Distribution of Exonic Variants in Glycogen Synthesis and Catabolism Genes in Late Onset Pompe Disease (LOPD).

Pompe disease (PD) is a monogenic autosomal recessive disorder caused by biallelic pathogenic variants of the GAA gene encoding lysosomal alpha-glucosidase; its loss causes glycogen storage in lysosomes, mainly in the muscular tissue. The genotype-phenotype correlation has been extensively discussed, and caution is recommended when interpreting the clinical significance of any mutation in a single patient. As there is no evidence that environmental factors can modulate the phenotype, the observed clinical variability in PD suggests that genetic variants other than pathogenic GAA mutations influence the mechanisms of muscle damage/repair and the overall clinical picture. Genes encoding proteins involved in glycogen synthesis and catabolism may represent excellent candidates as phenotypic modifiers of PD. The genes analyzed for glycogen synthesis included UGP2, glycogenin (GYG1-muscle, GYG2, and other tissues), glycogen synthase (GYS1-muscle and GYS2-liver), GBE1, EPM2A, NHLRC1, GSK3A, and GSK3B. The only enzyme involved in glycogen catabolism in lysosomes is α-glucosidase, which is encoded by GAA, while two cytoplasmic enzymes, phosphorylase (PYGB-brain, PGL-liver, and PYGM-muscle) and glycogen debranching (AGL) are needed to obtain glucose 1-phosphate or free glucose. Here, we report the potentially relevant variants in genes related to glycogen synthesis and catabolism, identified by whole exome sequencing in a group of 30 patients with late-onset Pompe disease (LOPD). In our exploratory analysis, we observed a reduced number of variants in the genes expressed in muscles versus the genes expressed in other tissues, but we did not find a single variant that strongly affected the phenotype. From our work, it also appears that the current clinical scores used in LOPD do not describe muscle impairment with enough qualitative/quantitative details to correlate it with genes that, even with a slightly reduced function due to genetic variants, impact the phenotype.

Dealing with dehydration in hospitalized oldest persons: accuracy of the calculated serum osmolarity.

BACKGROUND:  Assessment of hydration status is complex and difficult to detect in older persons. Different methods have been developed to determine hydration status in clinical settings, but their diagnostic accuracy remains questionable. AIMS: The aim of this study was to determine and compare the diagnostic accuracy of all methods routinely used in acute settings to detect dehydration in a cohort of hospitalized oldest-old persons, using as primary reference standard blood urea nitrogen (BUN) to creatinine ratio. METHODS:  This retrospective study was conducted on 59 oldest-old subjects at hospital admission in an acute setting, with complete physical, biochemical, bioelectrical impedance analysis (BIA) and ultrasound assessment, including inferior vena cava diameters. RESULTS: Fifty-nine (45 women/14 men) subjects, with a mean age of 87.4 ± 5.9 years, were studied. Based on the value of the BUN/creatinine ratio, the whole population was divided into hyperhydrated (n = 10), normohydrated (n = 42), and dehydrated (n = 7) groups. Among parameters indicating the hydration status, serum sodium levels (p < 0.0001), serum chloride levels (p = 0.010), calculated plasma osmolarity (p < 0.0001), and fat mass (FM) (p = 0.030) differed significantly among groups. A ROC analysis showed that the highest and most significant value for dehydration detection was the calculated plasma osmolarity (AUC: 0.820, p = 0.013), which significantly correlated with clinical parameters including heart rate (r = 0.300; p = 0.021), capillary refill (r = 0.379; p = 0.013) and systolic blood pressure (r = - 0.261; p = 0.046). DISCUSSION: The measurement of calculated serum osmolarity is simple and inexpensive and may quickly provide high sensitivity and specificity indication of dehydration in hospitalized oldest-old persons.

Lower serum levels of IL-13 is associated with increased carotid intima-media thickness in old age subjects.

BACKGROUND: Cardiovascular diseases due to atherosclerosis represent the major cause of disability and mortality in old age subjects. The atherosclerotic process is linked to a low grade of systemic inflammation with the involvement of many cytokines and inflammatory proteins. Among them, evidence from animal studies suggests that IL-13 has a protective property. However, the role of IL-13 in the pathogenesis of atherosclerosis in humans is still unknown. AIMS: With this study, we aim to investigate a potential association between IL-13 and carotid intima-media thickness (IMT) in old age subjects. METHODS: This is a retrospective study conducted among 79 old age subjects (over 75 years old). All subjects underwent IMT assessment by high-resolution B-mode ultrasonography and IL-13 measurement in serum by ELISA. RESULTS: Subjects (41 M/38F) had a mean age of 81.0 ± 4.5 years and were mostly overweight. Stratifying the whole cohort by IMT thickness (IMT ≤ 0.9, n = 17; IMT ≥ 1 and ≤ 1.3, n = 50; IMT ≥ 1.4, n = 12) among the main variables explored, only BMI and triglycerides differed among groups, having subjects with higher IMT significantly higher BMI and lower triglycerides. Serum IL-13 levels significantly differed among groups having subjects with IMT ≥ 1.4 lower levels as compared to other groups (p < 0.0001). In all sample population, IMT values significantly correlate with IL-13 levels (r = - 0.454, p < 0.0001). Indeed, a linear regression analysis showed that independent of age, gender, body mass index, triglycerides, systolic blood pressure, statin use and smoking habit, lower IL-13 serum levels were associated with higher IMT values. CONCLUSIONS: IL-13, an anti-inflammatory cytokine, may have a protective role in the human atherosclerotic process. It could be used as an effective and promising novel therapeutic target development.

Intrathecal production of anti-Epstein-Barr virus viral capsid antigen IgG is associated with neurocognition and tau proteins in people with HIV.

OBJECTIVE: HIV and Epstein-Barr virus (EBV) co-infection has been linked to increased immune activation and larger HIV reservoir. We assessed whether anti-EBV humoral responses are associated with increased cerebrospinal fluid (CSF) inflammation and with neurocognitive impairment (NCI) in people with HIV (PWH). DESIGN: Cross-sectional analysis in 123 EBV-seropositive PWH either on antiretroviral therapy ( n  = 70) or not. METHODS: Serum and CSF anti-EBV viral capsid antigen immunoglobulin G (anti-EVI) and CSF EBV DNA were measured by commercial immunoassay and RT-PCR. Seventy-eight participants without neurological confounding factors underwent neurocognitive assessment (Global Deficit Score, GDS). CSF total tau and 181-phosphorylated-tau (ptau) were measured by immunoassays together with biomarkers of blood-brain barrier (BBB) integrity, immune activation, astrocytosis, and intrathecal synthesis. Logistic and linear regressions and moderation analysis were used to investigate the relationships between CSF anti-EVI, GDS, and biomarkers. RESULTS: Twenty-one (17.1%) and 22 participants (17.9%) had detectable CSF anti-EVI (10.5-416.0 U/ml) and CSF EBV DNA (25-971 copies/ml). After adjusting for BBB integrity, age, and clinical factors, the presence of CSF anti-EVI was only associated with serum levels of anti-EVI, and not with CSF EBV DNA. CSF anti-EVI, tau and ptau showed reciprocal interactions affecting their associations with GDS. After adjusting for demographics and clinical parameters, higher CSF anti-EVI levels were associated with worse GDS (aß 0.45, P  < 0.001), and CSF levels of tau and ptau had a moderation effect on the strength of this association (models' P  < 0.001). CONCLUSION: Humoral immune responses against EBV within the central nervous system may contribute to NCI in PWH through mechanisms that involve neuronal injury.

Hypovitaminosis D: A Disease Marker in Hospitalized Very Old Persons at Risk of Malnutrition.

BACKGROUND: Hypovitaminosis D is a frequent condition in elderly subjects. Vitamin D adequacy is best determined by measurement of the 25-hydroxyvitamin D-25(OH)D-concentration in the serum. An inverse association exists between 25(OH)D and cardiovascular, infectious, glucose metabolism, cognitive disorders, and all-cause mortality. Whether 25(OH)D is a marker of organ diseases is still under debate. We aimed to investigate whether comorbidities were associated with serum 25(OH)D levels in geriatric inpatients. METHODS: This is a retrospective study, including 237 subjects consecutively admitted to an acute care geriatric unit, with available data of 25(OH)D serum concentrations. 25(OH)D serum levels were defined according to the following cutoffs: 50⁻30 ng/mL (125⁻75 nmol/L): optimal range; 30⁻20 ng/mL (75⁻50 nmol/L): insufficiency; 20⁻10 ng/mL (5⁻25 nmol/L): deficiency; and <10 ng/mL (<25 nmol/L): severe deficiency. Comorbidity was assessed using the Cumulative Illness Rating Scale-Geriatric (CIRS-G). Two summary measures were obtained, the Illness Severity Index (CIRS-SI) and the Comorbidity Index (CIRS-CI). RESULTS: 177 (74.68%) women and 60 (25.32%) men with mean age of 85 ± 6 years old were enrolled. The majority of subjects (68.6%) were at risk of malnutrition. Overall, the burden of comorbidity was 1.87 ± 1.33 for CIRS-CI and 1.18 ± 0.40 for CIRS-SI. 25(OH)D serum concentrations were 10.58 ± 7.68 ng/mL, with 98.7% of subjects having vitamin D below 30 ng/mL and 56.6% with severe deficiency. An inverse correlation was found between 25(OH)D and both CIRS-SI (r: -0.312; p < 0.0001) and CIRS-CI (r: -0.306; p < 0.0001). Independent of multiple covariates an inverse association between both CIRS-SI (p < 0.0001) and CIRS-CI (p < 0.0001) and 25(OH)D was confirmed. Both CIRS-SI (r = 0.251, p < 0.0001) and CIRS-CI (r = 0.137, p = 0.016) were positively correlated with the length of hospital stay. An inverse correlation was confirmed between serum 25(OH)D concentrations and CRP (r = -0.142; p = 0.041). CRP, in turn, positively correlated with CIRS-SI (r = 0.209, p = 0.003) and CIRS-CI (r = 0.158, p = 0.023). Both CIRS-SI (r = 0.251, p < 0.0001) and CIRS-CI (r = 0.137, p = 0.016) were positively correlated with the length of hospital stay. CONCLUSIONS: In hospitalized very old subjects, a higher comorbidity burden is associated with lower 25(OH)D serum levels. Hypovitaminosis D was correlated with higher inflammatory status, which, together with the comorbidities burden, negatively influenced the length of hospital stay.

Prevalence and Correlates of Behavioral Disorders in Old Age Subjects with Cognitive Impairment: Results from the ReGAl Project.

BACKGROUND: Presence of behavioral and psychological symptoms of dementia (BPSD) is very common in subjects with cognitive impairment, representing an important determinant of disease progression, institutionalization, and worse prognosis. Knowledge of the prevalence and correlates of BPSD in community-living old subjects with cognitive impairment is limited so far, but it is essential for establishing specifically tailored care and cure in such a vulnerable population. OBJECTIVE: With this study, we aimed at investigating, in a large sample of old age subjects with cognitive impairment, BPSD prevalence and correlates including the main demographic, clinical, and socio-environmental characteristics. METHODS: Data were gathered from the ReGAl project (Rete Geriatrica Alzheimer; Geriatric Network on Alzheimer's disease), a large longitudinal Italian multicentric clinical-based study, promoted by the Italian Society of Gerontology and Geriatrics (SIGG). RESULTS: We evaluated data from 4,157 old-age subjects affected by mild cognitive impairment (MCI) (541; 13%) or dementia (3616; 87%). 85.2% of all the population presented with at least one BPSD. Using a factor analysis, we identified four factors of BPSD: psychotic, affective, maniac, and impulse control behaviors. Logistic regression analyses revealed that among the main demographic, clinical, and socio-environmental aspects considered, only comorbidity was associated with all factors, independently of multiple covariates. CONCLUSION: Identification of BPSD is crucial in everyday clinical practice and necessary to develop specific interventions and to define appropriate outcomes in their management. BPSD occur in a complex psychopathological context, influenced by several demographic and environmental factors that must be taken into account for a correct diagnosis and treatment.