The impact of parallel regulatory-health technology assessment scientific advice on clinical development. Assessing the uptake of regulatory and health technology assessment recommendations.

AIMS: The parallel regulatory-health technology assessment scientific advice (PSA) procedure allows manufacturers to receive simultaneous feedback from both EU regulators and health technology assessment (HTA) bodies on development plans for new medicines. The primary objective of the present study is to investigate whether PSA is integrated in the clinical development programmes for which advice was sought. METHODS: Contents of PSA provided by regulators and HTA bodies for each procedure between 2010 and 2015 were analysed. The development of all clinical studies for which PSA had been sought was tracked using three different databases. The rate of uptake of the advice provided by regulators and HTA bodies was assessed on two key variables: comparator/s and primary endpoint. RESULTS: In terms of uptake of comparator recommendations at the time of PSA in the actual development, our analysis showed that manufacturers implemented comparators to address both the needs of regulators and of at least one HTA body in 12 of 21 studies. For primary endpoints, in all included studies manufacturers addressed both the needs of the regulators and at least one HTA body. CONCLUSIONS: One of the key findings of this analysis is that manufacturers tend to implement changes to the development programme based on both regulatory and HTA advice with regards to the choice of primary endpoint and comparator. It also confirms the challenging choice of the study comparator, for which manufacturers seem to be more inclined to satisfy the regulatory advice. Continuous research efforts in this area are of paramount importance from a public health perspective.

Neural correlates of short-term memory reorganization in humans with hippocampal damage.

Some patients with disorders affecting the hippocampus have relatively intact memory, but the mechanisms underlying this preservation of function are still debated. In particular, it is unclear whether preserved memory is attributable to significant residual function of unaffected hippocampus or to functional brain reorganization. Here, we investigated brain activation during an associative short-term memory task in two human patient groups matched for extent of postsurgical damage to the right hippocampal formation that differed in two key features, memory performance and preoperative disease course. Patients showed strikingly distinct activation patterns that correlated differentially with behavioral performance, strongly suggesting that intact associative short-term memory with hippocampal dysfunction is indeed related to compensatory brain reorganization. This process appears to depend both on activation of the contralesional hippocampus and on increased engagement of a distributed short-term memory network in neocortex. These data clarify the existence of an efficient hippocampal-neocortical mechanism that compensates for hippocampal dysfunction.

Increased prefrontal cortical thickness is associated with enhanced abilities to regulate emotions in PTSD-free women with borderline personality disorder.

Previous studies suggest that amygdala, insula and prefrontal cortex (PFC) disintegrity play a crucial role in the failure to adequately regulate emotions in Borderline Personality Disorder (BPD). However, prior results are confounded by the high rate of comorbidity with Posttraumatic Stress Disorder (PTSD), which itself has been associated with changes in frontolimbic circuitry. We thus scrutinized the link between PFC, amygdala, insula, and the ability to regulate emotions, contrasting 17 women with BPD without comorbid PTSD to 27 non-clinical control women and in addition to those with BPD and PTSD (n = 14). BPD women without PTSD, but not those with comorbid PTSD, had increased cortical thickness in the dorsolateral PFC (DLPFC) in comparison to control women. Furthermore, cortical thickness in the DLPFC of BPD women without PTSD positively correlated with emotion regulation scores and furthermore was positively associated with amygdala volume, as well as cortical thickness of the insula. Our findings highlight the importance of disentangling the impact of BPD and PTSD on the brain and suggest possible compensatory mechanisms for the impaired emotion regulation in BPD women without PTSD.

Obese Adolescents with Type 2 Diabetes Mellitus Have Hippocampal and Frontal Lobe Volume Reductions.

The rates of type 2 diabetes (T2DM) continue to parallel the rising rates of obesity in the United States, increasingly affecting adolescents as well as adults. Hippocampal and frontal lobe reductions have been found in older adults with type 2 diabetes, and we sought to ascertain if these brain alterations were also present in obese adolescents with T2DM. In a cross-sectional study we compared MRI-based regional brain volumes of 18 obese adolescents with T2DM and 18 obese controls without evidence of marked insulin resistance. Groups were matched on age, sex, school grade, ethnicity, socioeconomic status, body mass index, and waist circumference. Relative to obese controls, adolescents with T2DM had significantly reduced hippocampal and prefrontal volumes, and higher rates of global cerebral atrophy. Hemoglobin A1c, an index of long-term glycemic control, was inversely associated with prefrontal volume and positively associated with global cerebral atrophy (both p < 0.05). Brain integrity is negatively impacted by T2DM already during adolescence, long before the onset of overt macrovascular disease. Paralleling the findings of greater vascular and renal complications among obese adolescents with severe insulin resistance and T2DM relative to their age-matched peers with type 1 diabetes, we find clear evidence of possible brain complications. Our findings call for aggressive and early intervention to limit the negative impact of obesity-associated insulin resistance leading to T2DM on the developing brains of adolescents.

Metabolic syndrome is associated with learning and recall impairment in middle age.

AIMS: To determine whether middle-aged individuals with metabolic syndrome, both with and without type 2 diabetes, exhibit cognitive impairments, and to determine the role of each metabolic syndrome component in those associations. METHODS: 143 participants were drawn from ongoing studies of normal aging. Metabolic syndrome was diagnosed in 73 participants (age: 60.4 +/- 8.4 years), who were contrasted with 70 age- and education-matched controls. RESULTS: Metabolic syndrome was associated with reductions in recall (p = 0.006), lower overall intellectual functioning (p = 0.013), and nearly significant reductions in learning (p = 0.066) and executive functioning (p = 0.050). These effects were only marginally attenuated when controlling for type 2 diabetes diagnosis. Of the 5 components of the metabolic syndrome, insulin resistance was the only significant predictor of variance in learning and recall. In addition, the number of metabolic syndrome criteria met was inversely associated with cognitive performance. CONCLUSIONS: These results indicate that impairments in cognitive functioning associated with metabolic syndrome and type 2 diabetes may begin as early as middle age and are primarily due to insulin resistance. These results demonstrate the importance of screening at-risk adults for insulin resistance in order to initiate lifestyle modifications to reverse or prevent these cognitive changes.

Neuroimaging supports central pathology in familial dysautonomia.

Familial dysautonomia (FD) is a hereditary peripheral and central nervous system disorder with poorly defined central neuropathology. This prospective pilot study aimed to determine if MRI would provide objective parameters of central neuropathology. There were 14 study subjects, seven FD individuals (18.6 +/- 4.2 years, 3 female) and seven controls (19.1 +/- 5.8 years, 3 female). All subjects had standardized brain MRI evaluation including quantitative regional volume measurements, diffusion tensor imaging (DTI) for assessment of white matter (WM) microstructural integrity by calculation of fractional anisotropy (FA), and proton MR spectroscopy ((1)H MRS) to assess neuronal health. The FD patients had significantly decreased FA in optic radiation (p = 0.009) and middle cerebellar peduncle (p = 0.004). Voxel-wise analysis identified both GM and WM microstructural damage among FD subjects as there were nine clusters of WM FA reductions and 16 clusters of GM apparent diffusion coefficient (ADC) elevations. Their WM proportion was significantly decreased (p = 0.003) as was the WM proportion in the frontal region (p = 0.007). (1)H MRS showed no significant abnormalities. The findings of WM abnormalities and decreased optic radiation and middle cerebellar peduncle FA in the FD study group, suggest compromised myelination and WM micro-structural integrity in FD brains. These neuroimaging results are consistent with clinical visual abnormalities and gait disturbance. Furthermore the frontal lobe atrophy is consistent with previously reported neuropsychological deficits.

Emotional and neutral declarative memory impairments and associated white matter microstructural abnormalities in adults with type 2 diabetes.

Declarative memory impairment is frequently reported among adults with type 2 diabetes mellitus (T2DM), who also demonstrate hippocampal volume reduction. Our goals were to ascertain whether emotional memory, which is mediated by neural circuits overlapping those of declarative memory, is also affected. In addition we wanted to characterize cerebral white matter (WM) involvement in T2DM. We studied 24 middle-aged and elderly patients with T2DM who were free of obvious vascular pathology or a psychiatric disorder, and 17 age- and education-matched healthy individuals with no evidence of insulin resistance. We examined emotional and neutral memory and performed a whole-brain voxelwise WM assessment utilizing diffusion tensor imaging (DTI). We found clear evidence of impairment in declarative memory among diabetic subjects and in addition found some preliminary support to suggest a possible blunting of the memory facilitation by emotional material among female but not male diabetics. This report is also the first DTI assessment among individuals with T2DM, which after accounting for overt WM damage, revealed diffuse but predominantly frontal and temporal WM microstructural abnormalities, with extensive involvement of the temporal stem. Hierarchical regression analyses demonstrated that immediate, but not delayed, emotional memory performance was explained by temporal stem FA, independent of age, poor metabolic regulation, and systolic blood pressure. Given that the temporal lobe memory networks appear to be particularly vulnerable to the deleterious effects of T2DM, this may help explain the observed memory impairments among diabetics. Future efforts should better clarify, with a larger sample, whether emotional memory is affected in adults with T2DM and whether there are clear gender effects.

Plasma BDNF is reduced among middle-aged and elderly women with impaired insulin function: evidence of a compensatory mechanism.

Brain-derived neurotrophic factor (BDNF) plays a regulatory role in neuronal differentiation and synaptic plasticity and has been linked to glucose regulation and cognition. Associations among plasma BDNF, cognition, and insulin function were explored. Forty-one participants with impaired insulin function (IIF), ranging from insulin resistance to type 2 diabetes mellitus (T2DM), were matched with 41 healthy controls on gender, age, education, and IQ. Participants received complete medical, neurological, psychiatric, and neuropsychological evaluations. IIF individuals had significantly lower plasma BDNF levels than controls, particularly females, and higher BDNF levels were associated with poorer explicit memory in IIF females, suggesting that higher levels within this group may reflect the body's efforts to respond to damage. After accounting for age, education, and HbA1c, BDNF significantly predicted 13.1-23.5% of the variance in explicit memory in IIF women. These findings suggest that BDNF elevations within diseased groups may not always be a marker of health.

Modifiers of cognitive function and brain structure in middle-aged and elderly individuals with type 2 diabetes mellitus.

Cognitive deficits and hippocampal atrophy, features that are shared with aging and dementia, have been described in type 2 diabetes mellitus (T2DM). T2DM is associated with obesity, hypertension, dyslipidemia, hypothalamic pituitary adrenocortical (HPA) axis abnormalities and inflammation, all of which have been shown to negatively impact the brain. However, since most reports in T2DM focused on glycemic control, the relative contribution of these modifying factors to the impairments observed in T2DM remains unclear. We contrasted 41 middle-aged dementia-free volunteers with T2DM (on average 7 years since diagnosis) with 47 age-, education-, and gender-matched non-insulin resistant controls on cognition and brain volumes. HPA axis activity and other modifiers that accompany T2DM were assessed to determine their impact on brain and cognition. Individuals with T2DM had specific verbal declarative memory deficits, reduced hippocampal and prefrontal volumes, and impaired HPA axis feedback control. Diminished cortisol suppression after dexamethasone and dyslipidemia were associated with decreased cognitive performance, whereas obesity was negatively related to hippocampal volume. Moreover, prefrontal volume was influenced by worse glycemic control. Thus, obesity and altered cortisol levels may contribute to the impact of T2DM on the hippocampal formation, resulting in decreased verbal declarative memory performance.

Retinal vessel abnormalities are associated with elevated fasting insulin levels and cerebral atrophy in nondiabetic individuals.

OBJECTIVE: To determine the impact of insulin resistance short of diabetes on the arteriolar-to-venular ratio (AVR) and whether AVR is related to cerebral atrophy. DESIGN: Cross-sectional study. PARTICIPANTS: Forty-six nondiabetic subjects with normal glucose tolerance and varying degrees of insulin resistance ranging in age from 43 to 77 years. METHODS: Insulin resistance was assessed by fasting insulin and the homeostasis model assessment. Arteriolar-to-venular ratio was determined using digital retinal photography with a nonmydriatic camera, and retinal data were analyzed using a reliable semiautomated method. Cerebral atrophy was derived by means of manual tracing and thresholding procedures on structural magnetic resonance images. MAIN OUTCOME MEASURES: Arteriolar-to-venular ratio and cerebral atrophy. RESULTS: Hyperinsulinemia negatively impacted AVR. Furthermore, AVR was associated with cerebral atrophy. Both of these findings were independent of the effects of age and hypertension. CONCLUSIONS: These novel findings indicate that insulin resistance short of diabetes and independent of age and hypertension has a negative impact on retinal vessel health. Moreover, impaired retinal vessel health related to brain atrophy also was independent of hypertension and white matter hyperintensities. Given the connections between retinal and cerebral vasculature, this may offer a partial explanation for the presence of cognitive and brain abnormalities among individuals with insulin resistance. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

A blunted cortisol awakening response and hippocampal atrophy in type 2 diabetes mellitus.

There is emerging evidence from healthy individuals, as well as direct and indirect evidence from psychiatric and neurological patients with disease-related hippocampal atrophy, linking the cortisol awakening response (CAR) to hippocampal volume. Type 2 diabetes mellitus (T2DM) is a metabolic disease that is also accompanied by hippocampal atrophy, and therefore can serve as a model for ascertaining the relationship between CAR and hippocampal volume. We contrasted a group of 18 individuals with T2DM with 12 matched controls on MRI-based hippocampal volume and salivary diurnal cortisol profile including CAR. Individuals with T2DM had smaller hippocampal volumes and exhibited a blunting of the CAR relative to controls, while diurnal cortisol was not affected. Across all subjects, fasting insulin and hippocampal volume were associated with the CAR, independent of diagnosis. Our findings support the hypothesis that hippocampal integrity is an important predictor of the CAR.

Hypothalamic-pituitary-adrenal axis dysregulation and memory impairments in type 2 diabetes.

CONTEXT: There is evidence of both hypothalamic-pituitary-adrenocortical (HPA) axis and cognitive dysfunction in type 2 diabetes mellitus (T2DM). However, the exact nature and the associations between these abnormalities remain unclear. OBJECTIVES: The aim of the study was to characterize the nature of the HPA dysregulation in T2DM and ascertain whether impaired cognition in T2DM could be attributed to these abnormalities. DESIGN: A cross-sectional study was performed, contrasting matched groups on HPA axis function and cognition by using the combined dexamethasone (DEX)/CRH test and a neuropsychological battery assessing declarative and working memory, attention, and executive function. SETTING: The study was conducted in a research clinic in an academic medical center. PARTICIPANTS: Participants were volunteers functioning in the cognitively normal range. We studied 30 middle-aged individuals with T2DM, on average 7.5 yr since diabetes diagnosis, and 30 age-, gender-, and education-matched controls. MAIN OUTCOME MEASURES: Basal cortisol levels, cortisol levels during the DEX/CRH test, and performance on neuropsychological tests were measured. RESULTS: Individuals with T2DM had elevated basal plasma cortisol levels, higher levels after DEX suppression, and a larger response to CRH (all P