Faculty Bibliography

Alzheimer's disease (AD) is a devastating, age-associated neurodegenerative disorder and the most common cause of dementia. The clinical continuum of AD spans from preclinical disease to subjective cognitive decline, mild cognitive impairment, and dementia stages (mild, moderate, and severe). Neuropathologically, AD is defined by the accumulation of amyloid β (Aβ) into extracellular plaques in the brain parenchyma and in the cerebral vasculature, and by abnormally phosphorylated tau that accumulates intraneuronally forming neurofibrillary tangles (NFTs). Development of treatment approaches that prevent or even reduce the cognitive decline because of AD has been slow compared to other major causes of death. Recently, the United States Food and Drug Administration gave full approval to 2 different Aβ-targeting monoclonal antibodies. However, this breakthrough disease modifying approach only applies to a limited subset of patients in the AD continuum and there are stringent eligibility criteria. Furthermore, these approaches do not prevent progression of disease, because other AD-related pathologies, such as NFTs, are not directly targeted. A non-mutually exclusive alternative is to address lifestyle interventions that can help reduce the risk of AD and AD-related dementias (ADRD). It is estimated that addressing such modifiable risk factors could potentially delay up to 40% of AD/ADRD cases. In this review, we discuss some of the many modifiable risk factors that may be associated with prevention of AD/ADRD and/or increasing brain resilience, as well as other factors that may interact with these modifiable risk factors to influence AD/ADRD progression. ANN NEUROL 2024.

PURPOSE/OBJECTIVE:The pathological hallmarks of Alzheimer's disease (AD), amyloid, tau, and associated neurodegeneration, are present in the cortical gray matter (GM) years before symptom onset, and at significantly greater levels in carriers of the apolipoprotein E4 (APOE4) allele. Their respective biomarkers, A/T/N, have been found to correlate with aspects of brain biochemistry, measured with magnetic resonance spectroscopy (MRS), indicating a potential for MRS to augment the A/T/N framework for staging and prediction of AD. Unfortunately, the relationships between MRS and A/T/N biomarkers are unclear, largely due to a lack of studies examining them in the context of the spatial and temporal model of T/N progression. Advanced MRS acquisition and post-processing approaches have enabled us to address this knowledge gap and test the hypotheses, that glutamate-plus-glutamine (Glx) and N-acetyl-aspartate (NAA), metabolites reflecting synaptic and neuronal health, respectively, measured from regions on the Braak stage continuum, correlate with: (i) cerebrospinal fluid (CSF) p-tau181 level (T), and (ii) hippocampal volume or cortical thickness of parietal lobe GM (N). We hypothesized that these correlations will be moderated by Braak stage and APOE4 genotype. METHODS:We conducted a retrospective imaging study of 34 cognitively unimpaired elderly individuals who received APOE4 genotyping and lumbar puncture from pre-existing prospective studies at the NYU Grossman School of Medicine between October 2014 and January 2019. Subjects returned for their imaging exam between April 2018 and February 2020. Metabolites were measured from the left hippocampus (Braak II) using a single-voxel semi-adiabatic localization by adiabatic selective refocusing sequence; and from the bilateral posterior cingulate cortex (PCC; Braak IV), bilateral precuneus (Braak V), and bilateral precentral gyrus (Braak VI) using a multi-voxel echo-planar spectroscopic imaging sequence. Pearson and Spearman correlations were used to examine the relationships between absolute levels of choline, creatine, myo-inositol, Glx, and NAA and CSF p-tau181, and between these metabolites and hippocampal volume or parietal cortical thicknesses. Covariates included age, sex, years of education, Fazekas score, and months between CSF collection and MRI exam. RESULTS:There was a direct correlation between hippocampal Glx and CSF p-tau181 in APOE4 carriers (Pearson's r = 0.76, p = 0.02), but not after adjusting for covariates. In the entire cohort, there was a direct correlation between hippocampal NAA and hippocampal volume (Spearman's r = 0.55, p = 0.001), even after adjusting for age and Fazekas score (Spearman's r = 0.48, p = 0.006). This relationship was observed only in APOE4 carriers (Pearson's r = 0.66, p = 0.017), and was also retained after adjustment (Pearson's r = 0.76, p = 0.008; metabolite-by-carrier interaction p = 0.03). There were no findings in the PCC, nor in the negative control (late Braak stage) regions of the precuneus and precentral gyrus. CONCLUSIONS:Our findings are in line with the spatially- and temporally-resolved Braak staging model of pathological severity in which the hippocampus is affected earlier than the PCC. The correlations, between MRS markers of synaptic and neuronal health and, respectively, T and N pathology, were found exclusively within APOE4 carriers, suggesting a connection with AD pathological change, rather than with normal aging. We therefore conclude that MRS has the potential to augment early A/T/N staging, with the hippocampus serving as a more sensitive MRS target compared to the PCC.

We elucidated the molecular fingerprint of vulnerable excitatory neurons within select cortical lamina of individuals with Down syndrome (DS) for mechanistic understanding and therapeutic potential that also informs Alzheimer's disease (AD) pathophysiology. Frontal cortex (BA9) layer III (L3) and layer V (L5) pyramidal neurons were microisolated from postmortem human DS and age- and sex-matched controls (CTR) to interrogate differentially expressed genes (DEGs) and key biological pathways relevant to neurodegenerative programs. We identified > 2300 DEGs exhibiting convergent dysregulation of gene expression in both L3 and L5 pyramidal neurons in individuals with DS versus CTR subjects. DEGs included over 100 triplicated human chromosome 21 genes in L3 and L5 neurons, demonstrating a trisomic neuronal karyotype in both laminae. In addition, thousands of other DEGs were identified, indicating gene dysregulation is not limited to trisomic genes in the aged DS brain, which we postulate is relevant to AD pathobiology. Convergent L3 and L5 DEGs highlighted pertinent biological pathways and identified key pathway-associated targets likely underlying corticocortical neurodegeneration and related cognitive decline in individuals with DS. Select key DEGs were interrogated as potential hub genes driving dysregulation, namely the triplicated DEGs amyloid precursor protein (APP) and superoxide dismutase 1 (SOD1), along with key signaling DEGs including mitogen activated protein kinase 1 and 3 (MAPK1, MAPK3) and calcium calmodulin dependent protein kinase II alpha (CAMK2A), among others. Hub DEGs determined from multiple pathway analyses identified potential therapeutic candidates for amelioration of cortical neuron dysfunction and cognitive decline in DS with translational relevance to AD.

Cerebral amyloid angiopathy (CAA) is characterized by amyloid beta (Aβ) deposition in cerebrovasculature. It is prevalent with aging and Alzheimer's disease (AD), associated with intracerebral hemorrhage, and contributes to cognitive deficits. To better understand molecular mechanisms, CAA(+) and CAA(-) vessels were microdissected from paraffin-embedded autopsy temporal cortex of age-matched Control (n = 10), mild cognitive impairment (MCI; n = 4), and sporadic AD (n = 6) cases, followed by label-free quantitative mass spectrometry. 257 proteins were differentially abundant in CAA(+) vessels compared to neighboring CAA(-) vessels in MCI, and 289 in AD (p < 0.05, fold-change > 1.5). 84 proteins changed in the same direction in both groups, and many changed in the same direction among proteins significant in at least one group (p < 0.0001, R² = 0.62). In CAA(+) vessels, proteins significantly increased in both AD and MCI were particularly associated with collagen-containing extracellular matrix, while proteins associated with ribonucleoprotein complex were significantly decreased in both AD and MCI. In neighboring CAA(-) vessels, 61 proteins were differentially abundant in MCI, and 112 in AD when compared to Control cases. Increased proteins in CAA(-) vessels were associated with extracellular matrix, external encapsulating structure, and collagen-containing extracellular matrix in MCI; collagen trimer in AD. Twenty two proteins were increased in CAA(-) vessels of both AD and MCI. Comparison of the CAA proteome with published amyloid-plaque proteomic datasets identified many proteins similarly enriched in CAA and plaques, as well as a protein subset hypothesized as preferentially enriched in CAA when compared to plaques. SEMA3G emerged as a CAA specific marker, validated immunohistochemically and with correlation to pathology levels (p < 0.0001; R² = 0.90). Overall, the CAA(-) vessel proteomes indicated changes in vessel integrity in AD and MCI in the absence of Aβ, and the CAA(+) vessel proteome was similar in MCI and AD, which was associated with vascular matrix reorganization, protein translation deficits, and blood brain barrier breakdown.

This review highlights a key role of the serotonergic system in brain development and in distortions of normal brain development in early stages of fetal life resulting in cascades of abnormalities, including defects of neurogenesis, neuronal migration, neuronal growth, differentiation, and arborization, as well as defective neuronal circuit formation in the cortex, subcortical structures, brainstem, and cerebellum of autistic subjects. In autism, defects in regulation of neuronal growth are the most frequent and ubiquitous developmental changes associated with impaired neuron differentiation, smaller size, distorted shape, loss of spatial orientation, and distortion of cortex organization. Common developmental defects of the brain in autism include multiregional focal dysplastic changes contributing to local neuronal circuit distortion, epileptogenic activity, and epilepsy. There is a discrepancy between more than 500 reports demonstrating the contribution of the serotonergic system to autism's behavioral anomalies, highlighted by lack of studies of autistic subjects' brainstem raphe nuclei, the center of brain serotonergic innervation, and of the contribution of the serotonergic system to the diagnostic features of autism spectrum disorder (ASD). Discovery of severe fetal brainstem auditory system neuronal deficits and other anomalies leading to a spectrum of hearing deficits contributing to a cascade of behavioral alterations, including deficits of social and verbal communication in individuals with autism, is another argument to intensify postmortem studies of the type and topography of, and the severity of developmental defects in raphe nuclei and their contribution to abnormal brain development and to the broad spectrum of functional deficits and comorbid conditions in ASD.

APOE^ε4 is the major genetic risk factor for sporadic Alzheimer's disease (AD). Although APOE^ε4 is known to promote Aβ pathology, recent data also support an effect of APOE polymorphism on phosphorylated Tau (pTau) pathology. To elucidate these potential effects, the pTau interactome was analyzed across APOE genotypes in the frontal cortex of 10 advanced AD cases (n = 5 APOE^ε3/ε3 and n = 5 APOE^ε4/ε4), using a combination of anti-pTau pS396/pS404 (PHF1) immunoprecipitation (IP) and mass spectrometry (MS). This proteomic approach was complemented by an analysis of anti-pTau PHF1 and anti-Aβ 4G8 immunohistochemistry, performed in the frontal cortex of 21 advanced AD cases (n = 11 APOE^ε3/ε3 and n = 10 APOE^ε4/ε4). Our dataset includes 1130 and 1330 proteins enriched in IP_PHF1 samples from APOE^ε3/ε3 and APOE^ε4/ε4 groups (fold change ≥ 1.50, IP_PHF1 vs IP_{IgG ctrl}). We identified 80 and 68 proteins as probable pTau interactors in APOE^ε3/ε3 and APOE^ε4/ε4 groups, respectively (SAINT score ≥ 0.80; false discovery rate (FDR) ≤ 5%). A total of 47/80 proteins were identified as more likely to interact with pTau in APOE^ε3/ε3 vs APOE^ε4/ε4 cases. Functional enrichment analyses showed that they were significantly associated with the nucleoplasm compartment and involved in RNA processing. In contrast, 35/68 proteins were identified as more likely to interact with pTau in APOE^ε4/ε4 vs APOE^ε3/ε3 cases. They were significantly associated with the synaptic compartment and involved in cellular transport. A characterization of Tau pathology in the frontal cortex showed a higher density of plaque-associated neuritic crowns, made of dystrophic axons and synapses, in APOE^ε4 carriers. Cerebral amyloid angiopathy was more frequent and severe in APOE^ε4/ε4 cases. Our study supports an influence of APOE genotype on pTau-subcellular location in AD. These results suggest a facilitation of pTau progression to Aβ-affected brain regions in APOE^ε4 carriers, paving the way to the identification of new therapeutic targets.

BACKGROUND AND OBJECTIVES/OBJECTIVE:Chronic systemic inflammation has been hypothesized to be a mechanistic factor leading to post-acute cognitive dysfunction after COVID-19. However, little data exist evaluating longitudinal inflammatory markers. METHODS:We conducted a secondary analysis of data collected from the CONTAIN randomized trial of convalescent plasma in patients hospitalized for COVID-19, including patients who completed an 18-month assessment of cognitive symptoms and PROMIS Global Health questionnaires. Patients with pre-COVID-19 dementia/cognitive abnormalities were excluded. Trajectories of serum cytokine panels, D-dimer, fibrinogen, C-reactive peptide (CRP), ferritin, lactate dehydrogenase (LDH), and absolute neutrophil counts (ANCs) were evaluated over 18 months using repeated measures and Friedman nonparametric tests. The relationships between the area under the curve (AUC) for each inflammatory marker and 18-month cognitive and global health outcomes were assessed. RESULTS:< 0.05), with the exception of IL-1β, which remained stable over time. There were no significant associations between the AUC for any inflammatory marker and 18-month cognitive symptoms, any neurologic symptom, or PROMIS Global Physical or Mental health T-scores. Receipt of convalescent plasma was not associated with any outcome measure. DISCUSSION/CONCLUSIONS:At 18 months posthospitalization for COVID-19, cognitive abnormalities were reported in 27% of patients, and below average PROMIS Global Mental and Physical Health scores occurred in 24% and 51%, respectively. However, there were no associations with measured inflammatory markers, which decreased over time.

BACKGROUND:The choroid plexus (ChP), a densely vascularized structure, has drawn increasing attention for its involvement in brain homeostasis and waste clearance. While the volumetric changes have been explored in many imaging studies, few studies have investigated the vascular degeneration associated with aging in the ChP. PURPOSE/OBJECTIVE:To investigate the sub-structural characteristics of the ChP, particularly the vascular compartment using high-resolution 7T imaging enhanced with Ferumoxytol, an ultrasmall super-paramagnetic iron oxide, which greatly increase the susceptibility contrast for vessels. STUDY TYPE/METHODS:Prospective. SUBJECTS/METHODS:Forty-nine subjects without neurological disorders (age: 21-80 years; 42 ± 17 years; 20 females). FIELD STRENGTH/SEQUENCE/UNASSIGNED:7-T with 2D and 3D T2* GRE, 3D MPRAGE T1, 2D TSE T2, and 2D FLAIR. ASSESSMENT/RESULTS:ratio) and susceptibility change (Δχ) induced by Ferumoxytol were analyzed on 3D GRE-derived susceptibility-weighted imaging and quantitative susceptibility mapping, respectively. STATISTICAL TESTS/METHODS:Independent t-test, Mann-Whitney U test, and Chi-square test were utilized for group comparisons. The relationship between age and ChP's vascular alterations was examined using Pearson's correlation. Intra-class coefficient was calculated for inter-observer agreement. A P value <0.05 was considered statistically significant. RESULTS:2D GRE images demonstrated superior contrast and accurate delineation of ChP substructures (ICC = 0.86). Older subjects exhibited a significantly smaller vascular density (16.5 ± 4.34%) and lower Δχ (22.10 ± 12.82 ppb) compared to younger subjects (24.85 ± 6.84% and 34.64 ± 12.69 ppb). Vascular density and mean Δχ within the ChP negatively correlated with age (r = -0.48, and r = -0.45). DATA CONCLUSION/CONCLUSIONS:Ferumoxytol-enhanced 7T images can demonstrate ChP alterations in elderly with decreased vascular density and expansion of nonvascular compartment. EVIDENCE LEVEL/METHODS:1 TECHNICAL EFFICACY: Stage 2.