Age-related reduction in trait anxiety: Behavioral and neural evidence of automaticity in negative facial emotion processing.

Trait anxiety diminishes with age, which may result from age-related decline in registering salient emotional stimuli and/or enhancement in emotion regulation. We tested the hypotheses in 88 adults 21 to 85 years of age and studied with fMRI of the Hariri task. Age-related decline in stimulus registration would manifest in delayed reaction time (RT) and diminished saliency circuit activity in response to emotional vs. neutral stimuli. Enhanced control of negative emotions would manifest in diminished limbic/emotional circuit and higher prefrontal cortical (PFC) responses to negative emotion. The results showed that anxiety was negatively correlated with age. Age was associated with faster RT and diminished activation of the medial PFC, in the area of the dorsal and rostral anterior cingulate cortex (dACC/rACC) - a hub of the saliency circuit - during matching of negative but not positive vs. neutral emotional faces. A slope test confirmed the differences in the regressions. Further, age was not associated with activation of the PFC in whole-brain regression or in region-of-interest analysis of the dorsolateral PFC, an area identified from meta-analyses of the emotion regulation literature. Together, the findings fail to support either hypothesis; rather, the findings suggest age-related automaticity in processing negative emotions as a potential mechanism of diminished anxiety. Automaticity results in faster RT and diminished anterior cingulate activity in response to negative but not positive emotional stimuli. In support, analyses of psychophysiological interaction demonstrated higher dACC/rACC connectivity with the default mode network, which has been implicated in automaticity in information processing. As age increased, individuals demonstrated faster RT with higher connectivity during matching of negative vs. neutral images. Automaticity in negative emotion processing needs to be investigated as a mechanism of age-related reduction in anxiety.

The effects of age on the severity of problem drinking: Mediating effects of positive alcohol expectancy and neural correlates.

Aging is associated with reduction in the severity of alcohol misuse. However, the psychological and neural mechanisms underlying the age-related changes remain unclear. Here, we tested the hypothesis that age-related diminution of positive alcohol expectancy (AE) mediated the effects of age on problem drinking and investigated the neural correlates of the mediating effects. Ninety-six drinkers 21-85 years of age, including social drinkers and those with mild/moderate alcohol use disorder (AUD), were assessed for global positive (GP) AE and problem drinking, each with the Alcohol Expectancy Questionnaire and Alcohol Use Disorders Identification Test (AUDIT), and with brain imaging during alcohol cue exposure. We processed imaging data with published routines; identified the correlates shared between whole-brain regression against age, GP and AUDIT scores; and performed mediation and path analyses to explore the interrelationships between the clinical and neural variables. The results showed that age was negatively correlated with both GP and AUDIT scores, with GP score completely mediating the correlation between age and AUDIT score. Lower age and higher GP correlated with shared cue responses in bilateral parahippocampal gyrus and left middle occipital cortex (PHG/OC). Further, higher GP and AUDIT scores were associated with shared cue responses in bilateral rostral anterior cingulate cortex and caudate head (ACC/caudate). Path analyses demonstrated models with significant statistical fit and PHG/OC and ACC/caudate each interrelating age to GP and GP to AUDIT scores. These findings confirmed change in positive AE as a psychological mechanism mitigating alcohol misuse as individuals age and highlighted the neural processes of cue-reactivity interrelating age and alcohol use severity.

The effects of age on reward magnitude processing in the monetary incentive delay task.

Previous studies have suggested age-related differences in reward-directed behavior and cerebral processes in support of the age effects. However, it remains unclear how age may influence the processing of reward magnitude. Here, with 54 volunteers (22-74 years of age) participating in the Monetary Incentive Delay Task (MIDT) with explicit cues ($1, ¢1, or nil) and timed response to win, we characterized brain activations during anticipation and feedback and the effects of age on these regional activations. Behaviorally, age was associated with less reaction time (RT) difference between dollar and cent trials, as a result of slower response to the dollar trials; i.e., age was positively correlated with RT dollar - RT cent, with RT nil as a covariate. Both age and the RT difference ($1 - ¢1) were correlated with diminished activation of the right caudate head, right anterior insula, supplementary motor area (SMA)/pre-SMA, visual cortex, parahippocampal gyrus, right superior/middle frontal gyri, and left primary motor cortex during anticipation of $1 vs. ¢1 reward. Further, these regional activities mediated the age effects on RT differences. In responses to outcomes, age was associated with decreases in regional activations to dollar vs. cent loss but only because of higher age-related responses to cent losses. Together, these findings suggest age-related differences in sensitivity to the magnitude of reward. With lower cerebral responses during anticipation to win large rewards and higher responses to outcomes of small loss, aging incurs a constricted sensitivity to the magnitude of reward.

Androgen Deprivation Therapy and Cognitive Function in Prostate Cancer.

PURPOSE OF REVIEW: Androgen deprivation therapy (ADT) is widely used in prostate cancer. Interest in assessing how ADT impacts cognition is growing. RECENT FINDINGS: Studies in animals and humans suggest that androgens may affect cognitive function. However, extant studies utilizing common neurocognitive tests have not consistently demonstrated ADT-induced cognitive impairment. Retrospective analyses investigating the association between ADT and risk of dementia in large electronic patient databases have also produced conflicting results. There is only limited data on ADT-induced changes in the brain as detected by functional imaging. It remains unclear whether cognitive deficits can occur in a patient undergoing ADT. Commonly used neurocognitive tests may not be optimal for detection of more subtle but clinically relevant cognitive impairment. While large electronic patient databases are attractive sources of information, their heterogeneity, complexity, and potential reporting biases can be a challenge. Better tools are needed to assess the cognitive impact of ADT prospectively.

Catechol-O-Methyltransferase Gene Polymorphisms and the Risk of Chemotherapy-Induced Prospective Memory Impairment in Breast Cancer Patients with Varying Tumor Hormonal Receptor Expression.

BACKGROUND Existing research evidence indicates that breast cancer patients have different degrees of cognitive dysfunction after chemotherapy, and polymorphisms in 3 genes (catechol-O-methyltransferase, COMT; apolipoprotein E, APOE; and brain-derived neurotrophic factor, BDNF) have been associated with cognitive impairment. However, the role of these 3 gene polymorphisms in modulating cognitive impairment in breast cancer survivors with varying hormonal receptor expression is not clear at present. To explore the effects of genetic polymorphisms in BDNF, APOE, and COMT on the regulation of prospective memory impairments induced by chemotherapy in breast cancer patients with various expression levels of estrogen receptor (ER) and progesterone receptor (PR). MATERIAL AND METHODS A total of 232 patients with breast cancer (113 with ER-/PR- and 119 with ER+/PR+) were evaluated before and after chemotherapy for cognitive function, including prospective memory. Following previously published sequencing procedures, we assessed 6 single-nucleotide polymorphisms (SNPs), including BDNF (rs6265), APOE (rs429358, rs7412), and COMT (rs165599, rs4680, rs737865). RESULTS The patients showed poorer prospective memory scores after chemotherapy than before chemotherapy. Furthermore, the ER-/PR- group showed poorer event-based prospective memory (EBPM) scores than the ER+/PR+ group (z=-7.831, p<0.01) after chemotherapy. The patients with the COMT rs737865G/G genotype, compared with those with the A/A and A/G genotypes, showed a linear EBPM performance (ß=1.499, 95% confidence interval (CI)=1.017~2.211) and were less likely to have memory impairment. In contrast, APOE and BDNF polymorphisms did not influence cognitive performance. CONCLUSIONS The patterns of hormonal receptor expression may be related to prospective memory impairments induced by chemotherapy in breast cancer patients. Furthermore, the COMT polymorphism (rs737865) was linearly related to the extent of deficits in EBPM and may represent a potential genetic marker of risk for cognitive deficits triggered by chemotherapy in patients with breast cancer.

Structural and functional cerebral bases of diminished inhibitory control during healthy aging.

Inhibitory control or the ability to refrain from incorrect responses is a critical executive function known to diminish during aging. Imaging studies have elucidated cerebral changes that may underlie the age-related deficits. However, it remains unclear whether the structural and functional changes occur in the same brain regions and whether reduced gray matter volumes (GMV) mediate decreased activation during inhibition. Here, in a sample of 149 participants, we addressed the issues using structural and functional magnetic resonance imaging. Individual's response inhibition was evaluated by the stop signal reaction time (SSRT) in a stop signal task. The results showed that age was associated with prolonged SSRT across participants. Many cortical and subcortical regions demonstrated age-related reduction in GMV and activation to response inhibition. Additionally, age-related diminution in inhibitory control, as indexed by the SSRT, was associated with both shared and distinct morphometric and functional changes. Voxel-based morphometry demonstrated age-related reduction in GMV in the right dorsolateral prefrontal cortex and caudate head as well as bilateral insula, in association with prolonged SSRT. In a contrast of stop success versus go success trials, age was associated with lower activation in the medial and inferior frontal cortex and inferior parietal cortex. Further, reduction in GMV mediated age-related differences in activations only of the medial prefrontal cortex, providing limited evidence for structure function association. Thus, the decline in inhibitory control, as evidenced in the stop signal task, manifest with both shared and distinct structural and functional processes during aging.

Resting-State Functional Connectivity of the Locus Coeruleus in Humans: In Comparison with the Ventral Tegmental Area/Substantia Nigra Pars Compacta and the Effects of Age.

The locus coeruleus (LC) provides the primary noradrenergic inputs to the cerebral cortex. Despite numerous animal studies documenting the functions of the LC, research in humans is hampered by the small volume of this midbrain nucleus. Here, we took advantage of a probabilistic template, explored the cerebral functional connectivity of the LC with resting-state fMRI data of 250 healthy adults, and verified the findings by accounting for physiological noise in another data set. In addition, we contrasted connectivities of the LC and the ventral tegmental area/substantia nigra pars compacta. The results highlighted both shared and distinct connectivity of these 2 midbrain structures, as well as an opposite pattern of connectivity to bilateral amygdala, pulvinar, and right anterior insula. Additionally, LC connectivity to the fronto-parietal cortex and the cerebellum increases with age and connectivity to the visual cortex decreases with age. These findings may facilitate studies of the role of the LC in arousal, saliency responses and cognitive motor control and in the behavioral and cognitive manifestations during healthy and disordered aging. Although the first to demonstrate whole-brain LC connectivity, these findings need to be confirmed with high-resolution imaging.

A dual but asymmetric role of the dorsal anterior cingulate cortex in response inhibition and switching from a non-salient to salient action.

Response inhibition and salience detection are among the most studied psychological constructs of cognitive control. Despite a growing body of work, how inhibition and salience processing interact and engage regional brain activations remains unclear. Here, we examined this issue in a stop signal task (SST), where a prepotent response needs to be inhibited to allow an alternative, less dominant response. Sixteen adult individuals performed two versions of the SST each with 25% (SST25) and 75% (SST75) of stop trials. We posited that greater regional activations to the infrequent trial type in each condition (i.e., to stop as compared to go trials in SST25 and to go as compared to stop trials in SST75) support salience detection. Further, successful inhibition in stop trials requires attention to the stop signal to trigger motor inhibition, and the stop signal reaction time (SSRT) has been used to index the efficiency of motor response inhibition. Therefore, greater regional activations to stop as compared to go success trials in association with the stop signal reaction time (SSRT) serve to expedite response inhibition. In support of an interactive role, the dorsal anterior cingulate cortex (dACC) increases activation to salience detection in both SST25 and SST75, but only mediates response inhibition in SST75. Thus, infrequency response in the dACC supports motor inhibition only when stopping has become a routine. In contrast, although the evidence is less robust, the pre-supplementary motor area (pre-SMA) increases activity to the infrequent stimulus and supports inhibition in both SST25 and SST75. These findings clarify a unique role of the dACC and add to the literature that distinguishes dACC and pre-SMA functions in cognitive control.

Association of Drinking Problems and Duration of Alcohol Use to Inhibitory Control in Nondependent Young Adult Social Drinkers.

BACKGROUND: Deficits in inhibitory control have been widely implicated in alcohol misuse. However, the literature does not readily distinguish the effects of drinking problems and chronic alcohol use. Here, we examined how years of drinking and the Alcohol Use Disorders Identification Test (AUDIT) score each influences the cerebral responses to inhibitory control in nondependent drinkers. METHODS: Fifty-seven adult drinkers and 57 age- and gender-matched nondrinkers participated in one 40-minute functional magnetic resonance imaging scan of the stop signal task. Data were preprocessed and modeled using SPM8. In a regression model, we contrasted stop and go success trials for individuals and examined activities of response inhibition each in link with the AUDIT score and years of alcohol use in group analyses. We specified the effects of duration of use by contrasting regional activations of drinkers and age-related changes in nondrinkers. In mediation analyses, we investigated how regional activities mediate the relationship between drinking problems and response inhibition. RESULTS: Higher AUDIT score but not years of drinking was positively correlated with prolonged stop signal reaction time (SSRT) and diminished responses in the cerebellum, thalamus, frontal and parietal regions, independent of years of alcohol use. Further, activity of the thalamus, anterior cingulate cortex, and presupplementary motor area significantly mediates the association, bidirectionally, between the AUDIT score and SSRT. The duration of alcohol use was associated with decreased activation in the right inferior frontal gyrus extending to superior temporal gyrus, which was not observed for age-related changes in nondrinkers. CONCLUSIONS: The results distinguished the association of drinking problems and years of alcohol use to inhibitory control in young adult nondependent drinkers. These new findings extend the imaging literature of alcohol misuse and may have implications for treatment to prevent the escalation from social to dependent drinking. More research is needed to confirm age-independent neural correlates of years of alcohol use.

The effects of age on resting state functional connectivity of the basal ganglia from young to middle adulthood.

The basal ganglia nuclei are critical for a variety of cognitive and motor functions. Much work has shown age-related structural changes of the basal ganglia. Yet less is known about how the functional interactions of these regions with the cerebral cortex and the cerebellum change throughout the lifespan. Here, we took advantage of a convenient sample and examined resting state functional magnetic resonance imaging data from 250 adults 18 to 49 years of age, focusing specifically on the caudate nucleus, pallidum, putamen, and ventral tegmental area/substantia nigra (VTA/SN). There are a few main findings to report. First, with age, caudate head connectivity increased with a large region of ventromedial prefrontal/medial orbitofrontal cortex. Second, across all subjects, pallidum and putamen showed negative connectivity with default mode network (DMN) regions such as the ventromedial prefrontal cortex and posterior cingulate cortex, in support of anti-correlation of the "task-positive" network (TPN) and DMN. This negative connectivity was reduced with age. Furthermore, pallidum, posterior putamen and VTA/SN connectivity to other TPN regions, such as somatomotor cortex, decreased with age. These results highlight a distinct effect of age on cerebral functional connectivity of the dorsal striatum and VTA/SN from young to middle adulthood and may help research investigating the etiologies or monitoring outcomes of neuropsychiatric conditions that implicate dopaminergic dysfunction.

Independent component analysis of functional networks for response inhibition: Inter-subject variation in stop signal reaction time.

Cognitive control is a critical executive function. Many studies have combined general linear modeling and the stop signal task (SST) to delineate the component processes of cognitive control. For instance, by contrasting stop success (SS) and stop error (SE) trials in the SST, investigators examined regional responses to stop signal inhibition. In contrast to this parameterized approach, independent component analysis (ICA) elucidates brain networks subserving cognitive control. In our earlier work of 59 adults performing the SST during fMRI, we characterized six independent components (ICs). However, none of these ICs correlated with stop signal performance, raising questions about their behavioral validity. Here, in a larger sample (n = 100), we identified and explored 23 ICs for correlation with the stop signal reaction time (SSRT), a measure of the efficiency of response inhibition. At a corrected threshold (P < 0.0005), a paracentral lobule-midcingulate network and a left inferior parietal-supplementary motor-somatomotor network showed a positive correlation between SE beta weight and SSRT. In contrast, a midline cerebellum-thalamus-pallidum network showed a negative correlation between SE beta weight and SSRT. These findings suggest that motor preparation and execution prolongs the SSRT, likely via an interaction between the go and stop processes as suggested by the race model. Behaviorally, consistent with this hypothesis, the difference in G and SE reaction times is positively correlated with SSRT across subjects. These new results highlight the importance of cognitive motor regions in response inhibition and support the utility of ICA in uncovering functional networks for cognitive control in the SST.

Resting state functional connectivity of the basal nucleus of Meynert in humans: in comparison to the ventral striatum and the effects of age.

The basal nucleus of Meynert (BNM) provides the primary cholinergic inputs to the cerebral cortex. Loss of neurons in the BNM is linked to cognitive deficits in Alzheimer's disease and other degenerative conditions. Numerous animal studies described cholinergic and non-cholinergic neuronal responses in the BNM; however, work in humans has been hampered by the difficulty of defining the BNM anatomically. Here, on the basis of a previous study that delineated the BNM of post-mortem human brains in a standard stereotaxic space, we sought to examine functional connectivity of the BNM, as compared to the nucleus accumbens (or ventral striatum, VS), in a large resting state functional magnetic resonance imaging data set. The BNM and VS shared but also showed a distinct pattern of cortical and subcortical connectivity. Compared to the VS, the BNM showed stronger positive connectivity with the putamen, pallidum, thalamus, amygdala and midbrain, as well as the anterior cingulate cortex, supplementary motor area and pre-supplementary motor area, a network of brain regions that respond to salient stimuli and orchestrate motor behavior. In contrast, compared to the BNM, the VS showed stronger positive connectivity with the ventral caudate and medial orbitofrontal cortex, areas implicated in reward processing and motivated behavior. Furthermore, the BNM and VS each showed extensive negative connectivity with visual and lateral prefrontal cortices. Together, the distinct cerebral functional connectivities support the role of the BNM in arousal, saliency responses and cognitive motor control and the VS in reward related behavior. Considering the importance of BNM in age-related cognitive decline, we explored the effects of age on BNM and VS connectivities. BNM connectivity to the visual and somatomotor cortices decreases while connectivity to subcortical structures including the midbrain, thalamus, and pallidum increases with age. These findings of age-related changes of cerebral functional connectivity of the BNM may facilitate research of the neural bases of cognitive decline in health and illness.

Does ADT Influence the Risk of Suicidal Ideation among US Veteran Prostate Cancer Patients Pre-Exposed to PTSD?

Post-traumatic stress disorder (PTSD) is defined as a mental health disease that has a high probability of developing among individuals who have experienced traumatic events [...].

Sex differences in the effects of trait anxiety and age on resting-state functional connectivities of the amygdala.

Background: Numerous studies characterized how resting-state functional connectivities (rsFCs) of the amygdala were disrupted in emotional disorders and varied with emotional traits, including anxiety. With trait anxiety known to diminish with age, a critical issue concerns disambiguating the effects of age and anxiety on amygdala rsFCs in studying the neural bases of individual differences in anxiety. Methods: Two-hundred adults (83 women) 19-85 years of age underwent fMRI and assessment for trait anxiety. Amygdala rsFC correlates were identified using multiple regression with age and anxiety in the same model for all and separately in men and women. The rsFC correlates were examined for age-anxiety interaction. Results: Anxiety was negatively correlated with amygdala-temporooccipital gyri rsFC in all and in men alone. In women, amgydala rsFC with the thalamus/pallidum, angular/supramarginal gyri, inferior temporal gyrus, and posterior insula correlated positively and rsFC with calcarine cortex and caudate correlated negatively with anxiety. We also observed sex differences in age correlation of amgydala-posterior cingulate cortex/precuneus and -insula/temporoparietal rsFCs, with stronger associations in women. In women alone, anxiety and age interacted to determine amygdala rsFC with the thalamus/pallidum, calcarine cortex, and caudate, with older age associated with stronger correlation between anxiety and the rsFCs. Limitations: The findings need to be validated in an independent sample and further explored using task-based data. Conclusion: Highlighting anxiety- and age- specific as well as interacting correlates of amygdala rsFCs and sex differences in the correlates, the findings may shed light on the neural markers of anxiety.

Cerebral correlates of skin conductance responses in a cognitive task.

Changes in physiological arousal frequently accompany cognitive performance. Many studies sought to identify the neural correlates of heightened arousal as indexed by skin conductance responses (SCR). However, the observed regional activations may be confounded by task events. We addressed this issue by recording SCR in 25 adults performing a stop signal task (SST) during functional magnetic resonance imaging. We compared only go trials with high and low SCR in order to isolate the event-independent processes. Furthermore, we distinguished go trials that followed another go, a stop success, or a stop error trial to examine whether the neural activities are contingent on the local context in which changes in SCR occurred. The results showed that the supplementary motor area responded to increased SCR irrespective of the preceding trial. The dorsal anterior cingulate cortex increased activation to heightened arousal most significantly in response to stop errors. The medial prefrontal cortex increased activation to SCR following a stop error but decreased activation following a go or stop success trial. These new findings specify the regional activations that accompany changes in physiological arousal during the SST and support distinct processes for the changes that occur under different local contexts. In particular, the MPFC shows opposing responses by increasing activation to changes in arousal evoked by salient stimuli and decreasing activation to the control of arousal.

Effects of androgen deprivation on brain function in prostate cancer patients - a prospective observational cohort analysis.

BACKGROUND: Despite a lack of consensus regarding effectiveness, androgen deprivation therapy (ADT) is a common treatment for non-metastatic, low-risk prostate cancer. To examine a particular clinical concern regarding the possible impact of ADT on cognition, the current study combined neuropsychological testing with functional magnetic resonance imaging (fMRI) to assess both brain activation during cognitive performance as well as the integrity of brain connectivity. METHODS: In a prospective observational cohort analysis of men with non-metastatic prostate cancer at a Veterans Affairs medical center, patients receiving ADT were compared with patients not receiving ADT at baseline and at 6 months. Assessments included fMRI, the N-back task (for working memory), the stop-signal task (for cognitive control), and a quality of life questionnaire. RESULTS: Among 36 patients enrolled (18 in each group), 30 completed study evaluations (15 in each group); 5 withdrew participation and 1 died. Results for the N-back task, stop-signal task, and quality of life were similar at 6 months vs. baseline in each group. In contrast, statistically significant associations were found between ADT use (vs. non use) and decreased medial prefrontal cortical activation during cognitive control, as well as decreased connectivity between the medial prefrontal cortex and other regions involved with cognitive control. CONCLUSIONS: Although ADT for 6 months did not affect selected tests of cognitive function, brain activations during cognitive control and functional brain connectivity were impaired on fMRI. The long-term clinical implications of these changes are not known and warrant future study.

Emotion Processing Dysfunction in Alzheimer's Disease: An Overview of Behavioral Findings, Systems Neural Correlates, and Underlying Neural Biology.

We described behavioral studies to highlight emotional processing deficits in Alzheimer's disease (AD). The findings suggest prominent deficit in recognizing negative emotions, pronounced effect of positive emotion on enhancing memory, and a critical role of cognitive deficits in manifesting emotional processing dysfunction in AD. We reviewed imaging studies to highlight morphometric and functional markers of hippocampal circuit dysfunction in emotional processing deficits. Despite amygdala reactivity to emotional stimuli, hippocampal dysfunction conduces to deficits in emotional memory. Finally, the reviewed studies implicating major neurotransmitter systems in anxiety and depression in AD supported altered cholinergic and noradrenergic signaling in AD emotional disorders. Overall, the studies showed altered emotions early in the course of illness and suggest the need of multimodal imaging for further investigations. Particularly, longitudinal studies with multiple behavioral paradigms translatable between preclinical and clinical models would provide data to elucidate the time course and underlying neurobiology of emotion processing dysfunction in AD.

Effects of androgen deprivation on white matter integrity and processing speed in prostate cancer patients.

Studies have associated chemotherapy-elicited changes in cognitive function with impaired white matter integrity in cancer patients. Androgen deprivation therapy (ADT) may lead to cognitive deficits in prostate cancer patients; however, whether ADT influences white matter integrity has never been investigated. In a prospective study, 15 men with non-metastatic prostate cancer receiving ADT and 15 not receiving ADT (controls or CON), comparable in age and years of education, participated in N-back task, flankers' task, and quality-of-life (QoL) assessments. All participants underwent diffusion tensor imaging of the brain at baseline and at 6 months. Imaging data were processed with published routines. The results of a paired t-test of 6-month follow-up vs. baseline were evaluated at a corrected threshold for the whole brain each in ADT and CON. ADT patients showed significantly worse 1-back accuracy during follow-up, but the two groups did not differ in 2-back accuracy, 1- or 2-back reaction time (RT), flankers' task RT or QoL across time points. In ADT, significantly reduced fractional anisotropy (FA) was noted in the corpus callosum, forceps minor/anterior thalamic radiation, superior and posterior corona radiata. The differences in FA correlated significantly with changes in 2-back and flankers' task RT. No significant FA changes were noted during follow-up in CON. Six-month ADT affects white matter integrity, and the deficits were associated with slower processing speed. These findings add to the literature supporting the deleterious effects of androgen deprivation on the brain and cognition in prostate cancer patients.

Cerebral Volumetric Correlates of Apathy in Alzheimer's Disease and Cognitively Normal Older Adults: Meta-Analysis, Label-Based Review, and Study of an Independent Cohort.

BACKGROUND: Affecting nearly half of the patients with Alzheimer's disease (AD), apathy is associated with higher morbidity and reduced quality of life. Basal ganglia and cortical atrophy have been implicated in apathy. However, the findings have varied across studies and left unclear whether subdomains of apathy may involve distinct neuroanatomical correlates. OBJECTIVE: To identify neuroanatomical correlates of AD-associated apathy. METHODS: We performed a meta-analysis and label-based review of the literature. Further, following published routines of voxel-based morphometry, we aimed to confirm the findings in an independent cohort of 19 patients with AD/mild cognitive impairment and 25 healthy controls assessed with the Apathy Evaluation Scale. RESULTS: Meta-analysis of 167 AD and 56 healthy controls showed convergence toward smaller basal ganglia gray matter volume (GMV) in apathy. Label-based review showed anterior cingulate, putamen, insula, inferior frontal gyrus (IFG) and middle temporal gyrus (MTG) atrophy in AD apathy. In the independent cohort, with small-volume-correction, right putamen and MTG showed GMVs in negative correlation with Apathy Evaluation Scale total, behavioral, and emotional scores, and right IFG with emotional score (p < 0.05 family-wise error (FWE)-corrected), controlling for age, education, intracranial volume, and depression. With the Mini-Mental State Examination scores included as an additional covariate, the correlation of right putamen GMV with behavioral and emotional score, right MTG GMV with total and emotional score, and right IFG GMV with emotional score were significant. CONCLUSION: The findings implicate putamen, MTG and IFG atrophy in AD associated apathy, potentially independent of cognitive impairment and depression, and suggest potentially distinct volumetric correlates of apathy.

Hypothalamic Functional Connectivity and Apathy in People with Alzheimer's Disease and Cognitively Normal Healthy Controls.

BACKGROUND: Earlier studies have described the neural markers of apathy in Alzheimer's disease (AD) and mild cognitive impairment (MCI), but few focused on the motivation circuits. Here, we targeted hypothalamus, a hub of the motivation circuit. OBJECTIVE: To examine hypothalamic resting state functional connectivity (rsFC) in relation to apathy. METHODS: We performed whole-brain regression of hypothalamic rsFC against Apathy Evaluation Scale (AES) total score and behavioral, cognitive, and emotional subscores in 29 patients with AD/MCI and 28 healthy controls (HC), controlling for age, sex, education, cognitive status, and depression. We evaluated the results at a corrected threshold and employed path analyses to assess possible interaction between hypothalamic rsFCs, apathy and depression/memory. Finally, we re-examined the findings in a subsample of amyloid-ß-verified AD. RESULTS: AES total score correlated negatively with hypothalamic precuneus (PCu)/posterior cingulate cortex (PCC) and positively with left middle temporal gyrus (MTG) and supramarginal gyrus rsFCs. Behavioral subscore correlated negatively with hypothalamic PCu/PCC and positively with middle frontal gyrus rsFC. Cognitive subscore correlated positively with hypothalamic MTG rsFC. Emotional subscore correlated negatively with hypothalamic calcarine cortex rsFC. In path analyses, hypothalamic-PCu/PCC rsFC negatively modulated apathy and, in turn, depression. The model where hypothalamic MTG rsFC and memory independently modulated apathy also showed a good fit. The findings of diminished hypothalamic-PCu/PCC rsFC in relation to apathy and, in turn, depression were confirmed in amyloid-verified AD. CONCLUSION: The findings together support a role of altered hypothalamic connectivity in relation to apathy and depression, and modulation of apathy by memory dysfunction.