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Background: White matter hyperintensities (WMHs) are frequently seen on FLAIR MRI images in aging and Dementia. It has been hypothesized that an imbalance in norepinephrine (NE) signaling could lead to a "hypometabolism" by decreasing astrocyte metabolism which has been proposed as an important cause leading to local demyelination.We hypothesize that structural atrophy in human Locus Coeruleus (LC) leading to NE deficiencies could contribute to the pathophysiology of WMHs by affecting astrocytic metabolism through astrocytic beta‐adrenergic 2 receptors. Method: FLAIR na T1‐MPRAGE images were obtained from healthy elder subjects (n = 108). LC atrophy was calculated using gray matter mask. WMHs were calculated through both manual segmentation done by an expert, as well as with automatic segmentation. Gene‐expression gradient of beta‐adrenergic 2 receptor was obtained from the Allen Human Brain Atlas. Result: We found that LC atrophy is related to an increase of WMHs, mainly in frontal lobes. We replicated previous findings associating WMHs with Gait speed, where we found that this effect was significantly mediated by LC atrophy in structural correlation analysis. We developed Linear Mixed Model to account for Random Effects in the relation between WMHs local load and the expression of beta‐adrenergic 2 receptor, and found that subjects that had a higher random effect between these variables had significantly less LC atrophy. Conclusion: WMHs are correlated with LC atrohy, and spatially overlaps with beta‐adrenergic receptor 2 expression. We theorize that LC atrophy and subsequent decreased NE release disrupt normal astrocyte function through the beta 2 adrenergic receptor, leading to defective axonal metabolism and ultimately to axonal degeneration observed through WMHs with neuroimaging techniques. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease (AD) is the most prevalent cause of dementia in the elderly population. It is a multifactorial disease in which metabolic dysregulation and glucose metabolism impairment plays a major role in the etiopathogenesis. In this research, we evaluate the comorbidities in a clinical trial for the novel biomarker Alz‐tau®, based on platelet tau, in cognitive healthy controls, mild‐cognitive impairment (MCI) and AD patients, in particular TII diabetes. Alterations in this biomarker appear to indicate high risk of developing AD, as demonstrated in previous clinical trials. Methods: From a cohort of 111 subjects, neuropsychology tests were performed to assign the respective group (control, MCI or AD). In addition, a health questionnaire to evaluate comorbidities. For the Alz‐tau® biomarker, platelets were obtained from plasma by centrifugation, lysed to obtain platelet protein extracts (containing tau) and further processed for a western blot analysis. The immuno‐ detection was performed with our novel monoclonal antibody tau51, which detects two variants of tau protein: a high molecular weight variant (HMW) and a low molecular weight variant (LMW). The results obtained were subjected to a densitometric analysis with ImageJ and the algorithm HWM/LMW was obtained. Result: From 111 patients, 17 presented diabetes type 2 as a comorbidity (15,3%). Out of them, 11 were cognitive healthy subjects (64.7%), 4 EA patients (23.5%) and 2 MCI (11.8%). Out of the control patients, 6 have the Alz‐tau® biomarker altered (54.5%), which was similar to what was observed in the EA patients (2 patients, 50%) and the MCI (1 patient, 50%). Of the 17 patients with diabetes, 53% presented an altered Alz‐tau® biomarker (cut‐off 1.2 algorithm), which is considered a risk factor for AD. It should be considered that the area under the curve (AUC) of this novel biomarker Alz‐tau® is 0.69, appropriate for a novel technique. Conclusion: Here, we discovered that this early detection biomarker is correlated with the high‐risk factor of having AD in the future, since non‐symptomatic subjects exhibited an altered biomarker. Moreover, more than 50% of the TII diabetic positive cognitive healthy controls, exhibit an altered biomarker, sustaining our hypothesis of the correlation between glucose‐metabolism impairment, AD and oligomeric tau. [ABSTRACT FROM AUTHOR]

Background: LRP1 and P‐gp are the major efflux transporters of β‐amyloid peptide (Aβ) across the blood brain barrier and the expression of both transporters is mediated by the vitamin D receptor (VDR). Three single nucleotide VDR polymorphisms (SNPs) Taq I, Apa I and Fok I have been related to mild cognitive impairment (MCI); however, their functional effect on the expression of VDR and its target genes remains unclear. Method: 76 MCI patients and 133 elderly volunteers were cognitively screened with the Montreal Cognitive assessment (MoCA) and MoCA‐MIS after signing an informed consent approved by the Ethics Committee of Hospital Clínico Unversidad de Chile. The VDR SNPs Apa (rs7975232), Taq (rs731236) and Fok I (rs2228570) were determined by TaqMan SNP genotyping assay. mRNA levels of VDR, LRP1 and P‐gp were evaluated by qPCR. Result: The C and T alleles of Apa I and Taq I respectively were more frequent in the MCI (p < 0.05); additionally the odds ratio analysis (OR) was significant for both alleles (C allele OR: 1.5 p = 0.049; T allele OR: 1.89, p = 0.0044). There were no significant differences for Fok I polymorphism between the groups. Furthermore, the homozygous CC of Apa I had significantly lower mRNA levels of P‐gp and VDR than the homozygous AA and heterozygous AC (p < 0.05). The carriers of one copy of the C allele (TC) of Fok I had lower mRNA levels of VDR and of both transporters than the homozygous TT (p < 0.005). Conclusion: The C and T alleles of Apa I and Taq I respectively might be risk alleles for MCI, as reported in other populations. In addition, we found that SNPs of the VDR gene are related to the decrease of the mRNA levels of the Aβ transporter P‐gp and the transcription factor VDR. [ABSTRACT FROM AUTHOR]