Loss-of-Function Mutations in the ALPL Gene Presenting with Adult Onset Osteoporosis and Low Serum Concentrations of Total Alkaline Phosphatase

Hypophosphatasia (HPP) is a rare inherited disorder characterized by rickets and low circulating concentrations of total alkaline phosphatase (ALP) caused by mutations in ALPL. Severe HPP presents in childhood but milder forms can present in adulthood. The prevalence and clinical features of adult HPP are poorly defined. The aim of this study was to evaluate the prevalence and clinical significance of low serum total alkaline phosphatase (ALP) levels in a clinic-based population of adult osteoporotic patients. We searched for patients with low ALP in a cohort of 3285 patients referred to an osteoporosis clinic over a 10-year period and performed mutation screening of ALPL in those with low ALP (≤40 U/L) on two or more occasions. These individuals were matched with four clinic controls with a normal ALP. We also evaluated the prevalence of low ALP and ALPL mutations in 639 individuals from the general population from the same region. We identified 16/3285 (0.49%) clinic patients with low ALP and 14 (87.5%) had potentially pathogenic variants in ALPL. Eight of these individuals were heterozygous for mutations previously described in HPP and 2 were heterozygous for novel mutations (p.Arg301Trp and p.Tyr101X). These mutations were not found in clinic controls or in the general population. Eight patients with low ALP, including 4 with ALPL mutations, were treated with bisphosphonates for an average of 6.5 years. In these individuals, the rate of fractures during treatment was comparable to that in normal ALP clinic controls who were treated with bisphosphonates. We conclude that heterozygous loss-of-function mutations in ALPL are common in osteoporosis patients with low ALP. Further studies are required to determine how best these individuals should be treated. © 2019 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research.     

Brain volumetric changes and cognitive ageing during the eighth decade of life

Later‐life changes in brain tissue volumes—decreases in the volume of healthy grey and white matter and increases in the volume of white matter hyperintensities (WMH)—are strong candidates to explain some of the variation in ageing‐related cognitive decline. We assessed fluid intelligence, memory, processing speed, and brain volumes (from structural MRI) at mean age 73 years, and at mean age 76 in a narrow‐age sample of older individuals (n = 657 with brain volumetric data at the initial wave, n = 465 at follow‐up). We used latent variable modeling to extract error‐free cognitive levels and slopes. Initial levels of cognitive ability were predictive of subsequent brain tissue volume changes. Initial brain volumes were not predictive of subsequent cognitive changes. Brain volume changes, especially increases in WMH, were associated with declines in each of the cognitive abilities. All statistically significant results were modest in size (absolute r‐values ranged from 0.114 to 0.334). These results build a comprehensive picture of macrostructural brain volume changes and declines in important cognitive faculties during the eighth decade of life. Hum Brain Mapp 36:4910–4925, 2015. © 2015 The Authors. Human Brain Mapping Published by Wiley Periodicals, Inc     

Influence of maternal and paternal IQ on offspring health and health behaviours: Evidence for some trans-generational associations using the 1958 British birth cohort study

PurposeIndividuals scoring poorly on tests of intelligence (IQ) have been reported as having increased risk of morbidity, premature mortality, and risk factors such as obesity, high blood pressure, poor diet, alcohol and cigarette consumption. Very little is known about the impact of parental IQ on the health and health behaviours of their offspring.MethodsWe explored associations of maternal and paternal IQ scores with offspring television viewing, injuries, hospitalisations, long standing illness, height and BMI at ages 4 to 18 using data from the National Child Development Study (1958 birth cohort).ResultsData were available for 1446 mother-offspring and 822 father-offspring pairs. After adjusting for potential confounding/mediating factors, the children of higher IQ parents were less likely to watch TV (odds ratio (95% confidence interval) for watching 3+ vs. less than 3 hours per week associated with a standard deviation increase in maternal or paternal IQ: 0.75 (0.64, 0.88) or 0.78 (0.64, 0.95) respectively) and less likely to have one or more injuries requiring hospitalisation (0.77 (0.66, 0.90) or 0.72 (0.56, 0.91) respectively for maternal or paternal IQ).ConclusionsChildren whose parents have low IQ scores may have poorer selected health and health behaviours. Health education might usefully be targeted at these families.     

Acute hypoglycemia in humans causes attentional dysfunction while nonverbal intelligence is preserved

OBJECTIVE: Experimentally induced hypoglycemia in humans causes progressive but reversible cognitive dysfunction, but it is not known to what extent neuropsychological tests index abilities of cognitive functioning that are important in everyday life. This study examines the effects of acute insulin-induced hypoglycemia on attention and intelligence in nondiabetic humans. RESEARCH DESIGN AND METHODS: A hyperinsulinemic glucose clamp was used to achieve controlled euglycemia (4.50 [0.22] mmol/l) and hypoglycemia (blood glucose 2.59 [0.19] mmol/l) in 20 healthy volunteers. Subjects were studied on two occasions in a counterbalanced order. During each study condition, subjects completed parallel tests of cognitive function. Cognitive function was assessed by the Test of Everyday Attention and Raven's Progressive Matrices. RESULTS: Hypoglycemia induced a significant deterioration in tests sensitive to both visual and auditory selective attention. During hypoglycemia, attentional flexibility deteriorated and speed of information processing was delayed. Sustained attention was preserved and intelligence scores did not deteriorate during hypoglycemia. CONCLUSIONS: During hypoglycemia, a significant deterioration occurs in attentional abilities, whereas fluid intelligence is preserved. On the basis of these results, it can be surmised that many complex attention tasks relevant to everyday life are impaired during moderate hypoglycemia.     

Towards the automatic computational assessment of enlarged perivascular spaces on brain magnetic resonance images: A systematic review

Enlarged perivascular spaces (EPVS), visible in brain MRI, are an important marker of small vessel disease and neuroinflammation. We systematically evaluated the literature up to June 2012 on possible methods for their computational assessment and analyzed confounds with lacunes and small white matter hyperintensities. We found six studies that assessed/identified EPVS computationally by seven different methods, and four studies that described techniques to automatically segment similar structures and are potentially suitable for EPVS segmentation. T2‐weighted MRI was the only sequence that identified all EPVS, but FLAIR and T1‐weighted images were useful in their differentiation. Inconsistency within the literature regarding their diameter and terminology, and overlap in shape, intensity, location, and size with lacunes, conspires against their differentiation and the accuracy and reproducibility of any computational segmentation technique. The most promising approach will need to combine various MR sequences and consider all these features for accurate EPVS determination. J. Magn. Reson. Imaging 2013;38:774–785. © 2013 Wiley Periodicals, Inc.     

Mood and anxiety symptom questionnaire anxiety items in an adult british clinical sample: One scale or two?

In seeking to establish British clinical normative data for the two anxiety scales (anxious symptoms and anxious arousal) of the Mood and Anxiety Symptom Questionnaire (MASQ), the responses of 237 British National Health Service outpatients were examined. Factor analyses (exploratory and confirmatory) failed to confirm the expected structure. Data were presented and discussed, considering the 28 anxiety item pool in terms of being either two highly correlated scales of somatic anxiety versus psychological anxiety, or as a single general anxiety scale. As neither of these outcomes accorded with the test constructors' assumptions, it was concluded that the MASQ is not a suitable measure for assessing the tripartite model of adverse mood states in British clinical samples. Copyright © 2010 John Wiley & Sons, Ltd. Key Practitioner Message: ? Exploratory and confirmatory factor analyses failed to confirm the a priori MASQ anxiety items' structure. ? Alternative explanations were of either a) two highly correlated scales of somatic anxiety and psychological anxiety or b) a single general anxiety scale.     

Influence of hypoglycaemia, with or without caffeine ingestion, on visual sensation and performance

Full-field visual evoked potentials and visual information processing were measured in 16 normal, healthy subjects during a hyperinsulinaemic clamp. A randomized cross-over design was used across three conditions: hypoglycaemia and caffeine; hypoglycaemia and placebo; and euglycaemia and caffeine. The latency of the P100 component of the pattern-reversal visual evoked potential increased significantly from rest to hypoglycaemia, but no effect of caffeine was found. Subjects were subsequently divided into two median groups based on the increase in P100 latency in the placebo condition (Group 1, +0.5 ms; Group 2, +5.6 ms). In the absence of caffeine, an inverse correlation between the increase in P100 latency from rest and a deterioration in visual movement detection was found for Group 2, but not for Group 1. Caffeine ingestion resulted in a further increase in P100 latency, from rest to hypoglycaemia, for subjects in Group 2. Hypoglycaemia in the absence of caffeine produces changes in visual sensation from rest to hypoglycaemia. In those subjects most sensitive to the effects of hypoglycaemia (Group 2), the increase in P100 latency was associated with poorer performance in tests of visual information processing. Caffeine ingestion produced further increases in P100 latency in these subjects.     

Associations between Dietary Inflammatory Index Scores and Inflammatory Biomarkers among Older Adults in the Lothian Birth Cohort 1936 Study

The journal of nutrition, health & aging - Chronic low-grade inflammation is a key underlying mechanism in several age-related chronic conditions and previous studies have shown that diet can...