Network Localization of Spontaneous Confabulation.

OBJECTIVE: Spontaneous confabulation is a symptom in which false memories are conveyed by the patient as true. The purpose of the study was to identify the neuroanatomical substrate of this complex symptom and evaluate the relationship to related symptoms, such as delusions and amnesia. METHODS: Twenty-five lesion locations associated with spontaneous confabulation were identified in a systematic literature search. The network of brain regions functionally connected to each lesion location was identified with a large connectome database (N=1,000) and compared with networks derived from lesions associated with nonspecific (i.e., variable) symptoms (N=135), delusions (N=32), or amnesia (N=53). RESULTS: Lesions associated with spontaneous confabulation occurred in multiple brain locations, but they were all part of a single functionally connected brain network. Specifically, 100% of lesions were connected to the mammillary bodies (familywise error rate [FWE]-corrected p<0.05). This connectivity was specific for lesions associated with confabulation compared with lesions associated with nonspecific symptoms or delusions (FWE-corrected p<0.05). Lesions associated with confabulation were more connected to the orbitofrontal cortex than those associated with amnesia (FWE-corrected p<0.05). CONCLUSIONS: Spontaneous confabulation maps to a common functionally connected brain network that partially overlaps, but is distinct from, networks associated with delusions or amnesia. These findings lend new insight into the neuroanatomical bases of spontaneous confabulation.

Promoting Growth in Behavioral Neurology: A Path Forward.

Behavioral neurology & neuropsychiatry (BNNP) is a field that seeks to understand brain-behavior relationships, including fundamental brain organization principles and the many ways that brain structures and connectivity can be disrupted, leading to abnormalities of behavior, cognition, emotion, perception, and social cognition. In North America, BNNP has existed as an integrated subspecialty through the United Council for Neurologic Subspecialties since 2006. Nonetheless, the number of behavioral neurologists across academic medical centers and community settings is not keeping pace with increasing clinical and research demand. In this commentary, we provide a brief history of BNNP followed by an outline of the current challenges and opportunities for BNNP from the behavioral neurologist's perspective across clinical, research, and educational spheres. We provide a practical guide for promoting BNNP and addressing the shortage of behavioral neurologists to facilitate the continued growth and development of the subspecialty. We also urge a greater commitment to recruit trainees from diverse backgrounds so as to dismantle persistent obstacles that hinder inclusivity in BNNP-efforts that will further enhance the growth and impact of the subspecialty. With rapidly expanding diagnostic and therapeutic approaches across a range of conditions at the intersection of neurology and psychiatry, BNNP is well positioned to attract new trainees and expand its reach across clinical, research, and educational activities.

Associations among plasma, MRI, and amyloid PET biomarkers of Alzheimer's disease and related dementias and the impact of health-related comorbidities in a community-dwelling cohort.

INTRODUCTION: We evaluated associations between plasma and neuroimaging-derived biomarkers of Alzheimer's disease and related dementias and the impact of health-related comorbidities. METHODS: We examined plasma biomarkers (neurofilament light chain, glial fibrillary acidic protein, amyloid beta [Aß] 42/40, phosphorylated tau 181) and neuroimaging measures of amyloid deposition (Aß-positron emission tomography [PET]), total brain volume, white matter hyperintensity volume, diffusion-weighted fractional anisotropy, and neurite orientation dispersion and density imaging free water. Participants were adjudicated as cognitively unimpaired (CU; N = 299), mild cognitive impairment (MCI; N = 192), or dementia (DEM; N = 65). Biomarkers were compared across groups stratified by diagnosis, sex, race, and APOE ε4 carrier status. General linear models examined plasma-imaging associations before and after adjusting for demographics (age, sex, race, education), APOE ε4 status, medications, diagnosis, and other factors (estimated glomerular filtration rate [eGFR], body mass index [BMI]). RESULTS: Plasma biomarkers differed across diagnostic groups (DEM > MCI > CU), were altered in Aß-PET-positive individuals, and were associated with poorer brain health and kidney function. DISCUSSION: eGFR and BMI did not substantially impact associations between plasma and neuroimaging biomarkers. HIGHLIGHTS: Plasma biomarkers differ across diagnostic groups (DEM > MCI > CU) and are altered in Aß-PET-positive individuals. Altered plasma biomarker levels are associated with poorer brain health and kidney function. Plasma and neuroimaging biomarker associations are largely independent of comorbidities.

Network Localization of Unconscious Visual Perception in Blindsight.

OBJECTIVE: Blindsight is a disorder where brain injury causes loss of conscious but not unconscious visual perception. Prior studies have produced conflicting results regarding the neuroanatomical pathways involved in this unconscious perception. METHODS: We performed a systematic literature search to identify lesion locations causing visual field loss in patients with blindsight (n = 34) and patients without blindsight (n = 35). Resting state functional connectivity between each lesion location and all other brain voxels was computed using a large connectome database (n = 1,000). Connections significantly associated with blindsight (vs no blindsight) were identified. RESULTS: Functional connectivity between lesion locations and the ipsilesional medial pulvinar was significantly associated with blindsight (family wise error p = 0.029). No significant connectivity differences were found to other brain regions previously implicated in blindsight. This finding was independent of methods (eg, flipping lesions to the left or right) and stimulus type (moving vs static). INTERPRETATION: Connectivity to the ipsilesional medial pulvinar best differentiates lesion locations associated with blindsight versus those without blindsight. Our results align with recent data from animal models and provide insight into the neuroanatomical substrate of unconscious visual abilities in patients. ANN NEUROL 2022;91:217-224.

When prion disease Isn't suspected: prion disease as the cause of terminal decline in chronic mixed dementia.

Alzheimer's Disease (AD) is the most common cause of dementia, although multiple pathologies are found in nearly half of the cases with clinically diagnosed AD. Prion diseases, such as Creutzfeldt-Jakob disease (CJD), are rare causes of dementia and typically manifest as a rapidly progressive dementia, where symptom onset to dementia most often occurs over the course of months. In this brief report, we describe a patient's typically progressive dementia with a precipitous decline at the end of their life who, on neuropathological evaluation, was found to have multiple neurodegenerative proteinopathies as well as spongiform encephalopathy due to CJD. This case of unsuspected CJD highlights a rare, but epidemiologically important, cause of sudden decline in well-established neurodegenerative dementias.

Neighborhood segregation and cognitive change: Multi-Ethnic Study of Atherosclerosis.

INTRODUCTION: We investigated associations between neighborhood racial/ethnic segregation and cognitive change. METHODS: We used data (n = 1712) from the Multi-Ethnic Study of Atherosclerosis. Racial/ethnic segregation was assessed using Getis-Ord (Gi*) z-scores based on American Community Survey Census tract data (higher Gi* = greater spatial clustering of participant's race/ethnicity). Global cognition and processing speed were assessed twice, 6 years apart. Adjusted multilevel linear regression tested associations between Gi* z-scores and cognition. Effect modification by race/ethnicity, income, education, neighborhood socioeconomic status, and neighborhood social support was tested. RESULTS: Participants were on average 67 years old; 43% were White, 11% Chinese, 29% African American/Black, 17% Hispanic; 40% had high neighborhood segregation (Gi* > 1.96). African American/Black participants with greater neighborhood segregation had greater processing speed decline in stratified analyses, but no interactions were significant. DISCUSSION: Segregation was associated with greater processing speed declines among African American/Black participants. Additional follow-ups and comprehensive cognitive batteries may further elucidate these findings. HIGHLIGHTS: A study of neighborhood racial/ethnic segregation and change in cognition. Study was based on a racially and geographically diverse, population-based cohort of older adults. Racial/ethnic segregation (clustering) was measured by the Getis-ord (Gi*) statistic. We saw faster processing speed decline among Black individuals in segregated neighborhoods.

Blood-based bioenergetic profiling reveals differences in mitochondrial function associated with cognitive performance and Alzheimer's disease.

INTRODUCTION: Despite evidence for systemic mitochondrial dysfunction early in Alzheimer's disease (AD) pathogenesis, reliable approaches monitoring these key bioenergetic alterations are lacking. We used peripheral blood mononuclear cells (PBMCs) and platelets as reporters of mitochondrial function in the context of cognitive impairment and AD. METHODS: Mitochondrial function was analyzed using complementary respirometric approaches in intact and permeabilized cells from older adults with normal cognition, mild cognitive impairment (MCI), and dementia due to probable AD. Clinical outcomes included measures of cognitive function and brain morphology. RESULTS: PBMC and platelet bioenergetic parameters were lowest in dementia participants. MCI platelets exhibited higher maximal respiration than normocognitives. PBMC and platelet respiration positively associated with cognitive ability and hippocampal volume, and negatively associated with white matter hyperintensities. DISCUSSION: Our findings indicate blood-based bioenergetic profiling can be used as a minimally invasive approach for measuring systemic bioenergetic differences associated with dementia, and may be used to monitor bioenergetic changes associated with AD risk and progression. HIGHLIGHTS: Peripheral cell bioenergetic alterations accompanied cognitive decline in older adults with mild cognitive impairment (MCI) and Alzheimer's disease (AD) and related dementia (DEM). Peripheral blood mononuclear cells (PBMC) and platelet glucose-mediated respiration decreased in participants with dementia compared to normocognitive controls (NC). PBMC fatty-acid oxidation (FAO)-mediated respiration progressively declined in MCI and AD compared to NC participants, while platelet FAO-mediated respiration exhibited an inverse-Warburg effect in MCI compared to NC participants. Positive associations were observed between bioenergetics and Modified Preclinical Alzheimer's Cognitive Composite, and bioenergetics and hippocampal volume %, while a negative association was observed between bioenergetics and white matter hyperintensities. Systemic mitochondrial dysfunction is associated with cognitive decline.

The role of PTSD and TBI in post-deployment sleep outcomes.

The purpose of this study was to evaluate the main and interaction effects of PTSD and TBI on sleep outcomes in veterans. Post-deployment combat veterans (N = 293, 87.37% male) completed clinical interviews to determine diagnosis and severity of PTSD and deployment TBI history, as well as subjective measures of sleep quality, sleep duration, and restedness. Sleep-related medical diagnoses were extracted from electronic medical records for all participants. PTSD and TBI were each associated with poorer ratings of sleep quality, restedness, shorter sleep duration, and greater incidence of clinically diagnosed sleep disorders. Analyses indicated main effects of PTSD on sleep quality (p < .001), but no main effects of TBI. PTSD severity was significantly associated with poorer sleep quality (p < .001), restedness (p = .018), and shorter sleep duration (p = .015). TBI severity was significantly associated with restedness beyond PTSD severity (p = .036). There were no interaction effects between diagnostic or severity variables. PTSD severity is a driving factor for subjective ratings of sleep disturbance beyond PTSD diagnosis as well as TBI diagnosis and severity. Despite this, poor sleep was apparent throughout the sample, which suggests post-deployment service members may globally benefit from routine screening of sleep problems and increased emphasis on sleep hygiene.

Aprosodia and prosoplegia with right frontal neurodegeneration.

Affective prosody and facial expression are essential components of human communication. Aprosodic syndromes are associated with focal right cerebral lesions that impair the affective-prosodic aspects of language, but are rarely identified because affective prosody is not routinely assessed by clinicians. Inability to produce emotional faces (affective prosoplegia) is a related and important aspect of affective communication has overlapping neuroanatomic substrates with affective prosody. We describe a patient with progressive aprosodia and prosoplegia who had right greater than left perisylvian and temporal atrophy with an anterior predominance. We discuss the importance of assessing affective prosody and facial expression to arrive at an accurate clinical diagnosis.

Acute Pharmacological Management of Behavioral and Emotional Dysregulation Following a Traumatic Brain Injury: A Systematic Review of the Literature.

BACKGROUND: Traumatic brain injury (TBI) is an increasingly common cause of behavioral and emotional dysregulation among hospitalized patients. While consultation-liaison psychiatrists are often called to help manage these behaviors, acute pharmacological management guidelines are limited. OBJECTIVE: Conduct a systematic review to determine which pharmacological measures are supported by the literature for targeting agitation and aggression in the acute time period following a TBI. METHODS: In a systematic review of MEDLINE, Embase, PsycInfo, ClinicalTrials.gov and the Cochrane Library, we identified and then analyzed publications that investigated the pharmacological management of behavioral and emotional dysregulation following a TBI during the acute time period following injury. RESULTS: There were a limited number of high quality studies that met our inclusion criteria, including only five randomized controlled trials. The majority of the literature identified consisted of case reports or case series. Trends identified in the literature reviewed suggested that amantadine, propranolol, and anti-epileptics were the best supported medications to consider. For many medication classes, the time of medication initiation and duration of treatment, relative to the time of injury, may impact the effect observed. CONCLUSIONS: The pharmacological management of agitated patients immediately following a TBI is still an area of much-needed research, as there is limited data-driven guidance in the literature.

Biopsychosocial contexts influence adult cognitive function concurrently and longitudinally.

Background: Cognitive aging is a complex process that impacts human behavior. Identifying the factors that preserve cognitive functioning is a public health priority, given that 20% of the US population will be at least 65 years old in the next decade. Biopsychosocial determinants of cognitive decline across the lifespan are often examined as ecological factors that independently moderate cognitive aging, despite the known complexity surrounding these relationships. Objective: We aimed to address this gap by exploring the synergistic and simultaneous relationship between risk and protective factors on cognitive functioning. Method: Using the MIDUS study datasets, we examined the relationships among physiological markers, friendship quality, and global cognition functioning, concurrently and longitudinally over ten years. Our participants included 929 healthy (417 men, 512 women) adults (average age at Time 1: 54.6 ± 11.6 years). Exploratory analyses examining the effects of racial minority status were also conducted. Results: Cross-sectionally, age, and friendship quality moderated the relationship between vagally-mediated heart rate variability (vm-HRV) and cognition such that younger adults with greater friendship quality had a negative relationship between vm-HRV and cognitive performance; our unexpected finding suggests the heart-brain relationship is sensitive to the biopsychosocial environment. Longitudinally, higher IL-6 levels at Time 1 predicted poorer cognitive performance a decade later, but only among those with greater levels of friendship quality, especially for white-identifying individuals. Conclusions: The relationships among physiological risk factors, social protective factors and cognitive functioning appear to be temporally different during mid-adulthood. Given many of the whole sample findings were not replicated within the racial minority subgroup, we suggest that these relationships should be examined in a larger and more diverse racial minority sample to determine whether this study lacked the power necessary to detect a relationship or if the relationships are in fact different by racial minority sub-group. In addition, future research should overcome the study's reliance on healthy adults and self-report measures of friendship quality by including adults with pre-existing cognitive impairments, and employing more real-time measures of friendship quality, such as daily diary or ecological momentary assessment.

Depressive Symptoms Affect Cognitive Functioning from Middle to Late Adulthood: Ethnoracial Minorities Experience Greater Repercussions.

Cognitive deficits, a diagnostic criterion for depressive disorders, may precede or follow the development of depressive symptoms and major depressive disorder. However, an individual can report an increase in depressive symptoms without any change in cognitive functioning. While ethnoracial minority group differences exist, little is known to date about how the relationship between depressive symptoms and cognitive function may differ by ethnoracial minority status. Utilizing data from the Midlife in the United States (MIDUS) study waves II (M2) and III (M3), this study examines the relationship between depressive symptoms and cognitive functioning concurrently and longitudinally in community-dwelling adults, as well as whether the results differed by ethnoracial minority status. Our participants included 910 adults (43.8% male, 80.8% White, 54.4 ± 11.5 years old at M2). Cross-sectionally, depressive symptoms, ethnoracial minority status, and their interaction had significant effects on cognitive function, consistent with previous investigations. Longitudinally, higher M2 depressive symptoms predicted poorer cognitive function at M3 over and above M2 cognitive functioning, but only within the ethnoracial minority sample. Our finding suggests that depressive symptoms predict cognitive functioning both concurrently and across time, and this relationship is moderated by ethnoracial identity, resulting in greater cognitive deficits among ethnoracial minority groups compared to their non-Hispanic White counterparts.

Peripheral Blood Cells From Older Adults Exhibit Sex-Associated Differences in Mitochondrial Function.

Blood-based mitochondrial bioenergetic profiling is a feasible, economical, and minimally invasive approach that can be used to examine mitochondrial function and energy metabolism in human subjects. In this study, we use 2 complementary respirometric techniques to evaluate mitochondrial bioenergetics in both intact and permeabilized peripheral blood mononuclear cells (PBMCs) and platelets to examine sex dimorphism in mitochondrial function among older adults. Employing equal numbers of PBMCs and platelets to assess mitochondrial bioenergetics, we observe significantly higher respiration rates in female compared to male participants. Mitochondrial bioenergetic differences remain significant after controlling for independent parameters including demographic parameters (age, years of education), and cognitive parameters (mPACC5, COGDX). Our study illustrates that circulating blood cells, immune cells in particular, have distinctly different mitochondrial bioenergetic profiles between females and males. These differences should be taken into account as blood-based bioenergetic profiling is now commonly used to understand the role of mitochondrial bioenergetics in human health and aging.

Differential diagnosis of frontotemporal dementia subtypes with explainable deep learning on structural MRI.

Background: Frontotemporal dementia (FTD) represents a collection of neurobehavioral and neurocognitive syndromes that are associated with a significant degree of clinical, pathological, and genetic heterogeneity. Such heterogeneity hinders the identification of effective biomarkers, preventing effective targeted recruitment of participants in clinical trials for developing potential interventions and treatments. In the present study, we aim to automatically differentiate patients with three clinical phenotypes of FTD, behavioral-variant FTD (bvFTD), semantic variant PPA (svPPA), and nonfluent variant PPA (nfvPPA), based on their structural MRI by training a deep neural network (DNN). Methods: Data from 277 FTD patients (173 bvFTD, 63 nfvPPA, and 41 svPPA) recruited from two multi-site neuroimaging datasets: the Frontotemporal Lobar Degeneration Neuroimaging Initiative and the ARTFL-LEFFTDS Longitudinal Frontotemporal Lobar Degeneration databases. Raw T1-weighted MRI data were preprocessed and parcellated into patch-based ROIs, with cortical thickness and volume features extracted and harmonized to control the confounding effects of sex, age, total intracranial volume, cohort, and scanner difference. A multi-type parallel feature embedding framework was trained to classify three FTD subtypes with a weighted cross-entropy loss function used to account for unbalanced sample sizes. Feature visualization was achieved through post-hoc analysis using an integrated gradient approach. Results: The proposed differential diagnosis framework achieved a mean balanced accuracy of 0.80 for bvFTD, 0.82 for nfvPPA, 0.89 for svPPA, and an overall balanced accuracy of 0.84. Feature importance maps showed more localized differential patterns among different FTD subtypes compared to groupwise statistical mapping. Conclusion: In this study, we demonstrated the efficiency and effectiveness of using explainable deep-learning-based parallel feature embedding and visualization framework on MRI-derived multi-type structural patterns to differentiate three clinically defined subphenotypes of FTD: bvFTD, nfvPPA, and svPPA, which could help with the identification of at-risk populations for early and precise diagnosis for intervention planning.

Examining a Preclinical Alzheimer's Cognitive Composite for Telehealth Administration for Reliability Between In-Person and Remote Cognitive Testing with Neuroimaging Biomarkers.

Background: The preclinical Alzheimer's cognitive composite (PACC) was developed for in-person administration to capture subtle cognitive decline. At the outset of the COVID-19 pandemic, cognitive testing was increasingly performed remotely by telephone or video administration. It is desirable to have a harmonized composite measurement derived from both in-person and remote assessments for identifying cognitive changes and to examine its relationship with common neuroimaging biomarkers. Objective: We defined a telehealth compatible PACC (tPACC) and examined its relationship with neuroimaging biomarkers related to neurodegeneration, brain function and perfusion, white matter integrity, and amyloid-ß. Methods: We examined 648 participants' neuroimaging and in-person and remote cognitive testing data from the Wake Forest Alzheimer's Disease Research Center's Clinical Core cohort (observational study) to calculate a modified PACC (PACC5-RAVLT) score and tPACC scores (in-person and remote). We performed Spearman/intraclass correlation coefficient (ICC) analyses for reliability of tPACC scores and linear regression models to evaluate associations between tPACC and neuroimaging. Bland-Altman plots for agreement were constructed across cognitively normal and impaired (mild cognitive impairment and dementia) participants. Results: There was a significant positive relationship between tPACCin - person and PACC5-RAVLT (Overall group: r2 = 0.94, N = 648), and tPACCin - person and tPACCremote (validation subgroup: ICC = 0.82, n = 53). Overall, tPACC showed significant associations with brain thickness/volume, gray matter perfusion, white matter free water, and amyloid-ß deposition. Conclusions: There is a good agreement between tPACCand PACC5-RAVLTfor cognitively normal and impaired individuals. The tPACC is associated with common neuroimaging markers of Alzheimer's disease.

Feasibility of Remote Administration of the Uniform Data Set-Version 3 for Assessment of Older Adults With Mild Cognitive Impairment and Alzheimer's Disease.

OBJECTIVE: Assess the feasibility and concurrent validity of a modified Uniform Data Set version 3 (UDSv3) for remote administration for individuals with normal cognition (NC), mild cognitive impairment (MCI), and early dementia. METHOD: Participants (N = 93) (age: 72.8 [8.9] years; education: 15.6 [2.5] years; 72% female; 84% White) were enrolled from the Wake Forest ADRC. Portions of the UDSv3 cognitive battery, plus the Rey Auditory Verbal Learning Test, were completed by telephone or video within ~6 months of participant's in-person visit. Adaptations for phone administration (e.g., Oral Trails for Trail Making Test [TMT] and Blind Montreal Cognitive Assessment [MoCA] for MoCA) were made. Participants reported on the pleasantness, difficulty, and preference for each modality. Staff provided validity ratings for assessments. Participants' remote data were adjudicated by cognitive experts blinded to the in person-diagnosis (NC [N = 44], MCI [N = 35], Dementia [N = 11], or other [N = 3]). RESULTS: Remote assessments were rated as pleasant as in-person assessments by 74% of participants and equally difficult by 75%. Staff validity rating (video = 92%; phone = 87.5%) was good. Concordance between remote/in-person scores was generally moderate to good (r = .3 -.8; p < .05) except for TMT-A/OTMT-A (r = .3; p > .05). Agreement between remote/in-person adjudicated cognitive status was good (k = .61-.64). CONCLUSIONS: We found preliminary evidence that older adults, including those with cognitive impairment, can be assessed remotely using a modified UDSv3 research battery. Adjudication of cognitive status that relies on remotely collected data is comparable to classifications using in-person assessments.

Social genomics, cognition, and well-being during the COVID-19 pandemic.

INTRODUCTION: Adverse psychosocial exposure is associated with increased proinflammatory gene expression and reduced type-1 interferon gene expression, a profile known as the conserved transcriptional response to adversity (CTRA). Little is known about CTRA activity in the context of cognitive impairment, although chronic inflammatory activation has been posited as one mechanism contributing to late-life cognitive decline. METHODS: We studied 171 community-dwelling older adults from the Wake Forest Alzheimer's Disease Research Center who answered questions via a telephone questionnaire battery about their perceived stress, loneliness, well-being, and impact of COVID-19 on their life, and who provided a self-collected dried blood spot sample. Of those, 148 had adequate samples for mRNA analysis, and 143 were included in the final analysis, which including participants adjudicated as having normal cognition (NC, n = 91) or mild cognitive impairment (MCI, n = 52) were included in the analysis. Mixed effect linear models were used to quantify associations between psychosocial variables and CTRA gene expression. RESULTS: In both NC and MCI groups, eudaimonic well-being (typically associated with a sense of purpose) was inversely associated with CTRA gene expression whereas hedonic well-being (typically associated with pleasure seeking) was positively associated. In participants with NC, coping through social support was associated with lower CTRA gene expression, whereas coping by distraction and reframing was associated with higher CTRA gene expression. CTRA gene expression was not related to coping strategies for participants with MCI, or to either loneliness or perceived stress in either group. DISCUSSION: Eudaimonic and hedonic well-being remain important correlates of molecular markers of stress, even in people with MCI. However, prodromal cognitive decline appears to moderate the significance of coping strategies as a correlate of CTRA gene expression. These results suggest that MCI can selectively alter biobehavioral interactions in ways that could potentially affect the rate of future cognitive decline and may serve as targets for future intervention efforts.