Cerebrospinal fluid neurofilament light chain mediates age-associated lower learning and memory in healthy adults.

Multiple cognitive domains, including learning, memory, and psychomotor speed, show significant reductions with age. Likewise, several cerebrospinal fluid (CSF) neurodegenerative biomarkers, including total tau (t-tau, a marker of neuronal body injury) and neurofilament light chain (NfL, a marker of axonal injury) show age-related increases in normal aging. In the current study, we aimed to investigate whether the age-effect within different cognitive domains was mediated by age-associated CSF markers for neurodegenerative changes. We fitted 10 mediation models using structural equation modeling to investigate this in a cohort of 137 healthy adults, aged 40-80 years, from the Norwegian Dementia Disease Initiation (DDI) study. Here, t-tau and NfL were defined as mediators between age and different cognitive tests. The models showed that NfL mediated the age-effect for CERAD learning and memory recall (learning: ß = -0.395, p < 0.05; recall: ß = -0.261, p < 0.01). No such effect was found in the other models. Our findings suggest that the age-related lower performance in verbal learning and memory may be linked to NfL-associated neurodegenerative changes in cognitively healthy adults.

Longitudinal cerebrospinal fluid measurements show glial hypo- and hyperactivation in predementia Alzheimer's disease.

BACKGROUND: Brain innate immune activation is associated with Alzheimer's disease (AD), but degrees of activation may vary between disease stages. Thus, brain innate immune activation must be assessed in longitudinal clinical studies that include biomarker negative healthy controls and cases with established AD pathology. Here, we employ longitudinally sampled cerebrospinal fluid (CSF) core AD, immune activation and glial biomarkers to investigate early (predementia stage) innate immune activation levels and biomarker profiles. METHODS: We included non-demented cases from a longitudinal observational cohort study, with CSF samples available at baseline (n = 535) and follow-up (n = 213), between 1 and 6 years from baseline (mean 2.8 years). We measured Aß42/40 ratio, p-tau181, and total-tau to determine Ab (A+), tau-tangle pathology (T+), and neurodegeneration (N+), respectively. We classified individuals into these groups: A-/T-/N-, A+/T-/N-, A+/T+ or N+, or A-/T+ or N+. Using linear and mixed linear regression, we compared levels of CSF sTREM2, YKL-40, clusterin, fractalkine, MCP-1, IL-6, IL-1, IL-18, and IFN-γ both cross-sectionally and longitudinally between groups. A post hoc analysis was also performed to assess biomarker differences between cognitively healthy and impaired individuals in the A+/T+ or N+ group. RESULTS: Cross-sectionally, CSF sTREM2, YKL-40, clusterin and fractalkine were higher only in groups with tau pathology, independent of amyloidosis (p < 0.001, A+/T+ or N+ and A-/T+ or N+, compared to A-/T-/N-). No significant group differences were observed for the cytokines CSF MCP-1, IL-6, IL-10, IL18 or IFN-γ. Longitudinally, CSF YKL-40, fractalkine and IFN-γ were all significantly lower in stable A+/T-/N- cases (all p < 0.05). CSF sTREM2, YKL-40, clusterin, fractalkine (p < 0.001) and MCP-1 (p < 0.05) were all higher in T or N+, with or without amyloidosis at baseline, but remained stable over time. High CSF sTREM2 was associated with preserved cognitive function within the A+/T+ or N+ group, relative to the cognitively impaired with the same A/T/N biomarker profile (p < 0.01). CONCLUSIONS: Immune hypoactivation and reduced neuron-microglia communication are observed in isolated amyloidosis while activation and increased fractalkine accompanies tau pathology in predementia AD. Glial hypo- and hyperactivation through the predementia AD continuum suggests altered glial interaction with Ab and tau pathology, and may necessitate differential treatments, depending on the stage and patient-specific activation patterns.

Investigating the relationship between allocentric spatial working memory and biomarker status in preclinical and prodromal Alzheimer's disease.

The 4 Mountain Test (4MT) is a test of allocentric spatial working memory and has been proposed as an earlier marker of predementia Alzheimer's disease (AD) than episodic verbal memory. We here compare the 4MT to the CERAD word list memory recall in both cognitively normal (CN) and mild cognitive impairment (MCI) cases with or without cerebrospinal fluid markers (CSF) of Alzheimer's disease pathology. Linear regression was used to assess the influence of CSF determined Aß-plaque (Aß-/+) or neurofibrillary tau tangles (Tau-/+) on 4MT and CERAD recall performance. Analyses were performed in the full sample and the CN and MCI sub-samples. Pearson correlations were calculated to examine the relationship between 4MT and tests of psychomotor speed, verbal memory, cognitive flexibility, verbal fluency, and visuo-spatial perception. Analyses showed no significant differences in 4MT scores between Aß-/Aß+, nor Tau-/Tau + participants, irrespective of cognitive status. In contrast, CERAD recall scores were lower in both Aß+ compared to Aß- (p<.01), and Tau + compared to Tau- participants (p<.01) in the full sample analyses. There were no significant differences in CERAD recall performance between Aß- vs. Aß+ and Tau- vs. to Tau + in the in CN/MCI sub-samples. 4MT scores were significantly correlated with tests of psychomotor speed, cognitive flexibility, and visuo-spatial perception in the full sample analyses. In conclusion, the CERAD recall outperformed the 4MT as a cognitive marker of CSF determined AD pathology. This suggests that allocentric working memory, as measured by the 4MT, may not be used as an early marker of predementia AD.

Medial Temporal Lobe Atrophy in Predementia Alzheimer's Disease: A Longitudinal Multi-Site Study Comparing Staging and A/T/N in a Clinical Research Cohort.

BACKGROUND: Atrophy of the medial temporal lobe (MTL) is a biological characteristic of Alzheimer's disease (AD) and can be measured by segmentation of magnetic resonance images (MRI). OBJECTIVE: To assess the clinical utility of automated volumetry in a cognitively well-defined and biomarker-classified multi-center longitudinal predementia cohort. METHODS: We used Automatic Segmentation of Hippocampal Subfields (ASHS) to determine MTL morphometry from MRI. We harmonized scanner effects using the recently developed longitudinal ComBat. Subjects were classified according to the A/T/N system, and as normal controls (NC), subjective cognitive decline (SCD), or mild cognitive impairment (MCI). Positive or negative values of A, T, and N were determined by cerebrospinal fluid measurements of the Aß42/40 ratio, phosphorylated and total tau. From 406 included subjects, longitudinal data was available for 206 subjects by stage, and 212 subjects by A/T/N. RESULTS: Compared to A-/T-/N- at baseline, the entorhinal cortex, anterior and posterior hippocampus were smaller in A+/T+orN+. Compared to NC A- at baseline, these subregions were also smaller in MCI A+. Longitudinally, SCD A+ and MCI A+, and A+/T-/N- and A+/T+orN+, had significantly greater atrophy compared to controls in both anterior and posterior hippocampus. In the entorhinal and parahippocampal cortices, longitudinal atrophy was observed only in MCI A+ compared to NC A-, and in A+/T-/N- and A+/T+orN+ compared to A-/T-/N-. CONCLUSION: We found MTL neurodegeneration largely consistent with existing models, suggesting that harmonized MRI volumetry may be used under conditions that are common in clinical multi-center cohorts.

A Randomised Placebo-Controlled Study of Purified Anthocyanins on Cognition in Individuals at Increased Risk for Dementia.

IMPORTANCE: Identifying nutritional compounds which can reduce cognitive decline in older people is a hugely important topic. OBJECTIVE: To study the safety and effect of anthocyanins in maintaining cognitive functioning in people at increased risk for dementia. DESIGN, SETTING, AND PARTICIPANTS: Participants (206 individuals, aged 60-80 years) diagnosed with either mild cognitive impairment (MCI) or two or more cardiometabolic disorders (i.e., diabetes, hypertension, obesity) were enrolled at three different centres in Norway. INTERVENTION: Participants were randomly assigned to four capsules with a total of 320 mg/d of naturally purified anthocyanins or placebo 1:1 for 24 weeks. MAIN OUTCOMES AND MEASURES: The primary outcome was the Quality of Episodic Memory composite measure (0-100) from an online cognitive test battery CogTrack, which was administered at baseline and monthly for the next 24 weeks. Secondary outcomes included other cognitive scores from the CogTrack battery. We applied mixed effects models with a baseline test score, group, time and their interaction as fixed effects, as well as other predefined baseline covariates. The primary comparison was the group difference at week 24 based on a modified intention-to-treat principle. RESULTS: The primary analysis did not show a significant group difference at 24 weeks (78.2 versus 76.8; adjusted mean difference 1.4 (95% confidence interval -0.9-3.7); effect size 0.15; p = 0.23). However, there was a significant difference in slopes during weeks 8-24 (p = 0.007); the anthocyanin group improved while the placebo group worsened. No differences were found for the secondary cognitive outcomes. Anthocyanin capsules were well-tolerated and safe to use. CONCLUSION: Anthocyanin supplementation for 24 weeks was safe and well tolerated in people with MCI or cardiometabolic disorders. We found no significant group difference in episodic memory at the end of the study but statistically significant differences in slopes. Further studies are warranted to explore whether anthocyanins supplementation can reduce cognitive decline in people at increased risk of dementia. TRIAL REGISTRATION: ClinicalTrials.gov, (Identifier NCT03419039). http://www. CLINICALTRIALS: gov/, NCT03419039.

Brain amyloid and vascular risk are related to distinct white matter hyperintensity patterns.

White matter hyperintensities (WMHs) are associated with vascular risk and Alzheimer's disease. In this study, we examined relations between WMH load and distribution, amyloid pathology and vascular risk in 339 controls and cases with either subjective (SCD) or mild cognitive impairment (MCI). Regional deep (DWMH) and periventricular (PWMH) WMH loads were determined using an automated algorithm. We stratified on Aß1-42 pathology (Aß+/-) and analyzed group differences, as well as associations with Framingham Risk Score for cardiovascular disease (FRS-CVD) and age. Occipital PWMH (p = 0.001) and occipital DWMH (p = 0.003) loads were increased in SCD-Aß+ compared with Aß- controls. In MCI-Aß+ compared with Aß- controls, there were differences in global WMH (p = 0.003), as well as occipital DWMH (p = 0.001) and temporal DWMH (p = 0.002) loads. FRS-CVD was associated with frontal PWMHs (p = 0.003) and frontal DWMHs (p = 0.005), after adjusting for age. There were associations between global and all regional WMH loads and age. In summary, posterior WMH loads were increased in SCD-Aß+ and MCI-Aß+ cases, whereas frontal WMHs were associated with vascular risk. The differences in WMH topography support the use of regional WMH load as an early-stage marker of etiology.

In Brief Neuropsychological Assessment, Amnestic Mild Cognitive Impairment (MCI) Is associated with Cerebrospinal Fluid Biomarkers for Cognitive Decline in Contrast to the Prevailing NIA-AA MCI Criterion.

BACKGROUND: In the care of persons with cognitive problems, it is important to use a valid mild cognitive impairment (MCI) criterion that discriminates well between normal and pathological aging. OBJECTIVE: To find the brief neuropsychological screening criterion that best correlates with cerebrospinal fluid (CSF) biomarkers for cognitive decline and dementia in persons seeking help for cognitive problems. METHODS: 452 consecutively recruited patients (age 40-80 years) from memory-clinics in the Norwegian national multicentre longitudinal study Dementia Disease Initiation were included. CSF data as well as full data from brief neuropsychological screening were available for all patients. RESULTS: Amnestic MCI, including at least one memory test below T-score 40, outperformed the conventional US National Institute on Aging-Alzheimer's Association (NIA-AA) MCI criterion. Only amnestic MCI was significantly associated with biomarker pattern of NIA-AA stage 2 (low CSF Aß42 concentrations and elevated tau) in multivariate regression analysis. CONCLUSIONS: The finding that amnestic MCI based on brief neuropsychological assessment is significantly associated with CSF biomarkers for cognitive decline and Alzheimer's disease is in accordance with longitudinal studies that find memory impairment; both in itself and especially in combination with other cognitive deficit to constitute a risk factor for subsequent cognitive decline and dementia. The prevalence of pathological biomarkers for Alzheimer's disease is common in the elderly and the clinical significance of present findings depend on longitudinal validation.

Reduced Walking Speed in Subjective and Mild Cognitive Impairment: A Cross-Sectional Study.

BACKGROUND AND PURPOSE: Walking speed is reduced in people with dementia, but less is known about predementia conditions. We, therefore, studied the relationship between walking speed, cognition, and cerebrospinal fluid biomarkers in persons with subjective (SCI) and mild cognitive impairment (MCI). METHODS: We conducted a cross-sectional study of 22 healthy controls, 30 SCI and 17 MCI (N = 69). Walking speed was measured by a 10-m gait test at usual and fast pace. We analyzed the association between walking speed and the ordered categories of controls, SCI, and MCI in a generalized proportional odds model. Neuropsychological tests, Consortium to Establish a Registry for Alzheimer's Disease (delayed recall), and Trail Making (TMT) A and B, were analyzed by negative binomial, linear, and robust regression for association with walking speed. RESULTS: Walking speed at usual pace was slower moving from controls to SCI (odds ratio: 0.46, P = 0.031) and MCI (odds ratio: 0.44, P = .019) on an ordinal scale. In MCI, walking speed was reduced at fast speed (odds ratio: 0.46, P = 0.04). There were significant associations between walking speeds and neuropsychological test performance. Usual walking speed was associated with slower test performance on TMT-A (ß: -.02, P = .04) and fast pace with slower performance on TMT-B (ß: -.01, P = .03). There were no associations between cerebrospinal fluid biomarkers and walking speeds. CONCLUSION: Usual walking speed is reduced in a graded fashion with the early symptoms of cognitive impairment. Our results suggest that reduced walking speed at both usual and fast speed is associated with impaired cognitive function, and that walking speed could be affected at very early stages of neurodegeneration.

Cognitive Deficits in Chronic Stroke Patients: Neuropsychological Assessment, Depression, and Self-Reports.

BACKGROUND: Following stroke, clinicians are challenged to detect and untangle symptoms of cognitive dysfunction and mood disorders. Additionally, they need to evaluate the informative value of self-reports to identify patients in need of further attendance. AIMS: To examine the association between neuropsychological measures, symptoms of depression, and self-reported cognitive function. METHODS: One-hundred and five chronic stroke patients underwent assessment covering 6 cognitive domains and answered the Hospital Anxiety and Depression Scale and the Memory and Thinking Scale from the Stroke Impact Scale 1 year after stroke. Age and gender difference in cognitive impairment were examined; linear regression was used to predict depression scores. Sensitivity and specificity analyses were used to validate self-reported functioning against performance on cognitive tests. RESULTS: Cognitive impairment was observed in 60% of the patients in at least 1 cognitive domain. Cognitive performance was associated with symptoms of depression as well as with self-reported cognitive function. The final analyses revealed low sensitivity and specificity for the Memory and Thinking subscale from the Stroke Impact Scale. CONCLUSION: Cognitive impairment occurs frequently even in patients in a chronic phase after stroke and predicts symptoms of depression. Using the Stroke Impact Scale, clinicians should be aware of low sensitivity of self-reported cognitive function.

Detecting At-Risk Alzheimer's Disease Cases.

While APOEɛ4 is the major genetic risk factor for Alzheimer's disease (AD), amyloid dysmetabolism is an initial or early event predicting clinical disease and is an important focus for secondary intervention trials. To improve identification of cases with increased AD risk, we evaluated recruitment procedures using pathological CSF concentrations of Aß42 (pAß) and APOEɛ4 as risk markers in a multi-center study in Norway. In total, 490 subjects aged 40-80 y were included after response to advertisements and media coverage or memory clinics referrals. Controls (n = 164) were classified as normal controls without first-degree relatives with dementia (NC), normal controls with first-degree relatives with dementia (NCFD), or controls scoring below norms on cognitive screening. Patients (n = 301) were classified as subjective cognitive decline or mild cognitive impairment. Subjects underwent a clinical and cognitive examination and MRI according to standardized protocols. Core biomarkers in CSF from 411 and APOE genotype from 445 subjects were obtained. Cases (both self-referrals (n = 180) and memory clinics referrals (n = 87)) had increased fractions of pAß and APOEɛ4 frequency compared to NC. Also, NCFD had higher APOEɛ4 frequencies without increased fraction of pAß compared to NC, and cases recruited from memory clinics had higher fractions of pAß and APOEɛ4 frequency than self-referred. This study shows that memory clinic referrals are pAß enriched, whereas self-referred and NCFD cases more frequently are pAß negative but at risk (APOEɛ4 positive), suitable for primary intervention.