Senescence marker p16INK4a expression in patients with multiple sclerosis.

OBJECTIVES: Telomere attrition is associated with disability accumulation and brain atrophy in multiple sclerosis (MS). Downstream of telomere attrition is cellular senescence. We sought to determine differences in the cellular senescence marker p16INK4a expression between MS and healthy control participants and the association of p16INK4a expression with MS disability and treatment exposure. METHODS: Patients meeting diagnostic criteria for MS and healthy controls were recruited for a cross-sectional pilot study. RNA was extracted from peripheral blood mononuclear cells (PBMCs) and p16INK4a expression levels were measured using qRT PCR. Spearman correlation coefficients and regression models were applied to compare expression levels to chronological age, assess case control differences, and determine associations with clinical outcome measures. RESULTS: Fifty-two participants with MS (67 % female, ages 25-70) and 38 healthy controls (66 % female, ages 23-65) were included. p16INK4a levels were not linearly correlated with chronological age in MS (rhos = -0.01, p = 0.94) or control participants (rhos = 0.02, p = 0.92). Higher median p16INK4a levels were observed in the >50-year age group for MS (0.25, IQR 0.14-0.35) vs. controls (0.12, IQR 0.05-0.15) and in this age group B cell depletion therapy was associated with lower expression levels. p16INK4a expression was not associated with any of the measured MS disability outcomes. DISCUSSION: Caution is needed with using p16INK4a expression level from PBMCs as an aging biomarker in MS participants, given lack of correlation with chronological age or large associations with clinical outcomes.

The NHANES Biological Age Index demonstrates accelerated aging in MS patients.

BACKGROUND: Chronological age is associated with disability accumulation in multiple sclerosis (MS). Biological age may give more precise estimates of aging pathways associations with MS severity. Both normal aging and accelerated aging from MS may negatively impact disease course. Multi-marker indices of aging, such as the NHANES biological age index (BAI), may be more robust than single biomarkers in capturing biological age and are strongly associated with mortality risk and aging-related diseases. OBJECTIVE: We sought to investigate whether the NHANES BAI, utilizing readily available measures in the clinic, captures accelerating aging and correlates with disability in MS participants. METHODS: We conducted a prospective, cross-sectional case-control pilot study. Consecutive patients who met the 2017 McDonald's Criteria for MS were recruited from May 2020 to May 2022 along with age-similar healthy controls. BAI components included blood pressure, FEV1, serum creatinine, C-reactive protein, blood-urea nitrogen, albumin, alkaline phosphatase, cholesterol, CMV IgG, and hemoglobin A1c. The index was calculated using the Klemara and Doubal method. Spearman correlation and multivariable linear regression models were used to assess the association between BAI and MS clinical outcomes. RESULTS: A total of 51 MS (68.6% female) and 38 control (68.4% female) participants were recruited. BAI correlated with chronological age (CA) in MS (r2=0.90,p<0.0001) and control participants (r2 =0.87,p<0.0001). The mean BAI was 1.4 years older than CA in MS participants (range +15 to -10.5 years) and 2.2 years younger in control participants (range +11.2 to -14.1 years). In unadjusted Spearman analyses, BAI correlated with the timed 25-foot walk (T25FW, rhos=0.31, p = 0.045) and symbol digit modalities test (SDMT rhos = 0.35, p = 0.018). In a multivariable regression model, a 5-year older BAI was associated with a 1.2-point lower score on SDMT (95%CI -2.2 to -0.25, p = 0.014). CONCLUSIONS: MS participants were biologically older than their own chronological age and age-similar controls. In this modest-sized pilot sample, there was strongest correlation for MS outcome measures between BAI and the SDMT. These results support further study of the BAI as a marker of biological age variability in MS.

Novel Moving Steady-State Visual Evoked Potential Stimulus to Assess Afferent and Efferent Dysfunction in Multiple Sclerosis.

Afferent and efferent visual dysfunction are prominent features of multiple sclerosis (MS). Visual outcomes have been shown to be robust biomarkers of the overall disease state. Unfortunately, precise measurement of afferent and efferent function is typically limited to tertiary care facilities, which have the equipment and analytical capacity to make these measurements, and even then, only a few centers can accurately quantify both afferent and efferent dysfunction. These measurements are currently unavailable in acute care facilities (ER, hospital floors). We aimed to develop a moving multifocal steady-state visual evoked potential (mfSSVEP) stimulus to simultaneously assess afferent and efferent dysfunction in MS for application on a mobile platform. The brain-computer interface (BCI) platform consists of a head-mounted virtual-reality headset with electroencephalogram (EEG) and electrooculogram (EOG) sensors. To evaluate the platform, we recruited consecutive patients who met the 2017 MS McDonald diagnostic criteria and healthy controls for a pilot cross-sectional study. Nine MS patients (mean age 32.7 years, SD 4.33) and ten healthy controls (24.9 years, SD 7.2) completed the research protocol. The afferent measures based on mfSSVEPs showed a significant difference between the groups (signal-to-noise ratio of mfSSVEPs for controls: 2.50 ± 0.72 vs. MS: 2.04 ± 0.47) after controlling for age (p = 0.049). In addition, the moving stimulus successfully induced smooth pursuit movement that can be measured by the EOG signals. There was a trend for worse smooth pursuit tracking in cases vs. controls, but this did not reach nominal statistical significance in this small pilot sample. This study introduces a novel moving mfSSVEP stimulus for a BCI platform to evaluate neurologic visual function. The moving stimulus showed a reliable capability to assess both afferent and efferent visual functions simultaneously.

Longitudinal evaluation of neurologic-post acute sequelae SARS-CoV-2 infection symptoms.

OBJECTIVE: To assess the initial features and evolution of neurologic Postacute Sequelae of SARS-CoV-2 infection (neuro-PASC) in patients with and without prior neurologic disease. METHODS: Participants with neurologic symptoms following acute SARS-CoV-2 infection were recruited from October 9, 2020 to October 11, 2021. Clinical data included a SARS-CoV-2 infection history, neurologic review of systems, neurologic exam, Montreal cognitive assessment (MoCA), and symptom-based self-reported surveys at baseline (conducted after acute infection) and 6-month follow-up assessments. RESULTS: Fifty-six participants (69% female, mean age 50 years, 29% with prior neurologic disease such as multiple sclerosis) were enrolled, of which 27 had completed the 6-month follow-up visit in this ongoing study. SARS-CoV-2 infection severity was largely described as mild (39.3%) or moderate (42.9%). At baseline, following acute infection, the most common neurologic symptoms were fatigue (89.3%) and headaches (80.4%). At the 6-month follow-up, memory impairment (68.8%) and decreased concentration (61.5%) were the most prevalent, though on average all symptoms showed a reduction in reported severity score at the follow-up. Complete symptom resolution was reported in 33.3% of participants by 6 months. From baseline to 6 months, average MoCA scores improved overall though 26.3% of participants' scores decreased. A syndrome consisting of tremor, ataxia, and cognitive dysfunction (PASC-TAC) was observed in 7.1% of patients. INTERPRETATION: Early in the neuro-PASC syndrome, fatigue and headache are the most commonly reported symptoms. At 6 months, memory impairment and decreased concentration were most prominent. Only one-third of participants had completed resolution of neuro-PASC at 6 months, although persistent symptoms trended toward improvement at follow-up.

What telomeres teach us about MS.

While the precise mechanisms driving progressive forms of MS are not fully understood, patient age has clear impact on disease phenotype. The very young with MS have high relapse rates and virtually no progressive disease, whereas older patients tend to experience more rapid disability accumulation with few relapses. Defining a patient's biological age may offer more precision in determining the role of aging processes in MS phenotype and pathophysiology than just working with an individual's birthdate. The most well recognized measurement of an individual's "biological clock" is telomere length (TL). While TL may differ across tissue types in an individual, most cells TL correlate well with leukocyte TL (LTL), which is the most common biomarker used for aging. LTL has been associated with risk for aging related diseases and most recently with higher levels of disability and brain atrophy in people living with MS. LTL explains 15% of the overall association of chronological age with MS disability level. While LTL may be used just as a biomarker of overall somatic aging processes, triggering of the DNA damage response by telomere attrition leads to senescence pathways that are likely highly relevant to a chronic autoimmune disease. Considering reproductive aging factors, particularly ovarian aging in women, which correlates with LTL and oocyte telomere length, may complement measurements of somatic aging in understanding MS progression. The key to stopping non-relapse related progression in MS might lie in targeting pathways related to biological aging effects on the immune and nervous systems.

Quantification of smooth pursuit dysfunction in multiple sclerosis.

BACKGROUND: Smooth pursuit dysfunction is common in MS, but rarely quantified and may be missed on exam. METHODS: NeuroFitONE™ smooth pursuit performance measures were compared between MS (n = 20) and healthy control (n = 19) participants. RESULTS: Compared to controls, MS patients had lower proportion of smooth pursuit (0.63 vs. 0.73; p = 0.047), increased directional (10.1 vs. 8°; p = 0.014) and speed noise (4.3 vs. 3.1°/sec; p = 0.021) and reduced initiation acceleration (96.83 vs. 115.33°/sec2; p = 0.061). Significant univariate correlations with clinical scores (EDSS, T25-FW) were observed. CONCLUSION: Smooth pursuit dysfunction in MS can be readily quantified and distinguishes MS eyes from healthy controls.

Is working memory inherently more "precise" than long-term memory? Extremely high fidelity visual long-term memories for frequently encountered objects.

Long-term memory is often considered easily corruptible, imprecise, and inaccurate, especially in comparison to working memory. However, most research used to support these findings relies on weak long-term memories: those where people have had only one brief exposure to an item. Here we investigated the fidelity of visual long-term memory in more naturalistic setting, with repeated exposures, and ask how it compares to visual working memory fidelity. Using psychophysical methods designed to precisely measure the fidelity of visual memory, we demonstrate that long-term memory for the color of frequently seen objects is as accurate as working memory for the color of a single item seen 1 s ago. In particular, we show that repetition greatly improves long-term memory, including the ability to discriminate an item from a very similar item (fidelity), in both a lab setting (Experiments 1-3) and a naturalistic setting (brand logos, Experiment 4). Overall, our results demonstrate the impressive nature of visual long-term memory fidelity, which we find is even higher fidelity than previously indicated in situations involving repetitions. Furthermore, our results suggest that there is no distinction between the fidelity of visual working memory and visual long-term memory, but instead both memory systems are capable of storing similar incredibly high-fidelity memories under the right circumstances. Our results also provide further evidence that there is no fundamental distinction between the "precision" of memory and the "likelihood of retrieving a memory," instead suggesting a single continuous measure of memory strength best accounts for working and long-term memory. (PsycInfo Database Record (c) 2020 APA, all rights reserved).