Frontal Brain Volumes Research Articles

Frontal brain volume correlates of impaired executive function in schizophrenia

Cognitive impairments affect functional capacity in individuals with schizophrenia (SZH), but their neural basis remains unclear. The Wisconsin Card Sorting Test (WCST), and the Stroop Task (SCWT), are paradigmatic tests which have been used extensively for examining executive function in SZH. However, few studies have explored how deficits on these tasks link to brain volume differences commonly seen in SZH. Here, for the first time, we tested associations between FreeSurfer-derived frontal brain volumes and performance on both WCST and SCWT, in a well-matched sample of 57 SZH and 32 control subjects. We also explored whether these associations were dissociable from links to symptom severity in SZH. Results revealed correlations between volumes and task performance which were unique to SZH. In SZH only, volumes of right middle frontal regions correlated with both WCST and Stroop performance: correlation coefficients were significantly different to those present in the control group, highlighting their specificity to the patient group. In the Stroop task, superior frontal regions also showed associations with Stroop interference scores which were unique to SZH. These findings provide important detail around how deficits on these two paradigmatic executive function tasks link to brain structural differences in SZH. Results align with converging evidence suggesting that neuropathology within right middle frontal regions (BA9 and BA46) might be of particular import in SZH. No volumetric associations with symptom severity were found, supporting the notion that the structural abnormalities underpinning cognitive deficits in SZH differ from those associated with symptomatology.

Bilingualism in the Clinical Diagnosis of Mild Cognitive Impairment and Dementia

AbstractBackgroundNeuropsychological assessments determine the presence of cognitive impairment in Alzheimer’s Disease and Related Dementias (ADRD). These tests are susceptible to the influence of cultural and linguistic variables. Bilingualism is a potential contributor to cognitive reserve in elderly individuals. Positive effects of bilingualism have been observed in executive function tasks, while negative effects have been reported on verbal fluency tests. Maintaining two active languages may modify cognitive and brain reserve among bilinguals, but evidence is inconsistent and contradictory. We investigated the relationship between bilingualism and neuropsychological test performance in aging participants from the 1Florida ADRC using a longitudinal design.MethodsWe studied 238 Latino older adults (age 71.79 ± 8.01 years old, 65% female). 158 Latino participants were Spanish‐English bilinguals; 80 were Spanish monolinguals. Bilingualism was assessed by a proficiency questionnaire. Six cognitive composites were developed (Figure 1). We investigated cognitive test change scores between language group, visit (2 visits: M = 14.61 months; SD = 3.52), and diagnosis (normal, MCI, dementia) using 2×2×3 repeated measures ANCOVAs (age and level of education). Cognitive scores were correlated with frontal and temporal brain volumes in bilinguals and monolinguals separately.ResultsMain effects of the diagnostic group and visit were significant for all composites (ps < .001), with the dementia group showing the lowest scores. No significant main effect of Bilingualism was observed for any of the composites. An interaction between visit and bilingualism was seen for the Trail Making Test B‐ A. Three‐way interactions were found between diagnostic groups, visit, and bilingualism for the Verbal composite and the Logical Memory delay subtest (part of the Memory composite). A more significant decline in the monolingual groups was observed, more so in the dementia group. Significant correlations were found between most composites in both language groups, being more related to the temporal than frontal lobe areas, using MRI volumetric measures.ConclusionBilingualism seems to interact with cognitive decline in aging. It is essential to consider the individual’s level of bilingualism to obtain an accurate assessment of cognitive impairment. The interaction of bilingualism with other sociodemographic and cognitive variables will be discussed.

Complement component 4A protein levels are negatively related to frontal volumes in patients with schizophrenia spectrum disorders.

Excessive C4A-gene expression may result in increased microglia-mediated synaptic pruning. As C4A overexpression is observed in schizophrenia spectrum disorders (SSD), this mechanism may account for the altered brain morphology (i.e. reduced volume and cortical thickness) and cognitive symptoms that characterize SSD. Therefore, this study investigates the association of C4A serum protein levels with brain morphology and cognition, and in particular whether this association differs between recent-onset SSD (n=69) and HC (n=40). Serum C4A protein levels were compared between groups. Main outcomes included total gray matter volume, mean cortical thickness and cognitive performance. Regression analysis on these outcomes included C4A level, group (SSD vs. HC), and C4A*Group interactions. All statistical tests were corrected for age, sex, BMI, and antipsychotic medication dose. Follow-up analyses were performed on separate brain regions and scores on cognitive sub-tasks. The group difference in C4A levels was not statistically significant (p=0.86). The main outcomes did not show a significant interaction effect (p>0.13) or a C4A main effect (p>0.27). Follow-up analyses revealed significant interaction effects for the left medial orbitofrontal and left frontal pole volumes (p<0.001): C4A was negatively related to these volumes in SSD, but positively in HC. This study demonstrated that C4A was negatively related to - specifically - frontal brain volumes in SSD, but this relation was inverse for HC. The results support the hypothesis of complement-mediated brain volume reduction in SSD. The results also suggest that C4A has a differential association with brain morphology in SSD compared to HC.

Sex-specific association between prenatal androgenization (second-to-fourth digit length ratio) and frontal brain volumes in adolescents

Prenatal androgenization associates sex-dependently with behavior and mental health in adolescence and adulthood, including risk-taking, emotionality, substance use, and depression. However, still little is known on how it affects underlying neural correlates, like frontal brain control regions. Thus, we tested whether prenatal androgen load is sex-dependently related to frontal cortex volumes in a sex-balanced adolescent sample. In a cross-sectional magnetic resonance imaging study, we examined 61 adolescents (28 males, 33 females; aged 14 or 16 years) and analyzed associations of frontal brain region volumes with the second-to-fourth digit length ratio (2D:4D), an established marker for prenatal androgenization, using voxel-based morphometry in a region-of-interest approach. Lower 2D:4D (indicative of higher prenatal androgen load) correlated significantly with smaller volumes of the right anterior cingulate cortex (r-ACC; β = 0.45) in male adolescents and with larger volumes of the left inferior frontal gyrus orbital part (l-IFGorb; β = – 0.38) in female adolescents. The regression slopes of 2D:4D on the r-ACC also differed significantly between males and females. The study provides novel evidence that prenatal androgenization may influence the development of the frontal brain in a sex- and frontal brain region-specific manner. These effects might contribute to the well-known sex differences in risk-taking, emotionality, substance use, and depression. Future research is needed to elucidate the role of prenatal androgenization within the biopsychosocial model.

Clinical value of CSF tau, p‐tau181, neurogranin and neurofilaments in familial frontotemporal lobar degeneration

AbstractBackgroundBlood neurofilament light chain (NfL) is a robust predictor of phenoconversion in familial frontotemporal lobar degeneration (fFTLD). The comparative value of CSF NfL and other CSF markers of degeneration in fFTLD remains unexplored.MethodFLTD‐causing mutation carriers were recruited through ALLFTD (n = 113, 56.6% female, mean age 48.1 ± 13 years; 29 C9orf72, 16 GRN, 34 MAPT, 34 mutation non‐carriers) and prospectively evaluated for 3 years. Baseline CSF was analyzed for NfL, phosphorylated neurofilament heavy chain (p‐NfH), tau, phosphorylated tau181 (p‐tau) and neurogranin using fit‐for‐purpose immunoassays. Mixed effect linear models, with random slopes, corrected for age, sex, genotype and total intracranial volume related CSF biomarkers to longitudinal clinical variables.ResultNfL (β = 0.64, p &lt; 0.001), p‐NfH (β = 0.68, p &lt; 0.001) and tau (β = 0.46, p &lt; 0.001) correlated with age. There were no differences in biomarker concentrations by phenotype or severity, except for higher NfL and p‐NfH in full phenotype, compared to prodromal disease and asymptomatic carriers. Low neurogranin (β = ‐0.39, p &lt; 0.001), low p‐tau (β = ‐0.33, p &lt; 0.001) and high NfL (β = 0.42, p &lt; 0.001) correlated with worse baseline disease severity measured by the CDR® Dementia Staging Instrument plus behavior and language domains from the National Alzheimer’s Disease Coordinating Center FTLD module sum of boxes (CDR®+NACC‐FTLDsb), and with other measures of global cognition, instrumental and daily function, and frontal and temporal brain volumes. Regardless of genotype, the predicted annualized rate of CDR®+NACC‐FTLDsb score worsenings per higher baseline CSF biomarker Log pg/mL were tau: 3.0 ± 0.2, NfL: 2.8 ± 0.2 and p‐NfH: 2.8 ± 0.2. High tau, NfL and p‐NfH also predicted worsening in other measures of global cognition and instrumental and daily function. Neurogranin and p‐tau did not predict clinical decline.ConclusionCSF tau, p‐tau, neurogranin, NfL and p‐NfH reflect important aspects of disease severity in fFTLD. In contrast to Alzheimer’s disease, low p‐tau and neurogranin are inversely related to clinical severity, which suggests a distinctive pathophysiological process and has implications for therapeutic development. CSF NfL, p‐NfH and tau have strong prognostic value in fFTLD.

Longitudinal Neurocognitive and Pulmonological Profile of Long COVID-19: Protocol for the COVIMMUNE-Clin Study

BackgroundThere is a dearth of information about “brain fog,” characterized by concentration, word-finding, or memory problems, which has been listed in the new World Health Organization provisional classification “U09.9 Post-COVID-19 Condition.” Moreover, the extent to which these symptoms may be associated with neurological, pulmonary, or psychiatric difficulties is unclear.ObjectiveThis ongoing cohort study aims to carefully assess neurocognitive function in the context of the neurological, psychiatric, and pulmonary sequelae of SARS-CoV-2 infection among patients with asymptomatic/mild and severe cases of COVID-19 after remission, including actively recruited healthy controls.MethodsA total of 150 participants will be included in this pilot study. The cohort will comprise patients who tested positive for SARS-CoV-2 infection with either an asymptomatic course or a mild course defined as no symptoms except for olfactory and taste dysfunction (n=50), patients who tested positive for SARS-CoV-2 infection with a severe disease course (n=50), and a healthy control group (n=50) with similar age and sex distribution based on frequency matching. A comprehensive neuropsychological assessment will be performed comprising nuanced aspects of complex attention, including language, executive function, verbal and visual learning, and memory. Psychiatric, personality, social and lifestyle factors, sleep, and fatigue will be evaluated. Brain magnetic resonance imaging, neurological and physical assessment, and pulmonological and lung function examinations (including body plethysmography, diffusion capacity, clinical assessments, and questionnaires) will also be performed. Three visits are planned with comprehensive testing at the baseline and 12-month visits, along with brief neurological and neuropsychological examinations at the 6-month assessment. Blood-based biomarkers of neurodegeneration will be quantified at baseline and 12-month follow-up.ResultsAt the time of submission, the study had begun recruitment through telephone and in-person screenings. The first patient was enrolled in the study at the beginning of April 2021. Interim data analysis of baseline information is expected to be complete by December 2021 and study completion is expected at the end of December 2022. Preliminary group comparisons indicate worse word list learning, short- and long-delayed verbal recall, and verbal recognition in both patient cohorts compared with those of the healthy control group, adjusted for age and sex. Initial volumetric comparisons show smaller grey matter, frontal, and temporal brain volumes in both patient groups compared with those of healthy controls. These results are quite robust but are neither final nor placed in the needed context intended at study completion.ConclusionsTo the best of our knowledge, this is the first study to include objective and comprehensive longitudinal analyses of neurocognitive sequelae of COVID-19 in an extreme group comparison stratified by disease severity with healthy controls actively recruited during the pandemic. Results from this study will contribute to the nascent literature on the prolonged effects of COVID-19 on neurocognitive performance via our coassessment of neuroradiological, neurological, pulmonary, psychiatric, and lifestyle factors.Trial RegistrationInternational Clinical Trials Registry Platform DRKS00023806; https://trialsearch.who.int/Trial2.aspx?TrialID=DRKS00023806International Registered Report Identifier (IRRID)DERR1-10.2196/30259

Memory impairment in alcohol use disorder is associated with regional frontal brain volumes

BackgroundEpisodic memory deficits occur in alcohol use disorder (AUD), but their anatomical substrates remain in question. Although persistent memory impairment is classically associated with limbic circuitry disruption, learning and retrieval of new information also relies on frontal systems. Despite AUD vulnerability of frontal lobe integrity, relations between frontal regions and memory processes have been under-appreciated. MethodsParticipants included 91 AUD (49 with a drug diagnosis history) and 36 controls. Verbal and visual episodic memory scores were age- and education-corrected. Structural magnetic resonance imaging (MRI) data yielded regional frontal lobe (precentral, superior, orbital, middle, inferior, supplemental motor, and medial) and total hippocampal volumes. ResultsAUD were impaired on all memory scores and had smaller precentral frontal and hippocampal volumes than controls. Orbital, superior, and inferior frontal volumes and lifetime alcohol consumption were independent predictors of episodic memory in AUD. Selectivity was established with a double dissociation, where orbital frontal volume predicted verbal but not visual memory, whereas inferior frontal volumes predicted visual but not verbal memory. Further, superior frontal volumes predicted verbal memory in AUD alone, whereas orbital frontal volumes predicted verbal memory in AUD+drug abuse history. ConclusionsSelective relations among frontal subregions and episodic memory processes highlight the relevance of extra-limbic regions in mnemonic processes in AUD. Memory deficits resulting from frontal dysfunction, unlike the episodic memory impairment associated with limbic dysfunction, may be more amenable to recovery with cessation or reduction of alcohol misuse and may partially explain the heterogeneity in episodic memory abilities in AUD.

A systematic review of MRI studies of language development from birth to 2 years of age.

Neurocognitive functions supporting language development start to develop well before first words are spoken during the first years of life. This process coincides with the initial growth spurt of the brain. While the core components of the language network are well characterized in adults and children, the initial neural correlates of language skills are still relatively unknown. We reviewed 10 studies identified via a systematic search that combined magnetic resonance imaging and language-related measures in healthy infants from birth to 2years of age. We aimed to describe the current knowledge as well as point out viable future directions for similar studies. Expectedly, the implicated cerebral areas included many established components of the language networks, including frontal and temporal regions. A volumetric leftward asymmetry of the brain was suggested as a determinant of language skills, yet with marked interindividual variation. Overall, temporal and frontal brain volumes associated positively with language skills. Positive associations were described between the maturation of language related white matter tracts and language skills. The language networks showed adult-like structural similarities already in neonates, with weaker asymmetry compared to adults. In summary, we found some evidence that the language circuit described in older age groups is also associated to language skills during the first 2years of life. However, across the reviewed studies there were no systematic neural correlates of language skills, which is partly explained by a modest number of studies, scattered representation of ages in measurements and the variance in the used methods.

Protein contributions to brain atrophy acceleration in Alzheimer's disease and primary age-related tauopathy.

Alzheimer's disease is characterized by the presence of amyloid-β and tau deposition in the brain, hippocampal atrophy and increased rates of hippocampal atrophy over time. Another protein, TAR DNA binding protein 43 (TDP-43) has been identified in up to 75% of cases of Alzheimer's disease. TDP-43, tau and amyloid-β have all been linked to hippocampal atrophy. TDP-43 and tau have also been linked to hippocampal atrophy in cases of primary age-related tauopathy, a pathological entity with features that strongly overlap with those of Alzheimer's disease. At present, it is unclear whether and how TDP-43 and tau are associated with early or late hippocampal atrophy in Alzheimer's disease and primary age-related tauopathy, whether either protein is also associated with faster rates of atrophy of other brain regions and whether there is evidence for protein-associated acceleration/deceleration of atrophy rates. We therefore aimed to model how these proteins, particularly TDP-43, influence non-linear trajectories of hippocampal and neocortical atrophy in Alzheimer's disease and primary age-related tauopathy. In this longitudinal retrospective study, 557 autopsied cases with Alzheimer's disease neuropathological changes with 1638 ante-mortem volumetric head MRI scans spanning 1.0-16.8 years of disease duration prior to death were analysed. TDP-43 and Braak neurofibrillary tangle pathological staging schemes were constructed, and hippocampal and neocortical (inferior temporal and middle frontal) brain volumes determined using longitudinal FreeSurfer. Bayesian bivariate-outcome hierarchical models were utilized to estimate associations between proteins and volume, early rate of atrophy and acceleration in atrophy rates across brain regions. High TDP-43 stage was associated with smaller cross-sectional brain volumes, faster rates of brain atrophy and acceleration of atrophy rates, more than a decade prior to death, with deceleration occurring closer to death. Stronger associations were observed with hippocampus compared to temporal and frontal neocortex. Conversely, low TDP-43 stage was associated with slower early rates but later acceleration. This later acceleration was associated with high Braak neurofibrillary tangle stage. Somewhat similar, but less striking, findings were observed between TDP-43 and neocortical rates. Braak stage appeared to have stronger associations with neocortex compared to TDP-43. The association between TDP-43 and brain atrophy occurred slightly later in time (∼3 years) in cases of primary age-related tauopathy compared to Alzheimer's disease. The results suggest that TDP-43 and tau have different contributions to acceleration and deceleration of brain atrophy rates over time in both Alzheimer's disease and primary age-related tauopathy.

Brain structural correlates of functional capacity in first-episode psychosis

Impaired functional capacity is a core feature of schizophrenia and presents even in first-episode psychosis (FEP) patients. Impairments in daily functioning tend to persist despite antipsychotic therapy but their neural basis is less clear. Previous studies suggest that volume loss in frontal cortex might be an important contributor, but findings are inconsistent. We aimed to comprehensively investigate the brain structural correlates of functional capacity in FEP using MRI and a reliable objective measure of functioning [University of California, San Diego Performance-Based Skills Assessment (UPSA)]. In a sample of FEP (n = 39) and a well-matched control group (n = 21), we measured cortical thickness, gray matter volume, and white matter tract integrity (fractional anisotropy, FA) within brain regions implicated by previous work. The FEP group had thinner cortex in various frontal regions and fusiform, and reduced FA in inferior longitudinal fasciculus (ILF). In FEP, poorer functional capacity correlated with reduced superior frontal volume and lower FA in left ILF. Importantly, frontal brain volumes and integrity of the ILF were identified as the structural correlates of functional capacity in FEP, controlling for other relevant factors. These findings enhance mechanistic understanding of functional capacity deficits in schizophrenia by specifying the underlying neural correlates. In future, this could help inform intervention strategies.

M175. BRAIN STRUCTURAL CORRELATES OF FUNCTIONAL CAPACITY IN FIRST-EPISODE PSYCHOSIS

BackgroundImpaired functional capacity is a core feature of schizophrenia and present even in first episode psychosis (FEP) patients. Impairments in daily functioning tend to persist despite antipsychotic therapy but their neural basis is not clear. Previous studies suggest that volume loss in frontal cortex might be an important contributor but findings are inconsistent. We aimed to comprehensively investigate the brain structural correlates of functional capacity in first episode psychosis using MRI and a reliable objective measure of functioning (University of California, San Diego Performance-Based Skills Assessment (UPSA))MethodsIn FEP and a well-matched control group, we measured cortical thickness, gray matter volume, and white matter tract integrity (fractional anisotropy, FA) in specific regions implicated by previous work. Between-group differences in these parameters were assessed first. We then examined correlations between MRI measures and UPSA scores in the FEP group while controlling for negative symptomology and medication use.ResultsThe FEP group had thinner cortex in various frontal regions, fusiform, and insula, and reduced FA in inferior longitudinal fasciculus. In FEP, poorer functioning (UPSA) correlated with reduced superior frontal volume and lower FA in inferior longitudinal fasciculus.DiscussionIn accordance with previous findings, FEP exhibited widespread brain structural differences compared to controls. Importantly, frontal brain volumes and integrity of the inferior longitudinal fasciculus were identified as the structural correlates of functional capacity in FEP, after controlling for other relevant factors. These findings enhance mechanistic understanding of functional capacity deficits in schizophrenia by specifying the underlying neural correlates. In future, this could help inform intervention strategies.

A preliminary examination of brain morphometry in youth with Down syndrome with and without parent-reported sleep difficulties

BackgroundDown syndrome is associated with poor sleep but little is known about its neural correlates. AimsThe current research compared brain morphometry in youth with Down syndrome with parent-reported sleep problems (DS-S) to peers with Down syndrome (DS) and typical development (TD) without parent-reported sleep problems matched on age (M = 15.15) and sex ratio (62 % female). Methods and proceduresMagnetic resonance imaging was completed on a 3 T scanner. Participants were stratified into groups based on parent-report: DS-S (n = 17), DS (n = 9), TD (n = 22). Brain morphometry, processed with the FreeSurfer Image Analysis Suite, was compared across groups. In addition, the co-occurrence of medical conditions in the DS groups was examined. Outcomes and resultsYouth with DS-S had reduced total, frontal, parietal, and temporal brain volumes relative to DS and TD peers. They also had higher rates of congenital heart defects than the DS-only group; however, this comorbidity did not appear to account for morphometry differences. Conclusions and implicationsParent-reported sleep problems in DS appear to relate to global and localized volume reductions. These preliminary results have implications for understanding the neural correlates of poor sleep in DS; they also highlight the importance of examining relations between sleep and other medical comorbidities.

The Association Between Distinct Frontal Brain Volumes and Behavioral Symptoms in Mild Cognitive Impairment, Alzheimer's Disease, and Frontotemporal Dementia.

Our aim was to investigate the association between behavioral symptoms of agitation, disinhibition, irritability, elation, and aberrant motor behavior to frontal brain volumes in a cohort with various neurodegenerative diseases. A total of 121 patients with mild cognitive impairment (MCI, n = 58), Alzheimer's disease (AD, n = 45) and behavioral variant frontotemporal dementia (bvFTD, n = 18) were evaluated with a Neuropsychiatric Inventory (NPI). A T1-weighted MRI scan was acquired for each participant and quantified with a multi-atlas segmentation method. The volumetric MRI measures of the frontal lobes were associated with neuropsychiatric symptom scores with a linear model. In the regression model, we included CDR score and TMT B time as covariates to account for cognitive and executive functions. The brain volumes were corrected for age, gender and head size. The total behavioral symptom score of the five symptoms of interest was negatively associated with the volume of the subcallosal area (β = −0.32, p = 0.002). High disinhibition scores were associated with reduced volume in the gyrus rectus (β = −0.30, p = 0.002), medial frontal cortex (β = −0.30, p = 0.002), superior frontal gyrus (β = −0.28, p = 0.003), inferior frontal gyrus (β = −0.28, p = 0.005) and subcallosal area (β = −0.28, p = 0.005). Elation scores were associated with reduced volumes of the medial orbital gyrus (β = −0.30, p = 0.002) and inferior frontal gyrus (β = −0.28, p = 0.004). Aberrant motor behavior was associated with atrophy of frontal pole (β = −0.29, p = 0.005) and the subcallosal area (β = −0.39, p < 0.001). No significant associations with frontal brain volumes were found for agitation and irritability. We conclude that the subcallosal area may be common neuroanatomical area for behavioral symptoms in neurodegenerative diseases, and it appears to be independent of disease etiology.

Cognitive reserve attenuates age-related cognitive decline in the context of putatively accelerated brain ageing in schizophrenia-spectrum disorders.

In schizophrenia, relative stability in the magnitude of cognitive deficits across age and illness duration is inconsistent with the evidence of accelerated deterioration in brain regions known to support these functions. These discrepant brain-cognition outcomes may be explained by variability in cognitive reserve (CR), which in neurological disorders has been shown to buffer against brain pathology and minimize its impact on cognitive or clinical indicators of illness. Age-related change in fluid reasoning, working memory and frontal brain volume, area and thickness were mapped using regression analysis in 214 individuals with schizophrenia or schizoaffective disorder and 168 healthy controls. In patients, these changes were modelled as a function of CR. Patients showed exaggerated age-related decline in brain structure, but not fluid reasoning compared to controls. In the patient group, no moderation of age-related brain structural change by CR was evident. However, age-related cognitive change was moderated by CR, such that only patients with low CR showed evidence of exaggerated fluid reasoning decline that paralleled the exaggerated age-related deterioration of underpinning brain structures seen in all patients. In schizophrenia-spectrum illness, CR may negate ageing effects on fluid reasoning by buffering against pathologically exaggerated structural brain deterioration through some form of compensation. CR may represent an important modifier that could explain inconsistencies in brain structure - cognition outcomes in the extant literature.

Relationship of Cancer to Brain Aging Markers of Alzheimer's Disease: The Framingham Heart Study.

Previous studies have demonstrated a strong inverse association between cancer and risk of Alzheimer's disease (AD). This study aimed to further investigate this association by examining measures of cognitive performance and neuroimaging. Neuropsychological (NP) test batteries consisting of quantitative measures of memory and executive function and volumetric brain magnetic resonance imaging (MRI) scans measuring brain and white-matter hyperintensity volumes were administered to 2,043 dementia-free participants (54% women) in the Framingham Heart Study (FHS) Offspring cohort from 1999-2005. History of cancer was assessed at examination visits and through hospital records. Linear regression was used to examine the association between cancer history and NP/MRI variables. There were 252 and 1,791 participants with and without a previous history of cancer, respectively. Cancer survivors had an average time between diagnosis and NP/MRI exam of 9.8 years. History of any invasive cancer was associated with better executive function (Beta=0.16, p=0.04) but not memory function. Non-invasive cancer was not associated with any change in cognitive performance. Patients with prostate cancer had larger frontal brain volumes (Beta=4.13, p=0.03). Cancer history was not associated with any other MRI measure. We did not find any strong evidence linking cancer to cognitive or neuroimaging biomarkers that would explain a lower risk of subsequent AD, although a previous FHS study demonstrated a strong inverse association between cancer and risk of AD. Future work should examine the association between cancer and other biomarkers of AD as well as more sensitive metrics of AD-related brain aging markers.

Reduced regional volumes associated with total psychopathy scores in an adult population with childhood lead exposure

Childhood lead exposure has been correlated to acts of delinquency and criminal behavior; however, little research has been conducted to examine its potential long term influence on behavioral factors such as personality, specifically psychopathic personality. Neuroimaging studies have demonstrated that the effects of childhood lead exposure persist into adulthood, with structural abnormalities found in gray and white matter regions involved in behavioral decision making. The current study examined whether measurements of adult psychopathy were associated with neuroanatomical differences in structural brain volumes for a longitudinal cohort with measured childhood lead exposure. We hypothesized that increased total psychopathy scores and increased blood lead concentration at 78 months of age (PbB78) would be inversely associated with volumetric measures of gray and white matter brain structures responsible for executive and emotional processing. Analyses did not display a direct effect between total psychopathy score and gray matter volume; however, reduced white matter volume in the cerebellum and brain stem in relation to increased total psychopathy scores was observed. An interaction between sex and total psychopathy score was also detected. Females displayed increased gray matter volume in the frontal, temporal, and parietal lobes associated with increased total psychopathy score, but did not display any white matter volume differences. Males primarily displayed reductions in frontal gray and white matter brain volume in relation to increased total psychopathy scores. Additionally, reduced gray and white matter volume was associated with increased blood lead levels in the frontal lobes; reduced white matter volume was also observed in the parietal and temporal lobes. Females demonstrated gray and white matter volume loss associated with increased PbB78 values in the right temporal lobe, as well as reduced gray matter volume in the frontal lobe. Males displayed reduced white matter volumes associated with increased PbB78 values in the frontal, temporal, and parietal lobes. Comparison of the two primary models revealed a volumetric decrease in the white matter of the left prefrontal cortex associated with increased total psychopathy scores and increased blood lead concentration in males. The results of this study suggested that increased psychopathy scores in this cohort may be attributable to the neuroanatomical abnormalities observed and that childhood lead exposure may be influential to these outcomes.

Effects of DARPP-32 Genetic Variation on Prefrontal Cortex Volume and Episodic Memory Performance.

Despite evidence of a fundamental role of DARPP-32 in integrating dopamine and glutamate signaling, studies examining gene coding for DARPP-32 in relation to neural and behavioral correlates in humans are scarce. Post mortem findings suggest genotype specific expressions of DARPP-32 in the dorsal frontal lobes. Therefore, we investigated the effects of genomic variation in DARPP-32 coding on frontal lobe volumes and episodic memory. Volumetric data from the dorsolateral (DLPFC), and visual cortices (VC) were obtained from 61 younger and older adults (♀54%). The major homozygote G, T, or A genotypes in single nucleotide polymorphisms (SNPs: rs879606; rs907094; rs3764352, the two latter in complete linkage disequilibrium), at the DARPP-32 regulating PPP1R1B gene, influenced frontal gray matter volume and episodic memory (EM). Homozygous carriers of allelic variants with lower DARPP-32 expression had an overall larger prefrontal volume in addition to greater EM recall accuracy after accounting for the influence of age. The SNPs did not influence VC volume. The genetic effects on DLPFC were greater in young adults and selective to this group for EM. Our findings suggest that genomic variation maps onto individual differences in frontal brain volumes and cognitive functions. Larger DLPFC volumes were also related to better EM performance, suggesting that gene-related differences in frontal gray matter may contribute to individual differences in EM. These results need further replication from experimental and longitudinal reports to determine directions of causality.

Behavioral impulsivity mediates the relationship between decreased frontal gray matter volume and harmful alcohol drinking: A voxel-based morphometry study

Alcohol use disorder (AUD) with harmful drinking patterns is on the one hand characterized by impulsive behavior and is on the other hand known to involve structural brain alterations with lower gray matter volume (GMV), especially in the prefrontal cortex (PFC). So far it is unclear whether frontal brain volumes are associated to harmful alcohol drinking and impulsivity, while controlling simultaneously for a wide array of important confounding factors, which are related to alcohol consumption.We used voxel-based morphometry in 99 adults ranging within a continuum of normal to harmful drinking behavior and alcohol dependence, measured by the ‘Alcohol Use Disorders Identification Test’, to examine whether the severity of harmful drinking is correlated with structural markers, in particular in the PFC and whether such markers are linked to self-reported impulsivity. We included alcohol and nicotine lifetime exposure, age, education, and BMI as covariates to control that GMV decreases were not related to those factors.Harmful drinking was associated with lower GMV in the right frontal pole, left inferior frontal gyrus, and bilateral inferior parietal lobe. GMV loss in the PFC regions was correlated with increased impulsivity. Follow-up mediation analyses showed that the relationship between GMV in the frontal pole and harmful drinking was mediated by impulsivity.Our findings show that PFC reductions are associated with harmful drinking and impulsivity. Our data suggest that reduced frontal pole GM, independent of a number of alcohol drinking associated covariates, e.g. lifetime alcohol consumption, is related to impaired top-down control of alcohol drinking behavior.

Association between atrial fibrillation and volumetric magnetic resonance imaging brain measures: Framingham Offspring Study

The increased risk of stroke and cognitive impairment associated with atrial fibrillation (AF) is well documented. However, there is a paucity of research investigating the relations between AF and brain morphology. The purpose of this study was to investigate the association between AF and brain volume measures on magnetic resonance imaging (MRI). The study sample included stroke- and dementia-free participants who attended the Framingham Heart Study offspring cohort 7th examination cycle (1999-2005) and underwent contemporaneous MRI. We examined the association between prevalent AF and brain volume measures (total cerebral volume, frontal lobe volume, temporal lobe volume, temporal horn volume, hippocampal volume, and white matter hyperintensity volume) with linear regression. We first adjusted models for age and sex, and then for vascular risk factors and APOE4. We studied 2144 individuals (mean age 61.8 ± 9.3 years; 54% women); 73 participants (3.4%) had prevalent AF at the time of MRI. In age- and sex-adjusted models, AF was inversely associated with total cerebral brain volume, frontal brain volume, and temporal brain volume. After further adjustment for vascular risk factors and APOE4, AF remained associated with frontal brain volume. After accounting for vascular risk factor burden, prevalent AF was associated with lobar indexes of vascular brain aging but not with expected white matter changes.

Neck Circumference, Brain Imaging Measures, and Neuropsychological Testing Measures

Perivascular fat may have direct effects on local vascularity. Neck fat is associated with carotid intimal thickness, a predictor of brain aging outcomes. This study investigated whether neck circumference, an estimation of neck fat, has unique associations with brain aging outcomes. The study sample (n = 2082, 53.5% women, mean age 60.9 years) was derived from Framingham Heart Study participants with brain magnetic resonance imaging (MRI) and neuropsychological (NP) test measures. Multivariable-adjusted regressions examined cross-sectional associations of neck circumference with brain MRI and NP test measures. Models were also constructed with waist circumference and body mass index (BMI) as exposures. A 1 standard deviation (2.8 cm [women]; 2.9 cm [men]) increment in neck circumference was associated with lower total cerebral brain volume (β = -.22, P = .0006) and lower frontal brain volume (β = -.55, P < .0001). However, a similar association was observed for both waist circumference and BMI. There were no associations between neck circumference and NP test measures after full covariate adjustment. There were no unique associations between neck circumference and brain MRI or NP measures. Consistent with prior observations, all adiposity measures showed associations with more adverse brain MRI and NP measures, suggesting a global association of generalized adiposity.