Utility of learning ratio scores from the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) Word List Memory Test in distinguishing patterns of cognitive decline in veterans referred for neuropsychological evaluation.

Background: The Learning Ratio (LR) is a novel learning score that has shown improved utility over other learning metrics in detecting Alzheimer's disease (AD) across multiple memory tasks. However, its utility on the Consortium to Establish a Registry for Alzheimer's Disease Word List Memory Test (CERAD WLMT), a widely used list learning measure sensitive to decline in neurodegenerative disease, is unknown. The goal of the current study was to determine the utility of LR on the CERAD WLMT in differentiating between diagnostic (MiNCD vs MaNCD) and etiologic groups (VaD vs AD) in a veteran sample. Methods: Raw learning slope (RLS) and LR scores were examined in 168 veterans diagnosed with major neurocognitive disorder (MaNCD), mild neurocognitive disorder (MiNCD), or normal aging following neuropsychological evaluation. Patients with MaNCD were further classified by suspected etiology (i.e. microvascular disease vs AD). Results: Whereas RLS scores were not significantly different between MiNCD and MaNCD, LR scores were significantly different between all diagnostic groups (p's < .05). Those with AD had lower LR scores and RLS scores compared to those with VaD (p's < .05). LR classification accuracy was acceptable for MiNCD (AUC = .76), excellent for MaNCD (AUC = .86) and VaD (AUC = .81), and outstanding for AD (AUC = .91). Optimal cutoff scores for WLMT LR were derived from Youden's index. Conclusion: Results support the use of LR scores over RLS when interpreting the CERAD WLMT and highlight the clinical utility of LR in differentiating between diagnostic groups and identifying suspected etiology.

Specificity of Embedded Performance Validity Tests in Elderly Veterans with Mild and Major Neurocognitive Disorder.

OBJECTIVE: This study explored the specificity of four embedded performance validity tests (PVTs) derived from common neuropsychological tasks in a sample of older veterans with verified cognitive decline and whose performance was deemed valid by licensed psychologists. METHOD: Participants were 180 veterans who underwent comprehensive neuropsychological evaluation, were determined to have valid performance following profile analysis/conceptualization, and were diagnosed with mild neurocognitive disorder (i.e., MCI; n = 64) or major neurocognitive disorder (i.e., Dementia; n = 116). All participants completed at least one of four embedded PVTs: Reliable Digit Span (RDS), California Verbal Learning Test-2nd ed. Short Form (CVLT-II SF) Forced choice, Trails B:A, and Delis-Kaplan Executive Function System (DKEFS) Letter and Category Fluency. RESULTS: Adequate specificity (i.e., ≥90%) was achieved at modified cut-scores for all embedded PVTs across MCI and Dementia groups. Trails B:A demonstrated near perfect specificity at its traditional cut-score (Trails B:A < 1.5). RDS ≤ 5 and CVLT-II SF Forced Choice ≤7 led to <10% false positive classification errors across MCI and dementia groups. DKEFS Letter and Category Fluency achieved 90% specificity at extremely low normative cut-scores. CONCLUSIONS: RDS, Trails B:A, and CVLT-II SF Forced Choice reflect promising embedded PVTs in the context of dementia evaluations. DKEFS Letter and Category Fluency appear too sensitive to genuine neurocognitive decline and, therefore, are inappropriate PVTs in adults with MCI or dementia. Additional research into embedded PVT sensitivity (via known-groups or analogue designs) in MCI and dementia is needed.

Comparing Detection of Alzheimer's and Vascular Disease-Related Cognitive Impairment With Brief Cognitive Screens.

Objectives: The study compared the accuracy of the Mini-Mental State Examination (MMSE) with its modified version (3MS) in distinguishing healthy older adults from adults with cognitive impairment due to suspected Alzheimer's disease (AD) or vascular disease (VaD). Method: Participants were 98 veterans who underwent comprehensive neuropsychological evaluation due to concern for cognitive decline. Participants were selected via retrospective chart review on the basis of diagnosis. They had diagnoses of mild or major neurocognitive disorder due to suspected AD (N=20), mild or major neurocognitive disorder due to suspected VaD (N=44), or no neurocognitive diagnosis (i.e., healthy adult comparisons; HC, N=34). Results: The 3MS demonstrated superior detection of cognitive impairment. The extent of this enhanced detection was influenced by the suspected etiology of cognitive impairment. The 3MS and MMSE had comparable discrimination of AD and HC. With respect to VaD, the 3MS showed superior discriminability compared to the MMSE. Conclusions: Overall, results support the adoption of the 3MS over that of the MMSE. The 3MS is a superior (and free) tool for detecting cognitive impairment in geriatric populations. Its use is recommended for first-line screening of cognitive symptoms in older adult populations, especially those with concern for VaD.

Neuropsychology of COVID-19: Anticipated cognitive and mental health outcomes.

OBJECTIVE: Discuss anticipated patterns of cognitive and emotional dysfunction, prognostic indicators, and treatment considerations based on review of (a) neuroinvasive properties of prior human coronaviruses and (b) extensively researched disorders which share similar neurological mechanisms. METHOD: A web-based comprehensive search of peer-reviewed journals was conducted based on a variety of key terms (and variants of) including coronavirus, neuroinvasion, cognitive dysfunction, viral pandemics, respiratory illness, critical illness, and metabolic disease. Articles were chosen based on relevance to the current topic and ability to provide unique thematic information. Historical articles were included if these added scientific merit to recent literature. Review of information in widely disseminated news articles was followed-up with direct review of cited scientific literature. Databases searched included Google Scholar, PubMed, and Ovid Medline. RESULTS: Based on neuroinvasive properties of prior coronaviruses and existing research on similar neurophysiological conditions with detrimental cognitive effects, COVID-19-especially those with severe symptoms-are at risk for cognitive decline and significant psychiatric/behavioral sequela. CONCLUSIONS: There are few studies examining cognitive outcomes in COVID-19. This review argues that neuropsychological sequelae are to be expected in patients with COVID-19. Considerations for clinicians working with this unique population are discussed. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Comparing the North American Adult Reading Test (NAART) and the Test of Premorbid Functioning (TOPF) to estimate premorbid Wechsler Adult Intelligence Scale - 4th edition FSIQ in a clinical sample with epilepsy.

Estimating premorbid general cognitive functioning is an essential component to the neuropsychological evaluation process. The North American Adult Reading Test (NAART) is a method to predict premorbid general cognitive functioning based on word reading skills developed using the Wechsler Adult Intelligence Scale-Revised (WAIS-R), which is currently in its fourth edition (WAIS-IV). The Test of Premorbid Function (TOPF) was developed using the WAIS-IV, based on the same method as the NAART, to estimate premorbid intellectual ability. There is a paucity of research comparing estimates of premorbid general intellectual ability between the NAART and TOPF. This study evaluated the clinical utility of premorbid estimates of FSIQ derived from the NAART and TOPF in a sample of 101 patients with temporal lobe epilepsy (TLE). Differences between NAART-derived premorbid FSIQs and TOPF simple demographic predicted FSIQs were significant (p < .001) with large effect sizes. NAART estimated premorbid FSIQ (M = 104.04, SD = 8.42) was significantly greater than TOPF premorbid estimates (M = 99.83, SD = 9.26). Results suggested NAART-derived estimates of premorbid FSIQ may be more accurate than TOPF-based estimates, which likely underestimated premorbid FSIQ in this sample of patients with epilepsy. Limitations and future directions are discussed.

Concordance of Actigraphy With Polysomnography in Traumatic Brain Injury Neurorehabilitation Admissions.

OBJECTIVE: To examine concordance of accelerometer-based actigraphy (ACG) with polysomnography (PSG) in the determination of sleep states in inpatients with traumatic brain injury (TBI), and examine the impact of injury severity and comorbid conditions (spasticity, apnea) on concordance. PARTICIPANTS: This was a convenience sample of 50 participants with primarily severe TBI. DESIGN: This was a retrospective chart review of concurrent administration of PSG with ACG in nonconsecutive rehabilitation admissions with TBI. MAIN MEASURES: Total sleep time and sleep efficiency were measured by PSG and ACG. RESULTS: Moderate to strong correlations between ACG and PSG were observed for total sleep time (r = 0.78, P < .01) and sleep efficiency (r = 0.66, P < .01). PSG and ACG estimates of total sleep time (316 minutes vs 325 minutes, respectively) and sleep efficiency (78% vs 77%, respectively) were statistically indistinguishable. CONCLUSIONS: Actigraphy is a valid proxy for monitoring of sleep in this population across injury severity and common comorbidity groups. However, further research with larger sample sizes to examine concordance in patients with TBI with disorder of consciousness and spasticity is recommended.

The Relationship Between Sleep-Wake Cycle Disturbance and Trajectory of Cognitive Recovery During Acute Traumatic Brain Injury.

OBJECTIVE: Following traumatic brain injury, both sleep dysfunction and cognitive impairment are common. Unfortunately, little is known regarding the potential associations between these 2 symptoms during acute recovery. This study sought to prospectively examine the relationship between ratings of sleep dysfunction and serial cognitive assessments among traumatic brain injury acute neurorehabilitation admissions. METHODS: Participants were consecutive admissions to a free-standing rehabilitation hospital following moderate to severe traumatic brain injury (Median Emergency Department Glasgow Coma Scale = 7). Participants were assessed for sleep-wake cycle disturbance (SWCD) and cognitive functioning at admission and with subsequent weekly examinations. Participants were grouped on the basis of presence (SWCD+) or absence (SWCD-) of sleep dysfunction for each examination; groups were equivalent on demographic and injury variables. Individual Growth Curve modeling was used to examine course of Cognitive Test for Delirium performance across examinations. RESULTS: Individual Growth Curve modeling revealed a significant interaction between examination number (ie, time) and SWCD group (ß = -4.03, P < .001) on total Cognitive Test for Delirium score. The SWCD+ ratings on later examinations were predicted to result in lower Cognitive Test for Delirium scores and greater cognitive impairment over time. CONCLUSIONS: This study has implications for improving neurorehabilitation treatment, as targeting sleep dysfunction for early intervention may facilitate cognitive recovery.

Sex differences in lateralization of semantic verbal fluency in temporal lobe epilepsy.

When differences exist, women tend to outperform men on measures of verbal fluency, possibly due to greater bilateral language representation. Patients with temporal lobe epilepsy (TLE) have a higher rate of atypical cortical language representation than the general population, making them a population of interest for the study of language. For the current study, 78 TLE patients (51% male, 51% left temporal focus) underwent pre-surgical neuropsychological evaluations. Retrospective data analyses investigated the impact of seizure laterality and sex on letter and semantic verbal fluency. Results indicated an interaction between sex and laterality for semantic, but not letter, verbal fluency. Males with left TLE exhibited significantly worse semantic fluency than males with right TLE, whereas females' semantic fluency did not differ by seizure focus. These data indicate that females with TLE may indeed engage in more bilateral hemispheric processing of semantic verbal fluency, whereas males may be more reliant on left temporal cortical function for this task.

Juvenile traumatic brain injury evolves into a chronic brain disorder: behavioral and histological changes over 6months.

Traumatic brain injury (TBI) refers to physical trauma to the brain that can lead to motor and cognitive dysfunctions. TBI is particularly serious in infants and young children, often leading to long-term functional impairments. Although clinical research is useful for quantifying and observing the effects of these injuries, few studies have empirically assessed the long-term effects of juvenile TBI (jTBI) on behavior and histology. After a controlled cortical impact delivered to postnatal 17day old rats, functional abilities were measured after 3, 5, and 6months using open field (activity levels), zero maze (anxiety-like behaviors), rotarod (sensorimotor abilities, coordination, and balance), and water maze (spatial learning and memory, swim speed, turn bias). Sensorimotor function was impaired for up to 6months in jTBI animals, which showed no improvement from repeated test exposure. Although spatial learning was not impaired, spatial memory deficits were observed in jTBI animals starting at 3months after injury. Magnetic resonance imaging and histological data revealed that the effects of jTBI were evolving for up to 6months post-injury, with reduced cortical thickness, decreased corpus callosum area and CA1 neuronal cell death in jTBI animals distant to the impact site. These findings suggest that this model of jTBI produces long-term impairments comparable to those reported clinically. Although some deficits were stable over time, the variable nature of other deficits (e.g., memory) as well as changing properties of the lesion itself, suggest that the effects of a single jTBI produce a chronic brain disorder with long-term complications.

Tissue vulnerability is increased following repetitive mild traumatic brain injury in the rat.

Repetitive mild traumatic brain injury (rmTBI) is an important medical concern for active sports and military personnel. Multiple mild injuries may exacerbate tissue damage resulting in cumulative brain injury and poor functional recovery. In the present study, we investigated the time course of brain vulnerability to rmTBI in a rat model of mild cortical controlled impact. An initial mild injury was followed by a second injury unilaterally at an interval of 1, 3, or 7 days. RmTBI animals were compared to single mTBI and sham treated animals. Neuropathology was assessed using multi-modal magnetic resonance imaging (MRI), followed by ex vivo tissue immunohistochemistry. Neurological and behavioral outcomes were evaluated in a subset of animals receiving rmTBI 3 days apart and shams. RmTBI 1 or 3 days apart but not 7 days apart revealed significantly exacerbated MRI-definable lesion volumes compared to single mTBI and shams. Increases in cortical tissue damage, extravascular iron and glial activation assessed by histology/immunohistochemistry correlated with in vivo MRI findings where shorter intervals (1 or 3 days apart) resulted in greater tissue pathology. There were no neurological deficits associated with rmTBI 3 day animals. At 1 mo post-injury, animals with rmTBI 3 days apart showed reduced exploratory behaviors and subtle spatial learning memory impairments were observed. Collectively, our findings suggest that the mildly-impacted brain is more vulnerable to repetitive injury when delivered within 3 days following initial mTBI.

Early brain injury alters the blood-brain barrier phenotype in parallel with ß-amyloid and cognitive changes in adulthood.

Clinical studies suggest that traumatic brain injury (TBI) hastens cognitive decline and development of neuropathology resembling brain aging. Blood-brain barrier (BBB) disruption following TBI may contribute to the aging process by deregulating substance exchange between the brain and blood. We evaluated the effect of juvenile TBI (jTBI) on these processes by examining long-term alterations of BBB proteins, ß-amyloid (Aß) neuropathology, and cognitive changes. A controlled cortical impact was delivered to the parietal cortex of male rats at postnatal day 17, with behavioral studies and brain tissue evaluation at 60 days post-injury (dpi). Immunoglobulin G extravasation was unchanged, and jTBI animals had higher levels of tight-junction protein claudin 5 versus shams, suggesting the absence of BBB disruption. However, decreased P-glycoprotein (P-gp) on cortical blood vessels indicates modifications of BBB properties. In parallel, we observed higher levels of endogenous rodent Aß in several brain regions of the jTBI group versus shams. In addition at 60 dpi, jTBI animals displayed systematic search strategies rather than relying on spatial memory during the water maze. Together, these alterations to the BBB phenotype after jTBI may contribute to the accumulation of toxic products, which in turn may induce cognitive differences and ultimately accelerate brain aging.

Evaluation of the hematoma consequences, neurobehavioral profiles, and histopathology in a rat model of pontine hemorrhage.

OBJECT: Primary pontine hemorrhage (PPH) represents approximately 7% of all intracerebral hemorrhages (ICHs) and is a clinical condition of which little is known. The aim of this study was to characterize the early brain injury, neurobehavioral outcome, and long-term histopathology in a novel preclinical rat model of PPH. METHODS: The authors stereotactically infused collagenase (Type VII) into the ventral pontine tegmentum of the rats, in accordance with the most commonly affected clinical region. Measures of cerebrovascular permeability (brain water content, hemoglobin assay, Evans blue, collagen Type IV, ZO-1, and MMP-2 and MMP-9) and neurological deficit were quantified at 24 hours postinfusion (Experiment 1). Functional outcome was measured over a 30-day period using a vertebrobasilar scale (the modified Voetsch score), open field, wire suspension, beam balance, and inclined-plane tests (Experiment 2). Neurocognitive ability was determined at Week 3 using the rotarod (motor learning), T-maze (working memory), and water maze (spatial learning and memory) (Experiment 3), followed by histopathological analysis 1 week later (Experiment 4). RESULTS: Stereotactic collagenase infusion caused dose-dependent elevations in hematoma volume, brain edema, neurological deficit, and blood-brain barrier rupture, while physiological variables remained stable. Functional outcomes mostly normalized by Week 3, whereas neurocognitive deficits paralleled the cystic cavitary lesion at 30 days. Obstructive hydrocephalus did not develop despite a clinically relevant 30-day mortality rate (approximately 54%). CONCLUSIONS: These results suggest that the model can mimic several translational aspects of pontine hemorrhage in humans and can be used in the evaluation of potential preclinical therapeutic interventions.

Traumatic brain injury in young rats leads to progressive behavioral deficits coincident with altered tissue properties in adulthood.

Traumatic brain injury (TBI) affects many infants and children, and results in enduring motor and cognitive impairments with accompanying changes in white matter tracts, yet few experimental studies in rodent juvenile models of TBI (jTBI) have examined the timeline and nature of these deficits, histologically and functionally. We used a single controlled cortical impact (CCI) injury to the parietal cortex of rats at post-natal day (P) 17 to evaluate behavioral alterations, injury volume, and morphological and molecular changes in gray and white matter, with accompanying measures of electrophysiological function. At 60 days post-injury (dpi), we found that jTBI animals displayed behavioral deficits in foot-fault and rotarod tests, along with a left turn bias throughout their early developmental stages and into adulthood. In addition, anxiety-like behaviors on the zero maze emerged in jTBI animals at 60 dpi. The final lesion constituted only ∼3% of brain volume, and morphological tissue changes were evaluated using MRI, as well as immunohistochemistry for neuronal nuclei (NeuN), myelin basic protein (MBP), neurofilament-200 (NF200), and oligodendrocytes (CNPase). White matter morphological changes were associated with a global increase in MBP immunostaining and reduced compound action potential amplitudes at 60 dpi. These results suggest that brain injury early in life can induce long-term white matter dysfunction, occurring in parallel with the delayed development and persistence of behavioral deficits, thus modeling clinical and longitudinal TBI observations.

Motor and cognitive deficits in mice bred to have low or high blood pressure.

Deviations from normal blood pressure can lead to a number of physiological and behavioral complications. We tested the hypothesis that hyper- or hypotension is associated with significant differences in motor activity and coordination, anxiety levels, and spatial learning and memory in male and female mice. Compared to normotensive control mice, hypertensive mice were hyperactive and their performance was significantly worse on the rotarod (males only), cued learning (males only), spatial learning/re-learning, and spatial memory. Hypotensive mice of both genders swam more slowly and performed even worse than hypertensive mice on the rotarod, cued learning, spatial learning/re-learning, and spatial memory tasks. Across all phenotypes, females were generally more active than males in the open field and exhibited more anxiety-like behaviors in the elevated zero maze. Alterations in hemodynamics and/or neurovascular unit function may account for the observed behavioral changes in the hypo- and hypertensive mice.