Liana S. Rosenthal

GBA Variants are associated with a distinct pattern of cognitive deficits in Parkinson's disease

Loss‐of‐function mutations in the GBA gene are associated with more severe cognitive impairment in PD, but the nature of these deficits is not well understood and whether common GBA polymorphisms influence cognitive performance in PD is not yet known.

Cognitive profile of LRRK2-related Parkinson's disease.

Increasing evidence suggests that genetic factors play a role in the variability associated with cognitive performance in Parkinsons disease (PD). Mutations in the LRRK2 gene are the most common cause of monogenic PD; however, the cognitive profile of LRRK2‐related PD is not well‐characterized.

The NINDS Parkinson's disease biomarkers program

Neuroprotection for Parkinsons disease (PD) remains elusive. Biomarkers hold the promise of removing roadblocks to therapy development. The National Institute of Neurological Disorders and Stroke has therefore established the Parkinsons Disease Biomarkers Program to promote discovery of PD biomarkers for use in phase II and III clinical trials.

Next-generation sequencing reveals substantial genetic contribution to dementia with Lewy bodies

Dementia with Lewy bodies (DLB) is the second most common neurodegenerative dementia after Alzheimers disease. Although an increasing number of genetic factors have been connected to this debilitating condition, the proportion of cases that can be attributed to distinct genetic defects is unknown. To provide a comprehensive analysis of the frequency and spectrum of pathogenic missense mutations and coding risk variants in nine genes previously implicated in DLB, we performed exome sequencing in 111 pathologically confirmed DLB patients. All patients were Caucasian individuals from North America. Allele frequencies of identified missense mutations were compared to 222 control exomes. Remarkably, ~25% of cases were found to carry a pathogenic mutation or risk variant in APP, GBA or PSEN1, highlighting that genetic defects play a central role in the pathogenesis of this common neurodegenerative disorder. In total, 13% of our cohort carried a pathogenic mutation in GBA, 10% of cases carried a risk variant or mutation in PSEN1, and 2% were found to carry an APP mutation. The APOE ε4 risk allele was significantly overrepresented in DLB patients (p-value <0.001). Our results conclusively show that mutations in GBA, PSEN1, and APP are common in DLB and consideration should be given to offer genetic testing to patients diagnosed with Lewy body dementia.

Parkinson's disease biomarkers: perspective from the NINDS Parkinson's Disease Biomarkers Program

Biomarkers for Parkinsons disease (PD) diagnosis, prognostication and clinical trial cohort selection are an urgent need. While many promising markers have been discovered through the National Institute of Neurological Disorders and Stroke Parkinsons Disease Biomarker Program (PDBP) and other mechanisms, no single PD marker or set of markers are ready for clinical use. Here we discuss the current state of biomarker discovery for platforms relevant to PDBP. We discuss the role of the PDBP in PD biomarker identification and present guidelines to facilitate their development. These guidelines include: harmonizing procedures for biofluid acquisition and clinical assessments, replication of the most promising biomarkers, support and encouragement of publications that report negative findings, longitudinal follow-up of current cohorts including the PDBP, testing of wearable technologies to capture readouts between study visits and development of recently diagnosed (de novo) cohorts to foster identification of the earliest markers of disease onset.

The Benefits of Exercise in Parkinson Disease

Parkinson disease (PD) is a disabling neurodegenerative disease for which current treatments are suboptimal. As exercise is generally safe, inexpensive, and associated with secondary benefits, interest in exercise as a treatment for the motorsymptomsof thedisease is increasing. In this issue of the journal, Shulman and colleagues1 offer compelling evidence that exercise can improve gait and fitnessamongindividuals with PD. This research adds to the evidence regarding the value of interventions for PD beyond medications and surgery and offers an opportunity for patients to be active participants in their care. Shulman et al performed a comparative, prospective, randomized, single-blinded clinical trial of 3 types of exercise among patients with PD and gait impairment. Sixtyseven patients were randomized to either lower-intensity treadmill exercise, higher-intensity treadmill exercise, or a combination of stretching and resistance training. For their primary outcome of gait speed, all training types increased distance walked in 6 minutes at 4 months, but lower-intensity treadmill exercise led to the greatest increases. For their secondary outcome of cardiovascular fitness, both treadmill groups demonstrated improvement. In contrast, the stretching-resistance group improved muscle strength and motor scores on the Unified Parkinson Disease Rating Scale. The authors conclude that all 3 types of exercise have benefits, and patients may benefit most from a combination of lower-intensity training and stretching and resistance. The investigation by Shulman et al adds to the growing body of literature demonstrating the value of exercise in PD (Figure).2 In 2001, the Cochrane Collaboration examined randomized controlled trials that compared physiotherapy to placebo, and only 11 trials were eligible for their systematic review. At that time, authors concluded that there was “insufficient evidence to support or refute the efficacy of physiotherapy in Parkinson’s disease.”3 By 2012, the evidence had increased, and Cochrane’s updated review included 33 trials and discussed 6 additional ongoing studies.4 Using these new data, the authors concluded that while differences between physiotherapy and placebo groups in motor performance and other measures were small, they would be clinically meaningful to patients. The Table highlights the results of select randomized controlled trials from recent reviews4-12 or that were conducted. While the investigation by Shulman et al certainly stands out in its rigorous method and large patient participation, each study demonstrates the importance of exercise in improving the health and well-being of individuals with PD. Figure Publications of randomized controlled trials of exercise and Parkinson disease, 1996-2011. Databased on a MEDLINE search of Parkinson disease, Parkinson, or Parkinson’s and exercise conducted on August 21, 2012. The search was restricted to randomized ... Table Select Randomized Controlled Trials of Exercise as Treatment for Symptoms of Parkinson Disease Beyond its benefits on physical health, exercise gives patients amore active role in the management of their PD. Patients are thirsting for such a role, which is consistent with a patient-centered care model in which health care is “closely congruent with and responsive to patients’ wants, needs, and preferences.”13(p152) Patients with PD specifically want more information about nonpharmacological interventions and are not satisfied with the information that they receive.14 The study by Shulman et al provides physicians and patients with evidence about what patients can do to improve and take charge of their health. In 2001, the Institute of Medicine raised patientcentered care to a national priority by identifying patientcentered care as 1 of 6 core needs for health care.15 The Patient Protection and Affordable Care Act of 201016 took patient-centered care to a research and funding level by creating the Patient-Centered Outcomes Research Institute. In a 2012 JAMA article, the directors of the newly created Patient-Centered Outcomes Research Institute emphasized the importance of the patient in assessing health care options, saying, “Engagement of patients at every step of the research process is viewed as essential, including in the selection of research questions, study design, conduct, analysis, and implementation of findings.”17(p1636) The study by Shulman et al directly engages patients in research and in their health. Exercise programs among those with neurological disorders increase the patients’ sense of self-efficacy,18 their sense of involvement in their care and overall belief in their abilities to perform certain activities. In addition, patient involvement leads to higher satisfaction with care, and greater likelihood of following provider recommendations.19 In essence, exercise puts the patient—not a pill—at the center of care, which is exactly where patients want and ought to be.

The Preoperative Neurological Evaluation

Neurological diseases are prevalent in the general population, and the neurohospitalist has an important role to play in the preoperative planning for patients with and at risk for developing neurological disease. The neurohospitalist can provide patients and their families as well as anesthesiologists, surgeons, hospitalists, and other providers guidance in particular to the patient’s neurological disease and those he or she is at risk for. Here we present considerations and guidance for the neurohospitalist providing preoperative consultation for the neurological patient with or at risk of disturbances of consciousness, cerebrovascular and carotid disease, epilepsy, neuromuscular disease, and Parkinson disease.

C9orf72 Hexanucleotide Repeat Analysis in Cases with Pathologically Confirmed Dementia with Lewy Bodies

Background: Dementia with Lewy bodies (DLB) is the second most common neurodegenerative dementia affecting the elderly. The GGGGCC hexanucleotide expansion mutation at the C9orf72 locus has been identified as a major cause of amyotrophic lateral sclerosis and frontotemporal dementia, raising the question of whether this mutation is a factor in DLB. Furthermore, a small number of clinically diagnosed DLB patients have previously been reported to carry the pathologic C9orf72 hexanucleotide repeat expansion. Objective: To explore whether the C9orf72 mutation is present in pathologically confirmed DLB patients. Methods: We screened a cohort of 111 definite DLB cases with extensive Lewy body pathology for the C9orf72 hexanucleotide repeat expansion using the repeat-primed polymerase chain reaction assay. Results: No pathogenic expansions of the C9orf72 hexanucleotide repeat were found, suggesting that there is no causal relationship between C9orf72 and DLB. Conclusion: Our data illustrate that C9orf72 screening of clinically diagnosed DLB patients should only be considered in cases with a family history of motor neuron disease or frontotemporal dementia to distinguish between mimic diseases.

Finding useful biomarkers for Parkinson’s disease

The recent advent of an “ecosystem” of shared biosample biorepositories and data sets will aid efforts to define biomarkers for Parkinson’s disease. The recent advent of an “ecosystem” of shared biofluid sample biorepositories and data sets will focus biomarker efforts in Parkinson’s disease, boosting the therapeutic development pipeline and enabling translation with real-world impact.

Onset and Remission of Psychosis in Parkinson's Disease: Pharmacologic and Motoric Markers

Psychosis is among the most disabling complications of Parkinsons disease (PD). The chronicity of PD psychosis remains understudied, and the relative importance of dopaminergic therapy versus the disease process itself in engendering psychosis remains unclear. The objective of this study was to examine pharmacologic and motoric correlates of PD psychosis onset and remission in a longitudinally monitored PD cohort.