Circulating U13 Small Nucleolar RNA as a Potential Biomarker in Huntington's Disease: A Pilot Study.

Plasma small RNAs have been recently explored as biomarkers in Huntington's disease (HD). We performed an exploratory study on nine HD patients, eight healthy subjects (HS), and five psychiatric patients (PP; to control for iatrogenic confounder effects) through an Affymetrix-Gene-Chip-miRNA-Array. We validated the results in an independent population of 23 HD, 15 pre-HD, 24 PP, 28 Alzheimer's disease (AD) patients (to control the disease-specificity) and 22 HS through real-time PCR. The microarray results showed higher levels of U13 small nucleolar RNA (SNORD13) in HD patients than controls (fold change 1.54, p = 0.003 HD vs. HS, and 1.44, p = 0.0026 HD vs. PP). In the validation population, a significant increase emerged with respect to both pre-HD and the control groups (p < 0.0001). SNORD13 correlated with the status of the mutant huntingtin carrier (r = 0.73; p < 0.001) and the disease duration (r = 0.59; p = 0.003). The receiver operating characteristic (ROC) curve analysis showed the high accuracy of SNORD13 in discriminating HD patients from other groups (AUC = 0.963). An interactome and pathway analysis on SNORD13 revealed enrichments for factors relevant to HD pathogenesis. We report the unprecedented finding of a potential disease-specific role of SNORD13 in HD. It seems to peripherally report a 'tipping point' in the pathogenic cascade at the neuronal level.

Exploring the association of early life physical activity and risk of dementia: a systematic review.

INTRODUCTION: Physical activity has been included in the list of twelve modifiable risk factors for dementia, despite conflicting results from observational and controlled studies. In particular it is not clear whether physical inactivity near the time of dementia diagnosis is a consequence or cause of dementia. We review all available studies reporting the possible association between having engaged in PA before 60 years of age and the risk of dementia. EVIDENCE ACQUISITION: We performed a systematic review based on the methodology reported in the Cochrane handbook for systematic reviews and following the PRISMA statement. Bibliographic searches were carried out on the databases PubMed, ISI Web of Science and the Cochrane Database of Systematic Reviews. Further references were retrieved from published systematic reviews on the same topic. Included studies were assessed using the Newcastle Ottawa scale. EVIDENCE SYNTHESIS: The bibliographic search yielded 1381 records. A total of 11 studies were included. Three of the included studies were case control studies, while the remaining 8 were cohort studies The overall quality of included studies was high. However, clinical criteria for the diagnosis of dementia, criteria to define and measure and PA and time-reference of exposure were heterogeneous, with some studies considering specific age range of exposure, and other reports dealing with more generic "adult age." CONCLUSIONS: This review suggests that there is insufficient evidence to conclude whether PA in early life may affect the incidence of dementia in later life. Studies in this field are very complicated and recognizing the impact of PA in early life given all the confounding factors is very difficult. Further studies are warranted. In these studies, it will be crucial to define the type, quantity and intensity of PA as well as to stratify analysis by sex, cultures and social classes.

Corrigendum: Perivascular Unit: This Must Be the Place. The Anatomical Crossroad Between the Immune, Vascular and Nervous System.

[This corrects the article DOI: 10.3389/fnana.2020.00017.].

Perivascular Unit: This Must Be the Place. The Anatomical Crossroad Between the Immune, Vascular and Nervous System.

Most neurological disorders seemingly have heterogenous pathogenesis, with overlapping contribution of neuronal, immune and vascular mechanisms of brain injury. The perivascular space in the brain represents a crossroad where those mechanisms interact, as well as a key anatomical component of the recently discovered glymphatic pathway, which is considered to play a crucial role in the clearance of brain waste linked to neurodegenerative diseases. The pathological interplay between neuronal, immune and vascular factors can create an environment that promotes self-perpetration of mechanisms of brain injury across different neurological diseases, including those that are primarily thought of as neurodegenerative, neuroinflammatory or cerebrovascular. Changes of the perivascular space can be monitored in humans in vivo using magnetic resonance imaging (MRI). In the context of glymphatic clearance, MRI-visible enlarged perivascular spaces (EPVS) are considered to reflect glymphatic stasis secondary to the perivascular accumulation of brain debris, although they may also represent an adaptive mechanism of the glymphatic system to clear them. EPVS are also established correlates of dementia and cerebral small vessel disease (SVD) and are considered to reflect brain inflammatory activity. In this review, we describe the "perivascular unit" as a key anatomical and functional substrate for the interaction between neuronal, immune and vascular mechanisms of brain injury, which are shared across different neurological diseases. We will describe the main anatomical, physiological and pathological features of the perivascular unit, highlight potential substrates for the interplay between different noxae and summarize MRI studies of EPVS in cerebrovascular, neuroinflammatory and neurodegenerative disorders.

Neurocognitive Assessment and Retinal Thickness Alterations in Alzheimer Disease: Is There a Correlation?

BACKGROUND: The relation of retinal thickness to neuropsychological indexes of cognitive impairment in patients with Alzheimer disease (AD) remains an area of investigation. The scope of this investigation was to compare volume and thickness changes of neuronal retinal layers in subjects with AD with those of age-matched healthy controls and to estimate the relation between cognitive functioning evaluated by neuropsychological assessment and thickness changes of the retina. METHODS: This was a prospective single-site study where we evaluated 25 subjects with probable AD matched for age, sex, and education to 17 healthy control subjects (HC). All participants underwent a full medical evaluation, neuropsychological assessment, and optical coherence tomography (OCT) to evaluate the peripapillary retinal nerve fiber layer (pRNFL) thickness, ganglion cell complex (GCC) thickness, and macular volume. RESULTS: The pRNFL thickness of AD patients showed a significant overall reduction compared with healthy controls (P = <0.0001). Furthermore, pRNFL was reduced in each retinal quadrant, particularly the inferior, nasal, and superior quadrants. GCC thickness and macular volume were reduced in AD patients in comparison with HC (P = 0.004; P = 0.001). Of particular interest was the correlation between OCT findings and neuropsychological assessment; we did not find a significant association of retinal thinning with worse MMSE score, but reduction of macular volume was associated with worse constructional praxis performance. Impairment of semantic-lexical and processing speed was associated with attenuation of macular GCC thickness. CONCLUSIONS: OCT can show early thickness changes in AD patients with subtle memory disturbances. These results suggest that correlations between retinal thinning and cognitive performance warrant further investigation.

Neurovascular Dysfunction in Alzheimer Disease: Assessment of Cerebral Vasoreactivity by Ultrasound Techniques and Evaluation of Circulating Progenitor Cells and Inflammatory Markers.

AIMS: The aims of this study were to assess vascular dysfunction in patients with Alzheimer disease (AD) by investigating cerebral vasomotor reactivity using transcranial Doppler ultrasound (TCD) and to evaluate any correlations between cerebral vasoreactivity and endothelium dysfunction. Moreover, the frequency of circulating progenitor cells (CPCs) and the blood concentration of vascular/inflammatory markers were evaluated. MATERIALS AND METHODS: We recruited 35 AD subjects and 17 age-matched, sex-matched, and education-matched healthy control subjects. Cerebral vasomotor reactivity was assessed by means of the TCD-based breath-holding index test (BHI). The level of CPCs was evaluated by means of flow cytometry from venous blood samples, while blood vascular/inflammatory markers were measured by means of enzyme-linked immunosorbent assay. RESULTS: Both cerebral assay blood flow velocity in the middle cerebral artery (MCAFV) and BHI values were significantly lower in AD subjects than in healthy controls (P<0.05). A positive trend was found between MCAFV and BHI values and Mini-Mental State Evaluation (MMSE) scores. Moreover, the hematopoietic progenitor cells' count was found to be lower in patients with AD than in controls (P<0.05). Finally, a significantly higher expression of the plasma chemokine CCL-2 was observed in AD patients than in healthy controls. CONCLUSIONS: Our results confirm that cerebral hemodynamic deterioration may be a critical marker of cognitive decline. Further studies are needed to investigate the role of circulating CPCs and chemokines as potential contributors to neurovascular dysfunction.

Emerging Biomarkers in Vascular Cognitive Impairment and Dementia: From Pathophysiological Pathways to Clinical Application.

Vascular pathology is the second most common neuropathology of dementia after Alzheimer's disease (AD), with small vessels disease (SVD) being considered the major cause of vascular cognitive impairment and dementia (VCID). This review aims to evaluate pathophysiological pathways underlying a diagnosis of VCID. Firstly, we will discuss the role of endothelial dysfunction, blood-brain barrier disruption and neuroinflammation in its pathogenesis. Then, we will analyse different biomarkers including the ones of inflammatory responses to central nervous system tissue injuries, of coagulation and thrombosis and of circulating microRNA. Evidences on peripheral biomarkers for VCID are still poor and large-scale, prospectively designed studies are needed to translate these findings into clinical practice, in order to set different combinations of biomarkers to use for differential diagnosis among types of dementia.

Familial Alzheimer's disease sustained by presenilin 2 mutations: systematic review of literature and genotype-phenotype correlation.

Familial Alzheimer's disease (FAD), despite representing a rare condition, is attracting a growing interest in the scientific community. Improved phenotyping of FAD cases may have a relevant impact both in clinical and research contexts. We performed a systematic review of studies describing the phenotypic features of FAD cases sustained by PSEN2 mutations, the less common cause of monogenic AD. Special attention was given to the clinical manifestations as well as to the main findings coming from the most commonly and widely adopted diagnostic procedures. Basing on the collected data, we also attempted to conduct a genotype-phenotype correlation analysis. Overall, the mutations involving the PSEN2 gene represent an extremely rare cause of FAD, having been reported to date in less than 200 cases. They are mainly associated, despite some peculiar and heterogeneous features, to a typical AD phenotype. Nevertheless, the frequent occurrence of psychotic symptoms may represent a potential distinctive element. The scarcity of available phenotypic descriptions strongly limits the implementation of genotype-phenotype correlations.

Rivastigmine in the treatment of hypersexuality in Alzheimer disease.

Inappropriate sexual behaviors (ISB) represent uncommon and often misdiagnosed clinical disorders among patients with Alzheimer disease. So far, no randomized clinical trials regarding the treatment of ISB in demented people have been conducted, but available data from case series and isolated case reports suggest the efficacy of selective serotonin reuptake inhibitors (SSRIs), antipsychotics, antiandrogens, and H2-receptor antagonists. Controversial data exist on the therapeutic influence of cholinesterase inhibitors on sexual disorders. In the present article, we describe the case of an Alzheimer disease patient presenting hypersexuality, successfully treated with rivastigmine. Thus, we perform a revision of the existing literature regarding the therapeutical effect of cholinesterase inhibitors in the treatment of ISB.