Linking Type and Extent of Head Trauma to Cavum Septum Pellucidum in Older Adults With and Without Alzheimer Disease and Related Dementias.

BACKGROUND AND OBJECTIVES: Cavum septum pellucidum (CSP) is a common but nonspecific MRI finding in individuals with prior head trauma. The type and extent of head trauma related to CSP, CSP features specific to head trauma, and the impact of brain atrophy on CSP are unknown. We evaluated CSP cross-sectionally and longitudinally in healthy and clinically impaired older adults who underwent detailed lifetime head trauma characterization. METHODS: This is an observational cohort study of University of California, San Francisco Memory and Aging Center participants (healthy controls [HCs], those with Alzheimer disease or related dementias [ADRDs], subset with traumatic encephalopathy syndrome [TES]). We characterized traumatic brain injury (TBI) and repetitive head impacts (RHI) through contact/collision sports. Study groups were no RHI/TBI, prior TBI only, prior RHI only, and prior RHI + TBI. We additionally looked within TBI (1, 2, or 3+) and RHI (1-4, 5-10, and 11+ years). All underwent baseline MRI, and 67% completed a second MRI (median follow-up = 5.4 years). CSP measures included grade (0-4) and length (millimeters). Groups were compared on likelihood of CSP (logistic regression, odds ratios [ORs]) and whether CSP length discriminated groups (area under the curve [AUC]). RESULTS: Our sample included 266 participants (N = 160 HCs, N = 106 with ADRD or TES; age 66.8 ± 8.2 years, 45.3% female). Overall, 123 (49.8%) participants had no RHI/TBI, 52 (21.1%) had TBI only, 41 (16.6%) had RHI only, 31 (12.6%) had RHI + TBI, and 20 were classified as those with TES (7.5%). Compared with no RHI/TBI, RHI + TBI (OR 3.11 [1.23-7.88]) and TES (OR 11.6 [2.46-54.8]) had greater odds of CSP. Approximately 5-10 years (OR 2.96 [1.13-7.77]) and 11+ years of RHI (OR 3.14 [1.06-9.31]) had higher odds of CSP. CSP length modestly discriminated participants with 5-10 years (AUC 0.63 [0.51-0.75]) and 11+ years of prior RHI (AUC 0.69 [0.55-0.84]) from no RHI/TBI (cut point = 6 mm). Strongest effects were noted in analyses of American football participation. Longitudinally, CSP grade was unchanged in 165 (91.7%), and length was unchanged in 171 (95.5%) participants. DISCUSSION: Among older adults with and without neurodegenerative disease, risk of CSP is driven more by duration (years) of RHI, especially American football, than number of TBI. CSP length (≥6 mm) is relatively specific to individuals who have had substantial prior RHI. Neurodegenerative disease and progressive atrophy do not clearly influence development or worsening of CSP.

C9orf72 Repeat Expansion Initially Presenting as Late-Onset Bipolar Disorder With Psychosis.

INTRODUCTION: C9orf72 expansion is the most common genetic abnormality in behavioral variant frontotemporal dementia (bvFTD) and amyotrophic lateral sclerosis. Although psychiatric prodromes are common in C9orf72 expansion carriers, there are only scattered reported cases of primary psychiatric disorders, such as bipolar disorder, diagnosed at disease onset. Moreover, C9orf72 carrier status is rarely identified in bipolar disorder genetic studies. CASE REPORT: A 51-year-old, right-handed woman with 16 years of education presented for evaluation of long-standing cognitive and behavioral change. She initially displayed symptoms of mania and florid, multimodal psychotic symptoms at age 39. Her bipolar disorder symptoms were initially responsive to medication; however, she later developed executive dysfunction and behavioral symptoms consistent with bvFTD. She became progressively nonverbal, and her limited speech was notable for speech apraxia. At the time of presentation, she demonstrated cortical sensory deficit, ideomotor and oral-buccal apraxia, and unstable gait. Neuroimaging revealed diffuse brain atrophy. Postmortem histopathological evaluation revealed frontotemporal lobar degeneration with TDP-43 inclusions, type B, and genetic study identified C9orf72 expansion. A detailed review of family history found a strong paternal history of bipolar disorder and substance use disorder. CONCLUSIONS: We describe a rare case of C9orf72 expansion initially characterized by late-onset bipolar disorder and florid, multimodal psychotic symptoms, followed years later by bvFTD diagnosis. This report emphasizes the importance of completing a neurological examination, obtaining a detailed family history, and pursuing genetic screening to distinguish between primary psychiatric disorder and bvFTD in individuals who meet the criteria for late-onset bipolar disorder.

Alzheimer's pathology is associated with altered cognition, brain volume, and plasma biomarker patterns in traumatic encephalopathy syndrome.

BACKGROUND: Traumatic encephalopathy syndrome (TES) is a clinical phenotype sensitive but non-specific to underlying chronic traumatic encephalopathy (CTE) neuropathology. However, cognitive symptoms of TES overlap with Alzheimer's disease (AD), and features of AD pathology like beta-amyloid (Aß) plaques often co-occur with CTE, making clinical-to-pathological conclusions of TES diagnoses challenging. We investigated how Alzheimer's neuropathological changes associated with cognition, brain volume, and plasma biomarkers in patients with repetitive head impacts (RHI)/TES, clinical AD, or typically aging controls. METHODS: We studied 154 participants including 33 with RHI/TES (age 61.5 ± 11.5, 100% male, 11/33 Aß[ +]), 62 with AD and no known prior RHI (age 67.1 ± 10.2, 48% male, 62/62 Aß[ +]), and 59 healthy controls without RHI (HC; age 73.0 ± 6.2, 40% male, 0/59 Aß[ +]). Patients completed neuropsychological testing (memory, executive functioning, language, visuospatial) and structural MRI (voxel-based morphometry analysis), and provided plasma samples analyzed for GFAP, NfL, IL-6, IFN-γ, and YKL-40. For cognition and plasma biomarkers, patients with RHI/TES were stratified as Aß[ +] or Aß[ -] and compared to each other plus the AD and HC groups (ANCOVA adjusting for age and sex). Differences with at least a medium effect size (Cohen's d > 0.50) were interpreted as potentially meaningful. RESULTS: Cognitively, within the TES group, Aß[ +] RHI/TES performed worse than Aß[-] RHI/TES on visuospatial (p = .04, d = 0.86) and memory testing (p = .07, d = 0.74). Comparing voxel-wise brain volume, both Aß[ +] and Aß[ -] RHI/TES had lower medial and anterior temporal lobe volume than HC and did not significantly differ from AD. Comparing plasma biomarkers, Aß[ +] RHI/TES had higher plasma GFAP than HC (p = .01, d = 0.88) and did not significantly differ from AD. Conversely, Aß[ -] RHI/TES had higher NfL than HC (p = .004, d = 0.93) and higher IL-6 than all other groups (p's ≤ .004, d's > 1.0). CONCLUSIONS: Presence of Alzheimer's pathology in patients with RHI/TES is associated with altered cognitive and biomarker profiles. Patients with RHI/TES and positive Aß-PET have cognitive and plasma biomarker changes that are more like patients with AD than patients with Aß[ -] RHI/TES. Measuring well-validated Alzheimer's biomarkers in patients with RHI/TES could improve interpretation of research findings and heighten precision in clinical management.

Data-driven physical actigraphy patterns relate to cognitive and vascular health in older adults.

Health benefits of physical activity (PA) are well known; however, specific PA patterns that relate most strongly to cognitive aging outcomes are poorly understood. We characterized latent profiles of PA among older adults and examined associations with cognition and vascular burden. 124 functionally normal older adults wore a Fitbit™ for 30 days. Daily average step count, sedentary time (0 steps/min), and high-intensity time (≥120 steps/min) were calculated. Participants completed neurocognitive testing assessing cognitive domains of executive functioning and memory; medical history, from which vascular burden (i.e., a count of cardiovascular conditions) was calculated; and brain MRI (n = 44). Subgroups with similar PA patterns were identified via latent profile analysis. Three latent PA classes emerged: Class 1Low PA (n = 49), Class 2Average PA (n = 59), and Class 3High-intensity PA (n = 16). PA class related to executive functioning and vascular burden, driven by better outcomes in Class 3 than Class 1. Sex-stratified analyses revealed these associations were strongest in males. Post hoc analyses showed a positive association between high-intensity PA and white matter integrity among males. High-intensity PA related to better cognitive and vascular health, particularly among males. Findings inform physical activity-specific and person-specific recommendations for optimal cognitive aging.

Touchscreen-Based Cognitive Training Alters Functional Connectivity Patterns in Aged But Not Young Male Rats.

Age-related cognitive decline is related to cellular and systems-level disruptions across multiple brain regions. Because age-related cellular changes within different structures do not show the same patterns of dysfunction, interventions aimed at optimizing function of large-scale brain networks may show greater efficacy at improving cognitive outcomes in older adults than traditional pharmacotherapies. The current study aimed to leverage a preclinical rat model of aging to determine whether cognitive training in young and aged male rats with a computerized paired-associates learning (PAL) task resulted in changes in global resting-state functional connectivity. Moreover, seed-based functional connectivity was used to examine resting state connectivity of cortical areas involved in object-location associative memory and vulnerable in old age, namely the medial temporal lobe (MTL; hippocampal cortex and perirhinal cortex), retrosplenial cortex (RSC), and frontal cortical areas (prelimbic and infralimbic cortices). There was an age-related increase in global functional connectivity between baseline and post-training resting state scans in aged, cognitively trained rats. This change in connectivity following cognitive training was not observed in young animals, or rats that traversed a track for a reward between scan sessions. Relatedly, an increase in connectivity between perirhinal and prelimbic cortices, as well as reduced reciprocal connectivity within the RSC, was found in aged rats that underwent cognitive training, but not the other groups. Subnetwork activation was associated with task performance across age groups. Greater global functional connectivity and connectivity between task-relevant brain regions may elucidate compensatory mechanisms that can be engaged by cognitive training.

Sex Differences in the Relationship between Perceived Stress and Cognitive Trajectories.

OBJECTIVE: Chronic stress adversely affects cognition, in part due to stress-induced inflammation. Rodent models suggest females are more resilient against stress-related cognitive dysfunction than males; however, few studies have examined this in humans. We examined sex differences in the relationship between perceived stress, cognitive functioning, and peripheral inflammation over time among cognitively normal older adults. DESIGN: Longitudinal observational study. SETTING: University research center. PARTICIPANTS: 274 community-dwelling older adults (baseline age: M=70.7, SD=7.2; 58% women; Clinical Dementia Rating=0) who completed at least two study visits. MEASUREMENTS: Neurocognitive functioning and perceived stress (Perceived Stress Scale [PSS]) were assessed at each visit. Plasma was analyzed for interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-α) in a subset of 147 participants. Linear mixed effects models examined the interaction between average PSS (i.e., averaged within persons across visits), sex, and time on cognitive domains and on inflammatory markers. RESULTS: The interaction between stress, sex, and time predicted executive functioning (ß = 0.26, SE = 0.10, p = 0.01) such that higher average PSS related to steeper declines in men, but not in women. Among the 147 participants with inflammatory data, higher average PSS was associated with steeper increases in IL-6 over time in men, but not in women. CONCLUSION: Consistent with animal models, results showed older men were more vulnerable to negative effects of stress on cognitive aging, with domain-specific declines in executive function. Findings also suggest systemic immunological mechanisms may underlie increased risk for cognitive decline in men with higher levels of stress. Future work is needed to examine the potential efficacy of person-specific stress interventions.

Cross-national harmonization of cognitive measures across HRS HCAP (USA) and LASI-DAD (India).

BACKGROUND: As global populations age, cross-national comparisons of cognitive health and dementia risk are increasingly valuable. It remains unclear, however, whether country-level differences in cognitive function are attributable to population differences or bias due to incommensurate measurement. To demonstrate an effective method for cross-national comparison studies, we aimed to statistically harmonize measures of episodic memory and language function across two population-based cohorts of older adults in the United States (HRS HCAP) and India (LASI-DAD). METHODS: Data for 3,496 HRS HCAP (≥65 years) and 3,152 LASI-DAD (≥60 years) participants were statistically harmonized for episodic memory and language performance using confirmatory factor analysis (CFA) methods. Episodic memory and language factor variables were investigated for differential item functioning (DIF) and precision. RESULTS: CFA models estimating episodic memory and language domains based on a priori adjudication of comparable items fit the data well. DIF analyses revealed that four out of ten episodic memory items and five out of twelve language items measured the underlying construct comparably across samples. DIF-modified episodic memory and language factor scores showed comparable patterns of precision across the range of the latent trait for each sample. CONCLUSIONS: Harmonization of cognitive measures will facilitate future investigation of cross-national differences in cognitive performance and differential effects of risk factors, policies, and treatments, reducing study-level measurement and administrative influences. As international aging studies become more widely available, advanced statistical methods such as those described in this study will become increasingly central to making universal generalizations and drawing valid conclusions about cognitive aging of the global population.

Visual Object Discrimination Impairment as an Early Predictor of Mild Cognitive Impairment and Alzheimer's Disease.

OBJECTIVE: Detection of cognitive impairment suggestive of risk for Alzheimer's disease (AD) progression is crucial to the prevention of incipient dementia. This study was performed to determine if performance on a novel object discrimination task improved identification of earlier deficits in older adults at risk for AD. METHOD: In total, 135 participants from the 1Florida Alzheimer's Disease Research Center [cognitively normal (CN), Pre-mild cognitive impairment (PreMCI), amnestic mild cognitive impairment (aMCI), and dementia] completed a test of object discrimination and traditional memory measures in the context of a larger neuropsychological and clinical evaluation. RESULTS: The Object Recognition and Discrimination Task (ORDT) revealed significant differences between the PreMCI, aMCI, and dementia groups versus CN individuals. Moreover, relative risk of being classified as PreMCI rather than CN increased as an inverse function of ORDT score. DISCUSSION: Overall, the obtained results suggest that a novel object discrimination task improves the detection of very early AD-related cognitive impairment, increasing the window for therapeutic intervention. (JINS, 2019, 25, 688-698).

Impaired discrimination with intact crossmodal association in aged rats: A dissociation of perirhinal cortical-dependent behaviors.

The perirhinal cortex (PRC) supports associative memory and perception, and PRC dysfunction impairs animals' abilities to associate stimulus features across sensory modalities. PRC damage also leads to deficits in discriminating between stimuli that share features. Although PRC-dependent stimulus discrimination has been shown to be impaired with advanced age, data regarding the abilities of older adults and other animals to form PRC-dependent associations have been equivocal. Moreover, the extent to which similar neural computations within the PRC support associative memory versus discrimination abilities have not been directly examined. In the current study, young and aged rats were cross-characterized on two PRC-dependent crossmodal object recognition (CMOR) tasks to test associative memory, and a LEGO object discrimination task. In the CMOR tasks, rats were familiarized with an object with access to tactile input and then tested for recognition with visual input only. The relative exploration time of novel versus familiar objects indicated that aged rats showed preference for the novel over familiar object with and without an epoch of multimodal preexposure to the familiar object prior to the testing session. Furthermore, crossmodal recognition performance between young and aged rats was not significantly different. In contrast, for the LEGO object discrimination task, aged rats were impaired relative to young rats. Notably, aged rats that performed poorly on the LEGO object discrimination task had better performance on the CMOR tasks. The dissociation of discrimination and association abilities with age suggests that these behaviors rely on distinct neural computations within PRC-medial temporal lobe circuit. (PsycINFO Database Record

Shared Functions of Perirhinal and Parahippocampal Cortices: Implications for Cognitive Aging.

A predominant view of perirhinal cortex (PRC) and postrhinal/parahippocampal cortex (POR/PHC) function contends that these structures are tuned to represent objects and spatial information, respectively. However, known anatomical connectivity, together with recent electrophysiological, neuroimaging, and lesion data, indicate that both brain areas participate in spatial and nonspatial processing. Instead of content-based organization, the PRC and PHC/POR may participate in two computationally distinct cortical-hippocampal networks: one network that is tuned to process coarse information quickly, forming gist-like representations of scenes/environments, and a second network tuned to process information about the specific sensory details that are necessary for discrimination across sensory modalities. The available data suggest that the latter network may be more vulnerable in advanced age.

Concussion-Like Symptom Reporting in Non-Concussed Collegiate Athletes.

OBJECTIVE: Non-concussed individuals may report a variety of concussion-like symptoms even in the absence of a diagnosed brain injury. Previous studies described concussion-like symptom reporting in adolescent athletes. This study provides complementary data on concussion-like symptoms in collegiate athletes. METHODS: We analyzed baseline symptom scales from 738 collegiate athletes (452 men and 286 women) who completed either the Sport Concussion Assessment Tool, 3 Symptom Evaluation (S3SE; n = 377) or the Post-Concussion Scale (PCS; n = 361) and determined if subjects met criteria for diagnosis of International Classification of Diseases 10th Revision (ICD-10) postconcussional syndrome. Symptoms were grouped as somatic, cognitive, emotional, or sleep-related. We analyzed associations with medical history factors using chi-square analyses, and examined recovery time of a subset of concussed athletes based on baseline symptomatology (n = 117) with independent samples t-test. RESULTS: Across all athletes, 120 (16.3%) reported baseline symptoms meeting criteria for ICD-10 postconcussional syndrome. Women were 1.7 times more likely to meet these criteria (21.7% vs. 12.8%, p = .002). Athletes completing the S3SE were 1.5 times more likely to meet criteria than those completing the PCS (p = .011). Previously diagnosed psychiatric disorder was significantly associated with emotional domain symptom reporting, and attention deficit-hyperactivity disorder diagnosis was associated with cognitive domain symptom reporting. On average, athletes meeting ICD-10 postconcussional syndrome criteria at baseline experienced longer recovery from concussion (t[115] = 2.35, p = .020). CONCLUSIONS: Non-concussed collegiate athletes report concussion-like symptoms at a clinically significant rate. Pre-injury medical history and reporting rates of concussion-like symptoms may explain variance in post-concussion symptom expression. Measured incidence of baseline postconcussional syndrome may, in part, depend on the symptom report measure that is used.

Interaction between age and perceptual similarity in olfactory discrimination learning in F344 rats: relationships with spatial learning.

Emerging evidence suggests that aging is associated with a reduced ability to distinguish perceptually similar stimuli in one's environment. As the ability to accurately perceive and encode sensory information is foundational for explicit memory, understanding the neurobiological underpinnings of discrimination impairments that emerge with advancing age could help elucidate the mechanisms of mnemonic decline. To this end, there is a need for preclinical approaches that robustly and reliably model age-associated perceptual discrimination deficits. Taking advantage of rodents' exceptional olfactory abilities, the present study applied rigorous psychophysical techniques to the evaluation of discrimination learning in young and aged F344 rats. Aging did not influence odor detection thresholds or the ability to discriminate between perceptually distinct odorants. In contrast, aged rats were disproportionately impaired relative to young on problems that required discriminations between perceptually similar olfactory stimuli. Importantly, these disproportionate impairments in discrimination learning did not simply reflect a global learning impairment in aged rats, as they performed other types of difficult discriminations on par with young rats. Among aged rats, discrimination deficits were strongly associated with spatial learning deficits. These findings reveal a new, sensitive behavioral approach for elucidating the neural mechanisms of cognitive decline associated with normal aging.

Discrimination performance in aging is vulnerable to interference and dissociable from spatial memory.

Hippocampal-dependent episodic memory and stimulus discrimination abilities are both compromised in the elderly. The reduced capacity to discriminate between similar stimuli likely contributes to multiple aspects of age-related cognitive impairment; however, the association of these behaviors within individuals has never been examined in an animal model. In the present study, young and aged F344×BN F1 hybrid rats were cross-characterized on the Morris water maze test of spatial memory and a dentate gyrus-dependent match-to-position test of spatial discrimination ability. Aged rats showed overall impairments relative to young in spatial learning and memory on the water maze task. Although young and aged learned to apply a match-to-position response strategy in performing easy spatial discriminations within a similar number of trials, a majority of aged rats were impaired relative to young in performing difficult spatial discriminations on subsequent tests. Moreover, all aged rats were susceptible to cumulative interference during spatial discrimination tests, such that error rate increased on later trials of test sessions. These data suggest that when faced with difficult discriminations, the aged rats were less able to distinguish current goal locations from those of previous trials. Increasing acetylcholine levels with donepezil did not improve aged rats' abilities to accurately perform difficult spatial discriminations or reduce their susceptibility to interference. Interestingly, better spatial memory abilities were not significantly associated with higher performance on difficult spatial discriminations. This observation, along with the finding that aged rats made more errors under conditions in which interference was high, suggests that match-to-position spatial discrimination performance may rely on extra-hippocampal structures such as the prefrontal cortex, in addition to the dentate gyrus.