PURPOSE OF REVIEW: Clinical trials for Huntington disease (HD) have primarily focused on managing chorea and, more recently, the development of disease-modifying therapies (DMTs). Nonetheless, understanding health services among patients with HD is essential for assessing new therapeutics, development of quality metrics, and overall quality of life of patients and families with HD. Health services assess health care utilization patterns, outcomes, and health care-associated costs, which can help shape the development of therapeutics and aid in policies that affect patients with a specific condition. In this systematic literature review, we analyze data of published studies looking at causes of hospitalization, outcomes, and health care costs in HD. RECENT FINDINGS: The search yielded 8 articles published in the English language and comprising data from the United States, Australia, New Zealand, and Israel. The most common cause of hospitalization among patients with HD was dysphagia or dysphagia-related complications (e.g., aspiration pneumonia or malnutrition), followed by psychiatric or behavioral symptoms. Patients with HD had more prolonged hospitalizations than non-HD patients, and it was most prominent among those with advanced disease. Patients with HD were more likely to be discharged to a facility. A small percentage received inpatient palliative care consultation, and behavioral symptoms were a primary cause of discharge to another facility. Interventions such as gastrostomy tube placement had associated morbidity, and it was common among patients with HD with a diagnosis of dementia. Palliative care consultation and specialized nursing care were associated with more routine discharges and fewer hospitalizations. In terms of cost, patients with HD with private and public insurances had the highest expenditure with more advanced disease, and expenses were associated with hospitalization and medication costs. SUMMARY: In addition to DMTs, HD clinical trial development should also consider the leading causes of hospitalization, morbidity, and mortality in patients with HD, including dysphagia and psychiatric disease. No research study, to our knowledge, has systematically reviewed health services research studies in HD. Evidence from health services research is needed to evaluate the efficacy of pharmacologic and supportive therapies. This type of research is also critical in understanding health care costs associated with the disease and to better advocate and shape policies that can benefit this patient population.

Background

Several articles suggest that DNA methylation levels in blood relate to Parkinson's disease (PD) but there is a need for a large-scale study that involves suitable population based controls. The purposes of the study were: (1) to study whether PD status is associated with DNA methylation levels in blood/saliva; (2) to study whether observed associations relate to blood cell types; and (3) to characterize genome-wide significant markers ("CpGs") and clusters of CpGs (co-methylation modules) in terms of biological pathways.

Methods

In a population-based case control study of PD, we studied blood samples from 335 PD cases and 237 controls and saliva samples from another 128 cases and 131 controls. DNA methylation data were generated from over 486,000 CpGs using the Illumina Infinium array. We identified modules of CpGs (clusters) using weighted correlation network analysis (WGCNA).

Results

Our cross-sectional analysis of blood identified 82 genome-wide significant CpGs (including cg02489202 in LARS2 p = 8.3 × 10^-11 and cg04772575 in ABCB9 p = 4.3 × 10^-10). Three out of six PD related co-methylation modules in blood were significantly enriched with immune system related genes. Our analysis of saliva identified five significant CpGs. PD-related CpGs are located near genes that relate to mitochondrial function, neuronal projection, cytoskeleton organization, systemic immune response, and iron handling.

Conclusions

This study demonstrates that: (1) PD status has a profound association with DNA methylation levels in blood and saliva; and (2) the most significant PD-related changes reflect changes in blood cell composition. Overall, this study highlights the role of the immune system in PD etiology but future research will need to address the causal structure of these relationships.

Introduction

A high prevalence of vitamin D deficiency has been reported in Parkinson's disease (PD). Epidemiologic studies examining variability in genes involved in vitamin D metabolism have not taken into account level of exposure to ultraviolet radiation (UVR). We examined whether exposure to UVR (as a surrogate for vitamin D levels) and variations in the vitamin D receptor gene (VDR) are associated with PD.

Methods

Within a geographical information system (GIS) we linked participants' geocoded residential address data to ground level UV data to estimate historical exposure to UVR. Six SNPs in VDR were genotyped in non-Hispanic Caucasian subjects.

Results

Average lifetime UVR exposure levels were >5000 Wh/m(2), which was higher than levels for populations in previous studies, and UVR exposure did not differ between cases and controls. Homozygotes for the rs731236 TT (major allele) genotype had a 31% lower risk of PD risk (OR=0.69; 95% CI=0.49, 0.98; p=0.04 for TT vs. TC+CC). The rs7975232 GG (minor allele) genotype was also associated with decreased risk of PD (OR=0.63; 95% CI=0.42, 0.93; p=0.02 for GG vs. TG+TT). The association between PD risk and a third locus, rs1544410 (BsmI), was not statistically significant after adjustment for covariates, although there was a trend for lower risk with the GG genotype.

Conclusions

This study provides initial evidence that VDR polymorphisms may modulate risk of PD in a population highly exposed to UVR throughout lifetime.

Currently, there are no reported genetic predictors of motor symptom progression in Parkinson's disease (PD). In familial PD, disease severity is associated with higher α-synuclein (SNCA) expression levels, and in postmortem studies expression varies with SNCA genetic variants. Furthermore, SNCA is a well-known risk factor for PD occurrence. We recruited Parkinson's patients from the communities of three central California counties to investigate the influence of SNCA genetic variants on motor symptom progression in idiopathic PD. We repeatedly assessed this cohort of patients over an average of 5.1 years for motor symptom changes employing the Unified Parkinson's Disease Rating Scale (UPDRS). Of 363 population-based incident PD cases diagnosed less than 3 years from baseline assessment, 242 cases were successfully re-contacted and 233 were re-examined at least once. Of subjects lost to follow-up, 69% were due to death. Adjusting for covariates, risk of faster decline of motor function as measured by annual increase in motor UPDRS exam score was increased 4-fold in carriers of the REP1 263bp promoter variant (OR 4.03, 95%CI:1.57-10.4). Our data also suggest a contribution to increased risk by the G-allele for rs356165 (OR 1.66; 95%CI:0.96-2.88), and we observed a strong trend across categories when both genetic variants were considered (p for trend = 0.002). Our population-based study has demonstrated that SNCA variants are strong predictors of faster motor decline in idiopathic PD. SNCA may be a promising target for therapies and may help identify patients who will benefit most from early interventions. This is the first study to link SNCA to motor symptom decline in a longitudinal progression study.

Essential tremor and Parkinson's disease-associated tremor are extremely prevalent within the field of movement disorders. The ventral intermediate (VIM) nucleus of the thalamus has been commonly used as both a neuromodulatory and neuroablative target for the treatment of these forms of tremor. With both deep brain stimulation and Gamma Knife radiosurgery, there is an abundance of literature regarding the surgical planning, targeting, and outcomes of these methodologies. To date, there have been no reports of frameless, linear accelerator (LINAC)-based thalomotomies for tremor. The authors report the case of a patient with tremor-dominant Parkinson's disease, with poor tremor improvement with medication, who was offered LINAC-based thalamotomy. High-resolution 0.9-mm isotropic MR images were obtained, and simulation was performed via CT with 1.5-mm contiguous slices. The VIM thalamic nucleus was determined using diffusion tensor imaging (DTI)-based segmentation on FSL using probabilistic tractography. The supplemental motor and premotor areas were the cortical target masks. The authors centered their isocenter within the region of the DTI-determined target and treated the patient with 140 Gy in a single fraction. The DTI-determined target had coordinates of 14.2 mm lateral and 8.36 mm anterior to the posterior commissure (PC), and 3 mm superior to the anterior commissure (AC)-PC line, which differed by 3.30 mm from the original target determined by anatomical considerations (15.5 mm lateral and 7 mm anterior to the PC, and 0 mm superior to the AC-PC line). There was faint radiographic evidence of lesioning at the 3-month follow-up within the target zone, which continued to consolidate on subsequent scans. The patient experienced continued right upper-extremity resting tremor improvement starting at 10 months until it was completely resolved at 22 months of follow-up. Frameless LINAC-based thalamotomy guided by DTI-based thalamic segmentation is a feasible method for achieving radiosurgical lesions of the VIM thalamus to treat tremor.

Objective

To investigate three expression-altering NFE2L2 SNPs and four PPARGC1α previously implicated SNPs and pesticides on Parkinson's disease (PD) risk and symptom progression.

Methods

In 472 PD patients and 532 population-based controls, we examined variants and their interactions with maneb and paraquat (MB/PQ) pesticide exposure on PD onset (logistic regression) and progression of motor symptoms and cognitive decline (n = 192; linear repeated measures).

Results

NFE2L2 rs6721961 T allele was associated with a reduced risk of PD (OR = 0.70, 95% CI = 0.53, 0.94) and slower cognitive decline (β = 0.095; p = 0.0004). None of the PPARGC1α SNPs were marginally associated with PD risk. We estimate statistical interactions between MB/PQ and PPARGC1α rs6821591 (interaction p = 0.009) and rs8192678 (interaction p = 0.05), such that those with high exposure and the variant allele were at an increased risk of PD (OR ≥ 1.30, p ≤ 0.05). PPARGC1α rs6821591 was also associated with faster motor symptom progression as measured with the UPDRS-III (β = 0.234; p = 0.001).

Conclusion

Our study provides support for the involvement of both NFE2L2 and PPARGC1α in PD susceptibility and progression, marginally and through pathways involving MB/PQ exposure.

Background

Parkinson's disease (PD) has motor and non-motor features that contribute to its phenotype and functional decline. Organophosphate (OP) pesticides and PON1 L55M, which influences OP metabolism, have been implicated in multiple mechanisms related to neuronal cell death and may influence PD symptom progression.

Objective

To investigate whether ambient agricultural OP exposure and PON1 L55M influence the rate of motor, cognitive, and mood-related symptom progression in PD.

Methods

We followed a longitudinal cohort of 246 incident PD patients on average over 5years (7.5years after diagnosis), repeatedly measuring symptom progression with the Mini-Mental State Exam (MMSE), Unified Parkinson's Disease Rating Scale (UPDRS), and Geriatric Depressive Scale (GDS). OP exposures were generated with a geographic information system (GIS) based exposure assessment tool. We employed repeated-measures regression to assess associations between OP exposure and/or PON1 L55M genotype and progression.

Results

High OP exposures were associated with faster progression of motor (UPDRS β=0.24, 95% CI=-0.01, 0.49) and cognitive scores (MMSE β=-0.06, 95% CI=-0.11, -0.01). PON1 55MM was associated with faster progression of motor (UPDRS β=0.28, 95% CI=0.08, 0.48) and depressive symptoms (GDS β=0.07; 95% CI=0.01, 0.13). We also found the PON1 L55M variant to interact with OP exposures in influencing MMSE cognitive scores (β=-1.26, 95% CI=-2.43, -0.09).

Conclusion

Our study provides preliminary support for the involvement of OP pesticides and PON1 in PD-related motor, cognitive, or depressive symptom progression. Future studies are needed to replicate findings and examine whether elderly populations generally are similarly impacted by pesticides or PON1 55M genotypes.

We assessed degree of Parkinson disease motor symptom improvement with medication among subjects enrolled in an ongoing, population-based study in Central California. The motor section of the unified Parkinson disease rating scale (UPDRS) was performed on subjects in both OFF and ON medication states, and difference between these scores was used as an indicator of symptomatic benefit. Higher OFF minus ON scores correlated with more severe baseline symptoms. There was equivalent improvement on the motor UPDRS scale for subjects divided according to medication classes used: levodopa alone 7.3 points, levodopa plus other medications 8.5 points, and dopamine agonists but not levodopa 6.1 points. In addition, there was no difference in the magnitude of improvement when subjects were divided according to Parkinson disease subtype, defined as tremor dominant, akinetic-rigid, or mixed. In this community-based sample, these values are within the range of a clinically important difference as defined by previous studies.