Conceptual and Measurement Challenges in Research on Cognitive Reserve

Cognitive reserve, broadly conceived, encompasses aspects of brain structure and function that optimize individual performance in the presence of injury or pathology. Reserve is defined as a feature of brain structure and/or function that modifies the relationship between injury or pathology and performance on neuropsychological tasks or clinical outcomes. Reserve is challenging to study for two reasons. The first is: reserve is a hypothetical construct, and direct measures of reserve are not available. Proxy variables and latent variable models are used to attempt to operationalize reserve. The second is: in vivo measures of neuronal pathology are not widely available. It is challenging to develop and test models involving a risk factor (injury or pathology), a moderator (reserve) and an outcome (performance or clinical status) when neither the risk factor nor the moderator are measured directly. We discuss approaches for quantifying reserve with latent variable models, with emphasis on their application in the analysis of data from observational studies. Increasingly latent variable models are used to generate composites of cognitive reserve based on multiple proxies. We review the theoretical and ontological status of latent variable modeling approaches to cognitive reserve, and suggest research strategies for advancing the field

Biological correlates of elevated soluble TREM2 in cerebrospinal fluid

Cerebrospinal fluid (CSF) soluble triggering receptor expressed on myeloid cells-2 (sTREM2) is an emerging biomarker of neuroinflammation in Alzheimer's disease (AD). Yet, sTREM2 expression has not been systematically evaluated in relation to concomitant drivers of neuroinflammation. While associations between sTREM2 and tau in CSF are established, we sought to determine additional biological correlates of CSF sTREM2 during the prodromal stages of AD by evaluating CSF Aβ species (Aβx-40), a fluid biomarker of blood-brain barrier integrity (CSF/plasma albumin ratio), and CSF biomarkers of neurodegeneration measured in 155 participants from the Vanderbilt Memory and Aging Project. A novel association between high CSF levels of both sTREM2 and Aβx-40 was observed and replicated in an independent dataset. Aβx-40 levels, as well as the CSF/plasma albumin ratio, explained additional and unique variance in sTREM2 levels above and beyond that of CSF biomarkers of neurodegeneration. The component of sTREM2 levels correlated with Aβx-40 levels best predicted future cognitive performance. We highlight potential contributions of Aβ homeostasis and blood-brain barrier integrity to elevated CSF sTREM2, underscoring novel biomarker associations relevant to disease progression and clinical outcome measures

Exploring common genetic contributors to neuroprotection from amyloid pathology

Preclinical Alzheimer’s disease describes some individuals who harbor Alzheimer’s pathologies but are asymptomatic. For this study, we hypothesized that genetic variation may help protect some individuals from Alzheimer’s-related neurodegeneration. We therefore conducted a genome-wide association study using 5,891,064 common variants to assess whether genetic variation modifies the association between baseline beta-amyloid, as measured by both cerebrospinal fluid and positron emission tomography, and neurodegeneration defined using MRI measures of hippocampal volume. We combined and jointly analyzed genotype, biomarker, and neuroimaging data from non-Hispanic white individuals who were enrolled in four longitudinal aging studies (n=1065). Using regression models, we examined the interaction between common genetic variants (Minor Allele Frequency > 0.01), including APOE-ε4 and APOE-ε2, and baseline cerebrospinal levels of amyloid (CSF Aβ42) on baseline hippocampal volume and the longitudinal rate of hippocampal atrophy. For targeted replication of top findings, we analyzed an independent dataset (n=808) where amyloid burden was assessed by Pittsburgh Compound B ([{11}^C]-PiB) PET. In this study, we found that APOE-ε4 modified the association between baseline CSF Aβ42 and hippocampal volume such that APOE-ε4 carriers showed more rapid atrophy, particularly in the presence of enhanced amyloidosis. We also identified a novel locus on chromosome 3 that interacted with baseline CSF Aβ42. Minor allele carriers of rs62263260, an expression quantitative trait locus for the SEMA5B gene, (p=1.46x10^{-8}; 3:122675327) had more rapid neurodegeneration when amyloid burden was high and slower neurodegeneration when amyloid was low. The rs62263260 x amyloid interaction on longitudinal change in hippocampal volume was replicated in an independent dataset (p=0.0112) where amyloid burden was assessed by PET. In addition to supporting the established interaction between APOE and amyloid on neurodegeneration, our study identifies a novel locus that modifies the association between beta-amyloid and hippocampal atrophy. Annotation results may implicate SEMA5B, a gene involved in synaptic pruning and axonal guidance, as a high-quality candidate for functional confirmation and future mechanistic analysis

Visual and Verbal Serial List Learning in Patients with Statistically-Determined Mild Cognitive Impairment.

Background and Objective: Prior research with patients with mild cognitive impairment (MCI) suggests that visual versus verbal episodic memory test performance may be more sensitive to emergent illness. However, little research has examined visual versus verbal episodic memory performance as related to MCI subtypes. Research Design and Methods: Patients were diagnosed with non-MCI, amnestic MCI (aMCI), and combined mixed/dysexecutive MCI (mixed/dys MCI). Visual and verbal episodic memory were assessed with the Brief Visuospatial Memory Test-Revised (BVMT-R) and the 12-word Philadelphia (repeatable) Verbal Learning Test (P[r]VLT), respectively. Results: BVMT-R and P(r)VLT scores yielded similar between-group patterns of performance. Non-MCI patients scored better than other groups on all parameters. aMCI and mixed/dys MCI did not differ on immediate or delayed free recall. Both delayed BVMT-R and P(r)VLT recognition test performance dissociated all three groups. Logistic regression analyses found that BVMT-R delayed free recall and delayed recognition scores correctly classified more patients with MCI (75.40%) than analogous P(r)VLT scores (66.20%). Visual versus verbal memory within-group analyses found no differences among non-MCI patients; P(r)VLT immediate free recall was worse among aMCI patients, but BVMT-R immediate free recall and delayed recognition were worse among mixed/dys MCI patients. Discussion and Implications: Between-group analyses found convergent patterns of performance such that both tests identified elements of amnesia. However, logistic and within-group analyses found differing performance patterns suggesting that impaired visual episodic memory performance may be specific to emergent illness in mixed/dys MCI. Complementary but divergent neurocognitive networks may underlie visual versus verbal episodic memory performance in some patients with MCI

PLD3 is a neuronal lysosomal phospholipase D associated with β-amyloid plaques and cognitive function in Alzheimer\u27s disease.

Phospholipase D3 (PLD3) is a protein of unclear function that structurally resembles other members of the phospholipase D superfamily. A coding variant in this gene confers increased risk for the development of Alzheimer\u27s disease (AD), although the magnitude of this effect has been controversial. Because of the potential significance of this obscure protein, we undertook a study to observe its distribution in normal human brain and AD-affected brain, determine whether PLD3 is relevant to memory and cognition in sporadic AD, and to evaluate its molecular function. In human neuropathological samples, PLD3 was primarily found within neurons and colocalized with lysosome markers (LAMP2, progranulin, and cathepsins D and B). This colocalization was also present in AD brain with prominent enrichment on lysosomal accumulations within dystrophic neurites surrounding β-amyloid plaques. This pattern of protein distribution was conserved in mouse brain in wild type and the 5xFAD mouse model of cerebral β-amyloidosis. We discovered PLD3 has phospholipase D activity in lysosomes. A coding variant in PLD3 reported to confer AD risk significantly reduced enzymatic activity compared to wild-type PLD3. PLD3 mRNA levels in the human pre-frontal cortex inversely correlated with β-amyloid pathology severity and rate of cognitive decline in 531 participants enrolled in the Religious Orders Study and Rush Memory and Aging Project. PLD3 levels across genetically diverse BXD mouse strains and strains crossed with 5xFAD mice correlated strongly with learning and memory performance in a fear conditioning task. In summary, this study identified a new functional mammalian phospholipase D isoform which is lysosomal and closely associated with both β-amyloid pathology and cognition

Whole blood transcript and protein abundance of the vascular endothelial growth factor family relate to cognitive performance

The vascular endothelial growth factor (VEGF) family of genes has been implicated in the clinical development of Alzheimer's Disease (AD). A previous study identified associations between gene expression of VEGF family members in the prefrontal cortex and cognitive performance and AD pathology. This study explored if those associations were also observed in the blood. Consistent with previous observations in brain tissue, higher blood gene expression of placental growth factor (PGF) was associated with a faster rate of memory decline (p=0.04). Higher protein abundance of FMS-related receptor tyrosine kinase 4 (FLT4) in blood was associated with biomarker levels indicative of lower amyloid and tau pathology, opposite the direction observed in brain. Also, higher gene expression of VEGFB in blood was associated with better baseline memory (p=0.008). Notably, we observed that higher gene expression of VEGFB in blood was associated with lower expression of VEGFB in the brain (r=-0.19, p=0.02). Together, these results suggest that the VEGFB, FLT4, and PGF alterations in the AD brain may be detectable in the blood compartment

A prospective, multicenter, phase I matched-comparison group trial of safety, pharmacokinetics, and preliminary efficacy of riluzole in patients with traumatic spinal cord injury.

A prospective, multicenter phase I trial was undertaken by the North American Clinical Trials Network (NACTN) to investigate the pharmacokinetics and safety of, as well as obtain pilot data on, the effects of riluzole on neurological outcome in acute spinal cord injury (SCI). Thirty-six patients, with ASIA impairment grades A-C (28 cervical and 8 thoracic) were enrolled at 6 NACTN sites between April 2010 and June 2011. Patients received 50 mg of riluzole PO/NG twice-daily, within 12 h of SCI, for 14 days. Peak and trough plasma concentrations were quantified on days 3 and 14. Peak plasma concentration (Cmax) and systemic exposure to riluzole varied significantly between patients. On the same dose basis, Cmax did not reach levels comparable to those in patients with amyotrophic lateral sclerosis. Riluzole plasma levels were significantly higher on day 3 than on day 14, resulting from a lower clearance and a smaller volume of distribution on day 3. Rates of medical complications, adverse events, and progression of neurological status were evaluated by comparison with matched patients in the NACTN SCI Registry. Medical complications in riluzole-treated patients occurred with incidences similar to those in patients in the comparison group. Mild-to-moderate increase in liver enzyme and bilirubin levels were found in 14-70% of patients for different enzymes. Three patients had borderline severe elevations of enzymes. No patient had elevated bilirubin on day 14 of administration of riluzole. There were no serious adverse events related to riluzole and no deaths. The mean motor score of 24 cervical injury riluzole-treated patients gained 31.2 points from admission to 90 days, compared to 15.7 points for 26 registry patients, a 15.5-point difference (p=0.021). Patients with cervical injuries treated with riluzole had more-robust conversions of impairment grades to higher grades than the comparison group

Non‐canonical autophagy functions of ATG16L1 in epithelial cells limit lethal infection by influenza A virus

Influenza A virus (IAV) and SARS-CoV-2 (COVID-19) cause pandemic infections where cytokine storm syndrome and lung inflammation lead to high mortality. Given the high social and economic cost of respiratory viruses, there is an urgent need to understand how the airways defend against virus infection. Here we use mice lacking the WD and linker domains of ATG16L1 to demonstrate that ATG16L1-dependent targeting of LC3 to single-membrane, non-autophagosome compartments - referred to as non-canonical autophagy - protects mice from lethal IAV infection. Mice with systemic loss of non-canonical autophagy are exquisitely sensitive to low-pathogenicity IAV where extensive viral replication throughout the lungs, coupled with cytokine amplification mediated by plasmacytoid dendritic cells, leads to fulminant pneumonia, lung inflammation and high mortality. IAV was controlled within epithelial barriers where non-canonical autophagy reduced IAV fusion with endosomes and activation of interferon signalling. Conditional mouse models and ex vivo analysis showed that protection against IAV infection of lung was independent of phagocytes and other leucocytes. This establishes non-canonical autophagy in airway epithelial cells as a novel innate defence that restricts IAV infection and lethal inflammation at respiratory surfaces

Evaluation of Mean Shift, ComBat, and CycleGAN for Harmonizing Brain Connectivity Matrices Across Sites

Connectivity matrices derived from diffusion MRI (dMRI) provide an interpretable and generalizable way of understanding the human brain connectome. However, dMRI suffers from inter-site and between-scanner variation, which impedes analysis across datasets to improve robustness and reproducibility of results. To evaluate different harmonization approaches on connectivity matrices, we compared graph measures derived from these matrices before and after applying three harmonization techniques: mean shift, ComBat, and CycleGAN. The sample comprises 168 age-matched, sex-matched normal subjects from two studies: the Vanderbilt Memory and Aging Project (VMAP) and the Biomarkers of Cognitive Decline Among Normal Individuals (BIOCARD). First, we plotted the graph measures and used coefficient of variation (CoV) and the Mann-Whitney U test to evaluate different methods' effectiveness in removing site effects on the matrices and the derived graph measures. ComBat effectively eliminated site effects for global efficiency and modularity and outperformed the other two methods. However, all methods exhibited poor performance when harmonizing average betweenness centrality. Second, we tested whether our harmonization methods preserved correlations between age and graph measures. All methods except for CycleGAN in one direction improved correlations between age and global efficiency and between age and modularity from insignificant to significant with p-values less than 0.05.Comment: 11 pages, 5 figures, to be published in SPIE Medical Imaging 2024: Image Processin