Identification of miRNAs regulating MAPT expression and their analysis in plasma of patients with dementia.

Background: Dementia is one of the most common diseases in elderly people and hundreds of thousand new cases per year of Alzheimer's disease (AD) are estimated. While the recent decade has seen significant advances in the development of novel biomarkers to identify dementias at their early stage, a great effort has been recently made to identify biomarkers able to improve differential diagnosis. However, only few potential candidates, mainly detectable in cerebrospinal fluid (CSF), have been described so far. Methods: We searched for miRNAs regulating MAPT translation. We employed a capture technology able to find the miRNAs directly bound to the MAPT transcript in cell lines. Afterwards, we evaluated the levels of these miRNAs in plasma samples from FTD (n = 42) and AD patients (n = 33) and relative healthy controls (HCs) (n = 42) by using qRT-PCR. Results: Firstly, we found all miRNAs that interact with the MAPT transcript. Ten miRNAs have been selected to verify their effect on Tau levels increasing or reducing miRNA levels by using cell transfections with plasmids expressing the miRNAs genes or LNA antagomiRs. Following the results obtained, miR-92a-3p, miR-320a and miR-320b were selected to analyse their levels in plasma samples of patients with FTD and AD respect to HCs. The analysis showed that the miR-92a-1-3p was under-expressed in both AD and FTD compared to HCs. Moreover, miR-320a was upregulated in FTD vs. AD patients, particularly in men when we stratified by sex. Respect to HC, the only difference is showed in men with AD who have reduced levels of this miRNA. Instead, miR-320b is up-regulated in both dementias, but only patients with FTD maintain this trend in both genders. Conclusions: Our results seem to identify miR-92a-3p and miR-320a as possible good biomarkers to discriminate AD from HC, while miR-320b to discriminate FTD from HC, particularly in males. Combining three miRNAs improves the accuracy only in females, particularly for differential diagnosis (FTD vs. AD) and to distinguish FTD from HC.

A Plasma Circular RNA Profile Differentiates Subjects with Alzheimer's Disease and Mild Cognitive Impairment from Healthy Controls.

The most frequently used biomarkers to support the diagnosis of Alzheimer's Disease (AD) are Aß42, total-Tau, and phospho-tau protein levels in CSF. Moreover, magnetic resonance imaging is used to assess hippocampal atrophy, 18F-FDG PET to identify abnormal brain metabolism, and PET imaging for amyloid deposition. These tests are rather complex and invasive and not easily applicable to clinical practice. Circulating non-coding RNAs, which are inherently stable and easy to manage, have been reported as promising biomarkers for central nervous system conditions. Recently, circular RNAs (circRNAs) as a novel class of ncRNAs have gained attention. We carried out a pilot study on five participants with AD and five healthy controls (HC) investigating circRNAs by Arraystar Human Circular RNA Microarray V2.0. Among them, 26 circRNAs were differentially expressed (FC ≥ 1.5, p < 0.05) in participants with AD compared to HC. From a top 10 of differentially expressed circRNAs, a validation study was carried out on four up-regulated (hsa_circRNA_050263, hsa_circRNA_403959, hsa_circRNA_003022, hsa_circRNA_100837) and two down-regulated (hsa_circRNA_102049, hsa_circRNA_102619) circRNAs in a larger population. Moreover, five subjects with mild cognitive impairment (MCI) were investigated. The analysis confirmed the upregulation of hsa_circRNA_050263, hsa_circRNA_403959, and hsa_circRNA_003022 both in subjects with AD and in MCI compared to HCs. We also investigated all microRNAs potentially interacting with the studied circRNAs. The GO enrichment analysis shows they are involved in the development of the nervous system, and in the cellular response to nerve growth factor stimuli, protein phosphorylation, apoptotic processes, and inflammation pathways, all of which are processes related to the pathology of AD.

[18F] FBB cortical uptake is not related to the age of onset of Alzheimer's disease.

AIM: To investigate the relationships between amyloid burden in brain and the age of onset of Alzheimer's disease. MATERIALS AND METHODS: We examined 60 patients with clinical diagnosis of Alzheimer's disease. Of them, 22 were early-onset of Alzheimer's disease and 38 were late-onset of Alzheimer's disease. All of them underwent a brain PET scan 90 minutes after the injection of 4-[(E)-2-[4-[2-[2-(2-fluoranylethoxy)ethoxy]ethoxy]phenyl]ethenyl]-N-methylaniline ([F] FBB); 300 ± 10 MBq). Relationships between amyloid burden in brain and age of onset of Alzheimer's disease were assessed by means of statistical parametric mapping version 12. RESULTS: There were no significant differences [F] FBB uptake between early-onset of Alzheimer's disease and late-onset of Alzheimer's disease patients. CONCLUSION: In our study group, the age of onset is not related to brain amyloid burden in Alzheimer's disease patients.

Brain metabolic patterns in patients with suspected non-Alzheimer's pathophysiology (SNAP) and Alzheimer's disease (AD): is [18F] FDG a specific biomarker in these patients?

PURPOSE: The present study was conducted to compare the pattern of brain [18F] FDG uptake in suspected non-Alzheimer's pathophysiology (SNAP), AD, and healthy controls using 2-deoxy-2-[18F]fluoroglucose ([18F] FDG) positron emission tomography imaging. Cerebrospinal fluid (CSF) biomarkers amyloid-ß1-42 peptide (Aß1-42) and tau were used in order to differentiate AD from SNAP. METHODS: The study included 43 newly diagnosed AD patients (female = 23; male = 20) according to the NINCDS-ADRDA criteria, 15 SNAP patients (female = 12; male =3), and a group of 34 healthy subjects that served as the control group (CG), who were found to be normal at neurological evaluation (male = 20; female = 14). A battery of neuropsychological tests was administrated in AD and SNAP subjects; cerebrospinal fluid assay was conducted in both AD and SNAP as well. Brain PET/CT acquisition was started 30 ± 5 min after [18F] FDG injection in all subjects. SPM12 [statistical parametric mapping] implemented in MATLAB 2018a was used for the analysis of PET scans in this study. RESULTS: As compared to SNAP, AD subjects showed significant hypometabolism in a wide cortical area involving the right frontal, parietal, and temporal lobes. As compared to CG, AD subjects showed a significant reduction in [18F] FDG uptake in the parietal, limbic, and frontal cortex, while a more limited reduction in [18F] FDG uptake in the same areas was found when comparing SNAP to CG. CONCLUSIONS: SNAP subjects show milder impairment of brain [18F] FDG uptake as compared to AD. The partial overlap of the metabolic pattern between SNAP and AD limits the use of [18F] FDG PET/CT in effectively discriminating these clinical entities.

Circulating miR-127-3p as a Potential Biomarker for Differential Diagnosis in Frontotemporal Dementia.

Given the heterogeneous nature of frontotemporal dementia (FTD), sensitive biomarkers are greatly needed for the accurate diagnosis of this neurodegenerative disorder. Circulating miRNAs have been reported as promising biomarkers for neurodegenerative disorders and processes affecting the central nervous system, especially in aging. The objective of the study was to evaluate if some circulating miRNAs linked with apoptosis (miR-29b-3p, miR-34a-5p, miR-16-5p, miR-17-5p, miR-107, miR-19b-3p, let-7b-5p, miR-26b-5p, and 127-3p) were able to distinguish between FTD patients and healthy controls. For this study, we enrolled 127 subjects, including 54 patients with FTD, 20 patients with Alzheimer's disease (AD), and 53 healthy controls. The qRT-PCR analysis showed a downregulation of miR-127-3p in FTD compared to controls, while the levels of other miRNAs remained unchanged. Then, miR-127-3p expression was also analyzed in AD patients, finding a different expression between two patient groups. A receiver operating characteristic curve was then created for miR-127-3p to discriminate FTD versus AD (AUC: 0.8986), and versus healthy controls (AUC: 0.8057). In conclusion, miR-127-3p could help to diagnose FTD and to distinguish it from AD.

Coupled Imaging with [18F]FBB and [18F]FDG in AD Subjects Show a Selective Association Between Amyloid Burden and Cortical Dysfunction in the Brain.

PURPOSE: The present study was aimed to investigate the relationships between dysfunction of cortical glucose metabolism as detectable by means of 2-deoxy-2-[18F]fluoro -D-glucose ([18F]FDG) positron emission tomography/x-ray computed tomography (PET/CT) and amyloid burden as detectable by means of 4-{(E)-2-[4-(2-{2-[2-[18F]fluoroethoxy]ethoxy}ethoxy)phenyl]vinyl}-N-methylaniline (florbetaben; [18F]FBB) in a group of patients affected by Alzheimer's disease (AD). PROCEDURES: We examined 38 patients newly diagnosed with AD according to the NINCDS-ADRDA criteria. All the subjects underwent a PET/CT scan using both [18F]FDG and [18F]FBB with an average interval of 1 month. We used statistical parametric mapping (SPM8) implemented in Matlab R2012b and WFU pickatlas for the definition of a region of interest (ROI) mask including the whole cortex. These data were then normalized on the counts of the cerebellum and then used for a regression analysis on [18F]FDG scans in SPM. Furthermore, 58 control subjects were used as control group for [18F]FDG PET/CT scans. RESULTS: SPM analysis in AD patients showed a significant negative correlation between [18F] FBB and [18F] FDG uptake in temporal and parietal lobes bilaterally. Of note, these areas in AD patients displayed a marked glucose hypometabolism compared to control group. CONCLUSIONS: Combined imaging with [18F]FBB and [18FFDG shows that amyloid burden in the brain is related to cortical dysfunction of temporal and parietal lobes in AD.

A pilot study on the use of interferon beta-1a in early Alzheimer's disease subjects.

Despite the fact that multiple sclerosis (MS) and Alzheimer's disease (AD) share common neuroimmunological features, interferon beta 1a (IFNß1a), the well-established treatment for the prevention of disease progression and cognitive decline in MS patients, has never been used in AD. We evaluated the safety and efficacy of IFNß1a in subjects affected by mild-to-moderate AD in a double-blind, randomized, placebo-controlled, multicenter pilot study. Forty-two early Alzheimer's patients were randomized to receive either a 22 mcg subcutaneous injection of IFNß1a or placebo three times per week. A treatment period of 28 weeks was followed by 24 weeks of observation. IFNß1a was well tolerated and adverse events were infrequent and mild to moderate. Although not statistically significant, a reduction in disease progression during follow-up was measured in IFNß1a-treated patients by the Alzheimer's Disease Assessment Scale cognitive subscale. Interestingly, the treatment group showed significant improvements in the Instrumental Activities of Daily Living and Physical Self-maintenance Scale. This study suggests that IFNß1a is safe and well tolerated in early AD patients, and its possible beneficial role should be further investigated in larger studies.

Gender differences in Parkinson's disease: focus on plasma α-synuclein.

Among promising biological markers proposed for Parkinson's disease (PD) and other disorders related to Lewy bodies, plasma alpha-synuclein assay has provided conflicting results mainly owing to the various laboratory assay techniques used and protein forms assayed. In this observational and exploratory cross-sectional study, using an immunoenzymatic technique, we assayed and compared total plasma alpha-synuclein concentrations in 69 patients with PD and 110 age-matched healthy control subjects. Two previously unreported findings concerned gender. First, plasma alpha-synuclein concentrations measured in the more advanced parkinsonian disease stages decreased in men, but not in women. Second, again only in men, plasma alpha-synuclein concentration was associated with cognitive impairments, hallucinations, and sleep disorders. These findings underline the gender-related differences in parkinsonian patients and indicate plasma alpha-synuclein expression as a potential biological marker for PD progression in men.

Scintigraphic, neuroradiological and clinical comparison in two patients with primary sporadic and two with secondary Fahr's disease.

Bilateral striopallidodentate calcification, usually termed Fahr's disease, can give rise to various clinical manifestations including hyperkinetic movement disorders or a hypokinetic Parkinsonian syndrome, behavioural and mood changes, cognitive deficits and even frank dementia. We describe four patients all of whom underwent a detailed scintigraphic, neuroradiological and clinical work-up: two had primary, sporadic Fahr's disease and two had Fahr's disease secondary to hypoparathyroidism. The neuroradiological and clinical studies disclosed similar anatomical and pathological changes in the four patients but variable and sometimes unexpected clinical manifestations. Both patients with primary forms had hypokinetic Parkinsonian syndrome, both patients with secondary forms had hyperkinetic movements. Dopamine autotransporter scan brain scintigraphy disclosed an unexpected unilateral putamen involvement despite substantially symmetric calcifications.