Artificial intelligence classifies primary progressive aphasia from connected speech.

Neurodegenerative dementia syndromes, such as Primary Progressive Aphasias (PPA), have traditionally been diagnosed based in part on verbal and nonverbal cognitive profiles. Debate continues about whether PPA is best divided into three variants and also regarding the most distinctive linguistic features for classifying PPA variants. In this cross-sectional study, we first harnessed the capabilities of artificial intelligence (AI) and Natural Language Processing (NLP) to perform unsupervised classification of short, connected speech samples from 78 PPA patients. We then used NLP to identify linguistic features that best dissociate the three PPA variants. Large Language Models (LLMs) discerned three distinct PPA clusters, with 88.5% agreement with independent clinical diagnoses. Patterns of cortical atrophy of three data-driven clusters corresponded to the localization in the clinical diagnostic criteria. In the subsequent supervised classification, seventeen distinctive features emerged, including the observation that separating verbs into high and low-frequency types significantly improves classification accuracy. Using these linguistic features derived from the analysis of short, connected speech samples, we developed a classifier that achieved 97.9% accuracy in classifying the four groups (three PPA variants and healthy controls). The data-driven section of this study showcases the ability of LLMs to find natural partitioning in the speech of patients with PPA consistent with conventional variants. In addition, the work identifies a robust set of language features indicative of each PPA variant, emphasizing the significance of dividing verbs into high and low-frequency categories. Beyond improving diagnostic accuracy, these findings enhance our understanding of the neurobiology of language processing.

Anterior dorsal attention network tau drives visual attention deficits in posterior cortical atrophy.

Posterior cortical atrophy (PCA), usually an atypical clinical syndrome of Alzheimer's disease, has well-characterized patterns of cortical atrophy and tau deposition that are distinct from typical amnestic presentations of Alzheimer's disease. However, the mechanisms underlying the cortical spread of tau in PCA remain unclear. Here, in a sample of 17 biomarker-confirmed (A+/T+/N+) individuals with PCA, we sought to identify functional networks with heightened vulnerability to tau pathology by examining the cortical distribution of elevated tau as measured by 18F-flortaucipir (FTP) PET. We then assessed the relationship between network-specific FTP uptake and visuospatial cognitive task performance. As predicted, we found consistent and prominent localization of tau pathology in the dorsal attention network and visual network of the cerebral cortex. Elevated FTP uptake within the dorsal attention network (particularly the ratio of FTP uptake between the anterior and posterior nodes) was associated with poorer visuospatial attention in PCA; associations were also identified in other functional networks, although to a weaker degree. Furthermore, using functional MRI data collected from each patient at wakeful rest, we found that a greater anterior-to-posterior ratio in FTP uptake was associated with stronger intrinsic functional connectivity between anterior and posterior nodes of the dorsal attention network. Taken together, we conclude that our cross-sectional marker of anterior-to-posterior FTP ratio could indicate tau propagation from posterior to anterior dorsal attention network nodes, and that this anterior progression occurs in relation to intrinsic functional connectivity within this network critical for visuospatial attention. Our findings help to clarify the spatiotemporal pattern of tau propagation in relation to visuospatial cognitive decline and highlight the key role of the dorsal attention network in the disease progression of PCA.

Atrophy in behavioural variant frontotemporal dementia spans multiple large-scale prefrontal and temporal networks.

The identification of a neurodegenerative disorder's distributed pattern of atrophy-or atrophy 'signature'-can lend insights into the cortical networks that degenerate in individuals with specific constellations of symptoms. In addition, this signature can be used as a biomarker to support early diagnoses and to potentially reveal pathological changes associated with said disorder. Here, we characterized the cortical atrophy signature of behavioural variant frontotemporal dementia (bvFTD). We used a data-driven approach to estimate cortical thickness using surface-based analyses in two independent, sporadic bvFTD samples (n = 30 and n = 71, total n = 101), using age- and gender-matched cognitively and behaviourally normal individuals. We found highly similar patterns of cortical atrophy across the two independent samples, supporting the reliability of our bvFTD signature. Next, we investigated whether our bvFTD signature targets specific large-scale cortical networks, as is the case for other neurodegenerative disorders. We specifically asked whether the bvFTD signature topographically overlaps with the salience network, as previous reports have suggested. We hypothesized that because phenotypic presentations of bvFTD are diverse, this would not be the case, and that the signature would cross canonical network boundaries. Consistent with our hypothesis, the bvFTD signature spanned rostral portions of multiple networks, including the default mode, limbic, frontoparietal control and salience networks. We then tested whether the signature comprised multiple anatomical subtypes, which themselves overlapped with specific networks. To explore this, we performed a hierarchical clustering analysis. This yielded three clusters, only one of which extensively overlapped with a canonical network (the limbic network). Taken together, these findings argue against the hypothesis that the salience network is preferentially affected in bvFTD, but rather suggest that-at least in patients who meet diagnostic criteria for the full-blown syndrome-neurodegeneration in bvFTD encompasses a distributed set of prefrontal, insular and anterior temporal nodes of multiple large-scale brain networks, in keeping with the phenotypic diversity of this disorder.

The Sporadic Early-onset Alzheimer's Disease Signature Of Atrophy: Preliminary Findings From The Longitudinal Early-onset Alzheimer's Disease Study (LEADS) Cohort.

INTRODUCTION: Magnetic resonance imaging (MRI) research has advanced our understanding of neurodegeneration in sporadic early-onset Alzheimer's disease (EOAD) but studies include small samples, mostly amnestic EOAD, and have not focused on developing an MRI biomarker. METHODS: We analyzed MRI scans to define the sporadic EOAD-signature atrophy in a small sample (n = 25) of Massachusetts General Hospital (MGH) EOAD patients, investigated its reproducibility in the large longitudinal early-onset Alzheimer's disease study (LEADS) sample (n = 211), and investigated the relationship of the magnitude of atrophy with cognitive impairment. RESULTS: The EOAD-signature atrophy was replicated across the two cohorts, with prominent atrophy in the caudal lateral temporal cortex, inferior parietal lobule, and posterior cingulate and precuneus cortices, and with relative sparing of the medial temporal lobe. The magnitude of EOAD-signature atrophy was associated with the severity of cognitive impairment. DISCUSSION: The EOAD-signature atrophy is a reliable and clinically valid biomarker of AD-related neurodegeneration that could be used in clinical trials for EOAD. HIGHLIGHTS: We developed an early-onset Alzheimer's disease (EOAD)-signature of atrophy based on magnetic resonance imaging (MRI) scans. EOAD signature was robustly reproducible across two independent patient cohorts. EOAD signature included prominent atrophy in parietal and posterior temporal cortex. The EOAD-signature atrophy was associated with the severity of cognitive impairment. EOAD signature is a reliable and clinically valid biomarker of neurodegeneration.

Sex and APOE ε4 carrier effects on atrophy, amyloid PET, and tau PET burden in early-onset Alzheimer's disease.

INTRODUCTION: We used sex and apolipoprotein E ε4 (APOE ε4) carrier status as predictors of pathologic burden in early-onset Alzheimer's disease (EOAD). METHODS: We included baseline data from 77 cognitively normal (CN), 230 EOAD, and 70 EO non-Alzheimer's disease (EOnonAD) participants from the Longitudinal Early-Onset Alzheimer's Disease Study (LEADS). We stratified each diagnostic group by males and females, then further subdivided each sex by APOE ε4 carrier status and compared imaging biomarkers in each stratification. Voxel-wise multiple linear regressions yielded statistical brain maps of gray matter density, amyloid, and tau PET burden. RESULTS: EOAD females had greater amyloid and tau PET burdens than males. EOAD female APOE ε4 non-carriers had greater amyloid PET burdens and greater gray matter atrophy than female ε4 carriers. EOnonAD female ε4 non-carriers also had greater gray matter atrophy than female ε4 carriers. DISCUSSION: The effects of sex and APOE ε4 must be considered when studying these populations. HIGHLIGHTS: Novel analysis examining the effects of biological sex and apolipoprotein E ε4 (APOE Îµ4) carrier status on neuroimaging biomarkers among early-onset Alzheimer's disease (EOAD), early-onset non-AD (EOnonAD), and cognitively normal (CN) participants. Female sex is associated with greater pathology burden in the EOAD cohort compared to male sex. The effect of APOE ε4 carrier status on pathology burden was the most impactful in females across all cohorts.

White matter hyperintensities are higher among early-onset Alzheimer's disease participants than their cognitively normal and early-onset nonAD peers: Longitudinal Early-onset Alzheimer's Disease Study (LEADS).

INTRODUCTION: We compared white matter hyperintensities (WMHs) in early-onset Alzheimer's disease (EOAD) with cognitively normal (CN) and early-onset amyloid-negative cognitively impaired (EOnonAD) groups in the Longitudinal Early-Onset Alzheimer's Disease Study. METHODS: We investigated the role of increased WMH in cognition and amyloid and tau burden. We compared WMH burden of 205 EOAD, 68 EOnonAD, and 89 CN participants in lobar regions using t-tests and analyses of covariance. Linear regression analyses were used to investigate the association between WMH and cognitive impairment and that between amyloid and tau burden. RESULTS: EOAD showed greater WMHs compared with CN and EOnonAD participants across all regions with no significant differences between CN and EOnonAD groups. Greater WMHs were associated with worse cognition. Tau burden was positively associated with WMH burden in the EOAD group. DISCUSSION: EOAD consistently showed higher WMH volumes. Overall, greater WMHs were associated with worse cognition and higher tau burden in EOAD. HIGHLIGHTS: This study represents a comprehensive characterization of WMHs in sporadic EOAD. WMH volumes are associated with tau burden from positron emission tomography (PET) in EOAD, suggesting WMHs are correlated with increasing burden of AD. Greater WMH volumes are associated with worse performance on global cognitive tests. EOAD participants have higher WMH volumes compared with CN and early-onset amyloid-negative cognitively impaired (EOnonAD) groups across all brain regions.

Cerebrospinal fluid biomarkers in the Longitudinal Early-onset Alzheimer's Disease Study.

INTRODUCTION: One goal of the Longitudinal Early Onset Alzheimer's Disease Study (LEADS) is to define the fluid biomarker characteristics of early-onset Alzheimer's disease (EOAD). METHODS: Cerebrospinal fluid (CSF) concentrations of Aß1-40, Aß1-42, total tau (tTau), pTau181, VILIP-1, SNAP-25, neurogranin (Ng), neurofilament light chain (NfL), and YKL-40 were measured by immunoassay in 165 LEADS participants. The associations of biomarker concentrations with diagnostic group and standard cognitive tests were evaluated. RESULTS: Biomarkers were correlated with one another. Levels of CSF Aß42/40, pTau181, tTau, SNAP-25, and Ng in EOAD differed significantly from cognitively normal and early-onset non-AD dementia; NfL, YKL-40, and VILIP-1 did not. Across groups, all biomarkers except SNAP-25 were correlated with cognition. Within the EOAD group, Aß42/40, NfL, Ng, and SNAP-25 were correlated with at least one cognitive measure. DISCUSSION: This study provides a comprehensive analysis of CSF biomarkers in sporadic EOAD that can inform EOAD clinical trial design.

Baseline neuropsychiatric symptoms and psychotropic medication use midway through data collection of the Longitudinal Early-Onset Alzheimer's Disease Study (LEADS) cohort.

INTRODUCTION: We examined neuropsychiatric symptoms (NPS) and psychotropic medication use in a large sample of individuals with early-onset Alzheimer's disease (EOAD; onset 40-64 years) at the midway point of data collection for the Longitudinal Early-onset Alzheimer's Disease Study (LEADS). METHODS: Baseline NPS (Neuropsychiatric Inventory - Questionnaire; Geriatric Depression Scale) and psychotropic medication use from 282 participants enrolled in LEADS were compared across diagnostic groups - amyloid-positive EOAD (n = 212) and amyloid negative early-onset non-Alzheimer's disease (EOnonAD; n = 70). RESULTS: Affective behaviors were the most common NPS in EOAD at similar frequencies to EOnonAD. Tension and impulse control behaviors were more common in EOnonAD. A minority of participants were using psychotropic medications, and use was higher in EOnonAD. DISCUSSION: Overall NPS burden and psychotropic medication use were higher in EOnonAD than EOAD participants. Future research will investigate moderators and etiological drivers of NPS, and NPS differences in EOAD versus late-onset AD.

Influence of amyloid and diagnostic syndrome on non-traditional memory scores in early-onset Alzheimer's disease.

INTRODUCTION: The Rey Auditory Verbal Learning Test (RAVLT) is a useful neuropsychological test for describing episodic memory impairment in dementia. However, there is limited research on its utility in early-onset Alzheimer's disease (EOAD). We assess the influence of amyloid and diagnostic syndrome on several memory scores in EOAD. METHODS: We transcribed RAVLT recordings from 303 subjects in the Longitudinal Early-Onset Alzheimer's Disease Study. Subjects were grouped by amyloid status and syndrome. Primacy, recency, J-curve, duration, stopping time, and speed score were calculated and entered into linear mixed effects models as dependent variables. RESULTS: Compared with amyloid negative subjects, positive subjects exhibited effects on raw score, primacy, recency, and stopping time. Inter-syndromic differences were noted with raw score, primacy, recency, J-curve, and stopping time. DISCUSSION: RAVLT measures are sensitive to the effects of amyloid and syndrome in EOAD. Future work is needed to quantify the predictive value of these scores. HIGHLIGHTS: RAVLT patterns characterize various presentations of EOAD and EOnonAD Amyloid impacts raw score, primacy, recency, and stopping time Timing-based scores add value over traditional count-based scores.

Profiling baseline performance on the Longitudinal Early-Onset Alzheimer's Disease Study (LEADS) cohort near the midpoint of data collection.

OBJECTIVE: The Longitudinal Early-Onset Alzheimer's Disease Study (LEADS) seeks to provide comprehensive understanding of early-onset Alzheimer's disease (EOAD; onset <65 years), with the current study profiling baseline clinical, cognitive, biomarker, and genetic characteristics of the cohort nearing the data-collection mid-point. METHODS: Data from 371 LEADS participants were compared based on diagnostic group classification (cognitively normal [n = 89], amyloid-positive EOAD [n = 212], and amyloid-negative early-onset non-Alzheimer's disease [EOnonAD; n = 70]). RESULTS: Cognitive performance was worse for EOAD than other groups, and EOAD participants were apolipoprotein E (APOE) ε4 homozygotes at higher rates. An amnestic presentation was common among impaired participants (81%), with several clinical phenotypes present. LEADS participants generally consented at high rates to optional trial procedures. CONCLUSIONS: We present the most comprehensive baseline characterization of sporadic EOAD in the United States to date. EOAD presents with widespread cognitive impairment within and across clinical phenotypes, with differences in APOE ε4 allele carrier status appearing to be relevant. HIGHLIGHTS: Findings represent the most comprehensive baseline characterization of sporadic early-onset Alzheimer's disease (EOAD) to date. Cognitive impairment was widespread for EOAD participants and more severe than other groups. EOAD participants were homozygous apolipoprotein E (APOE) ε4 carriers at higher rates than the EOnonAD group. Amnestic presentation predominated in EOAD and EOnonAD participants, but other clinical phenotypes were present.

18F-AV-1451 positron emission tomography in neuropathological substrates of corticobasal syndrome.

Multiple neuropathological processes can manifest in life as a corticobasal syndrome. We sought to relate retention of the tau-PET tracer 18F-AV-1451 and structural magnetic resonance measures of regional atrophy to clinical features in clinically diagnosed and neuropathologically confirmed cases of corticobasal syndrome and to determine whether these vary with the underlying neuropathological changes. In this observational, cross-sectional study, 11 subjects (eight female and three male, median age 72 years) with corticobasal syndrome underwent structural MRI, tau-PET with 18F-AV-1451, amyloid-PET with 11C-Pittsburgh compound B, detailed clinical examinations and neuropsychological testing. Of the 11, three had evidence of high amyloid burden consistent with Alzheimer's disease while eight did not. Neuropathological evaluations were acquired in six cases. Mixed effects general linear models were used to compare 18F-AV-1451 retention and atrophy in amyloid-negative corticobasal syndrome cases to 32 age-matched healthy control subjects and to relate cortical and subcortical 18F-AV-1451 retention and atrophy to clinical features. Subjects without amyloid, including three with pathologically confirmed corticobasal degeneration, showed greater regional 18F-AV-1451 retention and associated regional atrophy in areas commonly associated with corticobasal degeneration pathology than healthy control subjects [retention was higher compared to healthy controls (P = 0.0011), driven especially by the precentral gyrus (P = 0.011) and pallidum (P < 0.0001), and greater atrophy was seen in subjects compared to control subjects (P = 0.0004)]. Both 18F-AV-1451 retention and atrophy were greater in the clinically more affected hemisphere [on average, retention was 0.173 standardized uptake value ratio units higher on the more affected side (95% confidence interval, CI 0.11-0.24, P < 0.0001), and volume was 0.719 lower on the more affected side (95% CI 0.35-1.08, P = 0.0001)]. 18F-AV-1451 retention was greater in subcortical than in cortical regions, P < 0.0001. In contrast to these findings, subjects with amyloid-positive corticobasal syndrome, including two neuropathologically confirmed cases of Alzheimer's disease, demonstrated greater and more widespread 18F-AV-1451 retention and regional atrophy than observed in the amyloid-negative cases. There was thalamic 18F-AV-1451 retention but minimal cortical and basal ganglia uptake in a single corticobasal syndrome subject without neuropathological evidence of tau pathology, likely representing non-specific signal. Asymmetric cortical and basal ganglia 18F-AV-1451 retention consonant with the clinical manifestations characterize corticobasal syndrome due to corticobasal degeneration, whereas the cortical retention in cases associated with Alzheimer's disease is greater and more diffuse.

Clinical, radiologic, and pathologic features of the globular glial tauopathy subtype of frontotemporal lobar degeneration in right temporal variant frontotemporal dementia with salient features of Geschwind syndrome.

Globular Glial Tauopathy (GGT) is a rare form of Frontotemporal Lobar Degeneration (FTLD) consisting of 4-repeat tau globular inclusions in astrocytes and oligodendrocytes. We present the pathological findings of GGT in a previously published case of a 73-year-old woman with behavioral symptoms concerning for right temporal variant frontotemporal dementia with initial and salient features of Geschwind syndrome. Clinically, she lacked motor abnormalities otherwise common in previously published GGT cases. Brain MRI showed focal right anterior temporal atrophy (indistinguishable from five FTLD-TDP cases) and subtle ipsilateral white matter signal abnormalities. Brain autopsy showed GGT type III and Alzheimer's neuropathologic changes. .

Greater Neural Differentiation in the Ventral Visual Cortex Is Associated with Youthful Memory in Superaging.

Superagers are older adults who maintain youthful memory despite advanced age. Previous studies showed that superagers exhibit greater structural and intrinsic functional brain integrity, which contribute to their youthful memory. However, no studies, to date, have examined brain activity as superagers learn and remember novel information. Here, we analyzed functional magnetic resonance imaging data collected from 41 young and 40 older adults while they performed a paired associate visual recognition memory task. Superaging was defined as youthful performance on the long delay free recall of the California Verbal Learning Test. We assessed the fidelity of neural representations as participants encoded and later retrieved a series of word stimuli paired with a face or a scene image. Superagers, like young adults, exhibited more distinct neural representations in the fusiform gyrus and parahippocampal gyrus while viewing visual stimuli belonging to different categories (greater neural differentiation) and more similar category representations between encoding and retrieval (greater neural reinstatement), compared with typical older adults. Greater neural differentiation and reinstatement were associated with superior memory performance in all older adults. Given that the fidelity of cortical sensory processing depends on neural plasticity and is trainable, these mechanisms may be potential biomarkers for future interventions to promote successful aging.

Stronger Functional Connectivity in the Default Mode and Salience Networks Is Associated With Youthful Memory in Superaging.

"Superagers" are older adults who, despite their advanced age, maintain youthful memory. Previous morphometry studies revealed multiple default mode network (DMN) and salience network (SN) regions whose cortical thickness is greater in superagers and correlates with memory performance. In this study, we examined the intrinsic functional connectivity within DMN and SN in 41 young (24.5 ± 3.6 years old) and 40 older adults (66.9 ± 5.5 years old). Superaging was defined as youthful performance on a memory recall task, the California Verbal Learning Test (CVLT). Participants underwent a resting-state functional magnetic resonance imaging (fMRI) scan and performed a separate visual-verbal recognition memory task. As predicted, within both DMN and SN, superagers had stronger connectivity compared with typical older adults and similar connectivity compared with young adults. Superagers also performed similarly to young adults and better than typical older adults on the recognition task, demonstrating youthful episodic memory that generalized across memory tasks. Stronger connectivity within each network independently predicted better performance on both the CVLT and recognition task in older adults. Variation in intrinsic connectivity explained unique variance in memory performance, above and beyond youthful neuroanatomy. These results extend our understanding of the neural basis of superaging as a model of successful aging.

Neuroimaging in Frontotemporal Lobar Degeneration: Research and Clinical Utility.

Frontotemporal lobar dementia (FTLD) is a clinically and pathologically complex disease. Advances in neuroimaging techniques have provided a specialized set of tools to investigate underlying pathophysiology and identify clinical biomarkers that aid in diagnosis, prognostication, monitoring, and identification of appropriate endpoints in clinical trials. In this chapter, we review data discussing the utility of neuroimaging biomarkers in sporadic FTLD, with an emphasis on current and future clinical applications. Among those modalities readily utilized in clinical settings, T1-weighted structural magnetic resonance imaging (MRI) and 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) are best supported in differential diagnosis and as targets for clinical trial endpoints. However, a number of nonclinical neuroimaging modalities, including diffusion tensor imaging and resting-state functional connectivity MRI, show promise as biomarkers to predict progression and as clinical trial endpoints. Other neuroimaging modalities, including amyloid PET, Tau PET, and arterial spin labeling MRI, are also discussed, though more work is required to establish their utility in FTLD in clinical settings.

Atrophy in Distinct Corticolimbic Networks Subserving Socioaffective Behavior in Semantic Variant Primary Progressive Aphasia.

BACKGROUND: Although traditionally conceptualized as a language disorder, semantic variant primary progressive aphasia (svPPA) is often accompanied by significant behavioral and affective symptoms which considerably increase disease morbidity. Specifically, these neuropsychiatric symptoms are characterized by breaches in normative socioaffective function, for example, an inability to read social cues, excessive trusting of others, and decreased empathy. Our prior neuroimaging work identified 3 corticolimbic networks anchored in the amygdala, temporal pole, and frontoinsular cortex: an affiliation network, theorized to mediate social approach behavior; an aversion network, theorized to subserve the appraisal of social threat; and a perception network, theorized to mediate the detection of social cues. We hy-pothesized that degeneration of these networks could provide neuroanatomical substrates for socioaffective deficits in svPPA. METHODS: We examined hypothesized relationships between subscores on the Social Impairment Rating Scale (SIRS) and atrophy in each of these 3 networks in a group of 16 svPPA patients (using matched cognitively normal controls as a reference). RESULTS: Consistent with our predictions, the magnitude of atrophy in the affiliation network in svPPA patients correlated with the SIRS subscore of socioemotional detachment, while the magnitude of atrophy in the aversion network in svPPA patients correlated with the SIRS subscore of inappropriate trusting. We did not find the predicted association between perception network atrophy and the SIRS subscore of lack of attention to social cues. CONCLUSION: These findings highlight specific socioaffective deficits in svPPA and provide a neuroanatomical basis for these impairments by linking them to networks commonly targeted in this disorder.

Dopamine in the medial amygdala network mediates human bonding.

Research in humans and nonhuman animals indicates that social affiliation, and particularly maternal bonding, depends on reward circuitry. Although numerous mechanistic studies in rodents demonstrated that maternal bonding depends on striatal dopamine transmission, the neurochemistry supporting maternal behavior in humans has not been described so far. In this study, we tested the role of central dopamine in human bonding. We applied a combined functional MRI-PET scanner to simultaneously probe mothers' dopamine responses to their infants and the connectivity between the nucleus accumbens (NAcc), the amygdala, and the medial prefrontal cortex (mPFC), which form an intrinsic network (referred to as the "medial amygdala network") that supports social functioning. We also measured the mothers' behavioral synchrony with their infants and plasma oxytocin. The results of this study suggest that synchronous maternal behavior is associated with increased dopamine responses to the mother's infant and stronger intrinsic connectivity within the medial amygdala network. Moreover, stronger network connectivity is associated with increased dopamine responses within the network and decreased plasma oxytocin. Together, these data indicate that dopamine is involved in human bonding. Compared with other mammals, humans have an unusually complex social life. The complexity of human bonding cannot be fully captured in nonhuman animal models, particularly in pathological bonding, such as that in autistic spectrum disorder or postpartum depression. Thus, investigations of the neurochemistry of social bonding in humans, for which this study provides initial evidence, are warranted.

Youthful Brains in Older Adults: Preserved Neuroanatomy in the Default Mode and Salience Networks Contributes to Youthful Memory in Superaging.

UNLABELLED: Decline in cognitive skills, especially in memory, is often viewed as part of "normal" aging. Yet some individuals "age better" than others. Building on prior research showing that cortical thickness in one brain region, the anterior midcingulate cortex, is preserved in older adults with memory performance abilities equal to or better than those of people 20-30 years younger (i.e., "superagers"), we examined the structural integrity of two large-scale intrinsic brain networks in superaging: the default mode network, typically engaged during memory encoding and retrieval tasks, and the salience network, typically engaged during attention, motivation, and executive function tasks. We predicted that superagers would have preserved cortical thickness in critical nodes in these networks. We defined superagers (60-80 years old) based on their performance compared to young adults (18-32 years old) on the California Verbal Learning Test Long Delay Free Recall test. We found regions within the networks of interest where the cerebral cortex of superagers was thicker than that of typical older adults, and where superagers were anatomically indistinguishable from young adults; hippocampal volume was also preserved in superagers. Within the full group of older adults, thickness of a number of regions, including the anterior temporal cortex, rostral medial prefrontal cortex, and anterior midcingulate cortex, correlated with memory performance, as did the volume of the hippocampus. These results indicate older adults with youthful memory abilities have youthful brain regions in key paralimbic and limbic nodes of the default mode and salience networks that support attentional, executive, and mnemonic processes subserving memory function. SIGNIFICANCE STATEMENT: Memory performance typically declines with age, as does cortical structural integrity, yet some older adults maintain youthful memory. We tested the hypothesis that superagers (older individuals with youthful memory performance) would exhibit preserved neuroanatomy in key brain networks subserving memory. We found that superagers not only perform similarly to young adults on memory testing, they also do not show the typical patterns of brain atrophy in certain regions. These regions are contained largely within two major intrinsic brain networks: the default mode network, implicated in memory encoding, storage, and retrieval, and the salience network, associated with attention and executive processes involved in encoding and retrieval. Preserved neuroanatomical integrity in these networks is associated with better memory performance among older adults.

Salience Network Connectivity Modulates Skin Conductance Responses in Predicting Arousal Experience.

Individual differences in arousal experience have been linked to differences in resting-state salience network connectivity strength. In this study, we investigated how adding task-related skin conductance responses (SCR), a measure of sympathetic autonomic nervous system activity, can predict additional variance in arousal experience. Thirty-nine young adults rated their subjective experience of arousal to emotionally evocative images while SCRs were measured. They also underwent a separate resting-state fMRI scan. Greater SCR reactivity (an increased number of task-related SCRs) to emotional images and stronger intrinsic salience network connectivity independently predicted more intense experiences of arousal. Salience network connectivity further moderated the effect of SCR reactivity: In individuals with weak salience network connectivity, SCR reactivity more significantly predicted arousal experience, whereas in those with strong salience network connectivity, SCR reactivity played little role in predicting arousal experience. This interaction illustrates the degeneracy in neural mechanisms driving individual differences in arousal experience and highlights the intricate interplay between connectivity in central visceromotor neural circuitry and peripherally expressed autonomic responses in shaping arousal experience.