Serum neurofilament light and MRI predictors of cognitive decline in patients with secondary progressive multiple sclerosis: Analysis from the MS-STAT randomised controlled trial

Associations of cumulative Pb exposure and longitudinal changes in Mini-Mental Status Exam scores, global cognition and domains of cognition: The VA Normative Aging Study

Background:Alzheimer’s disease pathology and vascular burden are highly prevalent and often co-occur in elderly. It remains unclear how both relate to cognitive decline.Objective:To investigate whether amyloid abnormality and vascular burden synergistically contribute to cognitive decline in a memory clinic population.Methods:We included 227 patients from Maastricht and Aachen memory clinics. Amyloid abnormality (A+) was defined by CSF Aβ42 using data-driven cut-offs. Vascular burden (V+) was defined as having moderate to severe white matter hyperintensities, or any microbleeds, macrohemorrhage or infarcts on MRI. Longitudinal change in global cognition, memory, processing speed, executive functioning, and verbal fluency was analysed across the A-V-, A-V+, A+V-, A+V+ groups by linear mixed models. Additionally, individual MRI measures, vascular risk and vascular disease were used as V definitions.Results:At baseline, the A+V+ group scored worse on global cognition and verbal fluency compared to all other groups, and showed worse memory compared to A-V+ and A-V- groups. Over time (mean 2.7+ – 1.5 years), A+V+ and A+V- groups showed faster global cognition decline than A-V+ and A-V- groups. Only the A+V- group showed decline on memory and verbal fluency. The A-V+ group did not differ from the A-V- group. Individual MRI vascular measures only indicated an independent association of microbleeds with executive functioning decline. Findings were similar using other V definitions.Conclusions:Our study demonstrates that amyloid abnormality predicts cognitive decline independent from vascular burden in a memory clinic population. Vascular burden shows a minor contribution to cognitive decline in these patients. This has important prognostic implications.

We read with great interest the study by Aamodt and colleagues reporting that plasma neurofilament light (NfL) chain levels are associated with UPDRS III (Unified Parkinson's Disease Rating Scale, Part III) score but not the Mattis Dementia Rating Scale (DRS-2), whereas plasma NfL predicted cognitive decline (DRS-2 change) but not motor worsening (UPDRS III ≥5 points).1 Interestingly, these findings are in line with our results that serum NfL was associated with UPDRS III but not Montreal Cognitive Assessment (MoCA) score, whereas serum NfL predicted cognitive decline (decrease in MoCA score >2 points) but not motor worsening (increase in UPDRS III >4 points) in the Biomarkers in Parkinson's Disease (MARK-PD) study.2 Numerous studies have shown that blood NfL predicts cognitive decline in patients with Parkinson's disease, but cutoff values determined by receiver operating characteristic (ROC) analysis revealed very different results.1-3 Given that serum NfL levels increase by 3.35% per year in PD patients and double in individuals above 70 years compared with those below 50 years in the normal population, age is the most important covariate of NfL variability.4, 5 Consequently, we hypothesize that age-adjusted NfL percentiles might reveal more consistent results among cohort studies compared with absolute NfL values for the prediction of disease progression in PD patients. Therefore, we evaluated if the plasma NfL cutoff value of 14.6 pg/mL determined by Aamodt and colleagues also predicts cognitive decline in the Mark-PD study.6 Furthermore, we analyzed if age-adjusted serum NfL above the 95th percentile predicts cognitive decline in MARK-PD. In MARK-PD, serum NfL and cognitive outcome (initial and follow-up MoCA scores) were available for 106 patients with PD (age: 64.6 ± 8.8 years, men: 60.4%, disease duration: 12 [7.5, 15.5] years, follow-up: 512 [365, 680] days). During follow-up, we registered 21 patients with cognitive decline (decrease in MoCA score >2 points). In a Kaplan–Meier analysis, we observed no association between serum NfL levels and faster cognitive decline using a cutoff value of 14.6 pgl/mL (log-rank test: P = 0.322) (Fig. 1A). However, patients with NfL levels above the age-adjusted 95th percentile revealed a significantly faster cognitive decline (P = 0.026) than those below (Fig. 1B). This difference remained significant after further adjustment for age, sex, disease duration, and initial MoCA score (P = 0.017) (Fig. 1C). In summary, both studies using different cognitive scales (ie, DRS-2 and MoCA) show that increased NfL levels predict cognitive decline in PD patients. We suggest that NfL levels above the age-adjusted 95th percentile are independently associated with cognitive decline. We propose that age-adjusted NfL cutoffs might reveal more consistent results across different cohort studies and therefore facilitate the establishment of NfL as a clinically useful blood-based biomarker in patients with PD. The data that support the findings of this study are available from the corresponding author upon reasonable request.

Plasma biomarkers of Alzheimer’s disease (AD) pathology offer a non-invasive method to assess brain changes linked to dementia and cognitive decline. However, the associations with specific cognitive domains and subsequent cognitive change in participants with or without cognitive impairment is unclear. Plasma biomarkers were assayed in ARIC participants using Quanterix SiMoA technology on samples from midlife (visit 3, 1993-95, mean age 59) and late-life (visit 5, 2011-13, mean age 77). Biomarkers included Aβ42:Aβ40 ratio, p-Tau181, neurofilament light (NfL), and GFAP. Global and domain-specific cognitive factor scores were calculated from neuropsychological tests administered across multiple visits. Linear mixed effects models estimated the association between biomarkers and late-life cognitive change, adjusting for demographics, lifestyle and cardiovascular risk factors, and APOE-ε4 status. Exploratory analyses examined effect modification of the biomarker-global cognition associations by visit 5 cognitive impairment. Among 1515 participants with plasma biomarkers (60.7% female, 25.5% identified as Black), 39% had cognitive impairment in late-life. Higher midlife NfL and GFAP were associated with faster declines in global cognition and language. NfL also predicted faster memory decline. In late-life, lower Aβ42:Aβ40 and higher p-Tau181, NfL, and GFAP were associated with faster declines in global cognition, memory, and language. Changes in NfL, p-Tau181, and GFAP from midlife to late-life were associated with declines in global cognition and language. No consistent effect modification by cognitive impairment was observed. Plasma biomarkers of AD pathology, neuronal injury, and astrogliosis show distinct associations with cognitive decline across domains when measured in midlife and late-life.

Hearing loss (HL) has been associated with cognitive decline and dementia. We examined the temporal association between prevalent and incident HL and cognitive change. A total of 1823 participants (24-82 years) from the Maastricht Aging Study (MAAS) were assessed at baseline, 6 and 12 years, including pure-tone audiometry. Linear-mixed models were used to test the association between HL and cognition, adjusted for demographics and other dementia risk factors. Participants with prevalent and incident HL showed a faster decline in verbal memory, information processing speed, and executive function than participants without HL. Decline was steady from baseline to 6 and 12 years for prevalent HL, but time-delayed from 6 to 12 years for incident HL. Having a hearing aid did not change associations. Findings support the notion that HL is a risk factor for cognitive decline independent of other dementia risk factors. Onset of HL preceded onset of cognitive decline. We examined cognitive change in prevalent and incident hearing loss. Prevalent and incident hearing loss were associated with faster cognitive decline. For prevalent hearing loss, decline was steady from baseline to 6 and 12 years. Onset of hearing loss preceded the onset of cognitive decline. Having a hearing aid did not change the observed associations.

Post-traumatic stress disorder (PTSD) is associated with cognitive impairments. It is unclear whether problems persist after PTSD symptoms remit. Data came from 12 270 trauma-exposed women in the Nurses' Health Study II. Trauma and PTSD symptoms were assessed using validated scales to determine PTSD status as of 2008 (trauma/no PTSD, remitted PTSD, unresolved PTSD) and symptom severity (lifetime and past-month). Starting in 2014, cognitive function was assessed using the Cogstate Brief Battery every 6 or 12 months for up to 24 months. PTSD associations with baseline cognition and longitudinal cognitive changes were estimated by covariate-adjusted linear regression and linear mixed-effects models, respectively. Compared to women with trauma/no PTSD, women with remitted PTSD symptoms had a similar cognitive function at baseline, while women with unresolved PTSD symptoms had worse psychomotor speed/attention and learning/working memory. In women with unresolved PTSD symptoms, past-month PTSD symptom severity was inversely associated with baseline cognition. Over follow-up, both women with remitted and unresolved PTSD symptoms in 2008, especially those with high levels of symptoms, had a faster decline in learning/working memory than women with trauma/no PTSD. In women with remitted PTSD symptoms, higher lifetime PTSD symptom severity was associated with a faster decline in learning/working memory. Results were robust to the adjustment for sociodemographic, biobehavioral, and health factors and were partially attenuated when adjusted for depression. Unresolved but not remitted PTSD was associated with worse cognitive function assessed six years later. Accelerated cognitive decline was observed among women with either unresolved or remitted PTSD symptoms.

INTRODUCTIONWith anti‐amyloid beta (Aβ) therapies approved for Alzheimer's disease (AD), surrogate biomarkers are needed to monitor clinical treatment efficacy. Therefore, we systematically compared longitudinal changes in A/T/N biomarkers (amyloid‐positron emission tomography [PET], tau‐PET, plasma phosphorylated tau at threonine 217 [p‐tau217], and magnetic resonance imaging) for tracking cognitive changes.METHODSWe analyzed longitudinal biomarker and cognitive change rates from the Alzheimer's Disease Neuroimaging Initiative (N = 141) and Anti‐Amyloid Treatment in Asymptomatic Alzheimer's (A4) and Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) (N = 151), estimated using linear mixed models. Using linear models, we tested biomarker changes as predictors of cognitive changes, comparing predictive strengths across biomarkers using bootstrapping.RESULTSTau‐PET, plasma p‐tau217, and cortical thickness changes accurately tracked change rates in Mini‐Mental State Examination, Alzheimer's Disease Assessment Scale‐Cognitive Subscale 13‐item version, Clinical Dementia Rating‐Sum of Boxes, and Preclinial Alzheimer Cognitive Composite scores. In contrast, amyloid‐PET change rates were not linked to cognitive changes.DISCUSSIONPlasma p‐tau217 offers a cost‐effective AD‐specific alternative to tau‐PET and could potentially be implemented for monitoring cognitive changes in AD trials, while amyloid‐PET lacks utility. Cortical thickness changes accurately track cognitive changes but may be confounded by pseudo‐atrophy in anti‐Aβ treatments.HighlightsLongitudinal changes in tau‐PET, plasma p‐tau217, cortical thickness – but not amyloid‐PET – effectively track cognitive decline.Cortical thickness may be confounded by pseudo‐atrophy in anti‐Aβ trials.Plasma p‐tau217 is a robust and cost‐effective alternative to tau‐PET as an AD‐specific surrogate biomarker for monitoring cognitive changes.

As persons with human immunodeficiency virus (PWH) live longer, interactions between human immunodeficiency virus (HIV), aging, and structural brain integrity become increasingly vital for understanding cognitive disorders. This study analyzed the effects of aging, HIV serostatus, and viral load on cognition and brain volumes in a large cohort of persons without HIV (PWOH), PWH with undetectable virus (PWHU) (HIV RNA ≤50 copies/mL), and PWH with detectable virus (PHWD) (HIV RNA >50 copies/mL). Cross-sectional and longitudinal data were included. Cognitive composites (NPZ4) and brain volumes were obtained from 259 PWOH, 264 PWHU, and 84 PWHD with a total of 841 sessions. A series of generalized additive mixed models explored group differences in the relationship between age and cognition, age and regional brain volumes, and interactions between age and brain volumes on cognition. PWOH and PWHU exhibited similar change in cognitive performance with age, while PWHD exhibited a steeper decline compared to both. While both PWH groups had significantly smaller regional brain volumes compared to PWOH, the slopes of volume loss with age were similar across all groups except in the lentiform regions. Smaller brain volumes and increased age interacted for greater cognitive decline in PWHD. PWH who achieve viral suppression do not exhibit accelerated decline in cognition or brain volumes compared to PWOH, while PWHD may be at an increased risk for accelerated cognitive decline. These findings highlight the clinical importance of managing viral load in aging PWH and suggest that once viral suppression is achieved, changes to brain integrity are not accelerated compared to PWOH.

Serum Neurofilament Light concentrations are not associated with renal function in secondary progressive multiple sclerosis

White matter hyperintensities (WMHs) are the commonest imaging marker of cerebral small vessel disease (SVD) and a major cause of cognitive decline and vascular dementia. WMHs typically accumulate over time, but recent studies show they can also regress, but potential clinical benefits have received little attention. We examined progressing, stable, and regressing WMH in people with stroke-related SVD and the effect on cognitive outcomes. We recruited patients with minor nondisabling ischemic stroke (modified Rankin score ≤2) from stroke services into our prospective longitudinal observational study. Participants underwent cognitive assessment and brain MRI within 3-month poststroke and 1 year later. We gathered information on vascular risk factors, stroke severity, global cognition (Montreal Cognitive Assessment [MoCA]), processing speed and executive functioning (Trail Making Test [TMT] A and B, and the B/A ratio with ratio ≥3 reflecting executive dysfunction), and the Letter Digit Substitution Test. We measured WMH volumes at baseline and 1 year and categorized net WMH volume change into quintiles: Q1 (most regression), Q3 (stable), and Q5 (most progression). We applied repeated-measures linear mixed models to analyze longitudinal WMH and cognitive changes, adjusting for age, sex, premorbid intelligence, stroke severity, disability, white matter structural integrity, and baseline WMH volume. One hundred ninety-eight of 229 participants had WMH volumes available at both time-points. At baseline, the mean age was 67.5 years (SD = 10.9), with 33% female. Mean net WMH volume change per quintile was Q1 -1.79 mL (SD = 1.54), Q2 -0.27 mL (0.20), Q3 0.35 mL (0.18), Q4 1.43 mL (0.48), and Q5 5.31 mL (3.07). MoCA deteriorated the most in participants with most WMH progression (Q5) (estimated β -0.428 [95% CI -0.750 to -0.106]), compared with stable WMH (Q3), with no clear deterioration in those with most WMH regression (Q1). TMT B/A ratio improved in participants with most WMH regression (Q1; -0.385 [-0.758 to -0.012]). WMH regression was associated with preserved global cognition and improved executive function, compared with stable WMH, while WMH progression was associated with global cognitive decline. Cognitive benefits of WMH regression suggest that WMH-affected tissue can recover, may explain variance in cognitive outcomes, offer an important intervention target, and should be assessed in other populations and longer follow-up times.

Dietary fats and the APOE-e4 risk allele in relation to cognitive decline: a longitudinal investigation in a biracial population sample

We aimed to compare the rate of cognitive decline in patients with early and late onset Alzheimer's disease (AD) and to investigate the potentially modifying influence of the apolipoprotein E (APOE) genotype. We included 99 patients with early onset AD (age 65 years) and 192 patients with late onset AD (age >65 years) who had at least two scores on the Mini-Mental State Examination (MMSE) (range 2-14) obtained at least 1 year apart. Linear mixed models were performed to investigate the rate of cognitive decline dependent on age at onset (AAO) and APOE genotype. The mean (S.D.) age for patients with early onset AD was 57.7 (4.5) years, and 74.5 (5.1) years for patients with late onset AD. AAO was not associated with baseline MMSE [beta (S.E.)=0.8 (0.5), p=0.14]. However, patients with early onset showed a faster decline on the MMSE [beta (S.E.)=2.4 (0.1) points/year] than those with late onset [beta (S.E.)=1.7 (0.1) points/year, p=0.00]. After stratification according to APOE genotype, APOE epsilon4 non-carriers with early onset showed faster cognitive decline than non-carriers with late onset [2.4 (0.3) v. 1.3 (0.3) points/year, p=0.01]. In APOE epsilon4 carriers, no difference in rate of cognitive decline was found between patients with early and late onset [beta (S.E.)=0.2 (0.2), p=0.47]. Patients with early onset AD show more rapid cognitive decline than patients with late onset, suggesting that early onset AD follows a more aggressive course. Furthermore, this effect seems to be most prominent in patients with early onset who do not carry the genetic APOE epsilon4 risk factor for AD.

BackgroundDementia is associated with psychiatric symptoms but the effects of antidepressants on cognitive function in dementia are understudied. We aimed to investigate the association between antidepressants and cognitive decline in patients with dementia, and the risk of severe dementia, fractures and death, depending on antidepressant class, drug, and dose.MethodsThis is a national cohort study. Patients with dementia registered in the Swedish Registry for Cognitive/Dementia Disorders-SveDem from May 1, 2007, until October 16, 2018, with at least one follow-up after dementia diagnosis, and who were new users of antidepressants, were included. Antidepressant use as a time varying exposure defined during the 6 months leading up to dementia diagnosis or each subsequent follow-up. We used linear mixed models to examine the association between antidepressant use and cognitive trajectories assessed by Mini-Mental State Examination (MMSE) scores. We used Cox proportional hazards models to calculate the hazard ratios for severe dementia (MMSE score < 10), fracture, and death. We compared antidepressant classes and drugs, and analyzed dose–response.ResultsWe included 18740 patients (10 205 women [54.5%]; mean [SD] age, 78.2[7.4] years), of which 4271 (22.8%) received at least one prescription for an antidepressant. During follow-up, a total of 11912 prescriptions for antidepressants were issued, with selective serotonin reuptake inhibitors (SSRI) being the most common (64.8%). Antidepressant use was associated with faster cognitive decline (β (95% CI) = − 0.30(− 0.39, − 0.21) points/year), in particular sertraline (− 0.25(− 0.43, − 0.06) points/year), citalopram (− 0.41(− 0.55, − 0.27) points/year), escitalopram (− 0.76(− 1.09, − 0.44) points/year), and mirtazapine (− 0.19(− 0.34, − 0.04) points/year) compared with non-use. The association was stronger in patients with severe dementia (initial MMSE scores 0–9). Escitalopram showed a greater decline rate than sertraline. Compared with non-use, dose response of SSRIs on greater cognitive decline and higher risks of severe dementia, all-cause mortality, and fracture were observed.ConclusionsIn this cohort study, current antidepressant use was associated with faster cognitive decline; furthermore, higher dispensed doses of SSRIs were associated with higher risk for severe dementia, fractures, and all-cause mortality. These findings highlight the significance of careful and regular monitoring to assess the risks and benefits of different antidepressants use in patients with dementia.

BackgroundSeminal studies on exposure to life course social determinants of health, such as neighborhood racial segregation and neighborhood poverty, suggest detrimental associations with poorer cognitive function. We aimed to test the opposite by examining the relationship between self‐reported exposure to health‐promoting neighborhood environments over the life course and cognitive function among older adults.MethodParticipants were persons living without dementia at three US Alzheimer’s Disease Research Centers (University of California, Davis in Sacramento (UCD); Washington University in Saint Louis (WU); and Wake Forest University in Winston‐Salem (WFU)). An ancillary study (K01AG063895, PI: Besser) included the Life Course Sociodemographics and Neighborhood Questionnaire (LSNEQ) comprised of indices like neighborhood measures of socioeconomic status (NSES), walking and biking frequency, and greenness from childhood, midlife, and late life. LSNEQ data were linked with late‐life cognitive test z‐scores (Animals and Vegetables Category Fluency, Trail Making Parts A and B) from the National Alzheimer’s Coordinating Center Uniform Data Set. Multivariable linear mixed effects models tested associations between the LSNEQ index scores (composite values over childhood and mid‐ and late‐life) and baseline and longitudinal change in cognitive function controlling for demographics, Center, and baseline global Clinical Dementia Rating (0 or 0.5).ResultThe sample (n = 322) included 65% women, 17% Black, 76% White, and 7% other/mixed racialized group participants and was, on average, 70±7 years old and followed for 2.5±3.2 years. Life Course NSES was lower for UCD (mean = 12.7, SD = 3.5) versus WU (mean = 13.9, SD = 3.2) and WFU (mean = 14.3, SD = 3.2). Life Course Neighborhood Walking and Biking frequency did not differ by Center. Life Course Neighborhood Greenness differed across Centers, and was lowest for WU (mean = 4.8, SD = 1.3) and highest for WFU (mean = 5.6; SD = 1.2). In multivariable analyses, greater Life Course Neighborhood Walking and Biking was associated with higher baseline Trail A scores (estimate = 0.83, 95% CI = 0.08‐1.58) and slower decline on Animals over time (estimate = 0.024, 95% CI = 0.002‐0.045). Greater Life Course Neighborhood Greenness was associated with slower decline on Vegetables over time (estimate = 0.035, 95% CI = 0.001‐0.069).ConclusionThese preliminary findings suggest self‐reported, life course neighborhood exposures and behaviors (i.e., greenness and neighborhood walking/biking) may be associated with better cognition and slower decline in later life.

Modifiable risk factors and symptom progression in dementia over up to 8 years-Results of the DelpHi-MV trial.