Alzheimer’s disease is the most common type of dementia, reaching 60–80% of case totals, and is one of the major global causes of the elderly population’s decline in functionality concerning daily life activities. Epidemiological research has already indicated that, in addition to several others metabolic factors, diabetes mellitus type 2 is a risk factor of Alzheimer’s disease. Many molecular pathways have been described, and at the same time, there are clues that suggest the connection between type 2 diabetes mellitus and Alzheimer’s disease, through specific genes, autophagy, and even inflammatory pathways. A systematic review with meta-analysis was conducted, and its main goal was to reveal the multilevel connection between these diseases.

The process of memory entails the activation of numerous neural networks and biochemical pathways throughout the brain. The phenomenon of memory decline in relation to aging has been the subject of extensive research for several decades. The correlation between the process of aging and memory is intricate and has various aspects to consider. Throughout the aging process, there are various alterations that take place within the brain and, as expected, affect other functions that have already been linked to memory and its function such as involving microcirculation and sleep. Recent studies provide an understanding of how these mechanisms may be interconnected through the relatively new concept of the glymphatic system. The glymphatic system is strongly correlated to sleep processes. Sleep helps the glymphatic system remove brain waste solutes. Astrocytes expand and contract to form channels for cerebrospinal fluid (CSF) to wash through the brain and eliminate waste. However, the details have not been totally elusive, but the discovery of what we call the glymphatic system enables us to connect many pieces of physiology to understand how such factors are interconnected and the interplay between them. Thus, the purpose of this review is to discuss how the glymphatic system, sleep, memory, and aging are interconnected through a network of complex mechanisms and dynamic interactions.

Vascular cognitive impairment (VCI) is a heterogeneous entity with multiple aetiologies, all linked to underlying vascular disease. Among these, VCI related to subcortical small vessel disease (SSVD) is emerging as a major homogeneous subtype. Its progressive course raises the need for biomarker identification and/or development for adequate therapeutic interventions to be tested. In order to shed light in the current status on biochemical markers for VCI-SSVD, experts in field reviewed the recent evidence and literature data. The group conducted a comprehensive search on Medline, PubMed and Embase databases for studies published until 15.01.2017. The proposal on current status of biochemical markers in VCI-SSVD was reviewed by all co-authors and the draft was repeatedly circulated and discussed before it was finalized. This review identifies a large number of biochemical markers derived from CSF and blood. There is a considerable overlap of VCI-SSVD clinical symptoms with those of Alzheimer’s disease (AD). Although most of the published studies are small and their findings remain to be replicated in larger cohorts, several biomarkers have shown promise in separating VCI-SSVD from AD. These promising biomarkers are closely linked to underlying SSVD pathophysiology, namely disruption of blood-CSF and blood–brain barriers (BCB-BBB) and breakdown of white matter myelinated fibres and extracellular matrix, as well as blood and brain inflammation. The leading biomarker candidates are: elevated CSF/blood albumin ratio, which reflects BCB/BBB disruption; altered CSF matrix metalloproteinases, reflecting extracellular matrix breakdown; CSF neurofilment as a marker of axonal damage, and possibly blood inflammatory cytokines and adhesion molecules. The suggested SSVD biomarker deviations contrasts the characteristic CSF profile in AD, i.e. depletion of amyloid beta peptide and increased phosphorylated and total tau. Combining SSVD and AD biomarkers may provide a powerful tool to identify with greater precision appropriate patients for clinical trials of more homogeneous dementia populations. Thereby, biomarkers might promote therapeutic progress not only in VCI-SSVD, but also in AD.

Background: There are limited data regarding the prevalence of distinct clinical, neuroimaging and genetic markers among patients diagnosed with cerebral amyloid angiopathy–related inflammation (CAA-ri). We sought to determine the prevalence of clinical, radiological, genetic and cerebrospinal fluid biomarker findings in patients with CAA-ri. Methods: A systematic review and meta-analysis of published studies including patients with CAA-ri was conducted to determine the prevalence of clinical, neuroimaging, genetic and cerebrospinal fluid biomarker findings. Subgroup analyses were performed based on (1) prospective or retrospective study design and (2) CAA-ri diagnosis with or without available biopsy. We pooled the prevalence rates using random-effects models and assessed the heterogeneity using Cochran-Q and I ² -statistics. Results: We identified 4 prospective and 17 retrospective cohort studies comprising 378 patients with CAA-ri (mean age, 71.5 years; women, 52%). The pooled prevalence rates were as follows: cognitive decline at presentation 70% ([95% CI, 54%–84%]; I ² =82%), focal neurological deficits 55% ([95% CI, 40%–70%]; I ² =82%), encephalopathy 54% ([95% CI, 39%–68%]; I ² =43%), seizures 37% ([95% CI, 27%–49%]; I ² =65%), headache 31% ([95% CI, 22%–42%]; I ² =58%), T2/fluid-attenuated inversion recovery-hyperintense white matter lesions 98% ([95% CI, 93%–100%]; I ² =44%), lobar cerebral microbleeds 96% ([95% CI, 92%–99%]; I ² =25%), gadolinium enhancing lesions 54% ([95% CI, 42%–66%]; I ² =62%), cortical superficial siderosis 51% ([95% CI, 34%–68%]; I ² =77%) and lobar macrohemorrhage 40% ([95% CI, 11%–73%]; I ² =88%). The prevalence rate of the ApoE (Apolipoprotein E) ε4/ε4 genotype was 34% ([95% CI, 17%–53%]; I ² =76%). Subgroup analyses demonstrated no differences in these prevalence rates based on study design and diagnostic strategy. Conclusions: Cognitive decline was the most common clinical feature. Hyperintense T2/fluid-attenuated inversion recovery white matter lesions and lobar cerebral microbleeds were by far the most prevalent neuroimaging findings. Thirty-four percent of patients with CAA-ri have homozygous ApoE ε4/ε4 genotype and scarce data exist regarding the cerebrospinal fluid biomarkers and its significance in these patients.

Background: Alzheimer’s disease dementia (ADD) may manifest with atypical phenotypes, resembling behavioral variant frontotemporal dementia (bvFTD) and corticobasal syndrome (CBS), phenotypes which typically have an underlying frontotemporal lobar degeneration with tau proteinopathy (FTLD-tau), such as Pick’s disease, corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), or FTLD with TDP-43 proteinopathy (FTLD-TDP). CSF biomarkers total and phosphorylated tau (τ_T and τ_P-181), and amyloid beta with 42 and 40 amino acids (Aβ₄₂ and Aβ₄₀) are biomarkers of AD pathology. The primary aim of this study was to compare the diagnostic accuracy of Aβ₄₂ to Aβ₄₂/Aβ₄₀ ratio in: (a) differentiating ADD vs. frontotemporal dementias; (b) patients with AD pathology vs. non-AD pathologies; (c) compare biomarker ratios and composite markers to single CSF biomarkers in the differentiation of AD from FTD; Methods: In total, 263 subjects were included (ADD: n = 98; bvFTD: n = 49; PSP: n = 50; CBD: n = 45; controls: n = 21). CSF biomarkers were measured by commercially available ELISAs (EUROIMMUN). Multiple biomarker ratios (Aβ₄₂/Aβ₄₀; τ_T/τ_P-181; τ_T/Aβ₄₂; τ_P-181/Aβ₄₂) and composite markers (t-tau: τ_T/(Aβ₄₂/Aβ40); p-tau: τ_P-181/(Aβ₄₂/Aβ₄₀) were calculated. ROC curve analysis was performed to compare AUCs of Aβ₄₂ and Aβ₄₂/Aβ₄₀ ratio and relevant composite markers between ADD and FTD, as defined clinically. BIOMARKAPD/ABSI criteria (abnormal τ_T, τ_P-181 Aβ₄₂, and Aβ₄₂/Aβ₄₀ ratio) were used to re-classify all patients into AD pathology vs. non-AD pathologies, and ROC curve analysis was repeated to compare Aβ₄₂ and Aβ₄₂/Aβ₄₀; Results: Aβ₄₂ did not differ from Aβ₄₂/Aβ₄₀ ratio in the differentiation of ADD from FTD (AUCs 0.752 and 0.788 respectively; p = 0.212). The τ_T/Aβ₄₂ ratio provided maximal discrimination between ADD and FTD (AUC:0.893; sensitivity 88.8%, specificity 80%). BIOMARKAPD/ABSI criteria classified 60 patients as having AD pathology and 211 as non-AD. A total of 22 had discrepant results and were excluded. Aβ₄₂/Aβ₄₀ ratio was superior to Aβ₄₂ in the differentiation of AD pathology from non-AD pathology (AUCs: 0.939 and 0.831, respectively; p < 0.001). In general, biomarker ratios and composite markers were superior to single CSF biomarkers in both analyses. Conclusions: Aβ₄₂/Aβ₄₀ ratio is superior to Aβ₄₂ in identifying AD pathology, irrespective of the clinical phenotype. CSF biomarker ratios and composite markers provide higher diagnostic accuracy compared to single CSF biomarkers.

Background: Limited data exist regarding the prevalence of clinical and neuroimaging manifestations among patients diagnosed with cerebral amyloid angiopathy (CAA). We sought to determine the prevalence of clinical phenotypes and radiological markers in patients with CAA. Methods: Systematic review and meta-analysis of studies including patients with CAA was conducted to primarily assess the prevalence of clinical phenotypes and neuroimaging markers as available in the included studies. Sensitivity analyses were performed based on the (1) retrospective or prospective study design and (2) probable or unspecified CAA status. We pooled the prevalence rates using random-effects models and assessed the heterogeneity using the Cochran Q and I ² statistics. Results: We identified 12 prospective and 34 retrospective studies including 7159 patients with CAA. The pooled prevalence rates were cerebral microbleeds (52% [95% CI, 43%–60%]; I ² =93%), cortical superficial siderosis (49% [95% CI, 38%–59%]; I ² =95%), dementia or mild cognitive impairment (50% [95% CI, 35%–65%]; I ² =97%), intracerebral hemorrhage (ICH; 44% [95% CI, 27%–61%]; I ² =98%), transient focal neurological episodes (48%; 10 studies [95% CI, 29%–67%]; I ² =97%), lacunar infarcts (30% [95% CI, 25%–36%]; I ² =78%), high grades of perivascular spaces located in centrum semiovale (56% [95% CI, 44%–67%]; I ² =88%) and basal ganglia (21% [95% CI, 2%–51%]; I ² =98%), and white matter hyperintensities with moderate or severe Fazekas score (53% [95% CI, 40%–65%]; I ² =91%). The only neuroimaging marker that was associated with higher odds of recurrent ICH was cortical superficial siderosis (odds ratio, 1.57 [95% CI, 1.01–2.46]; I ² =47%). Sensitivity analyses demonstrated a higher prevalence of ICH (53% versus 16%; P =0.03) and transient focal neurological episodes (57% versus 17%; P =0.03) among retrospective studies compared with prospective studies. No difference was documented between the prevalence rates based on the CAA status. Conclusions: Approximately one-half of hospital-based cohort of CAA patients was observed to have cerebral microbleeds, cortical superficial siderosis, mild cognitive impairment, dementia, ICH, or transient focal neurological episodes. Cortical superficial siderosis was the only neuroimaging marker that was associated with higher odds of ICH recurrence. Future population-based studies among well-defined CAA cohorts are warranted to corroborate our findings.