Interaction of Alzheimer Disease and Traumatic Brain Injury on Cortical Thickness.

INTRODUCTION: Traumatic brain injury (TBI) is associated with an accelerated course of dementia, although biological relationships are incompletely understood. METHODS: The study examined 1124 participants, including 343 with Alzheimer disease (AD), 127 with AD with TBI, 266 cognitively normal adults with TBI, and 388 cognitively normal adults without TBI. Cortical thickness was quantified from T1-weighted magnetic resonance imaging data. Multiple linear regression was used to determine the interaction between AD and TBI on cortical thickness. RESULTS: Among those with AD, TBI was associated with an earlier age of AD onset but, counterintuitively, less cortical thinning in frontotemporal regions relative to non-AD controls. DISCUSSION: AD with TBI represents a distinct group from AD, likely with distinct pathologic contributions beyond gray matter loss. This finding has important implications for the diagnosis and treatment of AD in the presence of TBI and indicates that models of AD, aging, and neural loss should account for TBI history.

Neuropsychiatric symptoms and brain morphology in patients with mild cognitive impairment, cerebrovascular disease and Parkinson disease: A cross sectional and longitudinal study.

OBJECTIVES: Neuropsychiatric symptoms (NPS) increase risk of developing dementia and are linked to various neurodegenerative conditions, including mild cognitive impairment (MCI due to Alzheimer's disease [AD]), cerebrovascular disease (CVD), and Parkinson's disease (PD). We explored the structural neural correlates of NPS cross-sectionally and longitudinally across various neurodegenerative diagnoses. METHODS: The study included individuals with MCI due to AD, (n = 74), CVD (n = 143), and PD (n = 137) at baseline, and at 2-years follow-up (MCI due to AD, n = 37, CVD n = 103, and PD n = 84). We assessed the severity of NPS using the Neuropsychiatric Inventory Questionnaire. For brain structure we included cortical thickness and subcortical volume of predefined regions of interest associated with corticolimbic and frontal-executive circuits. RESULTS: Cross-sectional analysis revealed significant negative correlations between appetite with both circuits in the MCI and CVD groups, while apathy was associated with these circuits in both the MCI and PD groups. Longitudinally, changes in apathy scores in the MCI group were negatively linked to the changes of the frontal-executive circuit. In the CVD group, changes in agitation and nighttime behavior were negatively associated with the corticolimbic and frontal-executive circuits, respectively. In the PD group, changes in disinhibition and apathy were positively associated with the corticolimbic and frontal-executive circuits, respectively. CONCLUSIONS: The observed correlations suggest that underlying pathological changes in the brain may contribute to alterations in neural activity associated with MBI. Notably, the difference between cross-sectional and longitudinal results indicates the necessity of conducting longitudinal studies for reproducible findings and drawing robust inferences.

Sex Differences in Cortical Thickness and Neuropsychiatric Symptom Burden Based on APOE4 Homozygosity in Alzheimer's Disease.

Sex differences in patterns of cortical thickness and neuropsychiatric symptom (NPS) burden were examined among individuals with Alzheimer's disease (AD) and two copies (homozygote carriers) of the e4 allele of the apolipoprotein gene (APOE). A total of 752 participants with a clinical etiologic diagnosis of AD were selected from the National Alzheimer's Coordinating Center (NACC) database. Bayesian multilevel regression was used to examine both the within- and between-sex differences in gray-matter cortical thickness and total NPS burden associated with APOE homozygosity. Female homozygote carriers displayed a high probability of having reduced cortical thickness primarily in medial-lateral temporal regions and a greater burden of NPS, relative to both non-homozygous females and homozygous males. These findings support the notion that APOE4 status affects cortical thickness and symptom burden in men and women with AD differentially, with females showing more pronounced effects in brain areas known to be vulnerable in early AD. Future investigations should attempt to elucidate the proposed pattern of decline longitudinally.

Cerebello-cerebral Functional Connectivity Networks in Major Depressive Disorder: a CAN-BIND-1 Study Report.

Neuroimaging studies have demonstrated aberrant structure and function of the "cognitive-affective cerebellum" in major depressive disorder (MDD), although the specific role of the cerebello-cerebral circuitry in this population remains largely uninvestigated. The objective of this study was to delineate the role of cerebellar functional networks in depression. A total of 308 unmedicated participants completed resting-state functional magnetic resonance imaging scans, of which 247 (148 MDD; 99 healthy controls, HC) were suitable for this study. Seed-based resting-state functional connectivity (RsFc) analysis was performed using three cerebellar regions of interest (ROIs): ROI1 corresponded to default mode network (DMN)/inattentive processing; ROI2 corresponded to attentional networks, including frontoparietal, dorsal attention, and ventral attention; ROI3 corresponded to motor processing. These ROIs were delineated based on prior functional gradient analyses of the cerebellum. A general linear model was used to perform within-group and between-group comparisons. In comparison to HC, participants with MDD displayed increased RsFc within the cerebello-cerebral DMN (ROI1) and significantly elevated RsFc between the cerebellar ROI1 and bilateral angular gyrus at a voxel threshold (p < 0.001, two-tailed) and at a cluster level (p < 0.05, FDR-corrected). Group differences were non-significant for ROI2 and ROI3. These results contribute to the development of a systems neuroscience approach to the diagnosis and treatment of MDD. Specifically, our findings confirm previously reported associations between MDD, DMN, and cerebellum, and highlight the promising role of these functional and anatomical locations for the development of novel imaging-based biomarkers and targets for neuromodulation therapies. ClinicalTrials.gov TRN: NCT01655706; Date of Registration: August 2nd, 2012.

Altered connectivity of default mode and executive control networks among female patients with persistent post-concussion symptoms.

OBJECTIVE: To examine the roles of the default mode network (DMN) and executive control network (ECN) in prolonged recovery after mild traumatic brain injury (mTBI), and relationships with indices of white matter microstructural injury. METHODS: Seventeen mTBI patients with persistent symptoms were imaged an average of 21.5 months post-injury, along with 23 healthy controls. Resting-state functional magnetic resonance imaging (rs-fMRI) was used to evaluate functional connectivity (FC) of the DMN and ECN. Diffusion tensor imaging (DTI) quantified fractional anisotropy, along with mean, axial and radial diffusivity of white matter tracts. RESULTS: Compared to controls, patients with mTBI had increased functional connectivity of the DMN and ECN to brain regions implicated in salience and frontoparietal networks, and increased white matter diffusivity within the cerebrum and brainstem. Among the patients, FC was correlated with better neurocognitive test scores, while diffusivity was correlated with more severe self-reported symptoms. The FC and diffusivity values within abnormal brain regions were not significantly correlated. CONCLUSION: For female mTBI patients with prolonged symptoms, hyper-connectivity may represent a compensatory response that helps to mitigate the effects of mTBI on cognition. These effects are unrelated to indices of microstructural injury, which are correlated with symptom severity, suggesting that rs-fMRI and DTI may capture distinct aspects of pathophysiology.

Comparing cardiovascular risk factors in older persons with mild cognitive impairment and lifetime history of major depressive disorder.

OBJECTIVES: To compare the prevalence of select cardiovascular risk factors (CVRFs) in patients with mild cognitive impairment (MCI) versus lifetime history of major depression disorder (MDD) and a normal comparison group using baseline data from the Prevention of Alzheimer's Dementia with Cognitive Remediation plus Transcranial Direct Current Stimulation (PACt-MD) study. DESIGN: Baseline data from a multi-centered intervention study of older adults with MCI, history of MDD, or combined MCI and history of MDD (PACt-MD) were analyzed. SETTING: Community-based multi-centered study based in Toronto across 5 academic sites. PARTICIPANTS: Older adults with MCI, history of MDD, or combined MCI and history of MDD and healthy controls. MEASUREMENTS: We examined the baseline distribution of smoking, hypertension and diabetes in three groups of participants aged 60+ years in the PACt-MD cohort study: MCI (n = 278), MDD (n = 95), and healthy older controls (n = 81). Generalized linear models were fitted to study the effect of CVRFs on MCI and MDD as well as neuropsychological composite scores. RESULTS: A higher odds of hypertension among the MCI cohort compared to healthy controls (p < .05) was noted in unadjusted analysis. Statistical significance level was lost on adjusting for age, sex and education (p > .05). A history of hypertension was associated with lower performance in composite executive function (p < .05) and overall composite neuropsychological test score (p < .05) among a pooled cohort with MCI or MDD. CONCLUSIONS: This study reinforces the importance of treating modifiable CVRFs, specifically hypertension, as a means of mitigating cognitive decline in patients with at-risk cognitive conditions.

Sex differences in acute and long-term brain recovery after concussion.

Concussion is associated with acute disturbances in brain function and behavior, with potential long-term effects on brain health. However, it is presently unclear whether there are sex differences in acute and long-term brain recovery. In this study, magnetic resonance imaging (MRI) was used to scan 61 participants with sport-related concussion (30 male, 31 female) longitudinally at acute injury, medical clearance to return to play (RTP), and 1-year post-RTP. A large cohort of 167 controls (80 male, 87 female) was also imaged. Each MRI session assessed cerebral blood flow (CBF), along with white matter fractional anisotropy (FA) and mean diffusivity (MD). For concussed athletes, the parameters were converted to difference scores relative to matched control subgroups, and partial least squares modeled the main and sex-specific effects of concussion. Although male and female athletes did not differ in acute symptoms or time to RTP , all MRI measures showed significant sex differences during recovery. Males had greater reductions in occipital-parietal CBF (mean difference and 95%CI: 9.97 ml/100 g/min, [4.84, 15.12] ml/100 g/min, z = 3.73) and increases in callosal MD (9.07 × 10-5 , [-14.14, -3.60] × 10-5 , z = -3.46), with greatest effects at 1-year post-RTP. In contrast, females had greater reductions in FA of the corona radiata (16.50 × 10-3 , [-22.38, -11.08] × 10-3 , z = -5.60), with greatest effects at RTP. These findings provide new insights into how the brain recovers after a concussion, showing sex differences in both the acute and chronic phases of injury.

Tablet Technology for Writing and Drawing during Functional Magnetic Resonance Imaging: A Review.

Functional magnetic resonance imaging (fMRI) is a powerful modality to study brain activity. To approximate naturalistic writing and drawing behaviours inside the scanner, many fMRI-compatible tablet technologies have been developed. The digitizing feature of the tablets also allows examination of behavioural kinematics with greater detail than using paper. With enhanced ecological validity, tablet devices have advanced the fields of neuropsychological tests, neurosurgery, and neurolinguistics. Specifically, tablet devices have been used to adopt many traditional paper-based writing and drawing neuropsychological tests for fMRI. In functional neurosurgery, tablet technologies have enabled intra-operative brain mapping during awake craniotomy in brain tumour patients, as well as quantitative tremor assessment for treatment outcome monitoring. Tablet devices also play an important role in identifying the neural correlates of writing in the healthy and diseased brain. The fMRI-compatible tablets provide an excellent platform to support naturalistic motor responses and examine detailed behavioural kinematics.

Scale-free functional brain dynamics during recovery from sport-related concussion.

Studies using blood-oxygenation-level-dependent functional magnetic resonance imaging (BOLD fMRI) have characterized how the resting brain is affected by concussion. The literature to date, however, has largely focused on measuring changes in the spatial organization of functional brain networks. In the present study, changes in the temporal dynamics of BOLD signals are examined throughout concussion recovery using scaling (or fractal) analysis. Imaging data were collected for 228 university-level athletes, 61 with concussion and 167 athletic controls. Concussed athletes were scanned at the acute phase of injury (1-7 days postinjury), the subacute phase (8-14 days postinjury), medical clearance to return to sport (RTS), 1 month post-RTS and 1 year post-RTS. The wavelet leader multifractal approach was used to assess scaling ( c1 ) and multifractal ( c2 ) behavior. Significant longitudinal changes were identified for c1 , which was lowest at acute injury, became significantly elevated at RTS, and returned near control levels by 1 year post-RTS. No longitudinal changes were identified for c2 . Secondary analyses showed that clinical measures of acute symptom severity and time to RTP were related to longitudinal changes in c1 . Athletes with both higher symptoms and prolonged recovery had elevated c1 values at RTS, while athletes with higher symptoms but rapid recovery had reduced c1 at acute injury. This study provides the first evidence for long-term recovery of BOLD scale-free brain dynamics after a concussion.

Neural Basis of Long-term Musical Memory in Cognitively Impaired Older Persons.

OBJECTIVE: The objective of this study was to determine whether exposure to long-known music would evoke more extensive activation of brain regions minimally affected by Alzheimer disease (AD) pathology and outside traditional memory networks using a functional magnetic resonance imaging paradigm involving listening to long-known and recently-learned music in older adults with cognitive impairment to provide insight into mechanisms of long-term musical memory preservation in cognitively impaired older persons. METHODS: Seventeen subjects with a diagnosis of mild AD or mild cognitive impairment were recruited for this study. Subjects were scanned using functional magnetic resonance imaging while they performed a music listening task, which included short clips of personally selected music from the patient's past and newly-composed music heard for the first time 60 minutes before scanning. From this task, we obtained group-level maps comparing brain areas associated with long-known and recently-heard music in all subjects. RESULTS: Exposure to long-known music preferentially activated brain regions including the medial prefrontal cortex, precuneus, anterior insula, basal ganglia, hippocampus, amygdala, and cerebellum relative to recently-heard music. These areas are involved in autobiographical memory and associated emotional responses. In addition, they are minimally affected by early stage AD pathology, thus providing a neural basis for long-known musical memory survival. CONCLUSIONS: Long-known music activates a bilateral network of prefrontal, emotional, motor, auditory, and subcortical regions (cerebellum, putamen, limbic structures). This extensive activation, relative to recently-heard music, may offer structural and functional clues as to why long-term musical memory appears to be relatively preserved among cognitively impaired older persons.