Axonal damage and astrocytosis are biological correlates of grey matter network integrity loss: a cohort study in autosomal dominant Alzheimer disease.

Brain development and maturation leads to grey matter networks that can be measured using magnetic resonance imaging. Network integrity is an indicator of information processing capacity which declines in neurodegenerative disorders such as Alzheimer disease (AD). The biological mechanisms causing this loss of network integrity remain unknown. Cerebrospinal fluid (CSF) protein biomarkers are available for studying diverse pathological mechanisms in humans and can provide insight into decline. We investigated the relationships between 10 CSF proteins and network integrity in mutation carriers (N=219) and noncarriers (N=136) of the Dominantly Inherited Alzheimer Network Observational study. Abnormalities in Aß, Tau, synaptic (SNAP-25, neurogranin) and neuronal calcium-sensor protein (VILIP-1) preceded grey matter network disruptions by several years, while inflammation related (YKL-40) and axonal injury (NfL) abnormalities co-occurred and correlated with network integrity. This suggests that axonal loss and inflammation play a role in structural grey matter network changes. Key points: Abnormal levels of fluid markers for neuronal damage and inflammatory processes in CSF are associated with grey matter network disruptions.The strongest association was with NfL, suggesting that axonal loss may contribute to disrupted network organization as observed in AD.Tracking biomarker trajectories over the disease course, changes in CSF biomarkers generally precede changes in brain networks by several years.

Associations of Stages of Objective Memory Impairment with Cerebrospinal Fluid and Neuroimaging Biomarkers of Alzheimer's Disease.

OBJECTIVE: To investigate cerebrospinal fluid (CSF) and neuroimaging correlates of Stages of Objective Memory Impairment (SOMI) based on Free and Cued Selective Reminding Test (FCSRT) performance, and to evaluate the effect of APOE ε4 status on this relationship. METHODS: Data from 586 cognitively unimpaired individuals who had FCSRT, CSF, and volumetric magnetic resonance imaging (MRI) measures available was used. We compared CSF measures of ß-amyloid (Aß42/Aß40 ratio), phosphorylated tau (p-Tau181), total tau (t-Tau), hippocampal volume, and PIB-PET mean cortical binding potential with partial volume correction (MCBP) among SOMI groups in the whole sample and in subsamples stratified by APOE ε4 status. RESULTS: Participants had a mean age of 67.4 (SD=9.1) years, had 16.1 (SD=2.6) years of education, 57.0% were female, and 33.8% were APOE ε4 positive. In the entire sample, there was no significant difference between SOMI stages in Aß42/Aß40 ratio, p-Tau181, t-Tau, or PIB-PET MCBP when adjusted for age, sex, and education. However, higher SOMI stages had smaller hippocampal volume (F=3.29, p=0.020). In the stratified sample based on APOE ε4 status, in APOE ε4 positive individuals, higher SOMI stages had higher p-Tau181 (F=2.94, p=0.034) higher t-Tau (F=3.41, p=0.019), and smaller hippocampal volume (F=5.78, p<0.001). There were no significant differences in CSF or imaging biomarkers between SOMI groups in the APOE ε4 negative subsample. CONCLUSION: Cognitively normal older individuals with higher SOMI stages have higher in-vivo tau and neurodegenerative pathology only in APOE ε4 carriers. These original results indicate the potential usefulness of the SOMI staging system in assessing of tau and neurodegenerative pathology.

Glucose response to exercise in the post-prandial period is independent of exercise intensity.

This study investigated the acute glucose response to low-intensity, moderate-intensity, and high-intensity interval exercise compared to no-exercise in healthy insufficiently active males using a four-arm, randomized, crossover design. Ten males (age: 37.3 ± 7.3 years, BMI: 29.3 ± 6.5 kg·m-2 ) completed four 30-minute interventions at weekly intervals comprising low-intensity exercise (LIE) at ~35% V˙O2 R, moderate-intensity exercise (MIE) at ~50% V˙O2 R, high-intensity interval exercise (HIIE) at ~80% V˙O2 R, and a no-exercise control. Participants performed cycle ergometer exercise 30 minutes after finishing breakfast. Glucose response was assessed using a continuous glucose monitor under free-living conditions with dietary intake replicated. A significant effect for intensity on energy expenditure was identified (P < .001) with similar energy cost in MIE (mean ± SD: 869 ± 148 kJ) and HIIE (806 ± 145 kJ), which were both greater than LIE (633 ± 129 kJ). The pattern of glucose response between the interventions over time was different (P = .02). Glucose was lower 25 minutes into each of the HIIE, MIE and LIE trials respectively (mean difference ± SD: -0.7 ± 1.1; -0.9 ± 1.1; -0.6 ± 0.9 mmol·L-1 ; P < .05) than in the no-exercise trial. Glucose response was not different between exercise intensities (P > .05). Twenty-four-hour AUC was not affected by exercise intensity (P = .75). There was a significant effect for exercise enjoyment (P = .02), with LIE (69 ± 4) preferred less than HIIE (mean ± SD: 84 ± 14; P = .02), MIE (73 ± 5; P = .03), and no-exercise (75 ± 4; P = .03). Exercise at any intensity 30 minutes after a meal affects glycemic regulation equally in insufficiently active males. Moderate to vigorous exercise intensities were preferred, and therefore, the exercise guidelines appear appropriate for the prevention of cardiometabolic disease.

Prefrontal gray matter volume mediates age effects on memory strategies.

Age differences in the strategies that individuals spontaneously use to learn new information have been shown to contribute to age differences in episodic memory. We investigated the role of prefrontal structure in observed age effects on self-initiated use of memory strategies. The relationships among age, prefrontal regional gray matter volumes, and semantic and serial clustering during free recall on the California Verbal Learning Test-II were examined across the adult lifespan. Semantic clustering was negatively correlated with age and positively correlated with gray matter volumes in bilateral middle and left inferior frontal regions across the adult lifespan. Gray matter volumes in these regions mediated the effects of age on semantic clustering. Forward serial clustering was also negatively correlated with age. However, forward serial clustering was not significantly positively correlated with gray matter volumes in any region of lateral prefrontal cortex. These results suggest that bilateral middle and left inferior frontal regions support self-initiated semantic memory strategy use across the adult lifespan. They also suggest that age differences in prefrontal gray matter volume are a significant contributor to age differences in self-initiated use of elaborative memory strategies.

Insulin sensitivity not modulated 24 to 78 h after acute resistance exercise in type 2 diabetes patients.

Resistance exercise is recommended as part of the exercise guidelines to prevent and manage type 2 diabetes (T2D), however, the frequency of exercise required to improve glycaemic control and insulin sensitivity is not clear. We recruited and tested 10 individuals with T2D by collecting a fasting blood sample immediately prior to, a whole-body moderate-high intensity resistance exercise session, and 24, 48 and 72 h afterwards. No changes to estimates of insulin sensitivity (HOMA2), glucose or insulin were observed using a repeated measures analysis of variance (p > 0.05). Further, there were no changes observed to markers of inflammation at 24 h following the resistance exercise session (p > 0.05). These findings suggest that insulin sensitivity is not acutely modified, positively or negatively, at 24, 48 or 72 h after a bout of resistance exercise. Nor are markers of inflammation altered during this time frame in a way that could cause transient insulin resistance.

Insulin sensitivity in response to a single resistance exercise session in apparently healthy individuals.

BACKGROUND: Regular resistance exercise completed for a number of weeks has been shown to increase insulin sensitivity and reduce the risk of diabetes-related complications. However, the acute responses to resistance exercise have not been adequately investigated in relation to training frequency. AIM: To investigate the changes to insulin sensitivity in apparently healthy individuals following a single session of unaccustomed resistance exercise. SUBJECTS AND METHODS: Ten sedentary, apparently healthy individuals performed a baseline oral glucose tolerance test and maximal strength testing. Participants then performed a single session of moderate-high intensity resistance exercise which was followed by 4 consecutive days of oral glucose tolerance testing, for which participants replicated their initial diet. Mean estimated insulin sensitivity change scores from baseline values and their 95% confidence intervals were compared to the previously determined values for a clinically meaningful change. RESULTS: Two participants were identified as having hyperinsulinemia and their data were therefore removed from the main analysis. There was a clinically meaningful increase in insulin response (mean >7237 pmol·l⁻¹·120 min⁻¹) on all days following the exercise session and a clinically meaningful increase in glucose response (mean >81 mmol·l⁻¹·120 min⁻¹) on only the 3rd day following exercise. These changes suggest a potentially adverse short-term effect. Additionally, the 2 individuals with hyperinsulinemia displayed more extreme results. CONCLUSION: These results suggest that insulin sensitivity may be impaired following a single session of unaccustomed resistance exercise for approximately 4 days in healthy untrained, older individuals. Further research is required for individuals with hyperinsulinemia.

Reproducibility of multiple repeated oral glucose tolerance tests.

We assessed the oral glucose tolerance test's (OGTT) ability to produce consistent results for estimating insulin sensitivity over four consecutive days. Individual coefficients of variation for OGIS and Stumvoll-ISI were 7.8% and 14.4% with no statistically significant difference between days. Thereby, indicating repeated OGTT's are reliable for estimating insulin sensitivity.

Resistance training improves metabolic health in type 2 diabetes: a systematic review.

This paper systematically reviews the effect of resistance training (RT) on glycemic control and insulin sensitivity in adults with type 2 diabetes. Twenty studies were included, with the volume, frequency and intensity of RT varying markedly. Supervised RT improved glycemic control and insulin sensitivity, however, when supervision was removed compliance and glycemic control decreased. Evidence indicates the mechanisms behind the improvements to glucose tolerance require further elucidation. Although research demonstrates apparent benefits of RT for individuals with diabetes, further research is required to elucidate the minimum effective dose by describing frequency, intensity and the duration of acute and chronic improvements.

Aspartylglucosaminuria in a Canadian family.

Aspartylglucosaminuria (McKusick 208400) is a lysosomopathy associated with aspartylglucosaminidase (L-aspartamido-beta-N-acetylglucosamine amidohydrolase, EC 3.5.1.26) deficiency. It has been most frequently encountered in Finland, where the regional incidence may be as high as 1 in 3600 births. In North America it is very rare, having been reported in only 8 patients. We encountered 4 patients with aspartylglucosaminuria in a Canadian family of 12 siblings. The 4 siblings affected--2 brothers and 2 sisters--were apparently normal at birth; however, their developmental milestones, particularly speech, were slow, and they acquired only a simple vocabulary. Throughout life, there was a progressive coarsening of facial features; 3 had inguinal hernia and recurrent diarrhea; all became severely retarded and by the 4th decade showed evident deterioration of both cognitive and motor skills; 2 exhibited cyclical behavioural changes. Three of the siblings have died, at 33, 39 and 44 years of age. Two died of bronchopneumonia and 1 of asphyxiation following aspiration. In the urine of all 4 siblings, and in the 1 liver examined, we found 2-acetamido-1-N-(4-L-aspartyl)-2-deoxy-beta-D-glucosamine (GlcNAc-Asn) and alpha-D-mannose-(1,6)-beta-D-mannose-(1,4)-2-acetamido- 2-deoxy-beta-D-glucose-(1,4)-2-acetamido-1-N-(4-L-aspartyl)-2-deoxy-beta - D-glucosamine (Man2-GlcNAc2-Asn). Compared with the level of activity in controls, aspartylglucosaminidase activity was less than 2% in fibroblasts from 3 of the siblings, less than 0.5% in leukocytes from 1 sibling, and less than 1% in the liver of 1 sibling, whereas other acid hydrolase activities in these tissues were normal. Ultrastructural studies of skin showed that fibroblasts, endothelial cells and pericytes contained vacuoles with fine reticulo-floccular material. Glial and neuronal cells of the central nervous system showed similar inclusions as well as others composed of concentric or parallel membranous arrays intermingled with lipid droplets.

Isolated sulfite oxidase deficiency.

Isolated sulfite oxidase (SO) deficiency is an autosomal recessively inherited inborn error of sulfur metabolism. In this report of a ninth patient the clinical history, laboratory results, neuropathological findings and a mutation in the sulfite oxidase gene are described. The data from this patient and previously published patients with isolated sulfite oxidase deficiency and molybdenum cofactor deficiency are summarized to characterize this rare disorder. The patient presented neonatally with intractable seizures and did not progress developmentally beyond the neonatal stage. Dislocated lenses were apparent at 2 months. There was increased urine excretion of sulfite and S-sulfocysteine and a decreased concentration of plasma cystine. A lactic acidemia was present for 6 months. Liver sulfite oxidase activity was not detectable but xanthine dehydrogenase activity was normal. The boy died of respiratory failure at 32 months. Neuropathological findings of cortical necrosis and extensive cavitating leukoencephalopathy were reminiscent of those seen in severe perinatal asphyxia suggesting an etiology of energy deficiency. A point mutation that resulted in a truncated protein missing the molybdenum-binding site has been identified.

Heteroallelic missense mutations of the galactosamine-6-sulfate sulfatase (GALNS) gene in a mild form of Morquio disease (MPS IVA).

Morquio disease (MPS IVA) is an autosomal recessive disorder caused by a deficiency of N-acetylgalactosamine-6-sulfate sulfatase (GALNS) activity. Patients commonly present in early infancy with growth failure, spondyloepiphyseal dysplasia, corneal opacification, and keratan sulfaturia, but milder forms have been described. We report on a patient who grew normally until age 5 years. Her keratan sulfaturia was not detected until adolescence, and she now has changes restricted largely to the axial skeleton. She has experienced only mildly impaired vision. At age 22, thin-layer chromatography of purified glycosaminoglycans showed some keratan sulfaturia. GALNS activity in fibroblast homogenate supernatants was 20 +/- 5% of controls (as compared to 5 +/- 3% of controls in severe MPS IVA, P < .003). Kinetic analysis of residual fibroblast GALNS activity in patient and parents revealed decreased K(m) and increased Vmax in the mother and daughter, but not in the father, compatible with compound heterozygosity. GALNS exons were amplified from patient genomic DNA and screened by SSCP. Two missense mutations, a C to T transition at position 335 (predicting R94C) and a T to G transversion at position 344 (predicting F97V), were found on sequencing an abnormally migrating exon 3 amplicon. Digestion of the amplicon with FokI and AccI restriction enzymes (specific for the R94C and F97V mutations, respectively) confirmed heterozygosity. In fibroblast transfection experiments, heterozygous R94C and F97V mutants independently expressed as severe and mild GALNS deficiency, respectively. We interpret these findings to indicate that our patient bears heteroallelic GALNS missense mutations, leading to GALNS deficiency and mild MPS IVA. Our findings expand the clinical and biochemical phenotype of MPS IVA, but full delineation of the genotype-phenotype relationship requires further study of native and transfected mutant cell lines.

Hyperornithinemia-hyperammonemia-homocitrullinuria (HHH)-syndrome. Ultrastructural changes of mitochondria in cultured dermal fibroblasts of three patients.

Mitochondria of fibroblasts cultured from the skin obtained at biopsy from three patients with the hyperornithinemia-hyperammonemia-homocitrullinuria (HHH)-syndrome, one of the autosomal recessive, heritable urea cycle disorders, were studied with appropriate controls ultrastructurally. The patients were two severely retarded 10- and 12-year-old boys, and a 22-year-old sister of the former whose mental status was at the low normal range; she never had motor impairments or seizures. The mitochondria, similar in all three patients, were increased in number, very long, branching and/or "looping," and tortuous. "Spurs" or "buddings" extended from their lateral surfaces and the terminal segments were often bulbous. Other unusual configurations were also present. In addition, giant forms with large diameter contained innumerable closely-packed and parallel cristae which traversed the entire width of these mitochondria; at times they assumed a "whirled" pattern. The mitochondrial matrix was usually of high electron density. These changes were not a feature of fibroblastic mitochondria of controls. Several changes resembled those of hepatic mitochondria in this disorder. All features are interpreted as an attempt at expanding the mitochondrial volume (via structural substratum) to compensate for the metabolic incompetence of these organelles (a block in transmembranous transfer of ornithine from hyaloplasm into mitochondria for conversion to citrulline).

Fucosidosis with dystonia.

Fucosidosis, a progressive neurodegenerative disease, evident in early childhood, is associated with progressive loss of mental and motor function and increasing spasticity and hyperreflexia. We report a Canadian male, with clinical features similar to previously reported fucosidosis patients, however, since age 5 he has exhibited progressive dystonic posturing, initially unilateral, but recently involving both lower limbs. Extensive study of his cultured lymphoblasts demonstrated that alpha-fucosidase activity and immunoreactive alpha-fucosidase protein were absent. He is homozygous for the Q422X mutation, a C to T transition within exon 8 of the alpha-fucosidase gene which results in loss of an EcoR1 restriction enzyme cut site. Even among the 4 other reported fucosidosis families having one or more individuals homozygous for this same (Q422X) mutation there was no previous report of dystonia.

Pyomyositis: characteristics at CT and MR imaging.

PURPOSE: To establish imaging criteria for pyomyositis (PM). MATERIALS AND METHODS: Twenty-seven computed tomographic (CT) scans and 11 magnetic resonance (MR) images obtained in 32 patients with PM were reviewed. Images in 10 patients with PM and 16 with soft-tissue masses were evaluated blindly. RESULTS: At CT, all 27 patients had muscle enlargement with heterogeneous attenuation; 26 patients had a focal fluid collection, with rim enhancement in all 18 patients who underwent contrast material-enhanced CT. Twenty-four patients had cellulitis. At MR imaging, all 11 patients had both a subtle increase in signal intensity in the affected muscle(s) on T1-weighted images and cellulitis. Nine patients had a focal fluid collection, which had high signal intensity and a hypointense rim on T2-weighted images. In six patients, a rim of increased signal intensity was seen around the collection on T1-weighted images. Six gadolinium-enhanced examinations demonstrated rim enhancement. Eight patients had fluid in the distal joint. All patients with PM were correctly identified when evaluated with the control subjects; however, there were four false-positive results. CONCLUSION: CT and MR imaging can help characterize changes that are suspicious for PM.

Ataxia in institutionalized patients with epilepsy.

Fifty-four per cent of 41 chronically institutionalized adult patients with epilepsy had ataxia of gait (wide mean stride width). None of the following correlated with stride width: serum phenytoin, previous phenytoin toxicity, seizure frequency, or status epilepticus. Seventeen of the 41 patients had computed tomographic head scans. Patients with radiological evidence of cerebellar atrophy had a wider mean stride width, later age of onset of seizures, greater peak serum concentrations of phenytoin than did those without cerebellar atrophy. Ataxia of gait was inconsistently associated with cerebellar atrophy. Elevated serum/plasma concentrations of phenytoin may be a risk factor for cerebellar atrophy, but seizure frequency or status epilepticus are not independently related to this complication.

Retrospective diagnosis of medium chain acyl-CoA dehydrogenase deficiency.

A male infant is reported who died suddenly and who at post-mortem had pathological evidence suggestive of a genetic defect of fatty acid beta-oxidation. A specific diagnosis could not be made enzymatically because of unavailability of suitable tissue for assay. The diagnosis of medium chain acyl-CoA dehydrogenase (MCAD) deficiency was made by specific mutation analysis using the polymerase chain reaction and DNA extracted from the newborn screening card of this infant. This powerful new molecular diagnostic technique should prove to be of use in similar circumstances.