are warranted to investigate the longitudinal trajectory of arm swing dynamics throughout PD progression.

The Key Determinants to Quality of Life in Parkinson’s Disease Patients: Results from the Parkinson’s Disease Biomarker Program (PDBP)

BACKGROUND The impact of motor- and non-motor symptoms on health-related quality of life (HRQOL) in Parkinsons disease (PD) has received increasing attention. OBJECTIVES To address this, the study explored a large cohort of patients enrolled in the PD Biomarker Program. METHODS The PD Questionnaire-39 (PDQ-39) measured HRQOL, whereas the Unified PD Rating Scale (UPDRS) assessed motor and non-motor symptoms. Determinants of HRQOL in PD patients were identified by stepwise linear regression analysis. The relationship between the PDQ-39 and UPDRS subscale scores then was explored through structural equation modeling. RESULTS The mean disease duration was 6.8 years and the mean PDQ-39 summary index (PDQ-39SI) was 18.4. UPDRS-I (non-motor function) and UPDRS-II (motor questionnaire) scores demonstrated the strongest correlations with PDQ-39SI (r Ϡ 0.4, P < 0.05), whereas UPDRS-III (motor exam) and UPDRS-IV (motor complications) scores were correlated moderately with PDQ-39SI (0.3 < r < 0.4, P < 0.05). Multiple linear stepwise regression analyses showed that age (β= -0.13, P < 0.001), education (β= -0.07, P = 0.008), UPDRS-I (β= 0.32, P = 0.000), and UPDRS-II (β= 0.44, P < 0.001) significantly contributed to HRQOL, and cumulatively accounted for 69.1% of the PDQ-39SI variance. UPDRS-II score was the primary predictor of PDQ-39SI, accounting for 57.3% of the variance, whereas UPDRS-I score accounted for 7.5%. UPDRS-III and -IV and other factors measured did not survive stepwise regression. Structural equation modeling confirmed the association of UPDRS-II (β= 0.67, P < 0.001) and UPDRS-I (β= 0.35, P < 0.001) with the PDQ-39SI. CONCLUSION Both motor and non-motor function scores impacted significantly HRQOL in PD. UPDRS-III, however, has limited contributions to HRQOL although it is used as a main outcome in many clinical trials.

Lateralized Basal Ganglia Vulnerability to Pesticide Exposure in Asymptomatic Agricultural Workers

Pesticide exposure is linked to Parkinsons disease, a neurodegenerative disorder marked by dopamine cell loss in the substantia nigra of the basal ganglia (BG) that often presents asymmetrically. We previously reported that pesticide-exposed agricultural workers (AW) have nigral diffusion tensor imaging (DTI) changes. The current study sought to confirm this finding, and explore its hemisphere and regional specificity within BG structures using an independent sample population. Pesticide exposure history, standard neurological exam, high-resolution magnetic resonance imaging (T1/T2-weighted and DTI), and [123I]ioflupane SPECT images (to quantify striatal dopamine transporters) were obtained from 20 AW with chronic pesticide exposure and 11 controls. Based on median cumulative days of pesticide exposure, AW were subdivided into high (AWHi, n = 10) and low (AWLo, n = 10) exposure groups. BG (nigra, putamen, caudate, and globus pallidus [GP]) fractional anisotropy (FA), mean diffusivity (MD), and striatal [123I]ioflupane binding in each hemisphere were quantified, and compared across exposure groups using analysis of variance. Left, but not right, nigral and GP FA were significantly lower in AW compared with controls (ps < .029). None of the striatal (putamen and caudate) DTI or [123I]ioflupane binding measurements differed between AW and controls. Subgroup analyses indicated that significant left nigral and GP DTI changes were present only in the AWHi (p ≤ .037) but not the AWLo subgroup. AW, especially those with higher pesticide exposure history, demonstrate lateralized microstructural changes in the nigra and GP, whereas striatal areas appear relatively unaffected. Future studies should elucidate how environmental toxicants cause differential lateralized- and regionally specific brain vulnerability.

Combined Diffusion Tensor Imaging and Apparent Transverse Relaxation Rate Differentiate Parkinson Disease and Atypical Parkinsonism.

BACKGROUND AND PURPOSE: Both diffusion tensor imaging and the apparent transverse relaxation rate have shown promise in differentiating Parkinson disease from atypical parkinsonism (particularly multiple system atrophy and progressive supranuclear palsy). The objective of the study was to assess the ability of DTI, the apparent transverse relaxation rate, and their combination for differentiating Parkinson disease, multiple system atrophy, progressive supranuclear palsy, and controls. MATERIALS AND METHODS: A total of 106 subjects (36 controls, 35 patients with Parkinson disease, 16 with multiple system atrophy, and 19 with progressive supranuclear palsy) were included. DTI and the apparent transverse relaxation rate measures from the striatal, midbrain, limbic, and cerebellar regions were obtained and compared among groups. The discrimination performance of DTI and the apparent transverse relaxation rate among groups was assessed by using Elastic-Net machine learning and receiver operating characteristic curve analysis. RESULTS: Compared with controls, patients with Parkinson disease showed significant apparent transverse relaxation rate differences in the red nucleus. Compared to those with Parkinson disease, patients with both multiple system atrophy and progressive supranuclear palsy showed more widespread changes, extending from the midbrain to striatal and cerebellar structures. The pattern of changes, however, was different between the 2 groups. For instance, patients with multiple system atrophy showed decreased fractional anisotropy and an increased apparent transverse relaxation rate in the subthalamic nucleus, whereas patients with progressive supranuclear palsy showed an increased mean diffusivity in the hippocampus. Combined, DTI and the apparent transverse relaxation rate were significantly better than DTI or the apparent transverse relaxation rate alone in separating controls from those with Parkinson disease/multiple system atrophy/progressive supranuclear palsy; controls from those with Parkinson disease; those with Parkinson disease from those with multiple system atrophy/progressive supranuclear palsy; and those with Parkinson disease from those with multiple system atrophy; but not those with Parkinson disease from those with progressive supranuclear palsy, or those with multiple system atrophy from those with progressive supranuclear palsy. CONCLUSIONS: DTI and the apparent transverse relaxation rate provide different but complementary information for different parkinsonisms. Combined DTI and apparent transverse relaxation rate may be a superior marker for the differential diagnosis of parkinsonisms.