Parkinson's disease (PD) is characterized by progressive loss of nigral dopaminergic neurons, resulting in disabling motor symptoms. Intracerebral transplantation of stem cell-derived dopaminergic progenitors to replace lost endogenous dopaminergic neurons offers a new potentially restorative therapeutic approach for PD. Here we report the 12-month primary safety end point and interim efficacy outcomes from a phase 1/2, open-label, multicenter trial evaluating STEM-PD, a cryopreserved, off-the-shelf dopaminergic progenitor product derived from human pluripotent stem cells. Eight individuals with moderate PD underwent bilateral intraputaminal transplantation at two escalating doses (n = 4 per cohort), followed by 12 months of immunosuppression. Seven participants completed 12-month follow-up; one participant died from a pulmonary infection. No serious adverse events were attributed to the cell product, no graft-induced dyskinesias were observed and serial magnetic resonance imaging showed no evidence of tumor formation. These findings support the feasibility and favorable safety profile of human pluripotent stem cell-derived dopaminergic progenitor transplantation in this early-phase study, with risks primarily associated with the immunosuppression regimen. Ongoing follow-up to 36 months will further evaluate durability, clinical outcomes and graft function. ClinicalTrials.gov identifier: NCT05635409 .
G. Paul, H. Bjartmarz, A. Kirkeby et al.· Nature Medicine· 1 citation
Among soluble tau biomarkers, tau phosphorylation at position T205 (p-tau205) has been suggested to distinctly emergence across Alzheimer's disease (AD) continuum compared to other p-tau and non-phosphorylated tau forms, and a moderate relationship with both amyloid-β and tau aggregated pathologies. To evaluate this and further expand the characterization of this biomarker, we measured cerebrospinal fluid (CSF) p-tau205 using an in-house developed immunoassay in a total of 2069 samples from the BioFINDER-2 (n = 1364) and BioFINDER-1 (n = 705) cohorts. These two cohorts spanned the full AD continuum and were analyzed to assess cross-sectional and longitudinal associations with imaging and clinical measures. CSF p-tau205 levels were elevated in both biologically and clinically advanced disease stages. In Aβ-positive individuals, baseline p-tau205 levels correlated with Aβ-PET (R² = 0.28), tau-PET (medial temporal: R2 = 0.35, neocortical: R² = 0.29), cortical atrophy (R² = 0.15) and cognition (MMSE, R² = 0.15). Baseline p-tau205 predicted subsequent Aβ accumulation (R² = 0.44) and tau-accumulation measured by PET (R² = 0.33). Longitudinal p-tau205 levels increased more steeply longitudinally in Aβ-positive than Aβ-negative participants (β[95%CI] = 0.16[0.12-0.21], p < 0.001). Longitudinal p-tau205 changes were associated with cortical thinning (R² = 0.32) and cognitive decline (R² ≥ 0.41). When incorporating Aβ42/40, p-tau217 and p-tau205 into a conceptual CSF-based staging model, the final p-tau205-positive stage showed the strongest association with cortical atrophy, cognitive impairment, and risk of progression to dementia (HR = 6.40[4.28-9.59]). These findings support CSF p-tau205 as a biomarker of Alzheimer's disease pathology and progression with potential value for biological staging.
J. Lantero‐Rodriguez, S. Janelidze, S. Palmqvist et al.· Molecular Psychiatry· 0 citations
Importance
Amyloid positron emission tomography (PET) is increasingly used in research and clinical settings to determine the etiology of cognitive decline and eligibility for amyloid-targeting therapies. To assist with amyloid PET evaluation and to guide clinical decision-making, images can be quantified in a standardized unit called Centiloid, the interpretation of which can vary according to the method and threshold used.
Objective
To collect Centiloid values from available studies and determine robust positivity cutoffs using data-driven methods and correspondence with visual reads.
Data Sources
PubMed search (October 2024) identified studies with Centiloid values. Corresponding authors were invited to share individual participant data. Additional data were obtained through access-controlled repositories and conference outreach (July 2024-July 2025).
Study Selection
Studies were included if they provided Centiloids, radiotracer, age, and sex.
Data Extraction and Synthesis
Each study was analyzed using a unified statistical pipeline; study estimates were pooled using random-effects meta-analysis.
Main Outcomes and Measures
Gaussian mixture models (GMMs) were fitted to Centiloid values for each study. In studies with a bimodal distribution (per integrated completed likelihood), single cutoffs for positivity were set as mean plus 2 SDs of the lower gaussian component. Using GMMs, a double-cutoff approach defined a lower certainty range using a 90% posterior probability cutoff for assignment to the low (amyloid-negative) vs high (amyloid-positive) component. An alternative Centiloid cutoff was derived from maximizing the correspondence (Cohen κ) with the binary visual reads when available.
Results
This meta-analysis included cross-sectional amyloid PET scans acquired with 5 radiotracers from 49 227 participants across 53 studies from 15 countries (mean age, 71 years; 54% female, 62% cognitively impaired). The data-driven GMM approach identified a bimodal distribution in 51 studies (n = 48 786), resulting in a single cutoff for positivity of 18 Centiloids (95% CI,16-19; I2 = 97%). The double-cutoff approach revealed high confidence for interpreting scans as negative when Centiloid values were lower than 11 (95% CI, 9-13; I2 = 95%) and interpreting scans as positive if Centiloid values were higher than 26 (95% CI, 24-28; I2 = 95%). In analyses of correspondence with binary (positive or negative) visual reads of amyloid PET scans (n = 35 045; 36 studies), Centiloids were highly predictive of visual positivity (Cohen κ, 0.86; 95% CI, 0.83-0.89; I2 = 96%) with a cutoff of 27 Centiloids (95% CI, 24-30; I2 = 80%).
Conclusions and Relevance
In this individual participant data meta-analysis, positivity cutoffs converged around 18 Centiloids (data-driven) and 27 Centiloids (visual reads). Findings from a double-cutoff analysis suggest that scans in the 11 to 26 Centiloid range should be interpreted with caution depending on the context of use.
Ganna Blazhenets, David N Soleimani-Meigooni, Konstantinos Chiotis et al.· Journal of the American Medi...· 2 citations