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The genetic basis of Lewy body dementia (LBD) is not well understood. Here, we performed whole-genome sequencing in large cohorts of LBD cases and neurologically healthy controls to study the genetic architecture of this understudied form of dementia and to generate a resource for the scientific community. Genome-wide association analysis identified five independent risk loci, whereas genome-wide gene-aggregation tests implicated mutations in the gene GBA . Genetic risk scores demonstrate that LBD shares risk profiles and pathways with Alzheimer’s disease and Parkinson’s disease, providing a deeper molecular understanding of the complex genetic architecture of this age-related neurodegenerative condition.

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Dysfunction of the autonomic nervous system afflicts most patients with Parkinson disease and other synucleinopathies such as dementia with Lewy bodies, multiple system atrophy, and pure autonomic failure, reducing quality of life and increasing mortality. For example, gastrointestinal dysfunction can lead to impaired drug pharmacodynamics causing a worsening in motor symptoms, and neurogenic orthostatic hypotension can cause syncope, falls, and fractures. When recognized, autonomic problems can be treated, sometimes successfully. Discontinuation of potentially causative/aggravating drugs, patient education, and nonpharmacological approaches are useful and should be tried first. Pathophysiology-based pharmacological treatments that have shown efficacy in controlled trials of patients with synucleinopathies have been approved in many countries and are key to an effective management. Here, we review the treatment of autonomic dysfunction in patients with Parkinson disease and other synucleinopathies, summarize the nonpharmacological and current pharmacological therapeutic strategies including recently approved drugs, and provide practical advice and management algorithms for clinicians, with focus on neurogenic orthostatic hypotension, supine hypertension, dysphagia, sialorrhea, gastroparesis, constipation, neurogenic overactive bladder, underactive bladder, and sexual dysfunction. © 2018 International Parkinson and Movement Disorder Society.

Background Orthostatic hypotension (OH) is frequent in patients with Parkinson disease (PD) and can occur with or without symptoms. Pharmacological treatments are effective but often exacerbate supine hypertension. Guidelines exist for the diagnosis but not for the treatment of OH. We examined the relationship between blood pressure and symptoms in a cohort of PD patients with the goal of identifying a hemodynamic target to guide treatment. Methods We measured blood pressure supine and upright (tilt or active standing) and identified the presence or absence of symptomatic OH by using a validated patient-reported outcome questionnaire in 210 patients with PD. We evaluated the usefulness of the 20/10 and 30/15 mmHg diagnostic criteria (systolic/diastolic) to identify symptomatic OH. Results Fifty percent of the PD patient cohort met criteria for the 20/10 fall and 30% for the 30/15 blood pressure fall. Among the patients who met either OH criteria, the percentage of those with symptoms was small (33% of those with 20/10 and 44% of those with 30/15 mmHg; 16% and 13%, respectively overall). Symptomatic OH was associated with an upright mean blood pressure below 75 mmHg. A mean standing blood pressure <75 mmHg had a sensitivity of 97% and a specificity of 98% for detecting symptomatic OH. Conclusions Although the prevalence of OH in PD is high, not all patients have symptoms of organ hypoperfusion. A mean standing blood pressure below 75 mmHg appears to be a useful benchmark when deciding whether the benefits of initiating pharmacological treatment of OH outweigh the risks of exacerbating supine hypertension.

Multiple system atrophy (MSA) may be difficult to distinguish clinically from other disorders, particularly in the early stages of the disease. An autonomic-only presentation can be indistinguishable from pure autonomic failure. Patients presenting with parkinsonism may be misdiagnosed as having Parkinson disease. Patients presenting with the cerebellar phenotype of MSA can mimic other adult-onset ataxias due to alcohol, chemotherapeutic agents, lead, lithium, and toluene, or vitamin E deficiency, as well as paraneoplastic, autoimmune, or genetic ataxias. A careful medical history and meticulous neurological examination remain the cornerstone for the accurate diagnosis of MSA. Ancillary investigations are helpful to support the diagnosis, rule out potential mimics, and define therapeutic strategies. This review summarizes diagnostic investigations useful in the differential diagnosis of patients with suspected MSA. Currently used techniques include structural and functional brain imaging, cardiac sympathetic imaging, cardiovascular autonomic testing, olfactory testing, sleep study, urological evaluation, and dysphagia and cognitive assessments. Despite advances in the diagnostic tools for MSA in recent years and the availability of consensus criteria for clinical diagnosis, the diagnostic accuracy of MSA remains sub-optimal. As other diagnostic tools emerge, including skin biopsy, retinal biomarkers, blood and cerebrospinal fluid biomarkers, and advanced genetic testing, a more accurate and earlier recognition of MSA should be possible, even in the prodromal stages. This has important implications as misdiagnosis can result in inappropriate treatment, patient and family distress, and erroneous eligibility for clinical trials of disease-modifying drugs.

Multiple system atrophy (MSA) is a neurodegenerative disease with two motor phenotypes: parkinsonian (MSA-P) and cerebellar (MSA-C). To elucidate whether in addition to the motor abnormalities there are other significant differences between these phenotypes we performed a retrospective review of 100 patients (61 males, 39 females) with a diagnosis of possible (12%), or probable (88%). Four patients eventually had postmortem confirmation (i.e., definite MSA). Sixty percent were classified as having MSAP and 40% as MSA-C. MSA-C and MSA-P patients had similar male prevalence (60%), age of onset (56±9 years), and frequency of OH (69%). Brain MRI abnormalities were more frequent in MSA-C patients (p<0.001). Mean survival was 8±3 years for MSA-C and 9±4 years for MSA-P patients (p=0.22). Disease onset before 55 years predicted longer survival in both phenotypes. Initial autonomic involvement did not influence survival. We conclude that patients with both motor phenotypes have mostly similar survivals and demographic distributions. The differences here identified could help counseling of patients with MSA.

Introduction Familial dysautonomia (FD) is a rare hereditary sensory and autonomic neuropathy (type III). The disease is caused by a point mutation in the IKBKAP gene that affects the splicing of the elongator-1 protein (also known as IKAP). Patients have dramatic blood pressure instability due to baroreflex failure, chronic kidney disease, and impaired swallowing leading to recurrent aspiration pneumonia, which results in chronic lung disease. Diminished pain and temperature perception results in neuropathic joints and thermal injuries. Impaired proprioception leads to gait ataxia. Optic neuropathy and corneal opacities lead to progressive visual loss. Areas covered This article reviews current therapeutic strategies for the symptomatic treatment of FD, as well as the potential of new gene modifying agents. Expert opinion Therapeutic focus on FD is centered on reducing the catecholamine surges caused by baroreflex failure. Managing neurogenic dysphagia with effective protection of the airway passages and prompt treatment of aspiration pneumonias is necessary to prevent respiratory failure. Sedative medications should be used cautiously due to risk of respiratory depression. Non-invasive ventilation during sleep effectively manages apneas and prevents hypercapnia. Clinical trials of compounds that increase levels of IKAP (ELP-1) are underway and will determine whether they can reverse or slow disease progression.