Midlife managerial experience is linked to late life hippocampal morphology and function

An active cognitive lifestyle has been suggested to have a protective role in the long-term maintenance of cognition. Amongst healthy older adults, more managerial or supervisory experiences in midlife are linked to a slower hippocampal atrophy rate in late life. Yet whether similar links exist in individuals with Mild Cognitive Impairment (MCI) is not known, nor whether these differences have any functional implications. 68 volunteers from the Sydney SMART Trial, diagnosed with non-amnestic MCI, were divided into high and low managerial experience (HME/LME) during their working life. All participants underwent neuropsychological testing, structural and resting-state functional MRI. Group comparisons were performed on hippocampal volume, morphology, hippocampal seed-based functional connectivity, memory and executive function and self-ratings of memory proficiency. HME was linked to better memory function (p = 0.024), mediated by larger hippocampal volume (p = 0.025). More specifically, deformation analysis found HME had relatively more volume in the CA1 sub-region of the hippocampus (p  <  0.05). Paradoxically, this group rated their memory proficiency worse (p = 0.004), a result correlated with diminished functional connectivity between the right hippocampus and right prefrontal cortex (p  <  0.001). Finally, hierarchical regression modelling substantiated this double dissociation

Therapeutically relevant structural and functional mechanisms triggered by physical and cognitive exercise

Corrected by: Erratum: Molecular Psychiatry (2016) 21, 1645–1645; doi:10.1038/mp.2016.57; published online 19 April 2016. Following publication of the above article, the authors noticed that the second author’s name was presented incorrectly. The author’s name should have appeared as M Fiatarone Singh. The publisher regrets the error.Physical and cognitive exercise may prevent or delay dementia in later life but the neural mechanisms underlying these therapeutic benefits are largely unknown. We examined structural and functional magnetic resonance imaging (MRI) brain changes after 6 months of progressive resistance training (PRT), computerized cognitive training (CCT) or combined intervention. A total of 100 older individuals (68 females, average age=70.1, s.d.±6.7, 55-87 years) with dementia prodrome mild cognitive impairment were recruited in the SMART (Study of Mental Activity and Resistance Training) Trial. Participants were randomly assigned into four intervention groups: PRT+CCT, PRT+SHAM CCT, CCT+SHAM PRT and double SHAM. Multimodal MRI was conducted at baseline and at 6 months of follow-up (immediately after training) to measure structural and spontaneous functional changes in the brain, with a focus on the hippocampus and posterior cingulate regions. Participants' cognitive changes were also assessed before and after training. We found that PRT but not CCT significantly improved global cognition (F(90)=4.1, P<0.05) as well as expanded gray matter in the posterior cingulate (Pcorrected <0.05), and these changes were related to each other (r=0.25, P=0.03). PRT also reversed progression of white matter hyperintensities, a biomarker of cerebrovascular disease, in several brain areas. In contrast, CCT but not PRT attenuated decline in overall memory performance (F(90)=5.7, P<0.02), mediated by enhanced functional connectivity between the hippocampus and superior frontal cortex. Our findings indicate that physical and cognitive training depend on discrete neuronal mechanisms for their therapeutic efficacy, information that may help develop targeted lifestyle-based preventative strategies.Molecular Psychiatry advance online publication, 22 March 2016; doi:10.1038/mp.2016.19.C Suo, M Fiatarone Singh, N Gates, W Wen, P Sachdev, H Brodaty, N Saigal, GC Wilson, J Meiklejohn, N Singh, BT Baune, M Baker, N Foroughi, Y Wang, Y Mavros, A Lampit, I Leung, and MJ Valenzuel

Harmonisation and Between-Country Differences of the Lifetime of Experiences Questionnaire in Older Adults

Background: The Lifetime of Experiences Questionnaire (LEQ) assesses complex mental activity across the life-course and has been associated with brain and cognitive health. The different education systems and occupation classifications across countries represent a challenge for international comparisons. The objectives of this study were four-fold: to adapt and harmonise the LEQ across four European countries, assess its validity across countries, explore its association with brain and cognition and begin to investigate between-country differences in life-course mental activities. Method: The LEQ was administered to 359 cognitively unimpaired older adults (mean age and education: 71.2, 13.2 years) from IMAP and EU-funded Medit-Ageing projects. Education systems, classification of occupations and scoring guidelines were adapted to allow comparisons between France, Germany, Spain and United Kingdom. We assessed the LEQ's (i) concurrent validity with a similar instrument (cognitive activities questionnaire - CAQ) and its structural validity by testing the factors' structure across countries, (ii) we investigated its association with cognition and neuroimaging, and (iii) compared its scores between countries. Results: The LEQ showed moderate to strong positive associations with the CAQ and revealed a stable multidimensional structure across countries that was similar to the original LEQ. The LEQ was positively associated with global cognition. Between-country differences were observed in leisure activities across the life-course. Conclusions: The LEQ is a promising tool for assessing the multidimensional construct of cognitive reserve and can be used to measure socio-behavioural determinants of cognitive reserve in older adults across countries. Longitudinal studies are warranted to test further its clinical utility

Clinical Characteristics and Neuroanatomical Predictors of Acute Antidepressant Outcome for Patients with Comorbid Depression and Mild Cognitive Impairment

Background: Older adults presenting with both a depressive disorder (DEP) and cognitive impairment (CI) represent a unique, understudied population. The classification of cognitive impairment severity continues to be debated though it has recently been subtyped into late (LMCI) versus early (EMCI) stages. Previous studies have found associations between treatment outcome and both cortical thickness and white matter hyperintensities (WMH), though report inconsistent directionality and affected regions. In this study, we examined baseline clinical characteristics and neuroanatomical features as prognostic indicators for older adults with comorbid DEP and CI participating in an open antidepressant trial. EMCI is hypothesized to have greater cortical thickness and global cognition than LMCI. Antidepressant treatment remitters and responders are hypothesized to have greater cortical thickness and lower WMH burden than non-remitters and non-responders. Methods: Key inclusion criteria were diagnosis of major depression or dysthymic disorder with Hamilton Depression Rating Scale (HDRS) score \u3e14, and cognitive impairment defined by MMSE score ≥21 and impaired performance on the WMS-R Logical Memory II test. Patients were classified as EMCI or LMCI based on the 1.5 SD cutoff on tests of verbal memory, and compared on baseline clinical, neuropsychological, and anatomical characteristics. All patients underwent a baseline MRI scan and received open antidepressant treatment for 8 weeks. Cortical thickness was extracted using an automated brain segmentation and reconstruction program (FreeSurfer). Vertex-wise analyses were conducted using general linear models to evaluate the relationships between cortical thickness and clinical variables. Results: 79 DEP-CI patients were recruited, of whom 39 met criteria for EMCI and 40 for LMCI. The mean age was 68.9 and mean HDRS was 23.0. LMCI patients had significantly worse global cognition and smaller right hippocampal volume compared to EMCI patients. EMCI patients had thicker right medial orbitofrontal cortex than LMCI. MRI indices of cerebrovascular disease did not differ between MCI subtypes. Remitters had greater deep WMH burden, left medial orbitofrontal gyrus thickness, and right superior frontal gyrus thickness than non-remitters. Greater HDRS depressive severity was positively correlated with right pars triangularis thickness. Stronger ADAS-Cog global cognitive performance was positively correlated with thickness in diffuse cortical areas. Conclusions: Cognitive and neuronal loss markers differed between EMCI and LMCI among patients with DEP-CI, with LMCI being more likely to have the clinical and neuronal loss markers known to be associated with Alzheimer’s disease. Samples of DEP-CI exhibit unique patterns of cortical thickness and WMHs compared to their non-CI peers. Cortical thickness may serve as predictor of treatment remission and relates to both depressive severity and global cognition

Education modulates brain maintenance in presymptomatic frontotemporal dementia

Objective Cognitively engaging lifestyles have been associated with reduced risk of conversion to dementia. Multiple mechanisms have been advocated, including increased brain volumes (ie, brain reserve) and reduced disease progression (ie, brain maintenance). In cross-sectional studies of presymptomatic frontotemporal dementia (FTD), higher education has been related to increased grey matter volume. Here, we examine the effect of education on grey matter loss over time. Methods Two-hundred twenty-nine subjects at-risk of carrying a pathogenic mutation leading to FTD underwent longitudinal cognitive assessment and T1-weighted MRI at baseline and at 1 year follow-up. The first principal component score of the graph-Laplacian Principal Component Analysis on 112 grey matter region-of-interest volumes was used to summarise the grey matter volume (GMV). The effects of education on cognitive performances and GMV at baseline and on the change between 1 year follow-up and baseline (slope) were tested by Structural Equation Modelling. Results Highly educated at-risk subjects had better cognition and higher grey matter volume at baseline;moreover, higher educational attainment was associated with slower loss of grey matter over time in mutation carriers. Conclusions This longitudinal study demonstrates that even in presence of ongoing pathological processes, education may facilitate both brain reserve and brain maintenance in the presymptomatic phase of genetic FTD

Neuropathology and cognitive dysfunction after early hypoglycaemia

Hypoglycaemia is the most common metabolic problem in neonatal medicine, occurring during the first days of life and usually resolving within the same time frame. However, some neonates and infants experience severe and recurrent episodes of hypoglycaemia, the most common aetiologies being congenital hyperinsulinism (CHI) and ketotic hypoglycaemia (KH). Children with CHI are at risk of lasting brain injury, while children with KH are considered to be protected from adverse sequelae owing to the presence of ketone bodies during hypoglycaemia. This thesis investigated the neuropsychological and neuroimaging profiles of these two patient groups in neurologically normal school-aged children. Thirty-one patients with CHI and twenty-one patients with KH participated in the study alongside a cohort of healthy controls. A comprehensive battery of neuropsychological tests revealed specific impairments in attention and motor skills in both patient groups, with additional impairments observed in children with CHI. Automated and manual measurements of subcortical volumes, as well as whole brain analyses (voxel based morphometry and tract based spatial statistics) were conducted. Compared to controls, patients with CHI have reduced volume of subcortical structures, as well as extensive white matter volume loss (accompanied by decreased intracranial volume) and reduced white matter integrity across the entire brain. Patients with KH did not significantly differ from controls on any brain measures, but the only significant difference between patient groups was in thalamic and intracranial volumes. Integrity of subcortical structures and white matter was found to be predictive of scores in memory, motor skills and attention. This study is the first to show the extent of brain abnormality as a result of CHI in neurologically normal children. Furthermore, the finding that both patient groups share a similar cognitive profile refutes the notion that children with KH are protected from adverse sequelae. The implications of these findings are discussed

The effects of cognitive reserve and lifestyle on cognition and dementia in Parkinson's disease-a longitudinal cohort study

OBJECTIVE: Cognitive reserve theory seeks to explain the observed mismatch between the degree of brain pathology and clinical manifestations. Early-life education, midlife social and occupational activities and later-life cognitive and social interactions are associated with a more favourable cognitive trajectory in older people. Previous studies of Parkinson's disease (PD) have suggested a possible role for the effects of cognitive reserve, but further research into different proxies for cognitive reserve and longitudinal studies is required. This study examined the effects of cognitive lifestyle on cross-sectional and longitudinal measures of cognition and dementia severity in people with PD. METHODS: Baseline assessments of cognition, and of clinical, social and demographic information, were completed by 525 participants with PD. Cognitive assessments were completed by 323 participants at 4-year follow-up. Cognition was assessed using the measures of global cognition dementia severity. Cross-sectional and longitudinal serial analyses of covariance for cognition and binomial regression for dementia were performed. RESULTS: Higher educational level, socio-economic status and recent social engagement were associated with better cross-sectional global cognition. In those with normal cognition at baseline, higher educational level was associated with better global cognition after 4 years. Increasing age and low levels of a measure of recent social engagement were associated with an increased risk of dementia. CONCLUSIONS: Higher cognitive reserve has a beneficial effect on performance on cognitive tests and a limited effect on cognitive decline and dementia risk in PD

Cognitive reserve proxies do not differentially account for cognitive performance in patients with focal frontal and non-frontal lesions

Objective: Cognitive reserve (CR) suggests that premorbid efficacy, aptitude, and flexibility of cognitive processing can aid the brain\u2019s ability to cope with change or damage. Our previous work has shown that age and literacy attainment predict the cognitive performance of frontal patients on frontal-executive tests. However, it remains unknown whether CR also predicts the cognitive performance of non-frontal patients. Method: We investigated the independent effect of a CR proxy, National Adult Reading Test (NART) IQ, as well as age and lesion group (frontal vs. non-frontal) on measures of executive function, intelligence, processing speed, and naming in 166 patients with focal, unilateral frontal lesions; 91 patients with focal, unilateral non-frontal lesions; and 136 healthy controls. Results: Fitting multiple linear regression models for each cognitive measure revealed that NART IQ predicted executive, intelligence, and naming performance. Age also significantly predicted performance on the executive and processing speed tests. Finally, belonging to the frontal group predicted executive and naming performance, while membership of the non-frontal group predicted intelligence. Conclusions: These findings suggest that age, lesion group, and literacy attainment play independent roles in predicting cognitive performance following stroke or brain tumour. However, the relationship between CR and focal brain damage does not differ in the context of frontal and non-frontal lesions

Cholinergic system in sequelae of traumatic brain injury

Background: Traumatic brain injury (TBI) is one of the most significant causes of disability and lowered capacity. TBI cause also a considerable financial burden since the majority of patients are young at the time of injury. Though much scientific work has been conducted, the pathophysiological mechanisms behind the sequelae of TBI are still largely unknown. However, there is evidence emerging from experimental and clinical studies that the cholinergic system seems to be at least partly involved in the cognitive impairment associated with TBI. In the TBI aftermath, patients commonly experience problems with attention, initiative and processing speed, i.e. functions which are mainly regulated by the cholinergic system. Additionally, in particular there are indications that the structures containing acetylcholinecontaining neurons are commonly injured in TBI. Furthermore, there is preliminary evidence that at least some TBI patients may benefit from cholinergic medication. Aims of the study: Our aim was to utilize positron emission tomography (PET) and magnetic resonance imaging (MRI) to evaluate possible alterations in the cholinergic system after TBI. An additional goal was to clarify the association of these structural or functional changes to the patient’s response to cholinergic medication. Patients with moderate-to-severe TBI were compared to healthy controls with PET using the [11C]MP4A tracer. MP4A targets acetylcholinesterase (AChE), which is the pre- and post-synaptic acetylcholine degrading enzyme. The TBI patient group was divided into two depending on their response to rivastigmine (inhibitor of AChE) treatment. These patient groups were imaged with MP4A-PET at baseline (without medication) and after 4 weeks of rivastigmine therapy to compare differences in AChE activity. Cholinergic structures were also investigated with atlas-based MRI morphometry. It was also examined whether the atrophy rates of frontal cholinergic structures were associated with neuropsychological tests results. The subjects filled in a questionnaire to determine whether their smoking histories had any connection to the outcome of TBI. Results: The AChE activity in TBI patients was clearly lowered in cortical regions when compared to controls. Most significantly, AChE activity was reduced in parieto- and occipital-cortices. A comparison of the two TBI patient groups in the primary time point scan showed evidence of lowered AChE activity in frontal cortical structures in rivastigmine responders. However, the inhibitory effect of rivastigmine on AChE activity was similar with patient groups when scanned during drug therapy and there was no longer any significant difference between groups in their AChE activities. MRI morphometry revealed that the higher the atrophy rate in frontal cortical structures, the poorer the performance in neuropsychological tests measuring attention. Smoking history was not associated with TBI outcome. Conclusions: According to the results of this study, it appears that the cholinergic system is altered chronically after TBI. It also seems that these structural alterations and the consequential functional changes in the cholinergic system are connected to the response to cholinergic medication. Additionally, the atrophy rate of frontal cortical structures, which are mainly innervated by cholinergic neurons, appears to have correlation to neuropsychological performance concerning attention. There did not seem to be any link between smoking and TBI outcome