Benjamin S. Aribisala

Very-Low-Calorie Diet and 6 Months of Weight Stability in Type 2 Diabetes: Pathophysiological Changes in Responders and Nonresponders

OBJECTIVE Type 2 diabetes mellitus (T2DM) is generally regarded as an irreversible chronic condition. Because a very low-calorie diet (VLCD) can bring about acute return to normal glucose control in some people with T2DM, this study tested the potential durability of this normalization. The underlying mechanisms were defined. RESEARCH DESIGN AND METHODS People with a T2DM duration of 0.5–23 years (n = 30) followed a VLCD for 8 weeks. All oral agents or insulins were stopped at baseline. Following a stepped return to isocaloric diet, a structured, individualized program of weight maintenance was provided. Glucose control, insulin sensitivity, insulin secretion, and hepatic and pancreas fat content were quantified at baseline, after return to isocaloric diet, and after 6 months to permit the primary comparison of change between post–weight loss and 6 months in responders. Responders were defined as achieving fasting blood glucose <7 mmol/L after return to isocaloric diet. RESULTS Weight fell (98.0 ± 2.6 to 83.8 ± 2.4 kg) and remained stable over 6 months (84.7 ± 2.5 kg). Twelve of 30 participants achieved fasting plasma glucose <7 mmol/L after return to isocaloric diet (responders), and 13 of 30 after 6 months. Responders had a shorter duration of diabetes and a higher initial fasting plasma insulin level. HbA1c fell from 7.1 ± 0.3 to 5.8 ± 0.2% (55 ± 4 to 40 ± 2 mmol/mol) in responders (P < 0.001) and from 8.4 ± 0.3 to 8.0 ± 0.5% (68 ± 3 to 64 ± 5 mmol/mol) in nonresponders, remaining constant at 6 months (5.9 ± 0.2 and 7.8 ± 0.3% [41 ± 2 and 62 ± 3 mmol/mol], respectively). The responders were characterized by return of first-phase insulin response. CONCLUSIONS A robust and sustainable weight loss program achieved continuing remission of diabetes for at least 6 months in the 40% who responded to a VLCD by achieving fasting plasma glucose of <7 mmol/L. T2DM is a potentially reversible condition.

White matter hyperintensities and normal-appearing white matter integrity in the aging brain

White matter hyperintensities (WMH) of presumed vascular origin are a common finding in brain magnetic resonance imaging of older individuals and contribute to cognitive and functional decline. It is unknown how WMH form, although white matter degeneration is characterized pathologically by demyelination, axonal loss, and rarefaction, often attributed to ischemia. Changes within normal-appearing white matter (NAWM) in subjects with WMH have also been reported but have not yet been fully characterized. Here, we describe the in vivo imaging signatures of both NAWM and WMH in a large group of community-dwelling older people of similar age using biomarkers derived from magnetic resonance imaging that collectively reflect white matter integrity, myelination, and brain water content. Fractional anisotropy (FA) and magnetization transfer ratio (MTR) were significantly lower, whereas mean diffusivity (MD) and longitudinal relaxation time (T1) were significantly higher, in WMH than NAWM (p < 0.0001), with MD providing the largest difference between NAWM and WMH. Receiver operating characteristic analysis on each biomarker showed that MD differentiated best between NAWM and WMH, identifying 94.6% of the lesions using a threshold of 0.747 × 10−9 m2s−1 (area under curve, 0.982; 95% CI, 0.975–0.989). Furthermore, the level of deterioration of NAWM was strongly associated with the severity of WMH, with MD and T1 increasing and FA and MTR decreasing in NAWM with increasing WMH score, a relationship that was sustained regardless of distance from the WMH. These multimodal imaging data indicate that WMH have reduced structural integrity compared with surrounding NAWM, and MD provides the best discriminator between the 2 tissue classes even within the mild range of WMH severity, whereas FA, MTR, and T1 only start reflecting significant changes in tissue microstructure as WMH become more severe.

Blood Pressure, Internal Carotid Artery Flow Parameters, and Age-Related White Matter Hyperintensities

White matter hyperintensities (WMH) are associated with hypertension. We examined interactions among blood pressure (BP), internal carotid artery (ICA) flow velocity parameters, and WMH. We obtained BP measurements from 694 community-dwelling subjects at mean ages 69.6 (±0.8) years and again at 72.6 (±0.7) years, plus brain MRI and ICA ultrasound at age 73±1 years. Diastolic and mean BP decreased and pulse pressure increased, but systolic BP did not change between 70 and 73 years. Multiple linear regression, corrected for vascular disease and risk factors, showed that WMH at the age of 73 years were associated with history of hypertension (&bgr;=0.13; P<0.001) and with BP at the age of 70 years (systolic &bgr;=0.08, mean &bgr;=0.09, diastolic &bgr;=0.08; all P<0.05); similar but attenuated associations were seen for BP at the age of 73 years. Lower diastolic BP and higher pulse pressure were associated with higher ICA pulsatility index at the age 73 years (diastolic BP age 70 years: standardized &bgr;=−0.24, P<0.001; pulse pressure age 70 years: &bgr;=0.19, P<0.001). WMH were associated with higher ICA pulsatility index (&bgr;=0.13; P=0.002) after adjusting for BP and correction for multiple testing. Therefore, falling diastolic BP and increased pulse pressure are associated with increased ICA pulsatility index, which in turn is associated with WMH. This suggests that hypertension and WMH may either associate indirectly because hypertension increases arterial stiffness that leads to WMH over time, or coassociate through advancing age and stiffer vessels, or both. Reducing vascular stiffness may reduce WMH progression and should be tested in randomized trials, in addition to testing antihypertensive therapy.

Close Correlation between Quantitative and Qualitative Assessments of White Matter Lesions

Background: White matter lesions (WML) increase with age and are associated with stroke, cognitive decline and dementia. They can be visually rated or computationally assessed. Methods: We compared WML Fazekas visual rating scores and volumes, determined using a validated multispectral image-fusion technique, in Magnetic Resonance Imaging from 672 participants of the Lothian Birth Cohort 1936 and sought explanations for subjects in whom the correlation (Spearman’s ρ) between the total Fazekas score (summed deep and periventricular ratings, 0–6) and WML volume did not concur (z-score difference >1). Infarcts were identified separately. Results: The median WML Fazekas score was 2 [inter-quartile range (IQR): 2], median WML volume 7.7 ml (IQR: 13.6 ml) and median infarct volume (n = 95) 0.98 ml. Score and volume were highly correlated (Spearman’s ρ = 0.78, p < 0.001). Infarcts did not alter the correlation. Minor discordance occurred in 94/672 (14%) subjects, most with total Fazekas score of 1 (n = 20, WML volume = 4.5–14.8 ml) or 2 (n = 50, WML volume = 0.1–34.4 ml). The main reasons were: subtle WML identified visually but omitted from the volume; prominent ventricular caps but thin body lining giving a periventricular score of 1/2 but large WML volume, and small deep focal lesions which increase the score disproportionally when beginning to coalesce with little change in WML volume. Conclusions: WML rating scores and volumes provide near-equivalent estimates of WML burden, therefore either can be used depending on research circumstances. Even closer agreement could result from improved computational detection of subtle WML and modified visual ratings to differentiate prominent ventricular caps from thin periventricular linings, and small non-coalescent from early coalescent deep WML.

MR imaging in Duchenne muscular dystrophy: Quantification of T1‐weighted signal, contrast uptake, and the effects of exercise

To quantify the differences between normal and corticosteroid‐treated Duchenne muscular dystrophy (DMD) lower limb muscle using signal intensity measurements on T1‐weighted and gadolinium contrast‐enhanced images and by measurement of muscle T2 values, and to investigate the effect of exercise.

Weight Loss Decreases Excess Pancreatic Triacylglycerol Specifically in Type 2 Diabetes

OBJECTIVE This study determined whether the decrease in pancreatic triacylglycerol during weight loss in type 2 diabetes mellitus (T2DM) is simply reflective of whole-body fat or specific to diabetes and associated with the simultaneous recovery of insulin secretory function. RESEARCH DESIGN AND METHODS Individuals listed for gastric bypass surgery who had T2DM or normal glucose tolerance (NGT) matched for age, weight, and sex were studied before and 8 weeks after surgery. Pancreas and liver triacylglycerol were quantified using in-phase, out-of-phase MRI. Also measured were the first-phase insulin response to a stepped intravenous glucose infusion, hepatic insulin sensitivity, and glycemic and incretin responses to a semisolid test meal. RESULTS Weight loss after surgery was similar (NGT: 12.8 ± 0.8% and T2DM: 13.6 ± 0.7%) as was the change in fat mass (56.7 ± 3.3 to 45.4 ± 2.3 vs. 56.6 ± 2.4 to 43.0 ± 2.4 kg). Pancreatic triacylglycerol did not change in NGT (5.1 ± 0.2 to 5.5 ± 0.4%) but decreased in the group with T2DM (6.6 ± 0.5 to 5.4 ± 0.4%; P = 0.007). First-phase insulin response to a stepped intravenous glucose infusion did not change in NGT (0.24 [0.13–0.46] to 0.23 [0.19–0.37] nmol ⋅ min−1 ⋅ m−2) but normalized in T2DM (0.08 [−0.01 to –0.10] to 0.22 [0.07–0.30]) nmol ⋅ min−1 ⋅ m−2 at week 8 (P = 0.005). No differential effect of incretin secretion was observed after gastric bypass, with more rapid glucose absorption bringing about equivalently enhanced glucagon-like peptide 1 secretion in the two groups. CONCLUSIONS The fall in intrapancreatic triacylglycerol in T2DM, which occurs during weight loss, is associated with the condition itself rather than decreased total body fat.

White matter correlates of cognitive dysfunction after mild traumatic brain injury

Objective: To relate neurophysiologic changes after mild/moderate traumatic brain injury to cognitive deficit in a longitudinal diffusion tensor imaging investigation. Methods: Fifty-three patients were scanned an average of 6 days postinjury (range = 1–14 days). Twenty-three patients were rescanned 1 year later. Thirty-three matched control subjects were recruited. At the time of scanning, participants completed cognitive testing. Tract-Based Spatial Statistics was used to conduct voxel-wise analysis on diffusion changes and to explore regressions between diffusion metrics and cognitive performance. Results: Acutely, increased axial diffusivity drove a fractional anisotropy (FA) increase, while decreased radial diffusivity drove a negative regression between FA and Verbal Letter Fluency across widespread white matter regions, but particularly in the ascending fibers of the corpus callosum. Raised FA is hypothesized to be caused by astrogliosis and compaction of axonal neurofilament, which would also affect cognitive functioning. Chronically, FA was decreased, suggesting myelin sheath disintegration, but still regressed negatively with Verbal Letter Fluency in the anterior forceps. Conclusions: Acute mild/moderate traumatic brain injury is characterized by increased tissue FA, which represents a clear neurobiological link between cognitive dysfunction and white matter injury after mild/moderate injury.

Circulating Inflammatory Markers Are Associated With Magnetic Resonance Imaging-Visible Perivascular Spaces But Not Directly With White Matter Hyperintensities

Background and Purpose— White matter hyperintensities (WMH) and perivascular spaces (PVS) are features of small vessel disease, found jointly on MRI of older people. Inflammation is a prominent pathological feature of small vessel disease. We examined the association between inflammation, PVS, and WMH in the Lothian Birth Cohort 1936 (N=634). Methods— We measured plasma fibrinogen, C-reactive protein, and interleukin-6 and rated PVS in 3 brain regions. We measured WMH volumetrically and visually using the Fazekas scale. We derived latent variables for PVS, WMH, and Inflammation from measured PVS, WMH, and inflammation markers and modelled associations using structural equation modelling. Results— After accounting for age, sex, stroke, and vascular risk factors, PVS were significantly associated with WMH (&bgr;=0.47; P<0.0001); Inflammation was weakly but significantly associated with PVS (&bgr;=0.12; P=0.048), but not with WMH (&bgr;=0.02; P=NS). Conclusions— Circulating inflammatory markers are weakly associated with MR-visible PVS, but not directly with WMH. Longitudinal studies should examine whether visible PVS predate WMH progression and whether inflammation modulators can prevent small vessel disease.

Brain white matter damage in aging and cognitive ability in youth and older age

Cerebral white matter hyperintensities (WMH) reflect accumulating white matter damage with aging and impair cognition. The role of childhood intelligence is rarely considered in associations between cognitive impairment and WMH. We studied community-dwelling older people all born in 1936, in whom IQ had been assessed at age 11 years. We assessed medical histories, current cognitive ability and quantified WMH on MR imaging. Among 634 participants, mean age 72.7 (SD 0.7), age 11 IQ was the strongest predictor of late life cognitive ability. After accounting for age 11 IQ, greater WMH load was significantly associated with lower late life general cognitive ability (β = −0.14, p < 0.01) and processing speed (β = −0.19, p < 0.001). WMH were also associated independently with lower age 11 IQ (β = −0.08, p < 0.05) and hypertension. In conclusion, having more WMH is significantly associated with lower cognitive ability, after accounting for prior ability, age 11IQ. Early-life IQ also influenced WMH in later life. Determining how lower IQ in youth leads to increasing brain damage with aging is important for future successful cognitive aging.

Lithium, Gray Matter, and Magnetic Resonance Imaging Signal

BACKGROUND Magnetic resonance imaging studies have reported that lithium can increase the volume of gray matter in the human brain, a finding that has been ascribed to the established neurotrophic or neuroprotective effects of the drug. Lithium, however, might directly influence the intensity of the magnetic resonance signal so it is possible that the volumetric findings are artifactual, essentially a consequence of altered image contrast. METHODS Anatomical and quantitative magnetic resonance scans were acquired on 31 healthy young men before and after taking either lithium or placebo for 11 days. Brain volume change was derived with two established techniques: voxel-based morphometry (a statistical approach using signal intensity to segment images into tissue types), and Structural Image Evaluation, using Normalization, of Atrophy (a technique that operates by detecting changes in the position of the boundaries of the brain). In a subgroup (n = 12), tissue-specific magnetic resonance relaxation times were compared before and after lithium with quantitative T1-mapping techniques. RESULTS Voxel-based morphometry revealed that gray matter volume was increased by lithium but not placebo (p = .001), whereas Structural Image Evaluation, using Normalization, of Atrophy showed no difference between lithium and placebo (p = .23). Taking lithium reduced the T1 relaxation of the gray matter only (p = .008). CONCLUSION Magnetic resonance images of the brain differ before and after lithium, but this difference might derive from a change in the characteristics of the signal rather than a tangible increase in volume.