Journal Article Annotations
2025, 3rd Quarter

Neuropsychiatry

Annotations by Laura Duque, MD, Nathan Praschan, MD, MPH and Jacob Weiss, MD
September, 2025

Blood phosphorylated tau for the diagnosis of Alzheimer’s disease: a systematic review and meta-analysis.
Outcomes of specialist physiotherapy for functional motor disorder: the Physio4FMD RCT.

PUBLICATION #1 — Neuropsychiatry

Blood phosphorylated tau for the diagnosis of Alzheimer’s disease: a systematic review and meta-analysis.

Joseph Therriault, Wagner S Brum, Lydia Trudel, Arthur C Macedo, Fernando Valentim Bitencourt, Carolina Castro Martins-Pfeifer, Martin Nakouzi, Ilaria Pola, Matthew Wong, Przemysław R Kac, Ana Paula Real, Chloë Witherow, Thomas K Karikari, Alexis Moscoso, Eduardo R Zimmer, Michael Schöll, Tharick Pascoal, ndrea L Benedet, Nicholas J Ashton, Suzanne E Schindler, Henrik Zetterberg, Kaj Blennow, Pedro Rosa-Neto.

Abstract: Lancet Neurol. 2025 Sep;24(9):740-752. doi: 10.1016/S1474-4422(25)00227-3.

Background
Plasma phosphorylated tau (p-tau) biomarkers show promise to transform the clinical management of Alzheimer’s disease by providing more accessible and cost-effective diagnostic tools. p-tau biomarkers have emerged as leading contenders for clinical implementation; however, there have been no comprehensive meta-analyses of their diagnostic performance. We aimed to evaluate the diagnostic performance of plasma p-tau biomarkers and individual p-tau assays to identify biologically defined Alzheimer’s disease.

Methods
For this systematic review and meta-analysis, we searched Embase, MEDLINE, PubMed, Scopus, and Web of Science for articles published from July 1, 1984 up to Dec 9, 2024, that reported on the discriminative accuracy of plasma p-tau biomarkers for amyloid-PET, tau-PET, CSF, and neuropathological reference standards. We included cohort, case-control, cross-sectional, and randomised controlled studies that recruited adults from any setting. Articles were excluded if they did not contain data on a p-tau blood biomarker, did not contain an appropriate biological reference standard, did not report diagnostic accuracy data, included participants younger than 18 years, or reported duplicate or overlapping data from another publication. Summary data were independently extracted by eight authors. Risk of bias was assessed using QUADAS-2. The primary outcome was the diagnostic performance of plasma p-tau biomarkers for Alzheimer’s disease. We used a bivariate random-effects meta-analysis to estimate pooled sensitivity, specificity, diagnostics odds ratio and area under the receiver operating characteristic curve. We assessed the certainty of evidence using GRADE. This study was done following PRISMA-DTA guidelines and is registered with PROSPERO as CRD42023422143.

Findings
Of the 6429 studies identified by our search, 312 studies were assessed for eligibility, with 113 studies included in the final analysis, comprising 29 625 unique individuals. Plasma p-tau217 was the highest-performing biomarker for identifying biologically defined Alzheimer’s disease, with pooled sensitivity of 88·1% (95% CI 86·7–89·5, moderate certainty of evidence), specificity of 88·7% (87·4–89·9, moderate certainty of evidence), area under the receiver operating characteristic curve (AUROC) of 91·1% (88·9–92·4, moderate certainty of evidence), and diagnostic odds ratio of 50·7 (40·6–63·4). p-tau181 pooled sensitivity was 80·5% (78·4–82·4, low certainty of evidence), specificity was 76·4% (74·1–78·6, low certainty of evidence), AUROC was 81·5% (80·2–82·9, low certainty of evidence), and diagnostic odds ratio was 13·4 (11·4–16·7). p-tau205 pooled sensitivity was 76·6% (70·7–81·6, moderate certainty of evidence), specificity was 86·0% (78·6–91·2, moderate certainty of evidence), AUROC was 85·1% (80·7–89·6, moderate certainty of evidence), and diagnostic odds ratio was 20·2 (10·5–38·7). p-tau212 pooled sensitivity was 84·5% (75·5–90·6, moderate certainty of evidence), specificity was 87·3% (79·5–92·5, moderate certainty of evidence), AUROC was 90·3% (86·6–94·1, moderate certainty of evidence), and diagnostic odds ratio was 41·2 (22·0–77·3). p-tau231 pooled sensitivity was 75·2% (71·3–78·8, moderate certainty of evidence), specificity was 75·3% (71·2–78·9, moderate certainty of evidence), AUROC was 80·2 (77·6–82·7, moderate certainty of evidence), and diagnostic odds ratio was 9·3 (7·0–12·2). Approximately 90% of studies were rated as high risk of bias for not having used predefined or externally derived thresholds.

Interpretation
Plasma p-tau217 is a highly sensitive and specific biomarker for Alzheimer’s disease pathology, despite the high risk of bias of many studies. Prospective clinical implementation studies in real-world settings are needed to characterise the effect of plasma p-tau217 on Alzheimer’s disease diagnosis and clinical management.

Annotation

The finding:
This systematic review and meta-analysis of 113 studies (29,625 participants) found that plasma phosphorylated tau (especially p-tau217) is a highly accurate blood biomarker for Alzheimer’s disease. P-tau217 demonstrated diagnostic performance comparable to PET and CSF biomarkers, supporting its potential role in timely and accurate diagnosis of Alzheimer’s pathology in patients with cognitive impairment.

Strength and weaknesses:
Key strengths include the very large sample size, evaluation of multiple p-tau assays, and rigorous methodology following PRISMA-DTA guidelines, with subgroup analyses by cognitive status. Limitations include that most studies were cross-sectional, nearly 90% had high risk of bias from using non–pre-specified thresholds, and there was moderate heterogeneity across studies.

Relevance:
For C-L psychiatrists, these findings highlight the growing role of blood-based biomarkers in dementia evaluation. Although p-tau 217 is not yet clinically available or reimbursed, it may soon transform diagnostic pathways, potentially in hospital settings where access to PET or CSF testing may be limited. It may soon become a practical adjunct for diagnostic clarification, prognostication, and treatment eligibility discussions. The lower performance in asymptomatic individuals indicates these tests aren’t ready for screening purposes. As public awareness grows and patients may raise questions, C-L psychiatrists should be prepared to discuss the promise and current limitations of plasma p-tau assays.

PUBLICATION #2 — Neuropsychiatry

Outcomes of specialist physiotherapy for functional motor disorder: the Physio4FMD RCT.

Glenn Nielsen, Louise Marston, Rachael Maree Hunter, Alan Carson, Laura H Goldstein, ate Holt, Teresa C Lee, Marie Le Novere, Jonathan Marsden, Irwin Nazareth, Hayley Noble, Markus Reuber, Jon Stone, Ann-Marie Strudwick, Beatriz Santana Suarez, Mark J Edwards, Physio4FMD Study Group.

Abstract: Health Technol Assess. 2025 Jul;29(34):1-28. doi: 10.3310/MKAC9495.

Background:
Functional motor disorder often causes persistent disabling symptoms that are associated with high healthcare costs. In recent years, specialist physiotherapy, informed by an understanding of functional motor disorder, has emerged as a promising treatment, but there is an absence of evidence of its effectiveness from large randomised controlled trials.

Methods:
We conducted a pragmatic, multicentre, randomised controlled trial, comparing specialist physiotherapy for functional motor disorder to treatment as usual, which was defined as community neurological physiotherapy. The primary outcome was the Short Form questionnaire-36 items Physical Functioning domain at 12 months (scale range 0-100, with 100 indicating optimum health). The trial was powered to detect a 9-point difference in the primary outcome with 90% power at the 5% level of significance. Secondary domains of measurement included a patient perception of improvement, health-related quality of life, mobility, anxiety, depression and illness perception. We also completed a health economic analysis with the primary aim of calculating the mean incremental cost per quality-adjusted life-year over 12 months. In prespecified analysis plans, we excluded participants from the primary analysis if they were unable to receive their trial-allocated treatment due to COVID-19 lockdown restrictions. Sensitivity analysis explored the impact of this decision.

Results:
Between 19 October 2018 and 31 January 2022, 355 adults with functional motor disorder were randomised (1 : 1) to specialist physiotherapy (n = 179) and treatment as usual (n = 176). Eighty-nine participants were excluded due to COVID-19 disruptions. Retention for the primary analysis was 90% for both groups, leaving 241 participants in the primary analysis. At 12 months, there was no between-group difference in the primary outcome (adjusted mean difference 3.5, 95% confidence interval -2.3 to 9.3). However, several secondary outcomes favoured specialist physiotherapy, including the participant perception of improvement, Short Form questionnaire-36 items Mental Health domain, confidence in the diagnosis and two subscales (Personal Control and Illness Coherence) of the Revised Illness Perception Questionnaire. There were no differences in the remaining outcomes. At 6 months, the following outcome measures were significantly different, in favour of specialist physiotherapy: participant perception of improvement, the Short Form questionnaire-36 items Physical Role Limitations, Short Form questionnaire-36 items Social Functioning, Short Form questionnaire-36 items Mental Health, EuroQol-5 Dimensions five-level version utility score, confidence in the diagnosis and three subscales (Timeline Cyclical, Personal Control and Treatment Control) of the Revised Illness Perception Questionnaire. No outcomes significantly favoured treatment as usual. In the health economic analysis, the incremental cost per quality-adjusted life-year gained from a health and social care cost perspective was £4133 with an 86% probability that specialist physiotherapy is cost-effective compared to treatment as usual at a cost-effectiveness threshold of £20,000 per quality-adjusted life-year gained. There were no adverse events related to physiotherapy.

Conclusion:
Specialist physiotherapy was not superior to treatment as usual for the primary outcome, the Short Form questionnaire-36 items Physical Functioning domain at 12 months. However, a number of secondary outcome measures favoured specialist physiotherapy at 6 and 12 months. There is a high probability that specialist physiotherapy is cost-effective.

Limitations:
Participants in treatment as usual waited longer to start physiotherapy, which resulted in a shorter time between concluding treatment and completing the primary outcome. Most outcome measures, including the primary outcome, were participant reported, which may have been biased by perceptions of the randomised treatment allocation.

Future work:
Future work should identify or develop more suitable outcome measures for functional motor disorder research, explore who is most likely to benefit from specialist physiotherapy and identify alternative interventions for those unlikely to benefit from this treatment. Additional work is needed to adapt treatment to meet the needs of minority groups and young people.

Funding:
This synopsis presents independent research funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme as award number 16/31/63.

Annotation

The finding:
This study is one of the few randomized controlled trials in functional neurological disorder (FND) and the only on functional motor disorders (FMD) treatable primarily with physiotherapy. The authors developed a specialized physiotherapy program (Physio4FMD) informed by the biopsychosocial model, the predictive brain models of FND, and the physiotherapy consensus guidelines for FND. This intervention was compared to treatment as usual (TAU) involving neurological rehabilitative physiotherapy in the community. Participants were randomized to each group, and although the COVID-19 pandemic interrupted treatment in a significant portion of those enrolled, ultimately 152 and 114 were enrolled in the intervention and TAU, respectively. Outcomes were evaluated at 6 and 12 months; the primary outcome was a commonly used self-reported index of physical functioning in FND studies, the SF-36, and secondary outcomes include the patient-rated clinical global impression scale, a variety of metrics of psychiatric and physical distress, and the illness perception questionnaire. Although the primary outcome measure (total SF-36) was null, both groups demonstrated improvements, and a number of secondary endpoints favored the intervention over TAU—including the global impression scale.

Strength and weaknesses:
This is the first study of physiotherapy in FND and joins the few RCTs that have been completed in this population. The FND population is challenging to study, particularly when evaluating a physiotherapy intervention in the midst of the pandemic which may limit enrollment and follow-up in a group already prone to study dropout. Although the study evaluated a specialized physiotherapy program, the results indicated that any physical therapy program from a neurologically informed therapist may yield benefits. The authors were unable to control the type of therapy in the community, and so it is possible that the TAU group used similar techniques as those in Physio4FMD, thereby negating treatment differences. The authors decided to also describe the process of completing their study, including the challenges of the pandemic, in hopes that more evidence may be developed to help this population.

Relevance:
FND is a common illness seen in up to 20% of neurology office visits and up to 40% of inpatient epilepsy monitoring units. As FND is an illness at the boundaries of both neurology and psychiatry, CL psychiatrists should be familiar with its diagnosis and treatment beyond the management of psychiatric comorbidities. Familiarity with physiotherapy techniques used in FND is essential in the long-term management in FMD.