Outside-in induction of the IFITM3 trafficking system by infections, including SARS-CoV-2, in the pathobiology of Alzheimer's disease.

BACKGROUND: IFITM3 is a viral restriction protein that enables sequestration of viral particles and subsequent trafficking to lysosomes. Recently, IFITM3 upregulation was found to induce gamma - secretase activity and the production of amyloid beta. The purpose of this study was to determine whether dysregulation of IFITM3-dependent pathways was present in neurons and peripheral immune cells donated by AD patients. As a secondary aim, we sought to determine whether these perturbations could be induced by viruses, including SARS-CoV-2. METHODS: Gene set enrichment analyses (GSEA) previously performed on publicly available transcriptomic data from tissues donated by AD patients were screened for enriched pathways containing IFITM3. Subsequently, signature containing IFITM3, derived from entorhinal cortex (EC) neurons containing neurofibrillary tangles (NFT) was screened for overlap with curated, publicly available, viral infection-induced gene signatures (including SARS-CoV-2). RESULTS: GSEA determined that IFITM3 gene networks are significantly enriched both in CNS sites (entorhinal and hippocampal cortices) and in peripheral blood mononuclear cells (PBMCs) donated by AD patients. Overlap screening revealed that IFITM3 signatures are induced by several viruses, including SARS-CoV, MERS-CoV, SARS-CoV-2 and HIV-1 (adjusted p-value <0.001; Enrichr Database). DISCUSSION: A data-driven analysis of AD tissues revealed IFITM3 gene signatures both in the CNS and in peripheral immune cells. GSEA revealed that an IFITM3 derived gene signature extracted from EC/NFT neurons overlapped with those extracted from publicly available viral infection datasets, including SARS-CoV-2. Our results are in line with currently emerging evidence on IFITM3's role in AD, and SARS-CoV-2's potential contribution in the setting of an expanded antimicrobial protection hypothesis.

Double hit viral parasitism, polymicrobial CNS residency and perturbed proteostasis in Alzheimer's disease: A data driven, in silico analysis of gene expression data.

The aim of this study was to determine the interaction of peripheral immunity vs. the CNS in the setting of AD pathogenesis at the transcriptomic level in a data driven manner. For this purpose, publicly available gene expression data from the GEO Datasets repository. We performed differential gene expression and functional enrichment analyses were performed on the five retrieved studies: (a) three hippocampal cortex (HC) studies (b) one study of peripheral blood mononuclear cells (PBMC) and (c) one involving neurofibrillary tangle - containing neurons of the entorhinal cortex (NFT EC). Subsequently, BLAST was used to determine protein conservation between human proteins vs. microbial, whereas putative protein / oligopeptide antigenicity were determined via RANKPep. Gene ontology and pathway analyses revealed significantly enriched viral parasitism pathways in both PBMC and NFT - EC datasets, mediated by ribosomal protein families and epigenetic regulators. Among these, a salient viral pathway referred to Influenza A infection. NFT - EC annotations included leukocyte chemotaxis and immune response pathways. All datasets were significantly enriched for infectious pathways, as well as pathways involved in impaired proteostasis and non - phagocytic cell phagosomal cascades. In conclusion, our in silico analysis outlined an ad hoc model of AD pathophysiology in which double hit (PBMC and NFT-EC) viral parasitism is mediated by eukaryotic translational hijacking, and may be further implicated by impaired immune responses. Overall, our results overlap with the antimicrobial protection hypothesis of AD pathogenesis and support the notion of a pathogen - driven etiology.

The effect of menarche age, parity and lactation on bone mineral density in premenopausal ambulatory multiple sclerosis patients.

Although pregnancy and breast-feeding do not have any deleterious effect on disease activity in female multiple sclerosis (MS) patients, their role on bone mineral density (BMD) and osteoporosis risk is unknown. We investigated the role of age at menarche, parity and lactation on BMD expressed as percentage of the mean BMD (%BMD) in 46 pre-menopausal ambulatory female MS patients using dual-energy X-ray absorptiometry (DXA) scans in lumbar spine (LS) and hip. MS female patients with age at menarche ≥13 years old had reduced %BMD compared to those with menarche age <13 years (95.2±10.7 vs 102.1±13.3, p=0.05 in LS; 90.5±12.6 vs 99.8±12.6, p=0.02 in hip). Parity did not result in any statistically significant changes in either LS or hip. Patients that breastfed their offspring compared to those that did not had significantly lower BMD in both LS (93.9±9.3 vs 110.7±15.6, p=0.004) and hip (91.6±10.7 vs 105.6±15.3, p=0.02). MS female patients with menarche at age≥13 years and those who breastfed their offspring may have reduced BMD. Larger studies are needed to verify these findings and establish a definite role of menarche age and breast feeding with BMD.

Body composition in ambulatory patients with multiple sclerosis.

The aim of this study was to compare between ambulatory patients with multiple sclerosis (MS) and control subjects, bone mineral density (BMD), and body composition, that is, percent of bone minerals (M%), fat (F%), and remaining substances (L%). Total body composition and BMD were measured by dual-energy X-ray absorptiometry in 68 patients with definite MS and Expanded Disability Status Scale (EDSS) score ≤ 6.5 (41 females and 27 males) and 114 control individuals (72 females and 42 males). The amount of F%, L%, M%, and BMD in the whole body, arms, and trunk was not statistically different between MS patients (males and females) and controls, except in the lower extremities of female patients where there was increased F% and reduced L% compared with controls. There were no correlations between F%, L%, M%, and BMD at any anatomic region with EDSS or the cumulative corticosteroid dose. The reduced L% in the lower extremities of female patients suggests a possible increased subsequent risk of osteoporosis in the legs. Brief steroid courses administered during disease exacerbations in ambulatory MS patients did not result in obvious adverse consequences.

Vitamin D receptor gene polymorphisms in multiple sclerosis patients in northwest Greece.

BACKGROUND: Polymorphisms of the vitamin D receptor (VDR) gene have been linked to both multiple sclerosis (MS) and osteoporosis. We examined the frequency of the Taq-I and Bsm-I polymorphisms of the vitamin D receptor (VDR) gene in 69 patients with MS and 81 age and sex-matched healthy individuals. Genotyping of Taq-I (rs731236) and Bsm-I (rs1544410) was performed using TaqMan SNP Genotyping Assay. All patients and controls had determination of body mass index (BMI), bone mineral density (BMD) and smoking history. RESULTS: The mean age of patients was 39 ± 10.5 years compared to 38.7 ± 10.7 years of the controls (p = 0.86), the BMI was 24.8 ± 4.2 kg/m2 compared to 25.7 ± 4.8 kg/m2 of the controls (p = 0.23), the BMD in the lumbar spine 0.981 ± 0.15 compared to 1.025 ± 013 of the controls (p = 0.06) and the total hip BMD was 0.875 ± 0.14 compared to 0.969 ± 0.12 of the controls (p < 0.001). There were no differences of the Taq-I (TT, CT, CC) and Bsm-I genotypes (GG, GA, AA) and allelic frequencies between MS and control individuals. Multivariate analysis also failed to show any association of the Taq-I and Bsm-I polymorphisms and MS or sex, BMI, BMD and smoking history. CONCLUSIONS: This study suggests that the Taq-I and Bsm-I polymorphisms of the VDR gene are not associated with MS risk, BMI or BMD in the Greek population studied.

Bone mineral density in ambulatory patients with multiple sclerosis.

Multiple sclerosis (MS) may be associated with reduced bone mass and higher frequency of osteoporosis. Femoral and spinal bone mineral density (BMD) in 70 ambulatory MS patients (46 females and 24 males) was compared with 100 sex-, age-, and BMI-matched control individuals. BMD was reduced in male patients (lumbar spine 0.976 ± 0.114 g/cm(2) compared with 1.059 ± 0.147 g/cm(2) in controls, p = 0.024, total hip 0.946 ± 0.136 g/cm(2) compared to 1.036 ± 0.118 g/cm(2) in controls, p = 0.008, femoral neck 0.812 ± 0.136 g/cm(2) compared with 0.887 ± 0.135 g/cm(2) in controls p = 0.042), and only in the total hip in female patients (0.88 ± 0.127 g/cm(2) compared with 0.935 ± 0.112 g/cm(2) in controls, p = 0.018). Multivariate analysis demonstrated that the predominantly affected site was the hip. MS patients exhibit increased frequency of low bone mass compared with controls. Further studies should assess the etiologic factors and employ appropriate therapies.

Lateral medullary ischaemic events in young adults with hypoplastic vertebral artery.

OBJECTIVE: To present three cases of young adults with lateral medullary ischaemic events associated with a hypoplastic vertebral artery (VA). All three patients had two additional atherosclerotic or non-atherosclerotic risk factors for stroke. PATIENTS AND METHODS: One female, aged 40 years, and two males, aged 38 and 37 years, each with two risk factors for stroke, presented to the emergency department with acute onset of symptoms and findings consistent with lateral medullary syndrome. All three patients underwent emergency CT scan of the brain followed by MRI and magnetic resonance angiography (MRA). RESULTS: The CT scans were negative in all patients. MRI revealed a lateral medullary lesion in only one patient. All three patients had a hypoplastic VA ipsilateral to the clinical ischaemic event on MRA. CONCLUSIONS: Hypoplasia of VA is not considered a risk factor for stroke as it is a common variant in up to 75% of the general population. However, in our patients, hypoplastic VA coexisted with two risk factors and resulted in stroke. Thus although a hypoplastic VA may not be an uncommon asymptomatic finding, it may contribute to stroke if additional risk factors are present.