Roy Freeman

Background and ObjectivesDegeneration of the central autonomic network with relative sparing of peripheral autonomic neurons underlies neurogenic orthostatic hypotension in patients with multiple s...

Background: The Movement Disorder Society (MDS) research criteria for possible prodromal multiple system atrophy (PP‐MSA) have not been prospectively validated. Objective: To evaluate the diagnostic performance of the PP‐MSA criteria in a longitudinal cohort of patients with pure autonomic failure (PAF) and to assess whether additional clinical features improve their predictive value. Methods: Seventy‐six patients with PAF enrolled across eight centers in the Natural History Study of the Synucleinopathies were followed for ≥6 years or until phenoconversion. Participants were classified according to MDS PP‐MSA criteria and followed for development of MSA, Parkinson's disease, or dementia with Lewy bodies. Diagnostic performance was assessed longitudinally. Analyses were repeated using a stricter olfactory threshold (University of Pennsylvania Smell Identification Test [UPSIT]≤28) as an exclusion criterion. Results: Thirty‐eight participants met PP‐MSA criteria, of whom 12 phenoconverted to MSA within 6 years. Sensitivity was 100% at year 1 and 92% at year 6, whereas specificity ranged from 56% to 67%. Positive predictive value (PPV) ranged from 21% to 34%. Applying a stricter olfactory threshold improved specificity (90%–97%) and PPV (53%–83%), with a modest reduction in sensitivity (to 83%). Participants who phenoconverted to MSA were younger, had more severe urinary dysfunction, and greater orthostatic heart rate responses. Conclusions: The PP‐MSA criteria demonstrate high sensitivity but limited specificity in patients with PAF. A stricter olfactory threshold improves diagnostic performance and may enhance cohort enrichment for clinical trials. © 2026 International Parkinson and Movement Disorder Society. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.

Background: Pain affects up to 87% of people with multiple system atrophy (MSA), but it remains unclear which types of pain contribute most to the overall burden. Objective: To estimate the frequency of different types of pain in MSA individuals. Methods: In 2023, individuals with MSA completed a web‐based survey that included the King's Parkinson's Disease Pain Questionnaire (KPPQ) and additional questions addressing pain related to MSA core features (eg, coat‐hanger pain, pain due to bladder‐issues, cold extremities, bruises, and pressure sores). Respondents were matched by age, gender, and disease duration with historical cohorts of individuals with Parkinson's disease (PD) and healthy controls (n = 96 each) who had previously completed the KPPQ. Results: One hundred and fifty‐seven MSA individuals with pain completed the survey. The most frequently reported KPPQ types of pain were nocturnal pain (73%), musculoskeletal pain (63%), and fluctuation‐related pain (62%). Common additional pain sources included coat‐hanger pain (59%), cold extremities (48%), and bruises (44%). All KPPQ pain types were significantly more frequent in MSA than in healthy controls, except for musculoskeletal pain (63% vs. 66%, P = 0.722). Compared with PD, MSA individuals reported less musculoskeletal (63% vs. 78%, P = 0.023), but more orofacial pain (32% vs. 12%, P < 0.001) on the KPPQ. Conclusions: MSA is associated with both non‐specific and disease‐related pain types, which may be neuropathic, nociceptive, nociplastic, or mixed in nature. These findings inform the development of tailored tools for identifying distinct pain sources in MSA, as each may require a specific therapeutic approach, including targeted treatment of motor and non‐motor symptoms. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

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

Purpose: The purpose of this secondary analysis was to explore paclitaxel‐induced peripheral neuropathy severity patterns among women with breast cancer receiving weekly or dose dense paclitaxel regimens. Methods: Young adult women with breast cancer (18–39 years) beginning cancer treatment with dose dense (175 mg/m ² every 14 days) or weekly (80 mg/m ² ) paclitaxel completed the QLQ‐CIPN20 before the first paclitaxel infusion (T1) and then at two time points during paclitaxel chemotherapy (T2: 350 mg/m ² and T3: 700 mg/m ² ). QLQ‐CIPN20 scores were compared between women receiving dose dense or weekly paclitaxel across the three time points using mixed‐effect linear regression models. Results: Among women receiving dose dense paclitaxel ( n = 27), mean QLQ‐CIPN4 scores increased from 4.63 at T1 to 15.43 at T3, while among women receiving weekly paclitaxel ( n = 12), mean QLQ‐CIPN4 scores increased from 2.08 at T1 to 5.56 at T3. Similar trends were observed for changes in QLQ‐CIPN20 sensory and motor subscale scores among both groups. Overall, while CIPN severity was worse at each time point among women receiving dose dense paclitaxel relative to women receiving weekly paclitaxel, there were no statistically significant differences between groups for changes in QLQ‐CIPN4 ( p = 0.24), QLQ‐CIPN20 sensory ( p = 0.41), or QLQ‐CIPN20 motor score ( p = 0.68) over time. Conclusions: The results may be used to promote awareness among patients and clinicians regarding potential trajectories of paclitaxel‐induced peripheral neuropathy for women with breast cancer.

BACKGROUND: Neurogenic orthostatic hypotension (nOH) causes pathological falls in standing blood pressure that may or may not be symptomatic. nOH also raises the risk of poor neurological outcomes irrespective of symptom presence, possibly reflecting subclinical cerebral hypoperfusion. Dynamic changes in cerebral blood flow velocity (CBFv) help infer how blood pressure fluctuations influence CBFv and cerebral autoregulation. Whether CBFv is impacted in nOH relative to related conditions without nOH and healthy controls (HC) remains unresolved. Whether nOH symptoms reflect greater CBFv falls is also unclear. This review aimed to compare CBFv between nOH and HC, nOH and disease-matched controls (eg, Parkinson disease±nOH), and between symptomatic and asymptomatic nOH. METHODS: Embase and MEDLINE were searched up to April 2024. Means, SDs, and sample sizes for supine and upright CBFv were extracted to generate standardized effect sizes (Hedge g). Random-effects modeling compared postintervention between-group effect sizes. RESULTS: Seventeen studies were included for review. Thirteen studies were suitable for meta-analysis comparing nOH to HC, 2 comparing disease-matched controls to nOH and to HC, and 3 for symptomatic comparisons. Compared with HC, nOH had larger drops in CBFv (Hedge g, −0.64 [95% CI, −0.85 to −0.44]; P P =0.17). Symptomatic nOH had larger CBFv drops (Hedge g, 0.84 [95% CI, 0.212–1.461]; P =0.009) than asymptomatic nOH. CONCLUSIONS: nOH causes significant orthostatic reductions in CBFv compared with HC, and symptomatic patients experience greater falls in CBFv than asymptomatic patients. Recognizing the clinical implications of CBFv in nOH is crucial for mitigating adverse outcomes.

Pragmatic, randomized, controlled trials hold the potential to directly inform clinical decision making and health policy regarding the treatment of people experiencing pain. Pragmatic trials are designed to replicate or are embedded within routine clinical care and are increasingly valued to bridge the gap between trial research and clinical practice, especially in multidimensional conditions, such as pain and in nonpharmacological intervention research. To maximize the potential of pragmatic trials in pain research, the careful consideration of each methodological decision is required. Trials aligned with routine practice pose several challenges, such as determining and enrolling appropriate study participants, deciding on the appropriate level of flexibility in treatment delivery, integrating information on concomitant treatments and adherence, and choosing comparator conditions and outcome measures. Ensuring data quality in real-world clinical settings is another challenging goal. Furthermore, current trials in the field would benefit from analysis methods that allow for a differentiated understanding of effects across patient subgroups and improved reporting of methods and context, which is required to assess the generalizability of findings. At the same time, a range of novel methodological approaches provide opportunities for enhanced efficiency and relevance of pragmatic trials to stakeholders and clinical decision making. In this study, best-practice considerations for these and other concerns in pragmatic trials of pain treatments are offered and a number of promising solutions discussed. The basis of these recommendations was an Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) meeting organized by the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks.

In the traditional clinical research model, patients are typically involved only as participants. However, there has been a shift in recent years highlighting the value and contributions that patients bring as members of the research team, across the clinical research lifecycle. It is becoming increasingly evident that to develop research that is both meaningful to people who have the targeted condition and is feasible, there are important benefits of involving patients in the planning, conduct, and dissemination of research from its earliest stages. In fact, research funders and regulatory agencies are now explicitly encouraging, and sometimes requiring, that patients are engaged as partners in research. Although this approach has become commonplace in some fields of clinical research, it remains the exception in clinical pain research. As such, the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials convened a meeting with patient partners and international representatives from academia, patient advocacy groups, government regulatory agencies, research funding organizations, academic journals, and the biopharmaceutical industry to develop consensus recommendations for advancing patient engagement in all stages of clinical pain research in an effective and purposeful manner. This article summarizes the results of this meeting and offers considerations for meaningful and authentic engagement of patient partners in clinical pain research, including recommendations for representation, timing, continuous engagement, measurement, reporting, and research dissemination.