Leukocyte telomere length and plasma interleukin-1β and interleukin-18 levels in mild cognitive impairment and Alzheimer's disease: new biomarkers for diagnosis and disease progression?

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Peripheral Biomarkers in Manifest and Premanifest Huntington’s Disease

Huntington's disease (HD) is characterized by clinical motor impairment (e.g., involuntary movements, poor coordination, parkinsonism), cognitive deficits, and psychiatric symptoms. An inhered expansion of the CAG triplet in the huntingtin gene causing a pathogenic gain-of-function of the mutant huntingtin (mHTT) protein has been identified. In this review, we focus on known biomarkers (e.g., mHTT, neurofilament light chains) and on new biofluid biomarkers that can be quantified in plasma or peripheral blood mononuclear cells from mHTT carriers. Circulating biomarkers may fill current unmet needs in HD management: better stratification of patients amenable to etiologic treatment; the initiation of preventive treatment in premanifest HD; and the identification of peripheral pathogenic central nervous system cascades

Analysis of the Association Between <i>TERC</i> and <i>TERT</i> Genetic Variation and Leukocyte Telomere Length and Human Lifespan—A Follow-Up Study

We investigated the possible influence of TERC and TERT genetic variation and leukocyte telomere length (LTL) on human lifespan. Four polymorphisms of TERT and three polymorphisms of TERC were examined in a sample of elderly subjects (70&#8315;100 years). After nine years of follow-up, mortality data were collected, and sub-samples of long-lived/not long-lived were defined. TERT VNTR MNS16A L/L genotype and TERT rs2853691 A/G or G/G genotypes were found to be associated with a significantly higher risk to die before the age of 90 years, and with a significantly lower age at death. The association between lifespan and LTL at baseline was analyzed in a subsample of 163 subjects. Age at baseline was inversely associated with LTL (p &lt; 0.0001). Mean LTL was greater in the subjects still living than in those no longer living at follow-up (0.79 T/S &#177; 0.09 vs. 0.63 T/S &#177; 0.08, p &lt; 0.0001). Comparison of age classes showed that, among the 70&#8315;79-year-olds, the difference in mean LTL between those still living and those no longer living at follow-up was greater than among the 80&#8315;90-year-olds. Our data provide evidence that shorter LTL at baseline may predict a shorter lifespan, but the reliability of LTL as a lifespan biomarker seems to be limited to a specific age (70&#8315;79 years)

Leukocyte telomere length in mild cognitive impairment and Alzheimer's disease patients

Numerous studies have reported an association between shortened leukocyte telomere length (LTL) and increased risk of Alzheimer's disease (AD). In this study we investigated the relationship between LTL and AD development, including in the analysis patients with amnestic mild cognitive impairment (aMCI), a clinical entity considered prodromal of AD. LTL (T/S ratio) was measured in patients with AD (n=61) or aMCI (n=46), and compared with LTL of age-matched controls (n=56). Significant LTL differences were observed between controls, aMCI and AD patients (p<0.0001), with mean LTL values (\ub1s.d) in the order: AD patients (0.70\ub10.15)<aMCI patients (0.80\ub10.14)<controls (0.88\ub10.15). A positive relationship (linear regression p=0.004) was observed between LTL and cognitive performance (measured by Mini Mental State Examination score). LTL did not differ by APOE genotype. The shortened LTL observed in AD patients appears to stem from progressive telomere erosion possibly correlated with the cognitive decline characterizing conversion from aMCI to AD. LTL reduction, indicating active cell proliferation, may reflect immune system involvement in AD pathogenesis

Splicing of mRNA mediated by tRNA sequences in mouse cells

tRNA splicing is essential for the formation of tRNAs and therefore for gene expression. A circularly permuted sequence of an amber-suppressor pre-tRNA gene was inserted into the sequence encoding the mouse NEMO protein. We demonstrated that, in mouse cells, the hybrid pre-tRNA/pre-mRNAs can be spliced precisely at the sites of the pre-tRNA intron. This splicing reaction produces functional tRNAs that suppress amber codons as well as translatable mRNAs that sustain the NF-κB activation pathway. The RNA molecules extracted from mouse cells were amplified by RT-PCR, and their sequences were determined, confirming the identity of the splice junctions. We then applied the Archaea-express technology, in which an archaeal RNA endonuclease is expressed in mouse cells. We show that both the endogenous eukaryal endonuclease and the archaeal one cleave the hybrid pre-tRNA/pre-mRNAs in the same manner with an additive effect

Influence of family history of dementia in the development and progression of late-onset Alzheimer's disease

Family history of dementia (FH) is a recognized risk factor for developing late-onset Alzheimer’s disease (AD). We asked whether having FH increases AD risk and influences disease severity (age at onset and cognitive impairment) in 420 AD patients and 109 controls with (FHþ) or without (FH). The relationships of APOE and other AD risk genes with FH were analyzed as well. The proportion of APOE e4 allele carriers was higher among the FHþ than the FH AD patients (49.6% vs. 38.9%; P¼0.04). The distribution of the risk genotypes of nine AD susceptibility genes previously examined (CHAT, CYP17, CYP19, ESR1, FSHR, P53, P73, P21, PPARG) did not differ between the FHþ and the FH AD patients, indicating that none contributed significantly to familial clustering of disease. FH was associated with an increased AD risk (odds ratio [OR] 2.71, 95% confidence interval [CI] 1.44–5.09; P¼0.002) independent of carrying the APOE e4 allele (OR 2.61, 95%CI 1.53–4.44; P¼0.0004). Having a first-degree relative or a parent with dementia was significantly associated with AD risk (OR 2.9, 95%CI 1.3–6.4; P¼0.009 and OR 2.7, 95%CI 1.1–6.2; P¼0.02) but having a sibling with dementia was not (OR 1.7, 95%CI 0.2 to 14.7; P¼0.6). Among the FHþ AD patients, having one or both parents affected seemed to raise the risk of earlier onset age (P¼0.02) and greater cognitive impairment (P¼0.02) than having only an affected sibling, whereas having two or more affected relatives did not. 2015 Wiley Periodicals, Inc

Association study of two steroid biosynthesis genes (COMT and CYP17) with Alzheimer's disease in the Italian population

The greater predisposition of women to Alzheimer's disease (AD), owing to the decrease in postmenopausal estrogen, may be influenced by polymorphic variation in genes regulating estrogen metabolism (e.g., COMT) and estrogen biosynthesis (e.g., CYP17). In order to better understand how the estrogen pathway genetic variation might affect AD onset, we conducted a case-control study of two single nucleotide polymorphisms (SNPs) of these two genes (COMT rs4680 and CYP17 rs743572) in a sample of AD patients of Italian origin. The COMT allele and genotype were found associated neither with AD onset nor with parameters of AD severity, such as cognitive impairment, age at onset, or disease duration. In contrast, CYP17 was found to affect the age at disease onset mainly in males and, as compared with noncarriers, people carrying the A2 (C) allele had a 2.2-fold increased risk for AD. These findings suggest that the CYP17 A2 allele influences AD susceptibility in a sex-specific way by acting not only on AD risk but also on the age at disease onset, an important parameter of AD severity. © 2014 Elsevier B.V

Leukocyte Telomere Length as Potential Biomarker of HD Progression: A Follow-Up Study

The identification of biomarkers for neurodegenerative disorders such as Huntington&rsquo;s disease (HD) is crucial for monitoring disease progression and therapeutic trial outcomes, especially in the pre-manifest disease stage (pre-HD). In a previous study, we observed that leukocyte telomere length (LTL) was strongly correlated with the estimated time to clinical onset in pre-HD subjects. To validate this hypothesis, we designed a follow-up study in which we analyzed LTL in 45 pre-HD stage subjects at baseline (T0) and then again after clinical onset at follow-up (T1); the follow-up interval was about 3 years, and the CAG range was 39&ndash;51 repeats; 90 peripheral blood mononuclear cell samples (PBMCs) were obtained from the Enroll-HD biorepository. In pre-HD subjects at T0, LTL was significantly reduced by 22% compared to the controls and by 14% from T0 at T1. No relationship was observed between the LTL and CAG numbers in subjects carrying different CAG repeats at T0 and at T1, suggesting that LTL reduction occurs independently of CAG number in pre-HD subjects. ROC curve analysis was used to test the validity of LTL as a potential biomarker of HD progression and showed that LTL measurement is extremely accurate in discriminating pre-HD subjects from the controls and even pre-HD from manifest HD, thus yielding a robust prognostic value in pre-HD subjects

Leukocyte Telomere Length Variability as a Potential Biomarker in Patients with PolyQ Diseases

SCA1, SCA2, and SCA3 are the most common forms of SCAs among the polyglutamine disorders, which include Huntington&rsquo;s Disease (HD). We investigated the relationship between leukocyte telomere length (LTL) and the phenotype of SCA1, SCA2, and SCA3, comparing them with HD. The results showed that LTL was significantly reduced in SCA1 and SCA3 patients, while LTL was significantly longer in SCA2 patients. A significant negative relationship between LTL and age was observed in SCA1 but not in SCA2 subjects. LTL of SCA3 patients depend on both patient&rsquo;s age and disease duration. The number of CAG repeats did not affect LTL in the three SCAs. Since LTL is considered an indirect marker of an inflammatory response and oxidative damage, our data suggest that in SCA1 inflammation is present already at an early stage of disease similar to in HD, while in SCA3 inflammation and impaired antioxidative processes are associated with disease progression. Interestingly, in SCA2, contrary to SCA1 and SCA3, the length of leukocyte telomeres does not reduce with age. We have observed that SCAs and HD show a differing behavior in LTL for each subtype, which could constitute relevant biomarkers if confirmed in larger cohorts and longitudinal studies

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