The study population consisted of consecutively enrolled patients at the Department of Neurology of the North China University of Science and Technology Affiliated Hospital in Tangshan, China, between July 2022 and June 2024. Participants were 60 to 83 years old, with a mean age of 70.32 ± 5.30 years; 184 were men and 198 were women. All met diagnostic criteria for the arteriolosclerotic, or type 1, form of cerebral small-vessel disease, while patients with other recognized subtypes were excluded. Of the 382 participants, 232 had white-matter hyperintensities and 150 did not. The latter group still had cerebral small-vessel disease based on other imaging features, such as lacunar infarcts, cerebral microbleeds or enlarged perivascular spaces.

White-matter hyperintensities were identified on 3-T magnetic resonance imaging as areas that were hyperintense on T2-weighted and fluid-attenuated inversion recovery images, were not obviously bright on diffusion-weighted imaging and had corresponding T1-weighted characteristics. Two radiologists assessed the scans independently while blinded to clinical and laboratory information, resolving disagreements by consensus. Severity was classified with the Fazekas scale: patients with a total score of 1–2 were placed in the mild group, those scoring 3–4 in the moderate group and those scoring 5–6 in the severe group. Among the 232 patients with hyperintensities, 111 had mild disease, 71 moderate disease and 50 severe disease. The weighted Cohen’s kappa for the total Fazekas score was 0.859, indicating excellent agreement between the two readers.

All four investigated indicators were higher on average in patients with white-matter hyperintensities than in those without them. Mean serum homocysteine was 24.28 ± 11.68 μmol/L in the hyperintensity-positive group compared with 13.43 ± 5.79 μmol/L in the negative group. SAP concentrations were 8.80 ± 3.23 μg/L and 4.91 ± 1.50 μg/L, respectively; neurofilament light chain, or NfL, was 117.02 ± 35.77 ng/L versus 101.02 ± 36.75 ng/L; and the carotid plaque Crouse score was 3.06 ± 1.27 points versus 1.55 ± 1.11 points. Age was also higher among patients with hyperintensities, at 72.07 ± 4.83 years compared with 67.62 ± 4.87 years. The two groups did not differ significantly in body mass index, smoking or drinking history, hypertension, diabetes, coronary heart disease, fasting glucose, major blood lipid measures or creatinine.

A clear stepwise pattern emerged when the 232 patients with hyperintensities were divided by lesion severity. Mean homocysteine rose from 20.14 ± 8.18 μmol/L in the mild group to 24.20 ± 9.57 μmol/L in the moderate group and 33.60 ± 15.31 μmol/L in the severe group. SAP increased from 7.72 ± 3.03 μg/L to 8.89 ± 2.30 μg/L and then 11.06 ± 3.63 μg/L. NfL rose from 104.81 ± 31.15 ng/L to 118.29 ± 30.72 ng/L and 142.31 ± 38.88 ng/L, while the Crouse score rose from 2.62 ± 1.28 to 3.20 ± 0.75 and 3.86 ± 1.43 points. Pairwise comparisons showed statistically significant differences between all three severity categories for each indicator. Spearman correlation analysis also found positive relationships with Fazekas severity: SAP had the largest coefficient at 0.451, followed by homocysteine at 0.432, NfL at 0.389 and the Crouse score at 0.366, with all false-discovery-rate-corrected p-values below 0.001.

Multivariable analyses supported the same pattern. In binary logistic regression, each of the four indicators remained associated with the presence of white-matter hyperintensities after adjustment for measured confounders. The reported adjusted odds ratios were 1.219 per unit of homocysteine, 2.496 per unit of SAP, 1.015 per unit of NfL and 1.819 per unit of Crouse score; age also remained independently associated with hyperintensity presence. All five associations remained significant after false-discovery-rate correction. Ordinal logistic regression, with sex and creatinine included as prespecified potential confounders, likewise found independent positive associations with increasing severity. Adjusted odds ratios for a more severe WMH category were 1.109 for homocysteine, 1.133 for SAP, 1.024 for NfL and 2.157 for the Crouse score, while age had an odds ratio of 1.163. A parallel-lines test did not reject the proportional-odds assumption, with p = 0.56.

Exploratory receiver operating characteristic analyses produced an area under the curve of 0.880 for SAP, with a reported optimal cutoff of 6.18 μg/L, sensitivity of 85.3% and specificity of 84.5%. The Crouse score followed with an area under the curve of 0.822 and homocysteine with 0.813; both had relatively low sensitivity and high specificity. Age achieved an area under the curve of 0.744, while NfL had the weakest discrimination at 0.667, despite a sensitivity of 84.1%. These ROC results were treated as exploratory and did not receive the same false-discovery-rate correction as the regression and correlation tests. The findings therefore describe how well each measure separated groups in this particular hospitalized cohort, not their accuracy in an unselected population or their ability to predict future lesions.

The four indicators represent different biological dimensions. Homocysteine is a metabolism-related intermediate whose elevation has been linked in preclinical and previous clinical research to endothelial injury, oxidative stress, vascular inflammation and small-artery changes. NfL is a structural axonal protein that can enter peripheral blood after axonal injury, making it a marker of neuronal damage rather than one specific to cerebral small-vessel disease. The Crouse score sums the maximum thickness of discrete carotid plaques and therefore measures extracranial atherosclerotic burden; it does not describe plaque stability. SAP is a liver-produced pentraxin-family glycoprotein involved in immune and inflammatory responses. Prior evidence discussed by the researchers suggests that blood–brain-barrier disruption may permit circulating SAP to enter injured brain tissue, where experimental studies report inflammatory and potentially neurotoxic effects. The present data did not measure cerebrospinal-fluid markers or directly test any of these mechanisms.

Several limitations constrain the interpretation and generalizability of the findings. The study was conducted at one hospital among selected older inpatients, all of whom were of East Asian ancestry, so selection bias and residual confounding are possible and the results may not represent community-dwelling older adults. Its cross-sectional design cannot establish whether elevated biomarkers precede white-matter damage, contribute causally to it or merely co-occur with existing lesions. Blood concentrations may also differ from concentrations within the brain, particularly for SAP and NfL, and the Crouse score captures plaque thickness rather than the full vascular process. Validation in larger, multicenter and prospective cohorts is therefore needed to determine whether SAP or combinations of these markers can improve screening or severity assessment. The findings do not establish that lowering any biomarker, treating plaque or altering vascular risk factors will prevent or reduce white-matter lesions, and the authors draw no therapeutic conclusions from these data.

Subject of Research: Associations of four blood and vascular markers with white-matter hyperintensities in older adults with cerebral small-vessel disease

Article Title: Associations of serum Hcy, SAP, NfL, and carotid plaque Crouse score with white-matter hyperintensities in older patients with cerebral small-vessel disease

Article References: Ren, B., Ma, Y., Mao, W., & Wu, X. (2026). Associations of serum Hcy, SAP, NfL, and carotid plaque Crouse score with white-matter hyperintensities in older patients with cerebral small-vessel disease. Frontiers in Neurology, 17, 1977360. https://doi.org/10.3389/fneur.2026.1977360

Image Credits: AI Generated

DOI: 10.3389/fneur.2026.1977360

Keywords: cerebral small-vessel disease, white-matter hyperintensities, serum amyloid P component, homocysteine, neurofilament light chain, carotid plaque Crouse score, cerebrovascular biomarkers, brain MRI, older adults, Associations, serum, carotid

The research, published in Annals of Clinical and Translational Neurology, evaluated two FDA-cleared capillary blood collection devices, TAPII and Tasso+, for measuring four key Alzheimer’s plasma biomarkers: the amyloid-beta 42/40 ratio, phosphorylated tau 217 (pTau217), neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP). These analytes tell complementary stories about the disease. The Aβ42/40 ratio reflects amyloid deposition, pTau217 is currently the strongest single plasma marker for discriminating autopsy-confirmed Alzheimer’s disease from other neurodegenerative conditions, NfL signals neuroaxonal injury, and GFAP marks astrocyte activation associated with the onset of amyloid pathology. The team, led by researchers at the Johns Hopkins Center for CSF Disorders, compared capillary plasma measurements to simultaneously collected venous plasma and cerebrospinal fluid from the same individuals.

The cohort comprised 192 patients examined between October 2021 and April 2024, with a mean age of 61 years and a clinically diverse mix of diagnoses. The group included 25 patients with Alzheimer’s disease, 42 with idiopathic normal pressure hydrocephalus, 28 with vascular dementia, 61 with other neurological conditions such as dementia with Lewy bodies, frontotemporal dementia, Parkinson’s disease and idiopathic intracranial hypertension, and 36 cognitively normal participants split into younger and older normal groups. Each patient who could provide samples underwent venipuncture on one arm and capillary collection on the other using either TAPII or Tasso+, both containing EDTA as an anticoagulant. Twenty patients provided samples with both devices. Cerebrospinal fluid was obtained by diagnostic large-volume lumbar puncture under sterile conditions.

The devices themselves are compact, single-use tools designed to collect small amounts of capillary whole blood painlessly from capillaries in the skin. TAPII, approved in 2019, uses an array of 16 microneedles, each 500 micrometers in length, and gentle vacuum to draw blood. Tasso+, cleared in 2022, uses a single lancet 5 millimeters long. Both are described by their manufacturers as suitable for use by a caregiver or the patient themselves, if able, from the comfort of home. In this study, Tasso+ collected a mean volume of 294.1 microliters and TAPII 266.94 microliters, with Tasso+ succeeding in collecting more than 50 microliters of whole blood in 90.3 percent of attempts and TAPII in 86 percent, differences that were not statistically significant. Both devices yielded sufficient blood for multi-biomarker immunoassays in more than 85 percent of collections.

All biomarker levels were measured in singlicate on a Simoa HD-X analyzer using commercially available kits, with inter-assay coefficients of variation below 12 percent for all analytes. The results for three of the four biomarkers were strikingly positive. Capillary concentrations of NfL, GFAP and Aβ42/40 from both devices correlated strongly with their venous plasma counterparts. TAPII-derived NfL showed a correlation coefficient of 0.86 with venous NfL, GFAP 0.84 and Aβ42/40 0.74, all highly significant. Tasso+ performed similarly, with NfL at 0.91, GFAP at 0.80 and Aβ42/40 at 0.75. Pairwise comparisons found no significant differences between TAPII, Tasso+ and venous measurements for these three analytes, and Bland-Altman analysis revealed minimal bias and tight agreement for Aβ42/40 across the range of values, with wider limits of agreement for NfL and particularly GFAP, which showed substantial variability and multiple outliers for both devices.

Then came the surprise. pTau217, the biomarker that has consistently outperformed other phosphorylated tau isoforms in distinguishing Alzheimer’s disease from other dementias and in predicting PET positivity, failed to replicate between capillary and venous samples. Tasso+ capillary pTau217 correlated only weakly with venous pTau217 (r = 0.23, p = 0.04), and TAPII pTau217 did not correlate significantly at all (p = 0.12). Bland-Altman analysis demonstrated a consistent positive bias for both devices, with mean biases of approximately 7 picograms per milliliter for TAPII and 3 picograms per milliliter for Tasso+, and this overestimation became more pronounced at higher pTau217 concentrations. Passing-Bablok regression confirmed substantial proportional bias, with slope estimates markedly deviating from one for both devices. The practical consequence was dramatic: over 95 percent of capillary pTau217 concentrations across all patient groups, even cognitively normal controls, exceeded the preliminary cutoff of 0.42 picograms per milliliter used in established literature to indicate significant brain amyloid pathology. In venous plasma, only the Alzheimer’s disease group and the mixed neurodegenerative Other group exceeded that threshold on average. The study reports a nearly 30-fold difference between TAPII and venous measurements, a 10-fold difference between Tasso+ and venous, and a 3-fold difference between the two capillary devices themselves.

The authors propose several hypotheses for this pTau217 anomaly. Phosphorylated tau species, including pTau217, as well as alpha-synuclein aggregates, have been shown to exist in peripheral nerve terminals of the skin, raising the plausible hypothesis that capillary collection devices may release peripheral pTau217 into the whole blood sample collected, thereby inflating the overall concentration. Matrix effects unique to the pTau217 assay may also be involved, since all the other analytes were run on a different assay kit. Differences in the dimensions and number of needles utilized by the two devices may explain variation in pTau217 concentration as well as hemolysis, which was significantly higher in capillary samples (TAPII 2.08 out of 4, Tasso+ 1.37 out of 4) compared with venous. Notably, hemolysis did not significantly alter the strong relationship between capillary and venous measurements of Aβ42/40, NfL and GFAP, suggesting the pTau217 problem is specific rather than a general quality issue with capillary specimens.

When the researchers compared capillary and venous plasma to cerebrospinal fluid, venous NfL, GFAP and pTau217 all correlated significantly with CSF analytes (NfL r = 0.73, GFAP r = 0.59, pTau217 r = 0.33), consistent with previous CSF-plasma studies. Capillary NfL and GFAP also correlated modestly with CSF measures, whereas capillary Aβ42/40 and pTau217 did not correlate significantly with CSF. Age-adjusted logistic regression models constructed separately for each sample type found comparable discrimination of Alzheimer’s disease status across venous and capillary measurements for all four biomarkers, with no statistically significant differences in AUC. Venous pTau217 demonstrated the highest individual biomarker performance (AUC 0.88, 95 percent CI 0.82-0.94), while GFAP and Aβ42/40 showed similar diagnostic performance across capillary and venous sample types.

Lasso-regularized logistic regression, used to account for the small number of clinically diagnosed Alzheimer’s cases (n = 25) and reduce overfitting, identified age and plasma GFAP as the most consistent predictors of Alzheimer’s disease across all sample types. Models incorporating these two variables yielded AUC values of 0.75 for TAPII-derived capillary plasma, 0.87 for Tasso+-derived capillary plasma and 0.83 for venous plasma. Remarkably, the Tasso+ model, built from just age and GFAP, exceeded both the TAPII and venous models and fell close to AUC values generated by plasma Alzheimer’s biomarker testing in larger studies. The authors suggest that capillary GFAP, particularly in combination with age or APOE genotype, could serve as a scalable screening tool for Alzheimer’s disease in primary care or decentralized research settings. NfL, while elevated in Alzheimer’s disease, is also elevated in many other neurodegenerative conditions present in the cohort, explaining its weak discriminatory power between Alzheimer’s and non-Alzheimer’s participants. The reduced predictive utility of capillary Aβ42/40 concurs with previous studies citing the plasma amyloid ratio’s greatest diagnostic power in preclinical and mild cognitive impairment stages, whereas this cohort primarily comprised clinical Alzheimer’s dementia.

Pain scores, measured on a Numeric Rating Scale from 0 to 10, were dramatically lower for capillary collections than for traditional venipuncture. Tasso+ scored a mean of 0.2 out of 10, TAPII 0.73 out of 10, and venous collection 2.24 out of 10, with all pairwise comparisons highly significant. The authors note that lower pain associated with capillary collection may improve patient compliance for blood draws, a finding consistent with other studies using capillary collection devices. The study was conducted in a supervised clinical setting, and the authors caution that findings may differ in unsupervised or at-home collection environments. The cohort was also not randomized between devices, which may introduce bias but reflects real-world clinical conditions, and the number of clinically diagnosed Alzheimer’s cases was relatively small, limiting statistical power.

The overall conclusion is a nuanced one. The findings support the feasibility of capillary biomarker testing and the use of capillary collection devices in decentralized Alzheimer’s clinical trials and studies, with minimal loss of diagnostic signal for NfL, GFAP and Aβ42/40 compared with venous plasma. But a clear need exists for specific guidelines and assay optimization for capillary biomarkers, particularly pTau217, due to significant technical or biological differences between TAPII, Tasso+ and venous plasma samples. The authors envision a future in which patients or caregivers could provide a small capillary sample at home or in a clinic, and clinicians could triage them for confirmatory CSF or PET testing based on algorithmic risk. Before that vision becomes reality, capillary blood biomarker tests will need to be thoroughly evaluated as CSF and venous plasma assays have been over the past decade, potentially necessitating separate cutoffs and guidelines for different plasma sample types to account for the measurement gap that this study has now exposed.

Subject of Research: Validation of two capillary blood collection devices for measuring Alzheimer's disease plasma biomarkers against venous plasma and cerebrospinal fluid

Article Title: Alzheimer's Disease Biomarkers Measured by Capillary Blood Collection Versus Venous Plasma and Cerebrospinal Fluid

Article References: Ho, S., Shen, Z., Lewis, A., Patel, M., Zheng, A., Proscino, G., Ho, T., Wang, J., Albert, M., & Moghekar, A. (2026). Alzheimer's Disease Biomarkers Measured by Capillary Blood Collection Versus Venous Plasma and Cerebrospinal Fluid. Annals of Clinical and Translational Neurology, Article acn3.70524. https://doi.org/10.1002/acn3.70524

Image Credits: AI Generated

DOI: 10.1002/acn3.70524

Keywords: Alzheimer's disease, blood biomarkers, capillary blood collection, pTau217, GFAP, neurofilament light chain, amyloid beta 42/40, cerebrospinal fluid, Tasso+, TAPII, decentralized clinical trials, plasma biomarkers

The research, led by Margaret Gatz, a professor of psychology and gerontology at the University of Southern California and a senior scientist at the USC Center for Economic and Social Research, followed 730 adults who were free of dementia at their initial assessment. Nearly five years later, the teams returned to re-examine the same individuals. Over that interval, they identified 22 new cases of dementia, corresponding to an overall incidence of 7.40 cases per 1,000 person-years. At the follow-up assessments, the prevalence of dementia, meaning the proportion of the population living with the condition at any given moment, remained below two percent. Those numbers seem to confirm the impression of extraordinary brain health, but the comparison with industrialized nations is more nuanced than it first appears.

The crucial distinction is between incidence and prevalence, two measures that are often conflated in popular reporting. Incidence counts the new diagnoses that arise within a defined span of time, while prevalence includes everyone living with a disease regardless of when it began. Because prevalence is shaped both by how frequently a disease develops and by how long patients survive after it develops, a one-time snapshot can be deeply misleading. A population can show very low prevalence not because its members rarely develop a disease, but because those who do develop it do not survive long enough to be counted. Repeated assessments over time, as in the new study, are what allow researchers to separate these two forces.

When the researchers made that separation, the surprising result emerged. Among the Tsimané and Mosetén, dementia incidence did not dramatically differ from rates observed in U.S. and northern European populations, particularly for individuals under the age of 80. What differed sharply was survival. Participants with dementia faced more than six times the mortality risk of those with normal cognition, and compared with U.S. studies, the average survival time following a dementia diagnosis appeared two to three times shorter. Shorter survival after dementia develops, the authors conclude, plays a significant role in why the total proportion of people living with dementia in these communities is unusually low. The disease is not so much absent as it is rapidly fatal.

The reasons for that shortened survival are rooted in the realities of life in remote Amazonian communities. Households depend on every member contributing to farming, hunting, fishing and food preparation, so a person whose disabilities prevent them from helping to obtain food simultaneously increases the burden on the family while losing their own role and support. Gatz noted that limited access to medical care means that treatable infections and other acute illnesses can become deadly, a vulnerability that is compounded for someone already weakened by dementia. In industrialized settings, by contrast, formal caregiving systems, clinical services and social safety nets extend survival for people with cognitive impairment, inflating prevalence even where incidence is similar.

The findings complicate, without fully overturning, the earlier hypothesis that the Tsimané and Mosetén are protected by their pre-industrial lifestyle. Previous work by the Tsimané Health and Life History Project, a long-running collaboration that has studied these communities for decades, found that they experience less brain atrophy and better cardiovascular health than industrialized populations, which the authors at the time attributed in part to large amounts of physical activity and healthier food from a subsistence way of life. The new data suggest that healthy hearts do not guarantee healthy brains, and that the pathways leading to dementia in this population may run along routes quite different from the ones familiar in Western medicine.

Indeed, the dementia observed in the Bolivian communities may differ biologically from prototypical Alzheimer’s disease. Many affected participants showed more difficulty with attention, reasoning and the management of everyday tasks than with memory, which is the hallmark challenge of Alzheimer’s. Preliminary blood analyses found associations between dementia cases and the amount of neurofilament light chain proteins in the blood, a general indicator of neurodegeneration, but not with the amyloid or phosphorylated tau protein profiles that are characteristic of Alzheimer’s pathology. Imaging and vascular measures suggested contributions from disease of the blood vessels. In most Tsimané with cognitive impairment or dementia, Gatz explained, the pattern of brain atrophy is not typical of Alzheimer’s disease; rather, there are changes indicative of vascular contributions to cognitive impairment and dementia.

Genetics added a further layer of complexity. The APOE e4 gene variant, the best-known genetic risk factor for Alzheimer’s disease, was associated with dementia in the study. Yet Gatz cautioned that APOE4 also influences lipid transport and immune response, so the association does not necessarily establish Alzheimer’s pathology. Disentangling how lifestyle and genetic factors interact in this population will require far more data, she said, noting that the two are generally believed to play complementary roles. The methodological effort itself was substantial: the researchers adapted clinical interviews and cognitive tests for language, culture and limited literacy, conducting assessments in Tsimané or Spanish, while the project’s teams also provide medical examinations and help coordinate care for participants.

The study’s authors are careful about the limits of their data. With only 22 cases, they caution that the numbers are too few to fully discern all of the factors behind the community’s low prevalence. Even so, the work adds rare incidence data to dementia research among Indigenous peoples, a field where such longitudinal evidence is scarce. Some Indigenous communities report high dementia prevalence following disruptive integration into dominant societies and greater exposure to chronic disease risks, while several Indigenous and rural populations retaining subsistence lifestyles report low prevalence. Gatz framed this contrast as an important health-equity challenge, and Hillard Kaplan, a health economist at Chapman University and principal investigator of the Tsimané Health and Life History Project, said the findings indicate that brain aging occurs without significant heart disease and that much more remains to be learned about the pathways leading to dementia. Future phases of the research will deploy improved brain imaging and additional blood biomarkers to investigate vascular injury and Alzheimer’s pathology, work that Gatz described as immensely challenging and highly rewarding, and for which the research team remains grateful for the communities’ participation.

Subject of Research: Dementia incidence, survival and prevalence in two Indigenous Bolivian populations living pre-industrial lifestyles

Article Title: New study sheds light on dementia among Indigenous Bolivians

Article References: New study sheds light on dementia among Indigenous Bolivians. (n.d.). Original publication

Image Credits: AI Generated

DOI: Not provided

Keywords: dementia, Tsimané, Mosetén, Bolivia, Indigenous health, incidence, prevalence, vascular cognitive impairment, APOE4, neurofilament light chain, Alzheimer's disease, longitudinal study

The research team recruited adults with relapsing multiple sclerosis at two neurological centers in Rome and divided them into two cohorts. The first, an immunophenotyping cohort of 45 untreated patients and 25 patients treated with the anti-CD20 antibody ocrelizumab, underwent high-parameter flow cytometry that resolved more than 40 distinct immune cell populations across every major blood lineage. The second, an antiviral cohort of 24 untreated patients, 13 ocrelizumab-treated patients and 19 healthy donors, was tested for T-cell responses against three viruses: Epstein–Barr virus (EBV), cytomegalovirus (CMV) and SARS-CoV-2. The researchers also measured cytokine and chemokine release in culture supernatants and quantified serum neurofilament light chain, or sNfL, an ultrasensitive blood marker of neuroaxonal injury, using single-molecule array technology.

The immunophenotyping results confirmed what was expected and revealed what was not. As anticipated, ocrelizumab-treated patients showed profoundly reduced total B cells and switched-memory B cells, the long-lived reservoir in which EBV establishes latency. Antibody-secreting cells, which lack CD20, were spared in absolute terms. But the therapy’s fingerprints extended well beyond the B-cell compartment. T follicular helper cells, the CD4-positive helpers that shepherd B cells through germinal center reactions, and mucosal-associated invariant T cells, an innate-like population involved in early antimicrobial and antiviral responses, both showed significantly reduced absolute counts in treated patients. The loss of T follicular helper cells is consistent with the disruption of the cognate B-cell–T-cell interactions required for their maturation, while the contraction of MAIT cells may reflect the loss of B-cell-derived survival signals such as interleukin-23, which was also reduced in treated patients.

Innate immune function told an equally nuanced story. When whole blood was stimulated with R848, a synthetic agonist of toll-like receptors 7 and 8 that mimics viral RNA, monocytes from untreated patients stood out for their heightened inflammatory tone. These cells produced excess interleukin-1 beta and the chemokine MCP-3, both at rest and after stimulation, compared with monocytes from healthy donors. At the same time, plasmacytoid dendritic cells, the body’s principal source of type I interferons, were functionally impaired in untreated patients: their interferon-alpha response to stimulation was markedly blunted. Remarkably, in ocrelizumab-treated patients this pDC defect disappeared, with interferon-alpha responses returning to levels indistinguishable from healthy donors, while monocyte interleukin-1 beta was modestly attenuated. The combination of overactive monocytes and hyporesponsive interferon production in untreated disease, the authors suggest, may fuel chronic cellular activity without the negative feedback needed to restrain it.

The centerpiece of the study, however, was the virus-specific T-cell analysis. Using an activation-induced marker assay, in which virus-specific T cells are identified by their rapid upregulation of CD40L and CD69 on CD4 cells or CD137 and CD69 on CD8 cells after exposure to viral peptide pools, the team quantified memory T-cell responses in seropositive donors. EBV seroprevalence was near-universal, ranging from 95 percent in healthy donors to 100 percent in treated patients, confirming that the comparison was biologically meaningful. The result was unambiguous: absolute numbers of EBV-specific CD4-positive T cells and their stimulation index were significantly lower in ocrelizumab-treated patients than in both untreated patients and healthy donors. Responses to CMV and SARS-CoV-2, by contrast, were comparable across groups in both the CD4 and CD8 compartments.

The selectivity ran deeper than cell counts. Detailed phenotyping of the EBV-specific CD4 memory compartment showed significant decreases across central memory and effector memory subsets in treated patients, along with broad downregulation of activation markers including CD25, CD137 and ICOS. Intriguingly, both EBV-specific CD4 and CD8 cells from treated patients expressed less CCR6, a chemokine receptor that guides T cells across the choroid plexus into the central nervous system during early neuroinflammation. CCR6-positive T cells enriched in Th17-like and GM-CSF-secreting subsets are known to accumulate in the cerebrospinal fluid of people with multiple sclerosis and are considered pathogenic. Their reduction suggests that B-cell depletion may not merely remove EBV-infected B cells but also strip the residual EBV-specific T-cell pool of its neuroinvasive potential, a finding with direct implications for how the therapy works.

The authors interpret these results through the lens of EBV biology. Memory B cells are the principal site of viral latency, so their sustained depletion substantially reduces the EBV antigenic burden. With less virus to control, the large EBV-specific CD4 T-cell pool is no longer maintained, and it contracts. This mechanism aligns with recent independent work showing that anti-CD20 therapy reduces EBV-specific CD4 responses several-fold while leaving CMV, varicella-zoster and bacterial antigen responses largely untouched, and that it abolishes salivary EBV shedding. In this view, part of the clinical benefit of ocrelizumab derives not from generic immunosuppression but from dismantling a specific EBV-driven immunopathological circuit. Equally important for patient care, the preservation of CMV- and SARS-CoV-2-specific T cells, together with normalized pDC interferon responses, indicates that cellular antiviral defense is not globally eroded, providing a mechanistic counterpart to the clinical observation that infection risk under these drugs stems mainly from low antibody levels rather than lost T-cell immunity.

The study also delivered a candidate biomarker. Serum neurofilament light chain was significantly elevated in untreated patients and trended lower after treatment, consistent with reduced neuroaxonal damage under therapy. When the researchers stratified patients by sNfL levels, those above the cohort median showed higher concentrations of the chemokines MCP-3, MIP-1 alpha and MIP-1 beta, and MCP-3 was the only mediator that correlated positively with sNfL in untreated patients, both at baseline and after EBV peptide stimulation. This association was not detectable after ocrelizumab treatment, although a formal interaction test could not confirm that the correlation itself differed between treated and untreated groups. The authors are appropriately cautious, noting that no correction for multiple hypothesis testing was applied and that all soluble-mediator comparisons are exploratory. Still, MCP-3 has historical credentials in the field, having first been described in post-mortem multiple sclerosis lesions in 1998, and the new data position it as a candidate blood marker associated with ongoing neuroaxonal injury.

The study’s limitations frame how far its conclusions can travel. Its cross-sectional design precludes causal inference, the treated antiviral arm included only 13 patients, and all measurements came from peripheral blood rather than the central nervous system. Participants were recruited in Rome and predominantly reflect an Italian relapsing MS population, all treated patients received ocrelizumab specifically, and HLA typing and detailed vaccination histories were not available, leaving HLA-dependent differences in EBV responsiveness impossible to exclude. Even so, the central message carries weight for a therapy used by hundreds of thousands of patients worldwide. Anti-CD20 treatment is not a blunt instrument that dismantles antiviral immunity wholesale. It reshapes the immune system in a patterned way, depleting the B-cell reservoir that sustains EBV and, in doing so, selectively relaxing the T-cell response to that virus, while interferon production and immunity to CMV and SARS-CoV-2 remain substantially preserved. For a disease in which EBV infection raises the risk of onset roughly 32-fold, that pattern of selectivity looks less like a side effect and more like a glimpse of the therapy’s actual mechanism at work.

Subject of Research: Immune effects of anti-CD20 B-cell depletion therapy on antiviral T-cell responses in multiple sclerosis

Article Title: Antiviral and inflammatory immune signatures in anti-CD20-treated multiple sclerosis: a cross-sectional study

Article References: D’Orso, S., Picozza, M., Guerrera, G., Verdiani, A., Pirronello, M., Misiti, A., Olivieri, E., Corbisiero, S., Angelini, D. F., Ingrascì, A., Giardina, E., Ruggieri, S., Tortorella, C., Gasperini, C., Buscarinu, M. C., Salvetti, M., Gran, B., Battistini, L., & Borsellino, G. (2026). Antiviral and inflammatory immune signatures in anti-CD20-treated multiple sclerosis: a cross-sectional study. Journal of Neurology, 273(11), Article 664. https://doi.org/10.1007/s00415-026-14202-4

Image Credits: AI Generated

DOI: 10.1007/s00415-026-14202-4

Keywords: multiple sclerosis, ocrelizumab, anti-CD20, Epstein-Barr virus, B-cell depletion, T cells, neurofilament light chain, MCP-3, neuroimmunology, plasmacytoid dendritic cells, immunophenotyping, antiviral immunity

The research drew on participants from the Clinic substudy of the COcoa Supplement and Multivitamin Outcomes Study, or COSMOS, a large randomized trial run through Brigham and Women’s Hospital and Harvard Medical School that originally examined whether cocoa flavanols and multivitamins could prevent cardiovascular events. From this infrastructure, the team assembled a cohort of 506 older adults with a mean age of 69.7 years, nearly half of whom were women. Each participant underwent blood sampling at baseline and again two years later, with the researchers measuring four of the most scrutinized molecules in contemporary neurodegeneration science: N-terminal tau, known as NT1, a fragment of the tau protein that earlier work has flagged as a specific and early marker of Alzheimer’s pathology; neurofilament light chain, or NfL, which leaks into the bloodstream when neurons suffer structural damage; oligomeric amyloid-beta, or oAβ, the aggregated form of the sticky peptide central to Alzheimer’s disease; and phosphorylated tau 217, or pTau217, which was measured only once because of its more recent arrival in clinical assays.

On the physical side of the equation, the team employed three well-validated benchmarks of motor function. Walking speed, often described in gerontology as the sixth vital sign, captures the integrated output of the nervous system, muscles, joints, and cardiovascular machinery. Grip strength, measured with a dynamometer, serves as a surrogate for whole-body muscle capacity and has repeatedly been linked to mortality and disability risk. The Short Physical Performance Battery, or SPPB, combines gait speed, repeated chair stands, and balance tests into a composite score that predicts future dependency in daily living. The study’s primary analysis asked whether a person’s starting levels of these brain-derived proteins could forecast how much their physical performance would deteriorate over the following two years. A secondary analysis then asked the reverse question: whether changes in the biomarkers themselves tracked with concurrent changes in strength and mobility.

The statistical architecture of the study deserves attention, because it reflects a growing sophistication in how researchers interrogate biomarker data. The investigators adjusted their models for demographics, a comprehensive cardiovascular risk profile, body mass index, and, crucially, the baseline value of each physical performance measure, which strips away the misleading correlations that arise when people who start out weaker remain weaker throughout. They also considered all biomarkers jointly rather than one at a time, reducing the chance that a single protein would absorb variance that actually belonged to its molecular neighbors. This design choice matters, because neurodegeneration markers tend to rise together in aging bloodstreams, and naive single-biomarker models can manufacture associations that dissolve under stricter scrutiny.

When the results arrived, the silence was deafening. Baseline concentrations of NT1, NfL, and oAβ showed no statistically significant relationship with two-year changes in any physical performance measure. The effect estimates were not merely borderline; they hovered around zero with p-values ranging from 0.25 to 0.69 across the fully adjusted models. For NfL, the estimates ran from a beta of −0.046 for SPPB scores to a beta of 0.350 for grip strength, neither remotely close to conventional thresholds of significance. The story repeated itself for NT1 and oAβ across walking speed, grip strength, and the SPPB. In an era when pTau217 assays are being hailed for their diagnostic accuracy in detecting Alzheimer’s pathology, the failure of these circulating proteins to anticipate physical decline is a sobering reminder that prediction of one disease domain does not automatically generalize to another.

Yet the study was not a total null result. In the secondary longitudinal analysis, the researchers found one statistically significant signal: changes in plasma NT1 over the two-year window were associated with concurrent changes in grip strength, with a beta of 1.408 and a p-value of 0.01. This finding is intriguing precisely because it emerged from tracking within-person trajectories rather than comparing people to each other at baseline. It hints that tau dynamics and muscle strength may be coupled at the level of individual aging processes, even if a single snapshot of tau cannot forecast who will weaken. The researchers urge caution in interpretation, however, as this was one significant result among many tests performed, and no other biomarker change showed a meaningful relationship with any physical outcome.

The results complicate a growing literature that has linked amyloid burden and other neurodegenerative markers to gait slowing and motor decline. Previous studies, including analyses of brain amyloid imaging in dementia-free elderly individuals and population-based cohorts tracking plasma amyloid ratios and neurofilament light over longer horizons, have reported associations between Alzheimer-related pathology and slower walking or reduced strength. The new findings suggest that such relationships may depend on the timeframe examined, the specific biomarkers measured, or the composition of the cohort. Two years is a short window in the biology of aging, and the COSMOS participants were, on average, relatively healthy community-dwelling adults rather than patients with established cognitive impairment, which may have compressed the range of both biomarker levels and physical decline available for detection.

There are also mechanistic considerations worth unpacking. Physical performance depends on a sprawling network of systems, including sarcopenia, peripheral nerve function, vascular supply to muscle, vestibular and visual function, and central motor planning. Neurodegenerative proteins circulating in plasma may rise in response to synaptic injury or neuronal death in specific brain regions, but the path from hippocampal tau accumulation to a slower chair stand is neither direct nor necessarily mediated by the molecules measurable in blood. Exercise and physical activity themselves modulate peripheral inflammatory and neurotrophic factors, which means the relationship between brain and body biomarkers is bidirectional and confounded by behavior. The study’s authors acknowledge that overall, these biomarkers provided limited information about short-term physical performance decline, a conclusion that tempers the enthusiasm of clinicians hoping to fold motor-risk stratification into existing dementia screening panels.

What, then, is the takeaway for a field riding a wave of blood-based dementia diagnostics? The work does not diminish the genuine progress these assays represent for detecting Alzheimer’s pathology in symptomatic patients, where trials in primary and secondary care have shown impressive diagnostic performance. Instead, it draws a boundary around their utility, cautioning against the seductive assumption that a molecule diagnostic of one aspect of brain aging will serve as a universal barometer of the aging organism. For older adults, the practical message remains unchanged: walking speed, grip strength, and performance batteries like the SPPB continue to offer accessible, inexpensive, and proven measures of functional trajectory that no blood test currently replaces. For researchers, the study marks out a clearer roadmap, pointing toward longer follow-up periods, cohorts with greater baseline frailty, and integrated models that treat neurodegeneration as one thread in a much larger tapestry of biological aging. The hunt for a single drop of blood that reveals the whole aging body continues, but this study makes clear that the drop has not yet been found.

Subject of Research: Associations between plasma neurodegeneration biomarkers and physical performance decline in older adults

Article Title: Plasma biomarkers of neurodegeneration and physical performance in older adults

Article References: von Alvensleben, A. C., Kim, E., Kurth, T., LeBoff, M. S., Anderson, A. K., Yang, T., Xu, Y. R., Ostaszewski, B. L., Selkoe, D. J., Sesso, H. D., Manson, J. E., & Rist, P. M. (2026). Plasma biomarkers of neurodegeneration and physical performance in older adults. GeroScience. https://doi.org/10.1007/s11357-026-02570-8

Image Credits: AI Generated

DOI: 10.1007/s11357-026-02570-8

Keywords: plasma biomarkers, neurodegeneration, physical performance, aging, Alzheimer's disease, neurofilament light chain, NT1 tau, phosphorylated tau 217, grip strength, walking speed, Short Physical Performance Battery, COSMOS

The variant in question, known as rs10191329, sits in the stretch of DNA between two genes called DYSF and ZNF638. It does not change any protein sequence, yet a large genome-wide association study of more than 12,000 people with multiple sclerosis previously linked carrying its A allele to greater cross-sectional physical disability. Subsequent work connected the same allele to brain atrophy, thinning of the retinal nerve fibre layers, and elevated levels of serum neurofilament light chain, a blood biomarker of neuroaxonal damage. Together, these findings pointed toward a mechanism centred on the central nervous system itself rather than on the immune attack that defines relapsing disease.

That pattern intrigued the study’s authors. If the A allele erodes the nervous system’s resilience, they reasoned, its influence might not stop at physical disability. Cognitive impairment is one of the most common and disabling features of multiple sclerosis, and the concept of cognitive reserve, the brain’s capacity to tolerate damage while preserving function, is well established across neurodegenerative conditions including Alzheimer’s and Parkinson’s disease. The team therefore hypothesised that rs10191329 might influence cognition not only in multiple sclerosis but in healthy people and in other neurological disorders, and turned to the UK Biobank to test the idea at population scale.

The UK Biobank recruited roughly half a million participants aged 40 to 69 between 2006 and 2010, collecting genetic data alongside questionnaires, physical assessments, imaging and biological samples. From this resource the researchers constructed five mutually exclusive cohorts of European ancestry: people with a recorded multiple sclerosis diagnosis, people with Parkinson’s disease, people with all-cause dementia, people with migraine as a negative disease control, and healthy controls. After excluding participants with missing genotype data, the final analytical sample comprised 399,031 individuals, including 373,530 controls, 2,026 people with multiple sclerosis, 2,337 with dementia, 1,466 with Parkinson’s disease and 19,672 with migraine.

The cognitive outcomes came from three tests administered at recruitment. Reaction time was measured in a computerised card-matching task, with higher scores indicating slower responses. Fluid intelligence was scored as the number of correct answers out of 13 on a reasoning test, with higher scores indicating better performance. Prospective memory, the ability to remember to carry out an intended action, was assessed as a binary outcome based on whether participants correctly recalled a task instruction on their first attempt. The researchers confirmed that the multiple sclerosis, Parkinson’s and dementia cohorts showed the expected pattern of poorer performance compared with controls and the migraine group, validating the measures.

Statistical models adjusted for age, sex, the first four genetic principal components and the Townsend deprivation index, a measure of socioeconomic status. Linear outcomes were rank-inverse normal transformed to satisfy model assumptions, and false discovery rate correction was applied across all tests simultaneously. Sensitivity analyses added educational leaving age as a covariate and repeated the models under dominant and recessive genetic frameworks. As a positive control, the team also examined the relationship between the variant and self-reported disability claims among the multiple sclerosis cohort.

The results were striking in their direction, if modest in their magnitude. Among healthy controls, each copy of the A allele was associated with slower reaction time, a beta of 0.01 standard deviations per allele; lower fluid intelligence, a beta of minus 0.02 standard deviations; and higher error rates on the prospective memory task, an odds ratio of 1.06. All three associations reached study-wide significance. In the multiple sclerosis group, carriers of two A alleles were 5.9 percent more likely to claim disability allowance than common-allele homozygotes, 52.4 percent versus 46.5 percent, although the regression estimate did not reach statistical significance. In the other disease cohorts, associations were directionally concordant but not significant, with slower reaction time in multiple sclerosis, Parkinson’s and dementia, lower fluid intelligence across all cohorts, and impaired prospective memory in dementia.

Power calculations help explain the pattern of significance. Using reaction time as an example, the study had 98 percent power to detect a per-allele effect larger than 0.15 standard deviations in the multiple sclerosis cohort of roughly 2,000 people, but only 63 percent power for a 0.1 standard deviation effect. In other words, the analysis was well equipped to detect moderate genetic effects within disease groups but underpowered for the small effects observed in the enormous control sample. The authors are careful to note that the cognitive tests were designed as pragmatic population measures, not as validated outcomes for multiple sclerosis, and that prevalent cases in the Biobank are biased toward milder disease, both of which would attenuate detectable associations.

One obvious alternative explanation is education. A previous Mendelian randomisation analysis suggested genetic overlap between the severity locus and educational attainment, and cognitive reserve is strongly shaped by education. Yet adjusting for educational leaving age, a proxy for educational attainment, did not meaningfully attenuate the associations, making it unlikely that schooling alone accounts for the signal. The variant’s effects, whatever their mechanism, appear to operate at least partly independently of educational background, consistent with a direct influence on brain health rather than a purely sociodemographic confound.

The broader implication is that a variant discovered as a modifier of multiple sclerosis severity may act through general properties of central nervous system resilience, influencing how the brain performs even in the absence of disease. The effect sizes are small, and the authors emphasise that large disease-specific cohorts are needed to determine whether the variant shapes cognition within multiple sclerosis and other disorders, and whether its influence extends to populations of non-European ancestry, which this study did not examine. Still, the convergence of evidence, spanning disability, brain atrophy, neurofilament light chain, retinal thinning and now cognition, sketches a coherent picture of a genetic locus that quietly sets the baseline health of the nervous system, and in doing so helps determine how hard neurological disease hits when it arrives.

Subject of Research: Association between the multiple sclerosis severity allele rs10191329A and cognitive function in the UK Biobank

Article Title: The Multiple Sclerosis Severity Allele rs10191329A and Cognitive Function: A UK Biobank Study

Article References: Zimianiti, I., Waters, S., Harroud, A., Stridh, P., Dobson, R., & Jacobs, B. M. (2026). The Multiple Sclerosis Severity Allele rs10191329 A and Cognitive Function: A UK Biobank Study. Annals of Clinical and Translational Neurology, 13(10), 2143-2147. https://doi.org/10.1002/acn3.70458

Image Credits: AI Generated

DOI: 10.1002/acn3.70458

Keywords: multiple sclerosis, rs10191329, UK Biobank, cognitive function, genetics, neurodegeneration, DYSF-ZNF638 locus, neurofilament light chain, cognitive reserve, fluid intelligence, reaction time, prospective memory

The research team, based at Houston Methodist Hospital’s MDA/ALSA ALS clinic, took advantage of a longitudinal serum repository collected between January 2018 and December 2022. From 352 patients with stored, immediately frozen samples, the investigators used a computer-generated random sampling process to select 100 patients for exploratory analysis. Each patient contributed between four and eleven blood draws, averaging six per person, spanning the full arc of disease from diagnosis to samples taken at or near end stage. One hundred age- and gender-matched healthy controls, typically spouses and friends of the patients, provided comparison samples. Only about five percent of the cohort carried known ALS mutations such as C9orf72 or a family history, making the group overwhelmingly representative of sporadic disease.

The three biomarkers were chosen for their biological coherence with what is known about ALS pathophysiology. 4-hydroxy-2-nonenal, or 4-HNE, is a toxic product of lipid peroxidation, the chemical assault on cell membranes that follows when dysfunctional mitochondria churn out reactive oxygen species. Lipopolysaccharide binding protein, or LBP, is synthesized and secreted by hepatocytes in the liver as part of the acute phase response, the innate, nonspecific first reaction of the body to immunological stress; it binds bacterial lipopolysaccharide and presents it to immune receptors such as CD14 and Toll-like receptor 4, amplifying inflammatory signaling. Neurofilament light chain, or NfL, is a structural protein released when axons degenerate, and it has already emerged as one of the most scrutinized fluid markers in neurodegeneration. All three were quantified by standard enzyme-linked immunosorbent assays, the kind of procedure routinely available in clinical diagnostic laboratories.

The cross-sectional findings immediately set ALS apart from other neurodegenerative diseases. Rapidly progressing patients, defined as those losing one or more points per month on the revised ALS Functional Rating Scale, showed significantly higher 4-HNE than both healthy controls and slowly progressing patients. LBP was elevated in rapid progressors compared with slow progressors and controls, and even slow progressors had higher LBP than controls. NfL followed a similar pattern, higher in rapid progressors than in slow ones and controls. Crucially, 4-HNE and LBP showed no such elevations in patients with Parkinson’s disease or mild cognitive impairment and Alzheimer’s disease, whereas NfL rose in those conditions as expected. This dissociation suggests that oxidative stress and systemic inflammation are not generic accompaniments of neurodegeneration but are specifically intensified in ALS.

The longitudinal data revealed a compelling divergence in how the three markers behave over time. At diagnosis, NfL showed the largest elevation relative to controls, roughly 3.3-fold, with LBP at about 1.6-fold and 4-HNE at a modest 1.3-fold. Yet from diagnosis to the last available sample, the picture inverted: 4-HNE climbed 177 percent and LBP rose 80 percent, while NfL increased only 27 percent, effectively plateauing. In other words, axonal injury as reflected by NfL is largely front-loaded into the early disease course, whereas lipid peroxidation and systemic inflammation escalate continuously as the disease advances. This temporal architecture helps explain why NfL did not correlate with ALSFRS-R scores in this cohort, since the functional scale kept declining steadily while NfL had already peaked.

The correlation analyses underscored the primacy of the inflammatory and oxidative markers. LBP at diagnosis showed the strongest negative correlation with ALSFRS-R score at diagnosis (r = −0.688) and the strongest correlation with survival from diagnosis to death (r = −0.773), along with the strongest link to progression rate (r = 0.668). 4-HNE tracked closely behind, correlating with survival at r = −0.661 and with progression rate at r = 0.589. NfL, by contrast, correlated only weakly with survival (r = −0.325) and progression rate (r = 0.274). The biomarkers also correlated with one another, moderately so between LBP and 4-HNE and between NfL and 4-HNE, painting a picture of interacting pathways in which oxidative damage, inflammation, and axonal breakdown feed one another. As expected clinically, older age at diagnosis and faster progression each correlated with shorter survival.

Site of disease onset added further biological texture. Among the 97 patients with either bulbar or limb onset, those with bulbar onset survived significantly shorter periods. Their mean 4-HNE levels were approximately 1.5-fold higher and LBP levels approximately 1.7-fold higher than in limb-onset patients, yet NfL levels did not differ between the two groups. This pattern implies that the worse prognosis of bulbar-onset ALS is driven not by greater axonal injury per se but by a more intense burden of oxidative stress and systemic inflammation, consistent with the idea that these pathways accelerate the pace of the disease rather than merely marking it.

The centerpiece of the study was a series of receiver operating characteristic analyses testing how well each biomarker, alone and in combination, could discriminate poor survival and rapid progression. Individually, 4-HNE and LBP performed well, with area under the curve values of 0.78 and 0.75 for poor survival and 0.83 and 0.74 for rapid progression, while NfL was more modest at 0.66 and 0.61. Pairwise combinations improved performance, and the three-marker panel achieved the best results: an AUC of 0.86 for poor survival and 0.84 for rapid progression, both highly significant. For third-quartile progression rates, the three-biomarker combination again reached an AUC of 0.86. Because post hoc ROC analyses risk overfitting, the team performed internal validation using bootstrap resampling with 2000 iterations. The optimism estimates were small, below 0.02, and the optimism-adjusted AUCs closely mirrored the apparent ones, with the three-marker survival model holding at an adjusted AUC of 0.85, indicating stable and robust discriminative performance.

The authors are candid about the limitations. The study was retrospective and single-center, drawing 100 patients from a larger repository, which may limit generalizability, though computer-generated random sampling minimized systematic selection bias and potential confounders including age, sex, genetic status, onset site, and disease duration were accounted for in the design. The ROC analyses lack independent prospective validation, which the bootstrap procedure only partially addresses. The study was explicitly framed as exploratory. Still, the practical appeal of the approach is considerable: unlike multi-protein panels discovered through untargeted proteomics and machine learning, these three biomarkers were selected on biological grounds, target three distinct and interacting pathways, and can be measured with standardized ELISA kits already familiar to clinical laboratories.

The findings also open a therapeutic horizon. Plasma NfL has already been validated as a pharmacodynamic marker through its reduction in association with tofersen-mediated slowing of disease progression in SOD1-mediated ALS. Whether LBP and 4-HNE can similarly serve as readouts of treatment response remains an open question, and the authors highlight prospective therapeutic studies as the necessary next step. If the escalating oxidative and inflammatory burden measured in this cohort truly reflects the engine of disease acceleration, then serial monitoring of these markers could one day tell clinicians whether a therapy is working months before functional scales register a difference. For a disease in which every point on the ALSFRS-R matters, a three-protein blood panel that discriminates fast from slow trajectories with an AUC near 0.86 is a meaningful step toward personalized prognosis and, ultimately, more responsive care.

Subject of Research: Longitudinal serum biomarkers for predicting ALS disease progression and survival

Article Title: Longitudinal Assessment of Biomarkers in ALS: Discriminative Biomarkers for Disease Progression and Survival

Article References: Beers, D. R., Lin, Y.-Y., Thonhoff, J. R., Thome, A. D., Faridar, A., Zhao, W., Wen, S., & Appel, S. H. (2026). Longitudinal Assessment of Biomarkers in ALS : Discriminative Biomarkers for Disease Progression and Survival. Annals of Clinical and Translational Neurology, 13(10), 2102-2113. https://doi.org/10.1002/acn3.70381

Image Credits: AI Generated

DOI: 10.1002/acn3.70381

Keywords: ALS, biomarkers, 4-HNE, lipopolysaccharide binding protein, neurofilament light chain, lipid peroxidation, systemic inflammation, axonal injury, survival, disease progression, ROC analysis, neurodegeneration

The review, led by Steffen Tiedt of the Institute for Stroke and Dementia Research at LMU University Hospital in Munich and Michael D. Hill of the University of Calgary, lays out a comprehensive roadmap for moving molecular biomarkers from the research bench into routine clinical practice. The authors’ central argument is deceptively simple: imaging and clinical scores show what the brain looks like, but they cannot reveal what the brain is doing at the molecular level. Blood-based biomarkers, by contrast, can resolve the activity of specific disease pathways, detect tissue stress before structural damage becomes visible on a scanner, report on processes unfolding far beyond the brain, and be measured repeatedly with minimal burden to the patient.

The strongest evidence that this vision is achievable comes from neuronal injury markers. Neurofilament light chain, a structural protein released when axons are damaged, has been shown in multiple studies to rise in blood after ischaemic stroke, track the severity of neuroaxonal injury and predict mortality and functional outcome. Even more striking is brain-derived tau, a form of the tau protein that is highly specific to the brain. Recent work, including a 2026 study in Science Translational Medicine co-authored by members of the same group, demonstrated that plasma brain-derived tau can dynamically quantify ischaemic brain injury and even capture the effects of treatment in humans. In other words, clinicians can already, in principle, watch brain damage unfold — and recede — in real time through a blood draw.

But the roadmap goes well beyond markers of dead neurons. The authors organise the biomarker landscape around four interconnected, outcome-relevant pathomechanisms: ischaemic brain injury, metabolism, systemic inflammation and gut dysbiosis. Each of these domains produces a distinct molecular signature in the circulation, and each offers a different window into the biology that determines whether a patient recovers or deteriorates. This mechanism-first framing is deliberate. The authors argue that biomarkers should be prioritised as tools for elucidating human stroke pathophysiology, not merely as therapeutic targets — a subtle but consequential shift in emphasis for a field that has struggled to translate laboratory discoveries into effective drugs.

That struggle is well documented. More than a thousand experimental treatments have shown benefit in animal models of stroke, yet virtually none have succeeded in clinical trials. Neuroprotective agents such as nerinetide, tested in the recent ESCAPE-NEXT and FRONTIER trials, and anti-inflammatory strategies including natalizumab and interleukin-1 receptor antagonists, have produced disappointing or mixed results. The review suggests a key reason: without molecular readouts of what is actually happening in each patient’s brain and body, trials enrol biologically heterogeneous populations in which a drug that helps one subgroup may harm another. Mechanism-specific biomarkers could enable biologically coherent patient stratification, allowing investigators to select patients whose disease is actually driven by the pathway a drug targets.

The metabolic dimension of stroke illustrates this potential. When blood flow is cut off, the brain’s energy economy collapses: glucose is shunted into anaerobic glycolysis, lactate accumulates, tissue becomes acidotic, and metabolites such as succinate build up before reperfusion unleashes a surge of mitochondrial reactive oxygen species. Circulating metabolites have been shown to differentiate acute ischaemic stroke from stroke mimics, and metabolic signatures measured at admission correlate with infarct growth and outcome. Lactate and ketone bodies, once viewed purely as waste products, are now understood to play signalling and even neuroprotective roles, and studies in mice suggest that microbiota-derived metabolites such as short-chain fatty acids can promote post-stroke recovery. A blood test that reports the metabolic state of the penumbra — the salvageable tissue surrounding the infarct core — could guide decisions about reperfusion and adjunctive therapy in ways no scanner currently can.

Systemic inflammation adds another layer of complexity. A stroke is not confined to the brain: within hours, the peripheral immune system is massively activated, the gut barrier is compromised and commensal bacteria can translocate into the circulation, contributing to post-stroke infection. Recent translational studies have revealed that brain-released alarmins and cell-free DNA can accelerate atherosclerosis and destabilise plaques, raising the risk of recurrent stroke, while innate immune memory triggered by brain injury can drive inflammatory cardiac dysfunction. Inflammatory markers such as interleukin-6, C-reactive protein, complement components and circulating cell-free DNA all correlate with infarct volume, severity and long-term outcome. The disappointing results of broad immunomodulation trials, including the finding that prophylactic antibiotics do not improve outcome despite reducing infections, underscore the authors’ point: post-stroke complications arise from complex immune dysregulation, and only biomarker-guided, mechanism-specific interventions are likely to succeed.

The gut-brain axis, perhaps the most surprising entry in the roadmap, is emerging as both a source of biomarkers and a therapeutic target. Stroke alters gut transit, impairs enteric neuron function and reshapes the microbiome, and microbial metabolites such as trimethylamine N-oxide have been linked to stroke severity, recurrence and outcome in human cohorts. Because the microbiome can be sampled non-invasively and modulated by diet, probiotics and antibiotics, microbiota-derived signatures offer an unusually tractable route to personalised intervention — provided that the analytical and clinical validation work is done rigorously.

Turning this promise into practice is where the six-phase roadmap earns its name. The authors propose a pragmatic progression that begins with defining the context of use — the specific clinical question a biomarker is meant to answer, whether diagnosis, prognosis, patient stratification or treatment monitoring — and then moves through assay development, analytical and biological validation, clinical validation in deeply phenotyped longitudinal cohorts, biomarker-focused experimental work, and finally biomarker-guided randomised trials in which treatment decisions are made on the basis of molecular readouts. The framework borrows deliberately from other neurological fields: Alzheimer’s disease has already redefined itself around biological markers, and the regulatory approval of tofersen for ALS, using plasma neurofilament light as a surrogate endpoint reasonably likely to predict clinical benefit, provides a precedent that biomarker-driven development can succeed with regulators. Point-of-care technology is advancing in parallel, with DNA origami-based signal amplification now demonstrating large-fold sensitivity gains in lateral flow immunoassays, pointing toward minutes-level quantification at the bedside.

The authors are candid that substantial work remains. Coordinated efforts will be needed: deeply phenotyped longitudinal cohorts with systematic biosampling in clinical trials, omics-driven discovery programmes, biomarker-focused experimental studies that validate mechanisms rather than merely correlate molecules with outcomes, and sustained collaboration between academia, industry and regulators. But the destination is compelling. If the roadmap is followed, stroke medicine could move from a discipline that treats ‘time is brain’ as its only molecular insight to one in which a blood test, drawn in the ambulance or at the bedside, tells clinicians which pathways are driving a particular patient’s injury, which treatment will help, and whether it is working — closing, at last, the translational gap that has frustrated stroke research for decades.

Subject of Research: Molecular biomarkers for clinical use in acute ischaemic stroke

Article Title: A roadmap towards clinical use of molecular biomarkers in acute ischaemic stroke

Article References: Tiedt, S., Vlegels, N., Dimitriadis, K., Li, W., Jickling, G. C., McCullough, L. D., Liesz, A., Lo, E. H., & Hill, M. D. (2026). A roadmap towards clinical use of molecular biomarkers in acute ischaemic stroke. Nature Reviews Neurology. https://doi.org/10.1038/s41582-026-01270-3

Image Credits: AI Generated

DOI: 10.1038/s41582-026-01270-3

Keywords: stroke, biomarkers, neurofilament light chain, brain-derived tau, neuroinflammation, gut-brain axis, metabolomics, thrombectomy, neuroprotection, clinical trials, precision medicine, Nature Reviews Neurology

X-linked adrenoleukodystrophy is caused by pathogenic variants in the ABCD1 gene, which cripple the cellular machinery that breaks down very long-chain fatty acids. These fatty acids accumulate throughout the body, and in the nervous system they drive progressive destruction of myelin and axons. Roughly 60 percent of male patients develop a leukodystrophy, an inflammatory destruction of brain white matter, while virtually all men and most women eventually develop a slowly progressive disease of the spinal cord that targets the dorsal columns and corticospinal tracts. This spinal cord form, often called myeloneuropathy, erodes the ability to walk over decades, yet its pace varies enormously between individuals and is notoriously difficult to quantify with existing clinical scales.

That variability is precisely the problem the Amsterdam team set out to solve. Traditional outcome measures such as the Expanded Disability Status Scale, or EDSS, and the six-minute walk test change slowly, meaning clinical trials must follow patients for years to detect meaningful differences. Large patient numbers are needed because progression rates differ so widely. A biomarker that could sort patients at baseline into fast and slow progressors would allow smaller, faster, and cheaper trials, and would give clinicians and families a rational basis for decisions about when to intervene.

The study drew on the ongoing Dutch X-ALD cohort, using data collected between 2015 and 2024 at Amsterdam University Medical Centers. The researchers selected 66 adult men with spinal cord disease, excluding those with active leukodystrophy, prior hematopoietic stem cell transplantation, gene therapy, or compassionate use of the drug leriglitazone, because these interventions independently alter disease trajectories. Blood samples were processed within two hours of collection, centrifuged, aliquoted, and frozen at minus 80 degrees Celsius in a biobank. Plasma concentrations of neurofilament light chain and glial fibrillary acidic protein, a marker of astrocyte injury, were measured using single-molecule array technology, an ultra-sensitive immunoassay capable of detecting proteins at femtomolar concentrations. Assays were run by certified technicians blinded to all clinical data, with intra-assay coefficients of variation of just 4.8 percent for NfL and 3.3 percent for GFAP.

The stratification strategy was deliberately simple. Because NfL levels rise with age even in healthy people, and because no disease-specific reference values exist for adrenoleukodystrophy, the team divided patients using cohort-based thresholds. Men whose baseline plasma NfL was at or above 15.7 picograms per milliliter, the upper quartile, were classified as high; the rest as low. The differences at baseline were striking. The high-NfL group was significantly older, averaging 58.4 years against 36.4 years, and scored far worse on every clinical measure: higher EDSS disability scores, lower scores on the Severity Scoring System for Myelopathy, and dramatically shorter six-minute walk distances, averaging 333 meters compared with 529 meters in the low group.

The longitudinal results were even more consequential. Over up to seven years of follow-up, the high-NfL group showed significant, measurable worsening on the EDSS as early as the first year of follow-up, with an estimated mean change of 0.24 points, and the deterioration continued relentlessly, accumulating to 1.70 points by year seven. The low-NfL group, by contrast, showed minimal and statistically insignificant change over the same period. The difference in progression slopes between the two groups was highly significant, with a beta coefficient of minus 0.27 and a p-value below 0.001. Walking capacity declined significantly only in the high-NfL group, while patient-reported myelopathy scores fell in both groups but did not separate statistically between them.

Because age is such a strong confounder, the researchers performed a sophisticated sensitivity analysis. They log-transformed baseline NfL values, regressed them on age within the cohort, and calculated standardized residuals that capture NfL elevations beyond what would be expected for a given age within the X-ALD population itself. Patients were then grouped into four categories spanning minus one to plus two standard deviations. The gradient was unmistakable: men in the very high residual group showed EDSS worsening of 0.137 points per visit and SSPROM decline of 1.276 points per visit, both highly significant, while the low residual group showed no significant progression on any outcome measure. Pairwise comparisons confirmed that the mean, high, and very high groups differed significantly from one another in their EDSS and SSPROM slopes even after correction for multiple testing. Crucially, the association between higher age-adjusted NfL and faster clinical progression persisted, supporting the interpretation that the protein reflects disease-related axonal injury rather than aging alone.

GFAP told a very different story. Although plasma GFAP levels rose significantly over the study period overall, baseline GFAP stratification showed no significant differences in EDSS, SSPROM, or walking test scores, and no significant differences in progression slopes between high and low groups. The authors conclude that GFAP, which marks astroglial activation rather than axonal loss, has limited prognostic value in this context and may serve better as a complementary marker than a standalone predictor. The contrast is biologically informative: adrenoleukodystrophy-related myelopathy is fundamentally a degeneration of axons and their myelin sheaths, so a cytoskeletal protein shed from damaged axons tracks the disease process more faithfully than a marker of astrocytic response.

The findings dovetail with a growing literature on NfL in other forms of the disease. Previous work by the same group had shown correlations between NfL concentrations and spinal cord disease severity, and pediatric studies have demonstrated that plasma NfL is a sensitive monitor of cerebral lesion development in childhood cerebral adrenoleukodystrophy, with increases of more than 50 percent from baseline serving as a robust indicator of active inflammation. Other researchers have reported NfL elevations in myeloneuropathy patients who later developed the cerebral form, reaching levels comparable to those seen in amyotrophic lateral sclerosis during active disease. The new results extend this framework to the slow, chronic degeneration of the adult spinal cord, showing that the same molecule captures both explosive inflammatory damage and grinding degenerative loss.

The authors acknowledge limitations, including the modest sample size, the use of cohort-derived rather than population-based thresholds, and the insensitivity of clinical scales to early change in a disease where axonal degeneration precedes measurable disability until a critical threshold is crossed. Even so, the effect sizes were substantial and the trajectories separated early. Given that this represents the longest biochemical prospective follow-up in adult men with X-ALD-related myeloneuropathy, the researchers argue that serum NfL should be integrated into clinical trial protocols both as a stratification tool, to balance fast and slow progressors across treatment arms, and as a candidate surrogate outcome measure. For patients living with an unpredictable disease, a number drawn from a routine blood draw may soon transform both research and care.

Subject of Research: Prognostic biomarkers for spinal cord disease progression in X-linked adrenoleukodystrophy

Article Title: Prognostic Value of Neurofilament Light Chain and Glial Fibrillary Acidic Protein in ALD‐Related Myelopathy

Article References: Kabak, E. G., Voermans, M. M. C., Heijst, H., Teunissen, C. E., & Engelen, M. (2026). Prognostic Value of Neurofilament Light Chain and Glial Fibrillary Acidic Protein in ALD‐Related Myelopathy. Annals of Clinical and Translational Neurology, 13(10), 2114-2123. https://doi.org/10.1002/acn3.70386

Image Credits: AI Generated

DOI: 10.1002/acn3.70386

Keywords: X-linked adrenoleukodystrophy, neurofilament light chain, GFAP, biomarkers, myelopathy, spinal cord disease, ABCD1, clinical trials, neurodegeneration, Simoa, prognosis, longitudinal study

The research, led by Francesco Berinato and colleagues at the University of Brescia and ASST Spedali Civili Hospital in Italy, focused on two proteins that have become central to the emerging field of blood-based neurology: neurofilament light chain, abbreviated NfL, and glial fibrillary acidic protein, known as GFAP. NfL is a structural component of the long, cable-like projections of neurons, and when axons are injured, fragments of this protein leak into the surrounding fluid and eventually reach the bloodstream. GFAP, by contrast, is a scaffolding protein found in astrocytes, the star-shaped support cells of the brain, and it rises when these glial cells are damaged or activated. Because each protein reports on a different cellular population, measuring both together provides a two-channel view of brain injury, capturing damage to neurons and to their supporting architecture simultaneously.

The technical challenge has always been sensitivity. Concentrations of NfL and GFAP in blood are vanishingly small, measured in picograms per milliliter, or trillionths of a gram. Conventional immunoassays simply could not detect these levels reliably in plasma. The Brescia team turned to single molecule array technology, or Simoa, an ultrasensitive digital detection platform that counts individual protein molecules by trapping them in microscopic wells studded with magnetic beads and reading out fluorescent signals one bead at a time. This approach, which has transformed research into neurodegenerative disease, made it possible to quantify subtle elevations in proteins released by microscopic, transient brain injury that no scanner can see.

The study design was deliberately conservative. The researchers enrolled 36 patients who had experienced a clinically defined TIA but whose brain MRI showed no infarct, meaning no visible stroke lesion. Each patient was matched by age and sex to two healthy controls, yielding a comparison group of 72 individuals. Blood samples were drawn within 24 hours of hospital admission, a window chosen to capture proteins while injury-related release was still at or near its peak. The team then performed group comparisons, constructed receiver operating characteristic curves to identify optimal diagnostic thresholds, and ran a series of sensitivity analyses designed to strip out confounding factors that could artificially inflate biomarker levels.

The results were striking. Patients with MRI-negative TIA had plasma NfL concentrations averaging 27.22 picograms per milliliter, more than two and a half times the control average of 10.44 picograms per milliliter, a difference that was highly statistically significant. GFAP told a similar story, averaging 301.99 picograms per milliliter in patients versus 131.65 in controls. In other words, even when the brain looked perfectly normal on imaging, the blood carried a chemical record of injury. The findings held up when the researchers systematically excluded patients with pre-existing disability, previous stroke or TIA, impaired kidney function, a heavy burden of small vessel disease on MRI, and moderate to severe cortical atrophy, all conditions known to raise NfL or GFAP independently of any acute event.

The diagnostic performance of each marker revealed an interesting asymmetry. The optimal cutoff for NfL was 16.83 picograms per milliliter, a threshold that achieved remarkable specificity of 98.6 percent, meaning that almost no healthy individual exceeded it, but sensitivity of only 52.8 percent, meaning it flagged only about half of the TIA patients. GFAP at a cutoff of 179.23 picograms per milliliter was more balanced, with sensitivity of 69.4 percent and specificity of 81.9 percent. The most powerful result emerged when the two proteins were interpreted together. A combined assessment raised sensitivity to 80.6 percent while preserving specificity at 81.9 percent, and produced the highest discriminative accuracy of any configuration tested, with an area under the curve of 0.812. The complementary biology makes sense of this: axonal injury and astroglial activation are partially independent processes, so a patient whose injury is too subtle to push one marker over threshold may still push the other.

Why does this matter clinically? TIA is fundamentally a warning sign, a brief interruption of blood flow that predicts a substantial risk of subsequent full stroke, particularly in the days and weeks that follow. Current guidelines rely on clinical scoring systems, imaging to exclude stroke mimics, and urgent vascular workup to stratify risk. But a substantial fraction of suspected TIAs remain diagnostically ambiguous, especially when imaging is negative and symptoms have fully resolved. Objective blood markers could help confirm that a transient neurological event genuinely reflected brain ischemia rather than a mimic such as migraine aura, seizure, or peripheral vestibular disorder. They could also, in principle, help quantify the tissue impact of the event, complementing what imaging cannot show.

The broader context is a field in rapid motion. Prior work has established that NfL rises acutely after overt ischemic stroke, correlates with stroke severity, and predicts functional outcome, and a recent individual patient data meta-analysis consolidated the diagnostic and prognostic value of blood NfL in ischemic stroke. GFAP has shown promise in distinguishing stroke types and mapping the timeline of tissue impact after acute cerebrovascular events. What the Brescia study adds is a crucial piece of that puzzle: evidence that the biomarker signal is not merely a byproduct of large, scan-visible infarcts, but reflects genuine microscopic injury even in the mildest end of the ischemic spectrum. This aligns with a growing recognition that TIA is not a benign non-event but a real injury whose consequences, including subtle cognitive decline after first-time TIA, may be underestimated by conventional imaging.

Important caveats remain, and the authors are careful to acknowledge them. The study was single-center and retrospective, with a modest sample of 36 patients, and the control group, while carefully matched, cannot capture the full diversity of patients who present to emergency departments with TIA-like symptoms. Specificity figures derived from healthy controls will likely look different against real-world differential diagnoses, where conditions such as renal impairment, trauma, and neurodegenerative disease can elevate the same proteins. The sensitivity analyses go a long way toward addressing these concerns, but the authors themselves state that larger studies are needed to confirm clinical utility before such tests enter routine practice.

Even so, the trajectory is clear. Blood-based biomarkers are moving from the research bench toward the stroke unit, propelled by ultrasensitive platforms like Simoa and by accumulating evidence across the cerebrovascular disease spectrum. A simple blood draw taken within a day of a suspected TIA, interpreted alongside clinical scores and imaging, could one day transform one of neurology’s most uncertain diagnoses into a measurable, quantifiable event. For patients who are told their scan is clean but their symptoms were real, the blood may soon provide the answer that the scanner cannot, confirming that even the briefest storm in the brain leaves its mark, written in the language of proteins, detectable in a few milliliters of plasma.

Subject of Research: Blood biomarkers NfL and GFAP for detecting microscopic brain injury in MRI-negative transient ischemic attack

Article Title: Blood biomarkers of brain damage in Transient Ischemic Attack: the role of plasma NfL and GFAP

Article References: Berinato, F., Morotti, A., Baronchelli, G., Tolassi, C., Girotto, I., Pilotto, A., & Padovani, A. (2026). Blood biomarkers of brain damage in Transient Ischemic Attack: the role of plasma NfL and GFAP. Journal of Neurology, 273(10), Article 580. https://doi.org/10.1007/s00415-026-14097-1

Image Credits: AI Generated

DOI: 10.1007/s00415-026-14097-1

Keywords: transient ischemic attack, TIA, neurofilament light chain, GFAP, blood biomarkers, brain injury, stroke, Simoa, MRI, neurology, cerebrovascular disease, plasma biomarkers