Biocomplexity and Fractality in the Search of Biomarkers of Aging and Pathology: Focus on Mitochondrial DNA and Alzheimer's Disease

Alzheimer's disease (AD) represents one major health concern for our growing elderly population. It accounts for increasing impairment of cognitive capacity followed by loss of executive function in late stage. AD pathogenesis is multifaceted and difficult to pinpoint, and understanding AD etiology will be critical to effectively diagnose and treat the disease. An interesting hypothesis concerning AD development postulates a cause-effect relationship between accumulation of mitochondrial DNA (mtDNA) mutations and neurodegenerative changes associated with this pathology. Here we propose a computerized method for an easy and fast mtDNA mutations-based characterization of AD. The method has been built taking into account the complexity of living being and fractal properties of many anatomic and physiologic structures, including mtDNA. Dealing with mtDNA mutations as gaps in the nucleotide sequence, fractal lacunarity appears a suitable tool to differentiate between aging and AD. Therefore, Chaos Game Representation method has been used to display DNA fractal properties after adapting the algorithm to visualize also heteroplasmic mutations. Parameter β from our fractal lacunarity method, based on hyperbola model function, has been measured to quantitatively characterize AD on the basis of mtDNA mutations. Results from this pilot study to develop the method show that fractal lacunarity parameter β of mtDNA is statistically different in AD patients when compared to age-matched controls. Fractal lacunarity analysis represents a useful tool to analyze mtDNA mutations. Lacunarity parameter β is able to characterize individual mutation profile of mitochondrial genome and appears a promising index to discriminate between AD and aging

Plasma and cerebrospinal fluid ABeta42 for the differential diagnosis of Alzheimer's disease dementia in participants diagnosed with any dementia subtype in a specialist care setting

BackgroundDementia is a syndrome that comprises many differing pathologies, including Alzheimer's disease dementia (ADD), vascular dementia (VaD) and frontotemporal dementia (FTD). People may benefit from knowing the type of dementia they live with, as this could inform prognosis and may allow for tailored treatment. Beta-amyloid (1-42) (ABeta42) is a protein which decreases in both the plasma and cerebrospinal fluid (CSF) of people living with ADD, when compared to people with no dementia. However, it is not clear if changes in ABeta42 are specific to ADD or if they are also seen in other types of dementia. It is possible that ABeta42 could help differentiate ADD from other dementia subtypes.ObjectivesTo determine the accuracy of plasma and CSF ABeta42 for distinguishing ADD from other dementia subtypes in people who meet the criteria for a dementia syndrome.Search methodsWe searched MEDLINE, and nine other databases up to 18 February 2020. We checked reference lists of any relevant systematic reviews to identify additional studies.Selection criteriaWe considered cross-sectional studies that differentiated people with ADD from other dementia subtypes. Eligible studies required measurement of participant plasma or CSF ABeta42 levels and clinical assessment for dementia subtype.Data collection and analysisSeven review authors working independently screened the titles and abstracts generated by the searches. We collected data on study characteristics and test accuracy. We used the second version of the 'Quality Assessment of Diagnostic Accuracy Studies' (QUADAS-2) tool to assess internal and external validity of results. We extracted data into 2 x 2 tables, cross-tabulating index test results (ABeta42) with the reference standard (diagnostic criteria for each dementia subtype). We performed meta-analyses using bivariate, random-effects models. We calculated pooled estimates of sensitivity, specificity, positive predictive values, positive and negative likelihood ratios, and corresponding 95% confidence intervals (CIs). In the primary analysis, we assessed accuracy of plasma or CSF ABeta42 for distinguishing ADD from other mixed dementia types (non-ADD). We then assessed accuracy of ABeta42 for differentiating ADD from specific dementia types: VaD, FTD, dementia with Lewy bodies (DLB), alcohol-related cognitive disorder (ARCD), Creutzfeldt-Jakob disease (CJD) and normal pressure hydrocephalus (NPH). To determine test-positive cases, we used the ABeta42 thresholds employed in the respective primary studies. We then performed sensitivity analyses restricted to those studies that used common thresholds for ABeta42.Main resultsWe identified 39 studies (5000 participants) that used CSF ABeta42 levels to differentiate ADD from other subtypes of dementia. No studies of plasma ABeta42 met the inclusion criteria. No studies were rated as low risk of bias across all QUADAS-2 domains. High risk of bias was found predominantly in the domains of patient selection (28 studies) and index test (25 studies). The pooled estimates for differentiating ADD from other dementia subtypes were as follows: ADD from non-ADD: sensitivity 79% (95% CI 0.73 to 0.85), specificity 60% (95% CI 0.52 to 0.67), 13 studies, 1704 participants, 880 participants with ADD; ADD from VaD: sensitivity 79% (95% CI 0.75 to 0.83), specificity 69% (95% CI 0.55 to 0.81), 11 studies, 1151 participants, 941 participants with ADD; ADD from FTD: sensitivity 85% (95% CI 0.79 to 0.89), specificity 72% (95% CI 0.55 to 0.84), 17 studies, 1948 participants, 1371 participants with ADD; ADD from DLB: sensitivity 76% (95% CI 0.69 to 0.82), specificity 67% (95% CI 0.52 to 0.79), nine studies, 1929 participants, 1521 participants with ADD. Across all dementia subtypes, sensitivity was greater than specificity, and the balance of sensitivity and specificity was dependent on the threshold used to define test positivity.Authors' conclusionsOur review indicates that measuring ABeta42 levels in CSF may help differentiate ADD from other dementia subtypes, but the test is imperfect and tends to misdiagnose those with non-ADD as having ADD. We would caution against the use of CSF ABeta42 alone for dementia classification. However, ABeta42 may have value as an adjunct to a full clinical assessment, to aid dementia diagnosis

SARS-CoV-2 Morbidity in the CNS and the Aged Brain Specific Vulnerability

The infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can be the cause of a fatal disease known as coronavirus disease 2019 (COVID-19) affecting the lungs and other organs. Particular attention has been given to the effects of the infection on the brain due to recurring neurological symptoms associated with COVID-19, such as ischemic or hemorrhagic stroke, encephalitis and myelitis, which are far more severe in the elderly compared to younger patients. The specific vulnerability of the aged brain could derive from the impaired immune defenses, from any of the altered homeostatic mechanisms that contribute to the aging phenotype, and from particular changes in the aged brain involving neurons and glia. While neuronal modifications could contribute indirectly to the damage induced by SARS-CoV-2, glia alterations could play a more direct role, as they are involved in the immune response to viral infections. In aged patients, changes regarding glia include the accumulation of dystrophic forms, reduction of waste removal, activation of microglia and astrocytes, and immunosenescence. It is plausible to hypothesize that SARS-CoV-2 infection in the elderly may determine severe brain damage because of the frail phenotype concerning glial cells

Biocomplexity and Fractality in the Search of Biomarkers of Aging and Pathology: Mitochondrial DNA Profiling of Parkinson’s Disease

Increasing evidence implicates mitochondrial dysfunction in the etiology of Parkinson’s disease (PD). Mitochondrial DNA (mtDNA) mutations are considered a possible cause and this mechanism might be shared with the aging process and with other age-related neurodegenerative disorders such as Alzheimer’s disease (AD). We have recently proposed a computerized method for mutated mtDNA characterization able to discriminate betweenADand aging. The present study deals with mtDNA mutation-based profiling of PD. Peripheral blood mtDNA sequences from late-onset PD patients and age-matched controls were analyzed and compared to the revised Cambridge Reference Sequence (rCRS). The chaos game representation (CGR) method, modified to visualize heteroplasmic mutations, was used to display fractal properties of mtDNA sequences and fractal lacunarity analysis was applied to quantitatively characterize PD based on mtDNA mutations. Parameter , from the hyperbola model function of our lacunarity method, was statistically dierent between PD and control groups when comparing mtDNA sequence frames corresponding to GenBank np 5713-9713. Our original method, based on CGR and lacunarity analysis, represents a useful tool to analyze mtDNA mutations. Lacunarity parameter is able to characterize individual mutation profile of mitochondrial genome and could represent a promising index to discriminate between PD and agin

Effect of a Cognitive Training Program on the Platelet APP Ratio in Patients with Alzheimer’s Disease

In patients with Alzheimer’s disease (AD), synaptic plasticity seems to be involved in cognitive improvement induced by cognitive training. The platelet amyloid precursor protein (APP) ratio (APPr), i.e., the ratio between two APP isoforms, may be a useful peripheral biomarker to investigate synaptic plasticity pathways. This study evaluates the changes in neuropsychological/cognitive performance and APPr induced by cognitive training in AD patients participating in the “My Mind Project”. Neuropsychological/cognitive variables and APPr were evaluated in the trained group (n = 28) before a two-month experimental protocol, immediately after its termination at follow-up 1 (FU1), after 6 months at follow-up 2 (FU2), and after 24 months at follow-up 3 (FU3). The control group (n = 31) received general psychoeducational training for two months. Some memory and attention parameters were significantly improved in trained vs. control patients at FU1 and FU2 compared to baseline (Δ values). At FU3, APPr and Mini Mental State Examination (MMSE) scores decreased in trained patients. Δ APPr correlated significantly with the Δ scores of (i) MMSE at FU1, (ii) the prose memory test at FU2, and (iii) Instrumental Activities of Daily Living (IADL), the semantic word fluency test, Clinical Dementia Rating (CDR), and the attentive matrices test at FU3. Our data demonstrate that the platelet APPr correlates with key clinical variables, thereby proving that it may be a reliable biomarker of brain function in AD patients

New peptide having specific amino acid sequence with antiviral and antimycotic activity, useful in the treatment or prevention of HIV infection, and for eradication of HIV virus from viral reservoirs in individuals suffering from HIV

NOVELTY - A peptide having specific amino acid sequence with antiviral and antimycotic activity, is new. USE - In a medical treatment; in the treatment or prevention of HIV infection; and for eradication of HIV virus from viral reservoirs in individuals suffering from HIV or in therapy for AIDS (claimed). ADVANTAGE - The peptide exhibits antiviral and antimycotic activity; exhibits very low cytotoxicity, and very high stability; exhibits good antimycotic activity, tested in particular on fungi particularly aggressive and commonly active in immunocompromized patients such as patient suffering from AIDS; and exhibits exceptional set of features which make them suitable for medical use in the therapy against HIV infection. DETAILED DESCRIPTION - A peptide having amino acid sequence containing 20 amino acids (SEQ ID NO: 1), as given in the specification with antiviral and antimycotic activity, is new. INDEPENDENT CLAIMS are included for the following: (1) new nucleotide sequence coding for the peptide of (SEQ ID NO: 1); (2) a pharmaceutical composition comprising an antiviral peptide of (SEQ ID NO: 1) as active principle and carrier; and (3) a pharmaceutical kit for concomitant or sequential administration comprising at least one aliquot of the antiviral peptide of (SEQ ID NO: 1) as active principle in a carrier and at least one aliquot of at least one of the active principles selected from: peptide having amino acid sequence containing 28 amino acids (SEQ ID NO: 2), 15 amino acids (SEQ ID NO: 3), as given in the specification, nucleoside inhibitors; non-nucleoside inhibitors; reverse transcriptase inhibitors; integrase inhibitors; viral protease inhibitors; antimycotics; antibacterials; and virus-host cell fusion process inhibitors

New peptide, useful for treating and/or preventing HIV infection, and/or eradication of HIV virus from viral reservoirs in individuals suffering from HIV and/or in therapy for AIDS and has antifungal activity

USE - The peptide of SEQ ID NO: 3 is useful for treating and/or preventing HIV infection, and/or eradication of HIV virus from viral reservoirs in individuals suffering from HIV and/or in therapy for AIDS (claimed). The peptide of SEQ ID NO: 3 has antifungal activity. The antifungal activity of the peptide of SEQ ID NO: 3 (100 mu g/ml) was tested against Cryptococcus neoformans 6995. The result showed that the peptide exhibited an EC50 value of 1.764x 10-5 moles/l. ADVANTAGE - The peptide of SEQ ID NO: 3 is non-toxic and exhibits improved stability. DETAILED DESCRIPTION - Peptide of SEQ ID NO: 3 (comprising a fully defined 15 amino acids sequence given in the specification) is new. INDEPENDENT CLAIMS are included for: (1) a nucleotide sequence coding for the peptide of SEQ ID NO: 3; (2) a composition comprising the peptide of SEQ ID NO: 3 as active principle and a carrier; and (3) a kit for concomitant or sequential administration, comprising one or more aliquots of the antiviral peptide of SEQ ID NO: 3 as active principle in a carrier and one or more aliquots of one or more of a active principles comprising peptide of SEQ ID NO: 2 (comprising a fully defined 28 amino acids sequence given in the specification), peptide of SEQ ID NO: 1 (comprising a fully defined 20 amino acids sequence given in the specification), nucleoside inhibitors, non-nucleoside inhibitors, reverse transcriptase inhibitors, integrase inhibitors, viral protease inhibitors, antimycotics, antibacterials, and virus-host cell fusion process inhibitors

Contribution of non-reference alleles in mtDNA of Alzheimer’s disease patients.

Many observations suggest that mutations of mitochondrial DNA (mtDNA) could be responsible for the neurodegenerative changes of Alzheimer's disease (AD). Here we examined the signal intensity of the four alleles of each mtDNA nucleotide position (np) in whole blood of AD patients and age-matched controls using MitoChip v2.0 array. Our analysis identified 270 significantly different nps which, with one exception, showed an increased contribution of non-reference alleles in AD patients. Principal component analysis (PCA) and cluster analysis showed that five of these nps could discriminate AD from control subjects with 80% of cases correctly classified. Our data support the hypothesis of mtDNA alterations as an important factor in the etiology of AD