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

Retinal and Choriocapillaris Vascular Changes in Early Alzheimer Disease Patients Using Optical Coherence Tomography Angiography

Background: Alzheimer disease (AD) is a neurodegenerative disorder characterized by ß-amyloid accumulation in the brain. A simple and reliable biomarker for AD that is not invasive is urgently needed, particularly in the preclinical and early stages of the disease. The retina shares with the brain, the same embryologic origins and it is affected by similar vascular changes. The aim of this study was to analyze the characteristics of the retinal and choriocapillaris vascular structure through optical coherence tomography-angiography (OCTA) evaluation in patients with early AD. Methods: Eighteen patients with early AD (study group) and 18 healthy age-matched subjects (control group) were enrolled in the study. All patients underwent full neurologic and ophthalmologic examination, and OCTA scans. Results: We found a significant reduction in flow area of choriocapillaris in the study group compared with the control group (P-value: 0.006), suggesting an impairment of choriocapillaris circulation in patients with early AD. Conclusion: OCTA provides accumulative evidence on the microvasculature changes of the retina and choriocapillaris in patients with AD. Further studies and improved OCTA software are necessary to better evaluate the role of vascular changes shown with OCTA as potential biomarkers in early disease

Cognitive profiles in degenerative dementia without evidence of small vessel pathology and small vessel vascular dementia

Although a large number of studies have examined possible differences in cognitive performance between Alzheimer's disease (AD) and vascular dementia (VaD), the data in the literature are conflicting. The aims of this study were to analyze the neuropsychological pattern of subjects affected by degenerative dementia without evidence of small vessel pathology (DD) and small vessel VaD subjects in the early stages and to investigate differences in the progression of cognitive impairment. Seventy-five patients with probable VaD and 75 patients with probable DD were included. All the subjects underwent a standard neuropsychological evaluation, including the following test: Visual Search, Attentional matrices, Story Recall, Raven's Coloured Progressive Matrices, Phonological and Semantic Verbal Fluency, Token, and Copying Drawings. The severity of cognitive impairment was stratified according to the MMSE score. Fifteen subjects with probable DD and 10 subjects with probable VaD underwent a 12-month cognitive re-evaluation. No significant difference was found between DD and VaD subjects in any of the neuropsychological tests except Story Recall in the mild cognitive impairment (P < 0.001). The re-test value was significantly worse than the baseline value in the MMSE (P = 0.037), Corsi (P = 0.041), Story Recall (P = 0.032), Phonological Verbal Fluency (P = 0.02), and Copying Drawings (P = 0.043) in DD patients and in the Visual Search test (P = 0.036) in VaD subjects. These results suggest that a neuropsychological evaluation might help to differentiate degenerative dementia without evidence of small vessel pathology from small vessel VaD in the early stages of these diseases

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

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

Anosognosia in People with Cognitive Impairment: Association with Cognitive Deficits and Behavioral Disturbances

Aims: To investigate, in a group of subjects at an early stage of cognitive impairment, the relationship between anosognosia and both cognitive and behavioral symptoms by exploring the various domains of insight. Methods: One hundred and eight subjects affected by cognitive impairment were consecutively enrolled. The level of awareness was evaluated by means of the Clinical Insight Rating Scale (CIRS). Psychiatric symptoms were evaluated using the Italian version of the Neuropsychiatric Inventory (NPI), whereas memory (memory index, MI) and executive (executive index, EI) functions were explored using a battery of neuropsychological tests and qualified by means of a single composite cognitive index score for each function. Results: A significant positive correlation between the total NPI score and global anosognosia score was found. Furthermore, both the MI and EI scores were lower in subjects with anosognosia than in those without anosognosia (p Conclusions: Our study suggests that, in the early stage of cognitive impairment, anosognosia is associated with both cognitive deficits and behavioral disorders according to the specific functional anatomy of the symptoms

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&lt;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&lt;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

Circulating U13 Small Nucleolar RNA as a Potential Biomarker in Huntington&rsquo;s Disease: A Pilot Study

Plasma small RNAs have been recently explored as biomarkers in Huntington&rsquo;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&rsquo;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 &lt; 0.0001). SNORD13 correlated with the status of the mutant huntingtin carrier (r = 0.73; p &lt; 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 &lsquo;tipping point&rsquo; in the pathogenic cascade at the neuronal level

Circulating U13 small nucleolar RNA as a candidate biomarker for Huntington's disease

Background and Objectives Fluid biomarkers are a recent field of interest in Huntington disease (HD). We focused on small circulating RNAs from plasma of subjects with prodromal (pre-HD) and overt disease by a two-stage approach: an unbiased investigation by an array method and a validation study to quantify a significant small nucleolar RNA. Methods Through Affymetrix Gene-Chip-miRNA-Array we performed an exploratory study on 9 HD patients, 8 healthy subjects (HS) and 5 psychiatric patients (PP; who share drugs with HD patients, to control for iatrogenic effects). Through real time PCR we validated the results in an independent population of 24 HD patients, 15 pre-HD, 24 PP, 28 Alzheimer’s disease (AD) patients (added to control the disease-specificity of our finding) and 23 HS. A bioinformatic analysis was also performed to interpret our finding. Results The microarray results showed a significant signal for U13 small nucleolar RNA (SNORD13) that was increased in plasma of HD patients compared to controls (fold change, 1.54, p =0.003 HD vs. HS, and fold change 1.44 p = 0.0026 HD vs. PP). In the validation population the significant increase in HD patients was evident compared to both pre-HD and the three control groups (p&lt;0.00001). The plasma levels of SNORD13 correlated with the status of mutant huntingtin carrier and the disease duration (respectively R=0.69; p&lt;0.000001; R=0.49; p=0.015). Through receiver operating characteristic (ROC) curve analysis, we showed high accuracy of plasmatic SNORD13 in discriminating HD patients from pre-HD and control groups (AUC=0.963), outperforming values reported in another study for intrathecal or plasmatic mutant huntingtin and neurofilament light chain as biomarkers of overt HD. The bioinformatic analysis on SNORD13 interactome and pathway analysis showed enrichments for factors involved in nuclear functions beyond the ribosome biogenesis. Discussion We report the unprecedented finding of a potential role of small nucleolar RNAs in HD. Circulating SNORD13 seems a good biomarker for clinical purposes. It seems to be specific for HD and to peripherally report a plausible ‘tipping point’ in the pathogenic cascade at neuronal level, possibly paving the way for new therapeutic targets