Claassen, Daniel O.

ABSTRACT Objective To determine the test performance of cutaneous phosphorylated alpha‐synuclein (P‐SYN) in dementia with Lewy bodies (DLB), individuals with reduced Montreal Cognitive Assessment (MoCA) and healthy controls. Methods This is the first subgroup analysis of the Synuclein‐One study, a prospective, blinded study evaluating P‐SYN detection from skin biopsies in 218 subjects with a referral diagnosis of control ( N = 151) and DLB ( N = 67). All subjects completed detailed examinations, questionnaires, and had skin biopsies for detection of P‐SYN. DLB patients were included if meeting the 4th DLB consensus probable criteria. Control subjects, aged 40–99, had no history, examination findings, or symptoms suggestive of a synucleinopathy or neurodegenerative disease. An expert review panel, blinded to pathological data, determined the final diagnosis. Controls with reduced MoCA (MoCA < 26, N = 26) at screening were analyzed separately. Results After expert panel review, only 50/67 patients met consensus criteria for DLB, 26/151 controls had a reduced MoCA, and 120/151 controls had a normal MoCA. The proportions of subjects with cutaneous P‐SYN detected by skin biopsy were 96.0% (48 of 50) of the DLB group, 31% (8 of 26) of the controls with reduced MoCA, and 3.3% (4 of 120) of the controls with normal MoCA. Interpretation In this prospective, blinded, cross‐sectional study, a high proportion of subjects meeting clinical consensus criteria for DLB had P‐SYN detected in skin biopsies. Almost 1/3 of subjects with reduced MoCA testing also had P‐SYN detected. These results support a role for skin biopsy detection of P‐SYN in patients with DLB. Trial Registration NCT04700722

Objective: To understand the patient and caregiver experience with the management of neurogenic orthostatic hypotension (nOH) Background: nOH is a sustained reduction in blood pressure (BP) with postural change associated with autonomic dysfunction. Clinical symptoms may include falls, leading to activity limits and a diminished sense of well-being. Methods: A US-based survey designed by the authors was conducted by Harris Poll. Eligible participants had Parkinson disease (PD), multiple system atrophy, or pure autonomic failure and ≥1 of the following: orthostatic hypotension (OH), nOH, low BP, OH/nOH symptoms, or were caregivers of eligible patients. Descriptive statistics are reported. Results: PD was the most frequent underlying diagnosis (Table 1) . Healthcare provider (HCP) communication with patients was rated as satisfactory by ≥75% of respondents, yet when nOH symptoms were first discussed with the HCP, only 35% of patients and 31% of caregivers reported the patient received guidance on management. The most frequently recommended interventions are listed in Table 1 ; 25% of patients reported that no interventions were recommended. Medication prescribed to treat nOH was reported by 34% of patients and 45% of caregivers. Among patients treated, 79% of patients and 71% of caregivers said that the patient’s symptoms were somewhat to very well managed. Conclusions: Survey findings suggest the need for increased awareness of nOH and engagement with patients and caregivers regarding symptom management. A variety of interventions were recommended; no single treatment approach was noted. Respondents felt nOH symptoms were at least somewhat well managed with treatment.

Objective: To understand the burden and impact of symptoms of neurogenic orthostatic hypotension (nOH) on patients Background: nOH and its symptoms such as dizziness/lightheadedness are common in patients with Parkinson disease (PD) and other forms of autonomic dysfunction. Methods: An author-designed, US-based survey was conducted by Harris Poll. Eligible participants were aged ≥18 years with PD, multiple system atrophy (MSA), or pure autonomic failure and ≥1 of the following: orthostatic hypotension, nOH, low BP, OH/nOH symptoms, or were caregivers of eligible patients. Results: Most patients (90%) had a diagnosis of PD, and most caregivers (88%) cared for a patient with PD (Table 1) . Patients (34%) and caregivers (49%) reported experiencing nOH symptoms before PD or MSA motor symptoms and >40% indicated that nOH symptoms were more troublesome than motor manifestations of PD or MSA. Less than a quarter (22%) of respondents suggested symptoms were most severe in the morning; more (30%) reported a consistent severity throughout the day. Patients (40%) and caregivers (63%) reported trouble managing symptoms during the day. In the past 12 months, a fall due to nOH symptoms was reported by 57% of patients and 80% of caregivers. Conclusions: These findings suggest that nOH symptoms may predate the onset of motor symptoms in neurodegenerative conditions linked to alpha-synuclein pathology. Many respondents report nOH symptoms are the same severity through the day. Patients with nOH may have trouble managing symptoms and note an increased risk for falls.

Objective: To understand the challenges to diagnosis in patients with neurogenic orthostatic hypotension (nOH) Background: nOH is a sustained reduction in blood pressure (BP) with postural change associated with autonomic dysfunction. Despite symptoms of nOH, many patients struggle to find an accurate diagnosis. Methods: An online, US-based survey designed by the authors was conducted by Harris Poll. Eligible participants were ≥18 years of age with Parkinson disease, multiple system atrophy, or pure autonomic failure and ≥1 of the following: orthostatic hypotension (OH), nOH, low BP, OH/nOH symptoms, or were caregivers of eligible participants. Results: The survey included 363 patients and 128 caregivers. Groups were separate, where caregivers were not the caregivers to patient responders. Respondents indicated that patients experienced nOH symptoms long term (Table 1) . Most patients (69%) and caregivers (59%) reported discussing nOH symptoms with a healthcare provider (HCP) within the first year of symptom onset, but only 36% of patients and 16% of caregivers reported a formal diagnosis of OH or nOH. Of those with a formal diagnosis, the majority of patients (50%) were frustrated by the path to diagnosis and more than 40% of patients and caregivers reported that the patient saw ≥3 HCPs before diagnosis. After diagnosis, most patients (70%) and caregivers (60%) reported improved symptom management. Conclusions: This survey reveals that patients and caregivers may find the path to nOH diagnosis challenging and suggests increased awareness among HCPs is needed. Once a diagnosis is made nOH symptoms are better managed.

ObjectivePerirolandic atrophy occurs in corticobasal syndrome (CBS) but is not specific versus progressive supranuclear palsy (PSP). There is heterogeneity in the locations of atrophy outside the perirolandic cortex and it remains unknown why atrophy in different locations would cause the same CBS‐specific symptoms. In prior work, we used a wiring diagram of the brain called the human connectome to localize lesion‐induced disorders to symptom‐specific brain networks. Here, we use a similar technique termed “atrophy network mapping” to localize single‐subject atrophy maps to symptom‐specific brain networks.MethodsSingle‐subject atrophy maps were generated by comparing cortical thickness in patients with CBS versus controls. Next, we performed seed‐based functional connectivity using a large normative connectome to determine brain regions functionally connected to each patient's atrophied locations.ResultsPatients with CBS had perirolandic atrophy versus controls at the group level, but locations of atrophy in CBS were heterogeneous outside of the perirolandic cortex at the single‐subject level (mean spatial correlation = 0.04). In contrast, atrophy occurred in locations functionally connected to the perirolandic cortex in all patients with CBS (spatial correlation = 0.66). Compared with PSP, patients with CBS had atrophy connected to a network of higher‐order sensorimotor regions beyond perirolandic cortex, matching a CBS atrophy network from a recent meta‐analysis. Finally, atrophy network mapping identified a symptom‐specific network for alien limb, matching a lesion‐induced alien limb network and a network associated with agency in healthy subjects.InterpretationWe identified a syndrome‐specific network for CBS and symptom‐specific network for alien limb using single‐subject atrophy maps and the human connectome. ANN NEUROL 2020;88:1118–1131