Discrete Relationships between Spatiotemporal Gait Characteristics and Domain-Specific Neuropsychological Performance in Midlife.

Midlife risk factors such as type 2 diabetes mellitus (T2DM) confer a significantly increased risk of cognitive impairment in later life with executive function, memory, and attention domains often affected first. Spatiotemporal gait characteristics are emerging as important integrative biomarkers of neurocognitive function and of later dementia risk. We examined 24 spatiotemporal gait parameters across five domains of gait previously linked to cognitive function on usual-pace, maximal-pace, and cognitive dual-task gait conditions in 102 middle-aged adults with (57.5 ± 8.0 years; 40% female) and without (57.0 ± 8.3 years; 62.1% female) T2DM. Neurocognitive function was measured using a neuropsychological assessment battery. T2DM was associated with significant changes in gait phases and rhythm domains at usual pace, and greater gait variability observed during maximal pace and dual tasks. In the overall cohort, both the gait pace and rhythm domains were associated with memory and executive function during usual pace. At maximal pace, gait pace parameters were associated with reaction time and delayed memory. During the cognitive dual task, associations between gait variability and both delayed memory/executive function were observed. Associations persisted following covariate adjustment and did not differ by T2DM status. Principal components analysis identified a consistent association of slower gait pace (step/stride length) and increased gait variability during maximal-pace walking with poorer memory and executive function performance. These data support the use of spatiotemporal gait as an integrative biomarker of neurocognitive function in otherwise healthy middle-aged individuals and reveal discrete associations between both differing gait tasks and gait domains with domain-specific neuropsychological performance. Employing both maximal-pace and dual-task paradigms may be important in cognitively unimpaired populations with risk factors for later cognitive decline-with the aim of identifying individuals who may benefit from potential preventative interventions.

Gait Characteristics and Cognitive Function in Middle-Aged Adults with and without Type 2 Diabetes Mellitus: Data from ENBIND.

Type 2 Diabetes Mellitus (T2DM) in midlife is associated with a greater risk of dementia in later life. Both gait speed and spatiotemporal gait characteristics have been associated with later cognitive decline in community-dwelling older adults. Thus, the assessment of gait characteristics in uncomplicated midlife T2DM may be important in selecting-out those with T2DM at greatest risk of later cognitive decline. We assessed the relationship between Inertial Motion Unit (IMUs)-derived gait characteristics and cognitive function assessed via Montreal Cognitive Assessment (MoCA)/detailed neuropsychological assessment battery (CANTAB) in middle-aged adults with and without uncomplicated T2DM using both multivariate linear regression and a neural network approach. Gait was assessed under (i) normal walking, (ii) fast (maximal) walking and (iii) cognitive dual-task walking (reciting alternate letters of the alphabet) conditions. Overall, 138 individuals were recruited (n = 94 with T2DM; 53% female, 52.8 ± 8.3 years; n = 44 healthy controls, 43% female, 51.9 ± 8.1 years). Midlife T2DM was associated with significantly slower gait velocity on both slow and fast walks (both p < 0.01) in addition to a longer stride time and greater gait complexity during normal walk (both p < 0.05). Findings persisted following covariate adjustment. In analyzing cognitive performance, the strongest association was observed between gait velocity and global cognitive function (MoCA). Significant associations were also observed between immediate/delayed memory performance and gait velocity. Analysis using a neural network approach did not outperform multivariate linear regression in predicting cognitive function (MoCA) from gait velocity. Our study demonstrates the impact of uncomplicated T2DM on gait speed and gait characteristics in midlife, in addition to the striking relationship between gait characteristics and global cognitive function/memory performance in midlife. Further studies are needed to evaluate the longitudinal relationship between midlife gait characteristics and later cognitive decline, which may aid in selecting-out those with T2DM at greatest-risk for preventative interventions.

Rates of abnormal aldosterone/renin ratio in African-origin compared to European-origin patients: A retrospective study.

INTRODUCTION: The aldosterone/renin ratio is the initial screening test for primary hyperaldosteronism (PHA), but little data exists regarding ethnic variations in this. METHODS: Following clinical observation of a high prevalence of abnormal aldosterone/renin ratio (ARR) in patients of African-origin, we retrospectively reviewed all ARR measurements in a single centre over 10 years. Rates of hypokalaemia, intraventricular septal thickness (IVS, by echocardiography) and adrenal imaging were recorded when available. RESULTS: Aldosterone/renin ratio was available in 1473 patients, and abnormal in 374 (25.4%). Abnormal ARR was observed in 305/1349 (22.6%) of European-origin and 69/124 (55.6%) of African-origin patients (P < 0.001). Among those with abnormal ARR, hypokalaemia (<3.5 mmol/L) was documented on at least one occasion in 171/305 (56.1%) European-origin and 43/69 (62.3%) African-origin patients (P = 0.35). Median (range) IVS was 1.57 (0.78-2.80) cm in African-origin and 1.20 (0.69-2.18) cm in European-origin patients (P < 0.002); IVS did not correlate with aldosterone or ARR however. Adrenal adenoma was identified in 41/170 (24.1%) of European-origin and 4/29 (13.7%) African-origin patients (P = 0.15), while hyperplasia was identified in 35/170 (20.5%) of European and 8/29 (27.5%) African patients (P = 0.39). CONCLUSION: In summary, ARR was abnormal in 55.6% of African-origin patients screened at an Irish hospital. Rates of hypokalaemia were similar between European-origin and African-origin patients. These findings have implications for the use of current screening guidelines for ARR in African-origin patients and also for the mechanistic role of aldosterone in hypertensive complications in African-origin patients.

Increased central adiposity and decreased subcutaneous adipose tissue 11ß-hydroxysteroid dehydrogenase type 1 are associated with deterioration in glucose tolerance-A longitudinal cohort study.

OBJECTIVE AND CONTEXT: Increasing adiposity, ageing and tissue-specific regeneration of cortisol through the activity of 11ß-hydroxysteroid dehydrogenase type 1 have been associated with deterioration in glucose tolerance. We undertook a longitudinal, prospective clinical study to determine if alterations in local glucocorticoid metabolism track with changes in glucose tolerance. DESIGN, PATIENTS, AND MEASUREMENTS: Sixty-five overweight/obese individuals (mean age 50.3 ± 7.3 years) underwent oral glucose tolerance testing, body composition assessment, subcutaneous adipose tissue biopsy and urinary steroid metabolite analysis annually for up to 5 years. Participants were categorized into those in whom glucose tolerance deteriorated ("deteriorators") or improved ("improvers"). RESULTS: Deteriorating glucose tolerance was associated with increasing total and trunk fat mass and increased subcutaneous adipose tissue expression of lipogenic genes. Subcutaneous adipose tissue 11ß-HSD1 gene expression decreased in deteriorators, and at study completion, it was highest in the improvers. There was a significant negative correlation between change in area under the curve glucose and 11ß-HSD1 expression. Global 11ß-HSD1 activity did not change and was not different between deteriorators and improvers at baseline or follow-up. CONCLUSION: Longitudinal deterioration in metabolic phenotype is not associated with increased 11ß-HSD1 activity, but decreased subcutaneous adipose tissue gene expression. These changes may represent a compensatory mechanism to decrease local glucocorticoid exposure in the face of an adverse metabolic phenotype.

Baseline morning cortisol level as a predictor of pituitary-adrenal reserve: a comparison across three assays.

CONTEXT: The short ACTH stimulation test (250 µg) is the dynamic test most frequently used to assess adrenal function. It is possible that a single basal cortisol could be used to predict the dynamic response, but research has been hampered by the use of different assays and thresholds. OBJECTIVE: To propose a morning baseline cortisol criterion of three of the most commonly used modern cortisol immunoassays - Advia Centaur (Siemens), Architect (Abbott) and the Roche Modular System (Roche) - that could predict adrenal sufficiency. DESIGN: Observational, retrospective cross-sectional study at two centres. PATIENTS AND MEASUREMENTS: Retrospective analysis of the results of 1019 Short Synacthen tests (SSTs) with the Advia Centaur, 449 SSTs with the Architect and 2050 SSTs with the Roche Modular System assay. Serum cortisol levels were measured prior to injection of 250 µg Synacthen and after 30 min. Overall, we were able to collate data from a total of 3518 SSTs in 3571 patients. RESULTS: Using receiver-operator curve analysis, baseline cortisol levels for predicting passing the SST with 100% specificity were 358 nmol/l for Siemens, 336 nmol/l for Abbott and 506 nmol/l for Roche. Utilizing these criteria, 589, 158 and 578 SSTs, respectively, for Siemens, Abbott and Roche immunoassays could have been avoided. CONCLUSIONS: We have defined assay-specific morning cortisol levels that are able to predict the integrity of the hypothalamo-pituitary-adrenal axis. We propose that this represents a valid tool for the initial assessment of adrenal function and has the potential to obviate the need for dynamic testing in a significant number of patients.

Neuropsychological decrements in midlife type-2 diabetes are not associated with peripheral NLRP3 inflammasome responsiveness.

Midlife Type 2 Diabetes Mellitus (T2DM) is associated with an increased risk of Alzheimer Disease (AD) in later life, with altered inflammatory responses postulated as key pathological drivers. Previous studies have demonstrated increased responsiveness to NLR family pyrin domain containing 3 (NLRP3) inflammasome agonists, both in individuals with untreated T2DM in addition to those with established AD. We hypothesised that peripheral NLRP3 inflammasome responses may be altered during the early stages of T2DM-related cognitive dysfunction. Here, we assessed the relationship between NLPR3 responses in peripheral blood mononuclear cells (including to Aß-42, the putative pathogenic protein in AD) and neuropsychological performance in uncomplicated midlife T2DM to identify early signatures of immune dysregulation which may predispose to later cognitive decline. We recruited a cross-sectional cohort of middle-aged adults with uncomplicated T2DM and matched Healthy Controls (HCs) for comprehensive neuropsychological assessment and in vitro PBMC responses to a range of NLRP3 agonists were assessed. T2DM was associated with subtle decrements on neuropsychological tests of delayed memory and executive function (both p<0.05). Overall, there were no differences between T2DM and HCs in immune responses induced by NLRP3 agonists. Further, we observed no relationship between the subtle neuropsychological decrements observed in T2DM and PBMC responsiveness to NLRP3 agonists. Our data suggests that peripheral NLRP3 inflammasome response dysregulation may not play a role in the early stages of cognitive dysfunction in midlife T2DM. Further longitudinal studies are warranted to examine the contribution of peripheral NLRP3 responses towards disease pathology and as cognitive decline accelerates in T2DM.

Hyperglycaemic crisis secondary to emphysematous pyelonephritis.

A 49-year-old woman presented to the emergency department acutely unwell. Initial investigations revealed hyperglycaemia, ketosis and an acute kidney injury precipitated by urosepsis. She was found to have a new diagnosis of diabetes mellitus (type 2) with a glycated haemoglobin (HbA1c) of 156 mmol/mol. CT imaging of the abdomen and pelvis revealed unilateral emphysematous pyelonephritis (EPN), radiologically classified as stage 3 severity with gas extending beyond the renal collecting system. Escherichia coli was grown on blood and urine cultures. This was sensitive to second-generation cephalosporin cefuroxime. The patient was managed with fluid resuscitation, intravenous antibiotics and renal system decompression with urinary catheter insertion. She was commenced on an intravenous insulin infusion for hyperglycaemic crisis. This case illustrates a rare presentation of hyperglycaemic crisis precipitated by EPN in a patient without a previously known diagnosis of diabetes, successfully treated with medical management alone. Close clinical and radiological follow-up was arranged to monitor the need for future nephrectomy.

The prevalence and incidence of thyroid dysfunction in patients with diabetes - a longitudinal follow-up study.

BACKGROUND: Thyroid dysfunction (TD) occurs in 13.4% of diabetic patients, which has prompted recommendations for annual thyroid screening in patients with diabetes. However, recommendations for annual screening should be based on disease incidence rather than prevalence. METHODS: In 1997-1998, seven hundred and thirty patients (618 type 2 diabetes, 55% male; 112 type 1 diabetes, 47% male) were sequentially screened for TD. The 639 patients with normal thyroid function were followed from 1999 to 2006, with annual thyroid function tests. RESULTS: A total of 21/112 (19%) with type 1 diabetes (T1DM) and 70/618 (11%) with type 2 diabetes (T2DM) had TD. TD was more frequent in females (p < 0.05) and T1DM (p = 0.04). The mean annual rate of conversion to abnormal tests was 2.1%. At 8 years, there were 100 new cases of TD representing 15.6% of the cohort (17 T1DM and 83 T2DM). TD was more frequent in females (p < 0.05), but there was no difference in the incidence of new TD between T1DM and T2DM (p = 0.39). CONCLUSIONS: Our data confirms the high prevalence of TD in diabetic patients, in concordance with the results from other series. We found only 25 treatable cases of new thyroid disease from 639 patients in the 8-year follow-up, less than 0.5% per year. The low incidence of treatable thyroid disease challenges the need for annual screening for thyroid abnormalities in patients with type 2 diabetes.

Peripheral Inflammation and Cognitive Performance in Middle-Aged Adults With and Without Type 2 Diabetes: Results From the ENBIND Study.

Midlife Type 2 Diabetes Mellitus (T2DM) is associated with a greater risk of dementia in later life. Peripheral inflammation and its impact on cognition is proposed as one of the pathological mechanisms mediating this link. However, studies have primarily focused on older individuals with established cognitive impairment and a long duration of T2DM. Importantly, knowledge of which individuals with midlife T2DM who are at greatest risk of later cognitive decline is lacking. We examined the cross-sectional relationship between serum levels of 8 pro-inflammatory markers (IL-1ß, IL-6, TNF-α, IL-8, MCP-1, CXCL10, IL-12p70, CRP) and performance on a detailed neuropsychological assessment battery in middle-aged adults with uncomplicated T2DM (N = 89; 52 ± 8.1 years, 47% female) and matched healthy controls (N = 50; 52 ± 8.3 years, 59% female). Linear regression was used to analyze associations between serum markers and cognitive performance in the overall cohort, followed by a T2DM∗protein concentration interaction analysis to identify any T2DM-specific effects. We observed a significant T2DM-specific association between serum TNF-α levels and scores on the Paired Associates Learning (PAL) task (ß: -3.16, SE: 1.32, p = 0.01, Std. Beta: -0.94), a task with significant working memory demands previously implicated in T2DM-related cognitive dysfunction. However, this did not persist on controlling for multiple testing. We provide exploratory evidence for a significant T2DM-specific relationship between serum TNF-α and memory performance. These findings require further replication and longitudinal analysis with the aim of selecting-out individuals with midlife T2DM at risk of future cognitive decline for potential preventative interventions.

The Short Synacthen (Corticotropin) Test Can Be Used to Predict Recovery of Hypothalamo-Pituitary-Adrenal Axis Function.

Context: The 250-µg short Synacthen (corticotropin) test (SST) is the most commonly used tool to assess hypothalamo-pituitary-adrenal (HPA) axis function. There are many potentially reversible causes of adrenal insufficiency (AI), but no data to guide clinicians as to the frequency of repeat testing or likelihood of HPA axis recovery. Objective: To use the SST results to predict adrenal recovery. Design: A retrospective analysis of 1912 SSTs data. Patients: Seven hundred seventy-six patients with reversible causes of AI were identified who had at least two SSTs performed. A subgroup analysis was performed on individuals previously treated with suppressive doses of glucocorticoids (n = 110). Main Outcome Measures: Recovery of HPA axis function. Results: SST 30-minute cortisol levels above or below 350 nmol/L (12.7 µg/dL) best predicted HPA axis recovery [area under the curve (AUC) receiver operating curve (ROC) = 0.85; median recovery time: 334 vs 1368 days, P = 8.5 × 10-13]: 99% of patients with a 30-minute cortisol >350 nmol/L recovered adrenal function within 4 years, compared with 49% in those with cortisol levels <350 nmol/L. In the subgroup analysis, delta cortisol (30-minute-basal) best predicted the recovery (AUC ROC = 0.77; median recovery time: 262 vs 974 days, P = 7.0 × 10-6). No patient with a delta cortisol <100 nmol (3.6 µg/dL) and a subsequent 1-year random cortisol <200 nmol/L (7.3 µg/dL) recovered HPA axis function. Conclusions: Cortisol levels across an SST can be used to predict recovery of AI and may guide the frequency of repeat testing and inform both clinicians and patients as to the likelihood of restoration of HPA axis function.

Glucocorticoids and non-alcoholic fatty liver disease.

Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the global obesity and metabolic disease epidemic and is rapidly becoming the leading cause of liver cirrhosis and indication for liver transplantation worldwide. The hallmark pathological finding in NAFLD is excess lipid accumulation within hepatocytes, but it is a spectrum of disease ranging from benign hepatic steatosis to steatohepatitis through to fibrosis, cirrhosis and risk of hepatocellular carcinoma. The exact pathophysiology remains unclear with a multi-hit hypothesis generally accepted as being required for inflammation and fibrosis to develop after initial steatosis. Glucocorticoids have been implicated in the pathogenesis of NAFLD across all stages. They have a diverse array of metabolic functions that have the potential to drive NAFLD acting on both liver and adipose tissue. In the fasting state, they are able to mobilize lipid, increasing fatty acid delivery and in the fed state can promote lipid accumulation. Their action is controlled at multiple levels and in this review will outline the evidence base for the role of GCs in the pathogenesis of NAFLD from cell systems, rodent models and clinical studies and describe interventional strategies that have been employed to modulate glucocorticoid action as a potential therapeutic strategy.

Adrenal suppression in patients taking inhaled glucocorticoids is highly prevalent and management can be guided by morning cortisol.

CONTEXT: Up to 3% of US and UK populations are prescribed glucocorticoids (GC). Suppression of the hypothalamo-pituitary-adrenal axis with the potential risk of adrenal crisis is a recognized complication of therapy. The 250 µg short Synacthen stimulation test (SST) is the most commonly used dynamic assessment to diagnose adrenal insufficiency. There are challenges to the use of the SST in routine clinical practice, including both the staff and time constraints and a significant recent increase in Synacthen cost. METHODS: We performed a retrospective analysis to determine the prevalence of adrenal suppression due to prescribed GCs and the utility of a morning serum cortisol for rapid assessment of adrenal reserve in the routine clinical setting. RESULTS: In total, 2773 patients underwent 3603 SSTs in a large secondary/tertiary centre between 2008 and 2013 and 17.9% (n=496) failed the SST. Of 404 patients taking oral, topical, intranasal or inhaled GC therapy for non-endocrine conditions, 33.2% (n=134) had a subnormal SST response. In patients taking inhaled GCs without additional GC therapy, 20.5% (34/166) failed an SST and suppression of adrenal function increased in a dose-dependent fashion. Using receiver operating characteristic curve analysis in patients currently taking inhaled GCs, a basal cortisol ≥348 nmol/l provided 100% specificity for passing the SST; a cortisol value <34 nmol/l had 100% sensitivity for SST failure. Using these cut-offs, 50% (n=83) of SSTs performed on patients prescribed inhaled GCs were unnecessary. CONCLUSION: Adrenal suppression due to GC treatment, particularly inhaled GCs, is common. A basal serum cortisol concentration has utility in helping determine which patients should undergo dynamic assessment of adrenal function.