Updating the study protocol: Insight 46 - a longitudinal neuroscience sub-study of the MRC National Survey of Health and Development - phases 2 and 3.

BACKGROUND: Although age is the biggest known risk factor for dementia, there remains uncertainty about other factors over the life course that contribute to a person's risk for cognitive decline later in life. Furthermore, the pathological processes leading to dementia are not fully understood. The main goals of Insight 46-a multi-phase longitudinal observational study-are to collect detailed cognitive, neurological, physical, cardiovascular, and sensory data; to combine those data with genetic and life-course information collected from the MRC National Survey of Health and Development (NSHD; 1946 British birth cohort); and thereby contribute to a better understanding of healthy ageing and dementia. METHODS/DESIGN: Phase 1 of Insight 46 (2015-2018) involved the recruitment of 502 members of the NSHD (median age = 70.7 years; 49% female) and has been described in detail by Lane and Parker et al. 2017. The present paper describes phase 2 (2018-2021) and phase 3 (2021-ongoing). Of the 502 phase 1 study members who were invited to a phase 2 research visit, 413 were willing to return for a clinic visit in London and 29 participated in a remote research assessment due to COVID-19 restrictions. Phase 3 aims to recruit 250 study members who previously participated in both phases 1 and 2 of Insight 46 (providing a third data time point) and 500 additional members of the NSHD who have not previously participated in Insight 46. DISCUSSION: The NSHD is the oldest and longest continuously running British birth cohort. Members of the NSHD are now at a critical point in their lives for us to investigate successful ageing and key age-related brain morbidities. Data collected from Insight 46 have the potential to greatly contribute to and impact the field of healthy ageing and dementia by combining unique life course data with longitudinal multiparametric clinical, imaging, and biomarker measurements. Further protocol enhancements are planned, including in-home sleep measurements and the engagement of participants through remote online cognitive testing. Data collected are and will continue to be made available to the scientific community.

Rates of cortical thinning in Alzheimer's disease signature regions associate with vascular burden but not with ß-amyloid status in cognitively normal adults at age 70.

BACKGROUND: Consistent patterns of reduced cortical thickness have been identified in early Alzheimer's disease (AD). However, the pathological factors that influence rates of cortical thinning within these AD signature regions remain unclear. METHODS: Participants were from the Insight 46 substudy of the MRC National Survey of Health and Development (NSHD; 1946 British birth cohort), a prospective longitudinal cohort study. Linear regression was used to examine associations of baseline cerebral ß-amyloid (Aß) deposition, measured using florbetapir positron emission tomography, and baseline white matter hyperintensity volume (WMHV) on MRI, a marker of cerebral small vessel disease, with subsequent longitudinal changes in AD signature cortical thickness quantified from baseline and repeat MRI (mean [SD] interval 2.4 [0.2] years). RESULTS: In a population-based sample of 337 cognitively normal older white adults (mean [SD] age at baseline 70.5 [0.6] years; 48.1% female), higher global WMHV at baseline related to faster subsequent rates of cortical thinning in both AD signature regions (~0.15%/year faster per 10 mL additional WMHV), whereas baseline Aß status did not. Among Aß positive participants (n=56), there was some evidence that greater global Aß standardised uptake value ratio at baseline related to faster cortical thinning in the AD signature Mayo region, but this did not reach statistical significance (p=0.08). CONCLUSIONS: Cortical thinning within AD signature regions may develop via cerebrovascular pathways. Perhaps reflecting the age of the cohort and relatively low prevalence of Aß-positivity, robust Aß-related differences were not detected. Longitudinal follow-up incorporating additional biomarkers will allow assessment of how these relationships evolve closer to expected dementia onset.

Neuroimaging, clinical and life course correlates of normal-appearing white matter integrity in 70-year-olds.

We investigate associations between normal-appearing white matter microstructural integrity in cognitively normal ∼70-year-olds and concurrently measured brain health and cognition, demographics, genetics and life course cardiovascular health. Participants born in the same week in March 1946 (British 1946 birth cohort) underwent PET-MRI around age 70. Mean standardized normal-appearing white matter integrity metrics (fractional anisotropy, mean diffusivity, neurite density index and orientation dispersion index) were derived from diffusion MRI. Linear regression was used to test associations between normal-appearing white matter metrics and (i) concurrent measures, including whole brain volume, white matter hyperintensity volume, PET amyloid and cognition; (ii) the influence of demographic and genetic predictors, including sex, childhood cognition, education, socio-economic position and genetic risk for Alzheimer's disease (APOE-ɛ4); (iii) systolic and diastolic blood pressure and cardiovascular health (Framingham Heart Study Cardiovascular Risk Score) across adulthood. Sex interactions were tested. Statistical significance included false discovery rate correction (5%). Three hundred and sixty-two participants met inclusion criteria (mean age 70, 49% female). Higher white matter hyperintensity volume was associated with lower fractional anisotropy [b = -0.09 (95% confidence interval: -0.11, -0.06), P < 0.01], neurite density index [b = -0.17 (-0.22, -0.12), P < 0.01] and higher mean diffusivity [b = 0.14 (-0.10, -0.17), P < 0.01]; amyloid (in men) was associated with lower fractional anisotropy [b = -0.04 (-0.08, -0.01), P = 0.03)] and higher mean diffusivity [b = 0.06 (0.01, 0.11), P = 0.02]. Framingham Heart Study Cardiovascular Risk Score in later-life (age 69) was associated with normal-appearing white matter {lower fractional anisotropy [b = -0.06 (-0.09, -0.02) P < 0.01], neurite density index [b = -0.10 (-0.17, -0.03), P < 0.01] and higher mean diffusivity [b = 0.09 (0.04, 0.14), P < 0.01]}. Significant sex interactions (P < 0.05) emerged for midlife cardiovascular health (age 53) and normal-appearing white matter at 70: marginal effect plots demonstrated, in women only, normal-appearing white matter was associated with higher midlife Framingham Heart Study Cardiovascular Risk Score (lower fractional anisotropy and neurite density index), midlife systolic (lower fractional anisotropy, neurite density index and higher mean diffusivity) and diastolic (lower fractional anisotropy and neurite density index) blood pressure and greater blood pressure change between 43 and 53 years (lower fractional anisotropy and neurite density index), independently of white matter hyperintensity volume. In summary, poorer normal-appearing white matter microstructural integrity in ∼70-year-olds was associated with measures of cerebral small vessel disease, amyloid (in males) and later-life cardiovascular health, demonstrating how normal-appearing white matter can provide additional information to overt white matter disease. Our findings further show that greater 'midlife' cardiovascular risk and higher blood pressure were associated with poorer normal-appearing white matter microstructural integrity in females only, suggesting that women's brains may be more susceptible to the effects of midlife blood pressure and cardiovascular health.

Tau accumulation in autosomal dominant Alzheimer's disease: a longitudinal [18F]flortaucipir study.

Cortical tau accumulation is a key pathological event that partly defines Alzheimer's disease (AD) onset and is associated with cognitive decline and future disease progression. However, an improved understanding of the timing and pattern of early tau deposition in AD and how this may be tracked in vivo is needed. Data from 59 participants involved in two longitudinal cohort studies of autosomal dominant AD (ADAD) were used to investigate whether tau PET can detect and track presymptomatic change; seven participants were symptomatic, and 52 were asymptomatic but at a 50% risk of carrying a pathogenic mutation. All had baseline flortaucipir (FTP) PET, MRI and clinical assessments; 26 individuals had more than one FTP PET scan. Standardised uptake value ratios (SUVRs) in prespecified regions of interest (ROIs) were obtained using inferior cerebellar grey matter as the reference region. We compared the changes in FTP SUVRs between presymptomatic carriers, symptomatic carriers and non-carriers, adjusting for age, sex and study site. We also investigated the relationship between regional FTP SUVRs and estimated years to/from symptom onset (EYO). Compared to both non-carriers and presymptomatic carriers, FTP SUVRs were significantly higher in symptomatic carriers in all ROIs tested (p < 0.001). There were no significant regional differences between presymptomatic carriers and non-carriers in FTP SUVRs, or their rates of change (p > 0.05), although increased FTP signal uptake was seen posteriorly in some individuals around the time of expected symptom onset. When we examined the relationship of FTP SUVR with respect to EYO, the earliest significant regional difference between mutation carriers and non-carriers was detected within the precuneus prior to estimated symptom onset in some cases. This study supports preliminary studies suggesting that presymptomatic tau tracer uptake is rare in ADAD. In cases where early uptake was seen, there was often a predilection for posterior regions (the precuneus and post-cingulate) as opposed to the medial temporal lobe, highlighting the importance of examining in vivo tau uptake beyond the confines of traditional Braak staging.

Operationalizing the centiloid scale for [18F]florbetapir PET studies on PET/MRI.

INTRODUCTION: The Centiloid scale aims to harmonize amyloid beta (Aß) positron emission tomography (PET) measures across different analysis methods. As Centiloids were created using PET/computerized tomography (CT) data and are influenced by scanner differences, we investigated the Centiloid transformation with data from Insight 46 acquired with PET/magnetic resonanceimaging (MRI). METHODS: We transformed standardized uptake value ratios (SUVRs) from 432 florbetapir PET/MRI scans processed using whole cerebellum (WC) and white matter (WM) references, with and without partial volume correction. Gaussian-mixture-modelling-derived cutpoints for Aß PET positivity were converted. RESULTS: The Centiloid cutpoint was 14.2 for WC SUVRs. The relationship between WM and WC uptake differed between the calibration and testing datasets, producing implausibly low WM-based Centiloids. Linear adjustment produced a WM-based cutpoint of 18.1. DISCUSSION: Transformation of PET/MRI florbetapir data to Centiloids is valid. However, further understanding of the effects of acquisition or biological factors on the transformation using a WM reference is needed. HIGHLIGHTS: Centiloid conversion of amyloid beta positron emission tomography (PET) data aims to standardize results.Centiloid values can be influenced by differences in acquisition.We converted florbetapir PET/magnetic resonance imaging data from a large birth cohort.Whole cerebellum referenced values could be reliably transformed to Centiloids.White matter referenced values may be less generalizable between datasets.

Layer-dependent stability of intracortical recordings and neuronal cell loss.

Intracortical recordings can be used to voluntarily control external devices via brain-machine interfaces (BMI). Multiple factors, including the foreign body response (FBR), limit the stability of these neural signals over time. Current clinically approved devices consist of multi-electrode arrays with a single electrode site at the tip of each shank, confining the recording interface to a single layer of the cortex. Advancements in manufacturing technology have led to the development of high-density electrodes that can record from multiple layers. However, the long-term stability of neural recordings and the extent of neuronal cell loss around the electrode across different cortical depths have yet to be explored. To answer these questions, we recorded neural signals from rats chronically implanted with a silicon-substrate microelectrode array spanning the layers of the cortex. Our results show the long-term stability of intracortical recordings varies across cortical depth, with electrode sites around L4-L5 having the highest stability. Using machine learning guided segmentation, our novel histological technique, DeepHisto, revealed that the extent of neuronal cell loss varies across cortical layers, with L2/3 and L4 electrodes having the largest area of neuronal cell loss. These findings suggest that interfacing depth plays a major role in the FBR and long-term performance of intracortical neuroprostheses.

Cortical tau is associated with microstructural imaging biomarkers of neurite density and dendritic complexity in Alzheimer's disease.

INTRODUCTION: In Alzheimer's disease (AD), hyperphosphorylated tau is closely associated with focal neurodegeneration, but the mechanism remains uncertain. METHODS: We quantified cortical microstructure using neurite orientation dispersion and density imaging in 14 individuals with young onset AD. Diffusion tensor imaging measured mean diffusivity (MD). Amyloid beta and tau positron emission tomography were acquired and associations with microstructural measures were assessed. RESULTS: When regional volume was adjusted for, in the medial temporal lobe there was a significant negative association between neurite density and tau (partial R2  = 0.56, p = 0.008) and between orientation dispersion and tau (partial R2  = 0.66, p = 0.002), but not between MD and tau. In a wider cortical composite, there was an association between orientation dispersion and tau (partial R2  = 0.43, p = 0.030), but not between other measures and tau. DISCUSSION: Our findings are consistent with tau causing first dendritic pruning (reducing dispersion/complexity) followed by neuronal loss. Advanced magnetic resonance imaging (MRI) microstructural measures have the potential to provide information relating to underlying tau deposition.

Structural MRI predicts clinical progression in presymptomatic genetic frontotemporal dementia: findings from the GENetic Frontotemporal dementia Initiative cohort.

Biomarkers that can predict disease progression in individuals with genetic frontotemporal dementia are urgently needed. We aimed to identify whether baseline MRI-based grey and white matter abnormalities are associated with different clinical progression profiles in presymptomatic mutation carriers in the GENetic Frontotemporal dementia Initiative. Three hundred eighty-seven mutation carriers were included (160 GRN, 160 C9orf72, 67 MAPT), together with 240 non-carrier cognitively normal controls. Cortical and subcortical grey matter volumes were generated using automated parcellation methods on volumetric 3T T1-weighted MRI scans, while white matter characteristics were estimated using diffusion tensor imaging. Mutation carriers were divided into two disease stages based on their global CDR®+NACC-FTLD score: presymptomatic (0 or 0.5) and fully symptomatic (1 or greater). The w-scores in each grey matter volumes and white matter diffusion measures were computed to quantify the degree of abnormality compared to controls for each presymptomatic carrier, adjusting for their age, sex, total intracranial volume, and scanner type. Presymptomatic carriers were classified as 'normal' or 'abnormal' based on whether their grey matter volume and white matter diffusion measure w-scores were above or below the cut point corresponding to the 10th percentile of the controls. We then compared the change in disease severity between baseline and one year later in both the 'normal' and 'abnormal' groups within each genetic subtype, as measured by the CDR®+NACC-FTLD sum-of-boxes score and revised Cambridge Behavioural Inventory total score. Overall, presymptomatic carriers with normal regional w-scores at baseline did not progress clinically as much as those with abnormal regional w-scores. Having abnormal grey or white matter measures at baseline was associated with a statistically significant increase in the CDR®+NACC-FTLD of up to 4 points in C9orf72 expansion carriers, and 5 points in the GRN group as well as a statistically significant increase in the revised Cambridge Behavioural Inventory of up to 11 points in MAPT, 10 points in GRN, and 8 points in C9orf72 mutation carriers. Baseline regional brain abnormalities on MRI in presymptomatic mutation carriers are associated with different profiles of clinical progression over time. These results may be helpful to inform stratification of participants in future trials.

Investigating associations between blood metabolites, later life brain imaging measures, and genetic risk for Alzheimer's disease.

BACKGROUND: Identifying blood-based signatures of brain health and preclinical pathology may offer insights into early disease mechanisms and highlight avenues for intervention. Here, we systematically profiled associations between blood metabolites and whole-brain volume, hippocampal volume, and amyloid-ß status among participants of Insight 46-the neuroscience sub-study of the National Survey of Health and Development (NSHD). We additionally explored whether key metabolites were associated with polygenic risk for Alzheimer's disease (AD). METHODS: Following quality control, levels of 1019 metabolites-detected with liquid chromatography-mass spectrometry-were available for 1740 participants at age 60-64. Metabolite data were subsequently clustered into modules of co-expressed metabolites using weighted coexpression network analysis. Accompanying MRI and amyloid-PET imaging data were present for 437 participants (age 69-71). Regression analyses tested relationships between metabolite measures-modules and hub metabolites-and imaging outcomes. Hub metabolites were defined as metabolites that were highly connected within significant (pFDR < 0.05) modules or were identified as a hub in a previous analysis on cognitive function in the same cohort. Regression models included adjustments for age, sex, APOE genotype, lipid medication use, childhood cognitive ability, and social factors. Finally, associations were tested between AD polygenic risk scores (PRS), including and excluding the APOE region, and metabolites and modules that significantly associated (pFDR < 0.05) with an imaging outcome (N = 1638). RESULTS: In the fully adjusted model, three lipid modules were associated with a brain volume measure (pFDR < 0.05): one enriched in sphingolipids (hippocampal volume: ß = 0.14, 95% CI = [0.055,0.23]), one in several fatty acid pathways (whole-brain volume: ß = - 0.072, 95%CI = [- 0.12, - 0.026]), and another in diacylglycerols and phosphatidylethanolamines (whole-brain volume: ß = - 0.066, 95% CI = [- 0.11, - 0.020]). Twenty-two hub metabolites were associated (pFDR < 0.05) with an imaging outcome (whole-brain volume: 22; hippocampal volume: 4). Some nominal associations were reported for amyloid-ß, and with an AD PRS in our genetic analysis, but none survived multiple testing correction. CONCLUSIONS: Our findings highlight key metabolites, with functions in membrane integrity and cell signalling, that associated with structural brain measures in later life. Future research should focus on replicating this work and interrogating causality.

Predicting Cognitive Decline in Older Adults Using Baseline Metrics of AD Pathologies, Cerebrovascular Disease, and Neurodegeneration.

BACKGROUND AND OBJECTIVES: Dementia is a growing socioeconomic challenge that requires early intervention. Identifying biomarkers that reliably predict clinical progression early in the disease process would better aid selection of individuals for future trial participation. Here, we compared the ability of baseline, single time-point biomarkers (CSF amyloid 1-42, CSF ptau-181, white matter hyperintensities (WMH), cerebral microbleeds, whole-brain volume, and hippocampal volume) to predict decline in cognitively normal individuals who later converted to mild cognitive impairment (MCI) (CNtoMCI) and those with MCI who later converted to an Alzheimer disease (AD) diagnosis (MCItoAD). METHODS: Standardized baseline biomarker data from AD Neuroimaging Initiative 2 (ADNI2)/GO and longitudinal diagnostic data (including ADNI3) were used. Cox regression models assessed biomarkers in relation to time to change in clinical diagnosis using all follow-up time points available. Models were fit for biomarkers univariately and together in a multivariable model. Hazard ratios (HRs) were compared to evaluate biomarkers. Analyses were performed separately in CNtoMCI and MCItoAD groups. RESULTS: For CNtoMCI (n = 189), there was strong evidence that higher WMH volume (individual model: HR 1.79, p = 0.002; fully adjusted model: HR 1.98, p = 0.003) and lower hippocampal volume (individual: HR 0.54, p = 0.001; fully adjusted: HR 0.40, p < 0.001) were associated with conversion to MCI individually and independently. For MCItoAD (n = 345), lower hippocampal (individual model: HR 0.45, p < 0.001; fully adjusted model: HR 0.55, p < 0.001) and whole-brain volume (individual: HR 0.31, p < 0.001; fully adjusted: HR 0.48, p = 0.02), increased CSF ptau (individual: HR 1.88, p < 0.001; fully adjusted: HR 1.61, p < 0.001), and lower CSF amyloid (individual: HR 0.37, p < 0.001; fully adjusted: HR 0.62, p = 0.008) were most strongly associated with conversion to AD individually and independently. DISCUSSION: Lower hippocampal volume was a consistent predictor of clinical conversion to MCI and AD. CSF and brain volume biomarkers were predictive of conversion to AD from MCI, whereas WMH were predictive of conversion to MCI from cognitively normal. The predictive ability of WMH in the CNtoMCI group may be interpreted as some being on a different pathologic pathway, such as vascular cognitive impairment.

Adulthood cognitive trajectories over 26 years and brain health at 70 years of age: findings from the 1946 British Birth Cohort.

Few studies can address how adulthood cognitive trajectories relate to brain health in 70-year-olds. Participants (n = 468, 49% female) from the 1946 British birth cohort underwent 18F-Florbetapir PET/MRI. Cognitive function was measured in childhood (age 8 years) and across adulthood (ages 43, 53, 60-64 and 69 years) and was examined in relation to brain health markers of ß-amyloid (Aß) status, whole brain and hippocampal volume, and white matter hyperintensity volume (WMHV). Taking into account key contributors of adult cognitive decline including childhood cognition, those with greater Aß and WMHV at age 70 years had greater decline in word-list learning memory in the preceding 26 years, particularly after age 60. In contrast, those with smaller whole brain and hippocampal volume at age 70 years had greater decline in processing search speed, subtly manifest from age 50 years. Subtle changes in memory and processing speed spanning 26 years of adulthood were associated with markers of brain health at 70 years of age, consistent with detectable prodromal cognitive effects in early older age.

Life course, genetic, and neuropathological associations with brain age in the 1946 British Birth Cohort: a population-based study.

BACKGROUND: A neuroimaging-based biomarker termed the brain age is thought to reflect variability in the brain's ageing process and predict longevity. Using Insight 46, a unique narrow-age birth cohort, we aimed to examine potential drivers and correlates of brain age. METHODS: Participants, born in a single week in 1946 in mainland Britain, have had 24 prospective waves of data collection to date, including MRI and amyloid PET imaging at approximately 70 years old. Using MRI data from a previously defined selection of this cohort, we derived brain-predicted age from an established machine-learning model (trained on 2001 healthy adults aged 18-90 years); subtracting this from chronological age (at time of assessment) gave the brain-predicted age difference (brain-PAD). We tested associations with data from early life, midlife, and late life, as well as rates of MRI-derived brain atrophy. FINDINGS: Between May 28, 2015, and Jan 10, 2018, 502 individuals were assessed as part of Insight 46. We included 456 participants (225 female), with a mean chronological age of 70·7 years (SD 0·7; range 69·2 to 71·9). The mean brain-predicted age was 67·9 years (8·2, 46·3 to 94·3). Female sex was associated with a 5·4-year (95% CI 4·1 to 6·8) younger brain-PAD than male sex. An increase in brain-PAD was associated with increased cardiovascular risk at age 36 years (ß=2·3 [95% CI 1·5 to 3·0]) and 69 years (ß=2·6 [1·9 to 3·3]); increased cerebrovascular disease burden (1·9 [1·3 to 2·6]); lower cognitive performance (-1·3 [-2·4 to -0·2]); and increased serum neurofilament light concentration (1·2 [0·6 to 1·9]). Higher brain-PAD was associated with future hippocampal atrophy over the subsequent 2 years (0·003 mL/year [0·000 to 0·006] per 5-year increment in brain-PAD). Early-life factors did not relate to brain-PAD. Combining 12 metrics in a hierarchical partitioning model explained 33% of the variance in brain-PAD. INTERPRETATION: Brain-PAD was associated with cardiovascular risk, and imaging and biochemical markers of neurodegeneration. These findings support brain-PAD as an integrative summary metric of brain health, reflecting multiple contributions to pathological brain ageing, and which might have prognostic utility. FUNDING: Alzheimer's Research UK, Medical Research Council Dementia Platforms UK, Selfridges Group Foundation, Wolfson Foundation, Wellcome Trust, Brain Research UK, Alzheimer's Association.

Validation of the Alzheimer's disease-resemblance atrophy index in classifying and predicting progression in Alzheimer's disease.

Background: Automated tools for characterising dementia risk have the potential to aid in the diagnosis, prognosis, and treatment of Alzheimer's disease (AD). Here, we examined a novel machine learning-based brain atrophy marker, the AD-resemblance atrophy index (AD-RAI), to assess its test-retest reliability and further validate its use in disease classification and prediction. Methods: Age- and sex-matched 44 probable AD (Age: 69.13 ± 7.13; MMSE: 27-30) and 22 non-demented control (Age: 69.38 ± 7.21; MMSE: 27-30) participants were obtained from the Minimal Interval Resonance Imaging in Alzheimer's Disease (MIRIAD) dataset. Serial T1-weighted images (n = 678) from up to nine time points over a 2-year period, including 179 pairs of back-to-back scans acquired on same participants on the same day and 40 pairs of scans acquired at 2-week intervals were included. All images were automatically processed with AccuBrain® to calculate the AD-RAI. Its same-day repeatability and 2-week reproducibility were first assessed. The discriminative performance of AD-RAI was evaluated using the receiver operating characteristic curve, where DeLong's test was used to evaluate its performance against quantitative medial temporal lobe atrophy (QMTA) and hippocampal volume adjusted by intracranial volume (ICV)-proportions and ICV-residuals methods, respectively (HVR and HRV). Linear mixed-effects modelling was used to investigate longitudinal trajectories of AD-RAI and baseline AD-RAI prediction of cognitive decline. Finally, the longitudinal associations between AD-RAI and MMSE scores were assessed. Results: AD-RAI had excellent same-day repeatability and excellent 2-week reproducibility. AD-RAI's AUC (99.8%; 95%CI = [99.3%, 100%]) was equivalent to that of QMTA (96.8%; 95%CI = [92.9%, 100%]), and better than that of HVR (86.8%; 95%CI = [78.2%, 95.4%]) or HRV (90.3%; 95%CI = [83.0%, 97.6%]). While baseline AD-RAI was significantly higher in the AD group, it did not show detectable changes over 2 years. Baseline AD-RAI was negatively associated with MMSE scores and the rate of the change in MMSE scores over time. A negative longitudinal association was also found between AD-RAI values and the MMSE scores among AD patients. Conclusions: The AD-RAI represents a potential biomarker that may support AD diagnosis and be used to predict the rate of future cognitive decline in AD patients.

Reducing Behavioral Detection Thresholds per Electrode via Synchronous, Spatially-Dependent Intracortical Microstimulation.

Intracortical microstimulation (ICMS) has shown promise in restoring quality of life to patients suffering from paralysis, specifically when used in the primary somatosensory cortex (S1). However, these benefits can be hampered by long-term degradation of electrode performance due to the brain's foreign body response. Advances in microfabrication techniques have allowed for the development of neuroprostheses with subcellular electrodes, which are characterized by greater versatility and a less detrimental immune response during chronic use. These probes are hypothesized to enable more selective, higher-resolution stimulation of cortical tissue with long-term implants. However, microstimulation using physiologically relevant charges with these smaller-scale devices can damage electrode sites and reduce the efficacy of the overall device. Studies have shown promise in bypassing this limitation by spreading the stimulation charge between multiple channels in an implanted electrode array, but to our knowledge the usefulness of this strategy in laminar arrays with electrode sites spanning each layer of the cortex remains unexplored. To investigate the efficacy of simultaneous multi-channel ICMS in electrode arrays with stimulation sites spanning cortical depth, we implanted laminar electrode arrays in the primary somatosensory cortex of rats trained in a behavioral avoidance paradigm. By measuring detection thresholds, we were able to quantify improvements in ICMS performance using a simultaneous multi-channel stimulation paradigm. The charge required per site to elicit detection thresholds was halved when stimulating from two adjacent electrode sites, although the overall charge used by the implant was increased. This reduction in threshold charge was more pronounced when stimulating with more than two channels and lessened with greater distance between stimulating channels. Our findings suggest that these improvements are based on the synchronicity and polarity of each stimulus, leading us to conclude that these improvements in stimulation efficiency per electrode are due to charge summation as opposed to a summation of neural responses to stimulation. Additionally, the per-site charge reductions are seen regardless of the cortical depth of each utilized channel. This evocation of physiological detection thresholds with lower stimulation currents per electrode site has implications for the feasibility of stimulation regimes in future advanced neuroprosthetic devices, which could benefit from reducing the charge output per site.

Associations of ß-Amyloid and Vascular Burden With Rates of Neurodegeneration in Cognitively Normal Members of the 1946 British Birth Cohort.

BACKGROUND AND OBJECTIVES: The goals of this work were to quantify the independent and interactive associations of ß-amyloid (Aß) and white matter hyperintensity volume (WMHV), a marker of presumed cerebrovascular disease (CVD), with rates of neurodegeneration and to examine the contributions of APOE ε4 and vascular risk measured at different stages of adulthood in cognitively normal members of the 1946 British Birth Cohort. METHODS: Participants underwent brain MRI and florbetapir-Aß PET as part of Insight 46, an observational population-based study. Changes in whole-brain, ventricular, and hippocampal volume were directly measured from baseline and repeat volumetric T1 MRI with the boundary shift integral. Linear regression was used to test associations with baseline Aß deposition, baseline WMHV, APOE ε4, and office-based Framingham Heart Study Cardiovascular Risk Score (FHS-CVS) and systolic blood pressure (BP) at ages 36, 53, and 69 years. RESULTS: Three hundred forty-six cognitively normal participants (mean [SD] age at baseline scan 70.5 [0.6] years; 48% female) had high-quality T1 MRI data from both time points (mean [SD] scan interval 2.4 [0.2] years). Being Aß positive at baseline was associated with 0.87-mL/y faster whole-brain atrophy (95% CI 0.03, 1.72), 0.39-mL/y greater ventricular expansion (95% CI 0.16, 0.64), and 0.016-mL/y faster hippocampal atrophy (95% CI 0.004, 0.027), while each 10-mL additional WMHV at baseline was associated with 1.07-mL/y faster whole-brain atrophy (95% CI 0.47, 1.67), 0.31-mL/y greater ventricular expansion (95% CI 0.13, 0.60), and 0.014-mL/y faster hippocampal atrophy (95% CI 0.006, 0.022). These contributions were independent, and there was no evidence that Aß and WMHV interacted in their effects. There were no independent associations of APOE ε4 with rates of neurodegeneration after adjustment for Aß status and WMHV, no clear relationships between FHS-CVS or systolic BP and rates of neurodegeneration when assessed across the whole sample, and no evidence that FHS-CVS or systolic BP acted synergistically with Aß. DISCUSSION: Aß and presumed CVD have distinct and additive effects on rates of neurodegeneration in cognitively normal elderly. These findings have implications for the use of MRI measures as biomarkers of neurodegeneration and emphasize the importance of risk management and early intervention targeting both pathways.

Sex-related differences in whole brain volumes at age 70 in association with hyperglycemia during adult life.

Longitudinal studies of the relationship between hyperglycemia and brain health are rare and there is limited information on sex differences in associations. We investigated whether glycosylated hemoglobin (HbA1c) measured at ages of 53, 60-64 and 69 years, and cumulative glycemic index (CGI), a measure of cumulative glycemic burden, were associated with metrics of brain health in later life. Participants were from Insight 46, a substudy of the Medical Research Council National Survey of Health and Development (NSHD) who undertook volumetric MRI, florbetapir amyloid-PET imaging and cognitive assessments at ages of 69-71. Analyses were performed using linear and logistic regression as appropriate, with adjustment for potential confounders. We observed a sex interaction between HbA1c and whole brain volume (WBV) at all 3 time points. Following stratification of our sample, we observed that HbA1c at all ages, and CGI were positively associated with lower WBV exclusively in females. HbA1c (or CGI) was not associated with amyloid status, white matter hyperintensities (WMHs), hippocampal volumes (HV) or cognitive outcomes in either sex. Higher HbA1c in adulthood is associated with smaller WBV at 69-71 years in females but not in males. This suggests that there may be preferential target organ damage in the brain for females with hyperglycemia.

Closed-Loop, Cervical, Epidural Stimulation Elicits Respiratory Neuroplasticity after Spinal Cord Injury in Freely Behaving Rats.

Over half of all spinal cord injuries (SCIs) are cervical, which can lead to paralysis and respiratory compromise, causing significant morbidity and mortality. Effective treatments to restore breathing after severe upper cervical injury are lacking; thus, it is imperative to develop therapies to address this. Epidural stimulation has successfully restored motor function after SCI for stepping, standing, reaching, grasping, and postural control. We hypothesized that closed-loop stimulation triggered via healthy hemidiaphragm EMG activity has the potential to elicit functional neuroplasticity in spinal respiratory pathways after cervical SCI (cSCI). To test this, we delivered closed-loop, electrical, epidural stimulation (CLES) at the level of the phrenic motor nucleus (C4) for 3 d after C2 hemisection (C2HS) in freely behaving rats. A 2 × 2 Latin Square experimental design incorporated two treatments, C2HS injury and CLES therapy resulting in four groups of adult, female Sprague Dawley rats: C2HS + CLES (n = 8), C2HS (n = 6), intact + CLES (n = 6), intact (n = 6). In stimulated groups, CLES was delivered for 12-20 h/d for 3 d. After C2HS, 3 d of CLES robustly facilitated the slope of stimulus-response curves of ipsilesional spinal motor evoked potentials (sMEPs) versus nonstimulated controls. To our knowledge, this is the first demonstration of CLES eliciting respiratory neuroplasticity after C2HS in freely behaving animals. These findings suggest CLES as a promising future therapy to address respiratory deficiency associated with cSCI.

Loss and dispersion of superficial white matter in Alzheimer's disease: a diffusion MRI study.

Pathological cerebral white matter changes in Alzheimer's disease have been shown using diffusion tensor imaging. Superficial white matter changes are relatively understudied despite their importance in cortico-cortical connections. Measuring superficial white matter degeneration using diffusion tensor imaging is challenging due to its complex organizational structure and proximity to the cortex. To overcome this, we investigated diffusion MRI changes in young-onset Alzheimer's disease using standard diffusion tensor imaging and Neurite Orientation Dispersion and Density Imaging to distinguish between disease-related changes that are degenerative (e.g. loss of myelinated fibres) and organizational (e.g. increased fibre dispersion). Twenty-nine young-onset Alzheimer's disease patients and 22 healthy controls had both single-shell and multi-shell diffusion MRI. We calculated fractional anisotropy, mean diffusivity, neurite density index, orientation dispersion index and tissue fraction (1-free water fraction). Diffusion metrics were sampled in 15 a priori regions of interest at four points along the cortical profile: cortical grey matter, grey/white boundary, superficial white matter (1 mm below grey/white boundary) and superficial/deeper white matter (2 mm below grey/white boundary). To estimate cross-sectional group differences, we used average marginal effects from linear mixed effect models of participants' diffusion metrics along the cortical profile. The superficial white matter of young-onset Alzheimer's disease individuals had lower neurite density index compared to controls in five regions (superior and inferior parietal, precuneus, entorhinal and parahippocampus) (all P < 0.05), and higher orientation dispersion index in three regions (fusiform, entorhinal and parahippocampus) (all P < 0.05). Young-onset Alzheimer's disease individuals had lower fractional anisotropy in the entorhinal and parahippocampus regions (both P < 0.05) and higher fractional anisotropy within the postcentral region (P < 0.05). Mean diffusivity was higher in the young-onset Alzheimer's disease group in the parahippocampal region (P < 0.05) and lower in the postcentral, precentral and superior temporal regions (all P < 0.05). In the overlying grey matter, disease-related changes were largely consistent with superficial white matter findings when using neurite density index and fractional anisotropy, but appeared at odds with orientation dispersion and mean diffusivity. Tissue fraction was significantly lower across all grey matter regions in young-onset Alzheimer's disease individuals (all P < 0.001) but group differences reduced in magnitude and coverage when moving towards the superficial white matter. These results show that microstructural changes occur within superficial white matter and along the cortical profile in individuals with young-onset Alzheimer's disease. Lower neurite density and higher orientation dispersion suggests underlying fibres undergo neurodegeneration and organizational changes, two effects previously indiscernible using standard diffusion tensor metrics in superficial white matter.

Dissociable effects of APOE-ε4 and ß-amyloid pathology on visual working memory.

Although APOE-ε4 carriers are at significantly higher risk of developing Alzheimer's disease than non-carriers1, controversial evidence suggests that APOE-ε4 might confer some advantages, explaining the survival of this gene (antagonistic pleiotropy)2,3. In a population-based cohort born in one week in 1946 (assessed aged 69-71), we assessed differential effects of APOE-ε4 and ß-amyloid pathology (quantified using 18F-Florbetapir-PET) on visual working memory (object-location binding). In 398 cognitively normal participants, APOE-ε4 and ß-amyloid had opposing effects on object identification, predicting better and poorer recall respectively. ε4-carriers also recalled locations more precisely, with a greater advantage at higher ß-amyloid burden. These results provide evidence of superior visual working memory in ε4-carriers, showing that some benefits of this genotype are demonstrable in older age, even in the preclinical stages of Alzheimer's disease.