Premorbid IQ Research Articles

Associations of psychotic symptom dimensions with clinical and developmental variables in twin and general clinical samples.

Positive, negative and disorganised psychotic symptom dimensions are associated with clinical and developmental variables, but differing definitions complicate interpretation. Additionally, some variables have had little investigation. To investigate associations of psychotic symptom dimensions with clinical and developmental variables, and familial aggregation of symptom dimensions, in multiple samples employing the same definitions. We investigated associations between lifetime symptom dimensions and clinical and developmental variables in two twin and two general psychosis samples. Dimension symptom scores and most other variables were from the Operational Criteria Checklist. We used logistic regression in generalised linear mixed models for combined sample analysis (n = 875 probands). We also investigated correlations of dimensions within monozygotic (MZ) twin pairs concordant for psychosis (n = 96 pairs). Higher symptom scores on all three dimensions were associated with poor premorbid social adjustment, never marrying/cohabiting and earlier age at onset, and with a chronic course, most strongly for the negative dimension. The positive dimension was also associated with Black and minority ethnicity and lifetime cannabis use; the negative dimension with male gender; and the disorganised dimension with gradual onset, lower premorbid IQ and substantial within twin-pair correlation. In secondary analysis, disorganised symptoms in MZ twin probands were associated with lower premorbid IQ in their co-twins. These results confirm associations that dimensions share in common and strengthen the evidence for distinct associations of co-occurring positive symptoms with ethnic minority status, negative symptoms with male gender and disorganised symptoms with substantial familial influences, which may overlap with influences on premorbid IQ.

The association of pre-operative biomarkers of endothelial dysfunction with the risk of post-operative neurocognitive disorders: results fromthe BioCog study.

Endothelial dysfunction (ED) promotes the development of atherosclerosis, and studies suggest an association with age-related neurocognitive disorders. It is currently unclear whether ED is also associated with the risk of perioperative neurocognitive disorders. We included 788 participants aged ≥ 65 years of the BioCog study. Patients were scheduled to undergo elective surgery with expected duration > 60 min. Blood was collected before surgery for measurement of 5 biomarkers of ED: asymmetric and symmetric dimethylarginine (ADMA; SDMA), intercellular and vascular adhesion molecule (ICAM-1, VCAM-1), and von Willebrand factor (vWF). Patients were monitored for the occurrence of postoperative delirium (POD) daily until the 7th postoperative day. 537 (68.1%) patients returned for a 3-month follow-up. Post-operative cognitive dysfunction (POCD) was defined from the change in results on a battery of 6 neuropsychological tests between baseline and 3 months, compared to the change in results of a control group during the 3-month interval. The associations of each of the 5 ED biomarkers with POD and POCD respectively were determined using multiple logistic regression analyses with adjustment for age, sex, surgery type, pre-morbid IQ, body mass index,hypertension, diabetes,HbA1C, triglyceride, total and HDL cholesterol. 19.8% of 788 patients developed POD; 10.1% of 537 patientshad POCDat 3 months. Concentrations of ED biomarkers were not significantly associated with a POD. A higher VCAM-1 concentration was associated with a reduced POCD risk (adjustedodds ratio 0.55; 95% CI: 0.35-0.86). No further statistically significant results were found. Pre-operative concentrations of ED biomarkers werenot associated with POD risk. We unexpectedly found higher VCAM-1 to be associated with a reduced POCD risk. Further studies are needed to evaluate these findings.

Cognitive improvement after endoscopic third ventriculostomy surgery in long-standing overt ventriculomegaly in adults.

Long-standing overt ventriculomegaly in adults (LOVA) is a chronic form of hydrocephalus that can lead to cognitive deficits. Data on the cognitive profile of patients with LOVA and cognitive outcomes of endoscopic third ventriculostomy (ETV) are, however, scarce and mostly qualitative. Twenty-three consecutive patients with LOVA hydrocephalus underwent ETV surgery, and their cognitive status was assessed before surgery, immediately after surgery, and at the 5-month follow-up. Cognitive function was assessed using a neuropsychological battery measuring 6 cognitive domains: general cognitive status, attention/executive function, language, visuospatial skills, short-term memory, and long-term memory. Cognitive reserve was also estimated through a measure of premorbid IQ to assess its potential influence together with other clinical and demographic variables. Patients with LOVA did not experience general cognitive decline but rather selective long-term memory (p < 0.001) and visuospatial skills (p = 0.001) deficits alone. Moreover, ETV surgery led to significant immediate postoperative improvement in both domains (p = 0.002 and p < 0.001 respectively), that persisted at follow-up (p < 0.001 for both). However, improvement was observed only in patients with higher premorbid IQ (p < 0.001), while the others did not improve (p > 0.532). These findings confirm the effectiveness of ETV surgery and highlight the role of cognitive reserve in promoting plasticity of brain and cognitive functions thus fostering and predicting cognitive recovery.

The Cognitive Profile of Older Adults With Treatment-Resistant Depression: An Analysis of the OPTIMUM Randomized Controlled Trial

ObjectiveMajor depressive disorder in older adults (late-life depression; LLD) is frequently associated with cognitive impairment, and some deficits (e.g., executive function) have been associated with a higher level of treatment resistance. However, the cognitive profile of treatment-resistant LLD (TR-LLD) has not been characterized. We hypothesized that patients with TR-LLD would show deficits in cognitive function, especially executive function, and that executive function deficits would predict poorer response to pharmacotherapy. DesignSecondary analysis of baseline cognitive data from OPTIMUM, a multicenter RCT evaluating pharmacotherapy strategies for TR-LLD. SettingFive outpatient academic medical centers (4 US, 1 Canada). ParticipantsAbout 369 participants aged 60 and older from the OPTIMUM study. MeasurementsBaseline scores on individual tasks and composite scores from the NIH Toolbox-Cognition Battery were transformed into demographically-adjusted T-scores and compared to published norms. Impairments in the set shifting and inhibitory control tasks were investigated as predictors of depressive symptom change following treatment using ANCOVA models. ResultsParticipants had low performance on tasks evaluating inhibitory control, processing speed, verbal/nonverbal memory, and the fluid composite, but normative performance on working memory and set shifting. Participants had high estimated premorbid IQ (superior Performance on oral reading recognition). Age and physical comorbidity negatively associated with processing speed. Impairments in set shifting predicted less improvement in depressive symptoms; impairments in inhibitory control did not. ConclusionsParticipants with TR-LLD presented with broad cognitive deficits relative to healthy norms. Given poorer outcomes following standard pharmacotherapy associated with impaired set shifting, future research needs to identify alternative treatment strategies.

The prediction limits of the National Adult Reading Test and its abbreviated and international variants.

Premorbid tests estimate cognitive ability prior to neurological condition onset or brain injury. Tests requiring oral pronunciation of visually presented irregular words, such as the National Adult Reading Test (NART), are commonly used due to robust evidence that word familiarity is well-preserved across a range of neurological conditions and correlates highly with intelligence. Our aim is to examine the prediction limits of NART variants to assess their ability to accurately estimate premorbid IQ. We examine the prediction limits of 13 NART variants, calculate which IQ classification system categories are reachable in principle, and consider the proportion of the adult population in the target country falling outside the predictable range. Many NART variants cannot reach higher or lower IQ categories due to floor/ceiling effects and inherent limitations of linear regression (used to convert scores to predicted IQ), restricting clinical accuracy in evaluating premorbid ability (and thus the magnitude of impairment). For some variants this represents a sizeable proportion of the target population. Since both higher and lower IQ categories are unreachable in principle, we suggest that future NART variants consider polynomial or broken-stick fitting (or similar methods) and suggest that prediction limits should be routinely reported.

Multivariate brain-cognition associations in euthymic bipolar disorder.

People with bipolar disorder (BD) tend to show widespread cognitive impairment compared to healthy controls. Impairments in processing speed (PS), attention and executive function (EF) may represent 'core' impairments that have a role in wider cognitive dysfunction. Cognitive impairments appear to relate to structural brain abnormalities in BD, but whether core deficits are related to particular brain regions is unclear and much of the research on brain-cognition associations is limited by univariate analysis and small samples. Euthymic BD patients (n = 56) and matched healthy controls (n = 26) underwent T1-weighted MRI scans and completed neuropsychological tests of PS, attention and EF. We utilised public datasets to develop normative models of cortical thickness (n = 5977) to generate robust estimations of cortical abnormalities in patients. Canonical correlation analysis was used to assess multivariate brain-cognition associations in BD, controlling for age, sex and premorbid IQ. BD showed impairments on tests of PS, attention and EF, and abnormal cortical thickness in several brain regions compared to healthy controls. Impairments in tests of PS and EF were most strongly associated with cortical thickness in the left inferior temporal, right entorhinal and right temporal pole areas. Impairments in PS, attention and EF can be observed in euthymic BD and may be related to abnormal cortical thickness in temporal regions. Future research should continue to leverage normative modelling and multivariate methods to examine complex brain-cognition associations in BD. Future research may benefit from exploring covariance between traditional brain structural morphological metrics such as cortical thickness, cortical volume and surface area.

The role of cognitive reserve and depression on executive function in older adults: A 10-year study from the Wisconsin Registry for Alzheimer’s Prevention

Objective: The current study examined the longitudinal relationship between cognitive reserve (CR), depression, and executive function (EF) in a cohort of older adults. Methods: 416 participants were selected from the Wisconsin Registry for Alzheimer’s Prevention. They were native English speakers, aged ≥50+, and cognitively unimpaired at baseline, with no history of neurological or other psychiatric disorders aside from depression. Depression was assessed with the 20-item Center for Epidemiologic Studies Depression Scale (CES-D). A composite score, based on the premorbid IQ (WRAT-3 Reading subtest) and years of education was used to estimate CR. Another composite score from four cognitive tests was used to estimate EF. A moderation analysis was performed to evaluate the effects of CR and Depression on EF at follow-up after controlling for age, gender, and APOE risk score. Moreover, a multinomial logistic regression was used to predict conversion to Mild Cognitive Impairment (MCI) from the healthy baseline. Results: The negative relationship between depression and EF was stronger in individuals with higher CR levels, suggesting a possible floor effect at lower CR levels. In the multinomial regression, the interaction between CR and depression predicted conversion to MCI status, indicating that lower CR paired with more severe depression at baseline was associated with a higher risk of subsequent impairment. Conclusions: This study sheds light on the intricate relationship between depression and EF over time, suggesting that the association may be influenced by varying levels of CR. Further studies may replicate these findings in clinical populations.

Social exclusion as a major outcome domain of psychotic disorders: early predictors, and associations with non-recovery and clinical staging 21years after a first episode of psychosis.

People with psychotic disorders have high levels of social exclusion; however, little is known about its early predictors. We present a long-term observational cohort study aimed at examining early risk factors for later social exclusion. A total of 243 subjects were assessed at their first psychotic episode for early risk factors including sociodemographic variables, familial risk of major mental disorders, perinatal complications, childhood factors, and adolescent factors and re-assessed after a mean follow-up of 21years for 12 social exclusion domains: leisure activities, housing, work, income, neighborhood deprivation, educational attainment, physical and mental health, family and social support, legal competence, and discrimination. The ability of risk factors to predict social exclusion was examined using hierarchical linear regression. Overall social exclusion was independently predicted by low parental socio-economic status, length of follow-up, familial risk of schizophrenia, obstetric complications, neurodevelopmental delay, poor childhood adjustment, childhood adversity, poor adolescent social networks, poor adolescent adjustment, and low premorbid IQ. The model explained 58.2% of the variance in total social exclusion score. Each social exclusion domain was predicted by a different set of variables, which explained between 17.8 and 57.0% of their variance, although low socio-economic status, familial risk of schizophrenia, obstetric complications, childhood adversity, and poor social networks predicted most of the social exclusion domains. Early risk factors strongly predicted later social exclusion. A multifaceted approach to preventing later social exclusion is crucial in people with a first episode of psychosis and early risk factors of social exclusion.

Impact of long-term white matter hyperintensity changes on mobility and dexterity.

White matter hyperintensities (WMH), a common feature of cerebral small vessel disease, are related to worse clinical outcomes after stroke. We assessed the impact of white matter hyperintensity changes over 1 year after minor stroke on change in mobility and dexterity, including differences between the dominant and non-dominant hands and objective in-person assessment versus patient-reported experience. We recruited participants with lacunar or minor cortical ischaemic stroke, performed medical and cognitive assessments and brain MRI at presentation and at 1 year. At both time points, we used the timed-up and go test and the 9-hole peg test to assess mobility and dexterity. At 1 year, participants completed the Stroke Impact Scale. We ran two linear mixed models to assess change in timed-up and go and 9-hole peg test, adjusted for age, sex, stroke severity (National Institutes of Health Stroke Scale), dependency (modified Rankin Score), vascular risk factor score, white matter hyperintensity volume (as % intracranial volume) and additionally for 9-hole peg test: Montreal cognitive assessment, hand (dominant/non-dominant), National Adult Reading Test (premorbid IQ), index lesion side. We performed ordinal logistic regression, corrected for age and sex, to assess relations between timed-up and go and Stroke Impact Scale mobility, and 9-hole peg test and Stroke Impact Scale hand function. We included 229 participants, mean age 65.9 (standard deviation = 11.13); 66% male. 215/229 attended 1-year follow-up. Over 1 year, timed-up and go time increased with aging (standardized β [standardized 95% Confidence Interval]: 0.124[0.011, 0.238]), increasing National Institutes of Health Stroke Scale (0.106[0.032, 0.180]), increasing modified Rankin Score (0.152[0.073, 0.231]) and increasing white matter hyperintensity volume (0.176[0.061, 0.291]). Men were faster than women (-0.306[0.011, 0.238]). Over 1 year, slower 9-hole peg test was related to use of non-dominant hand (0.290[0.155, 0.424]), aging (0.102[0.012, 0.192]), male sex (0.182[0.008, 0.356]), increasing National Institutes of Health Stroke Scale (0.160 [0.094, 0.226]), increasing modified Rankin Score (0.100[0.032, 0.169]), decreasing Montreal cognitive assessment score (-0.090[-0.167, -0.014]) and increasing white matter hyperintensity volume (0.104[0.015, 0.193]). One year post-stroke, Stroke Impact Scale mobility worsened per second increase on timed-up and go, odds ratio 0.67 [95% confidence interval 0.60, 0.75]. Stroke Impact Scale hand function worsened per second increase on the 9-hole peg test for the dominant hand (odds ratio 0.79 [0.71, 0.86]) and for the non-dominant hand (odds ratio 0.88 [0.83, 0.93]). Decline in mobility and dexterity is associated with white matter hyperintensity volume increase, independently of stroke severity. Mobility and dexterity declined more gradually for stable and regressing white matter hyperintensity volume. Dominant and non-dominant hands might be affected differently. In-person measures of dexterity and mobility are associated with self-reported experience 1-year post-stroke.

The prevalence of mild cognitive impairment in breast cancer patients receiving chemotherapy according to the criteria of the National Institute on Aging-Alzheimer's Association (NIA-AA).

Breast cancer patients receiving chemotherapy can develop cognitive impairment. There is no gold standard for defining cognitive impairment. We applied the National Institute on Aging-Alzheimer's Association (NIA-AA) criteria for mild cognitive impairment (MCI) to determine its prevalence in breast cancer patients receiving adjuvant chemotherapy and examine differences between patients with and without MCI. We used pre-existing cognitive data on 5 neuropsychological test outcomes (verbal memory, processing speed, executive functioning, and verbal fluency) gathered from 240 breast cancer patients who received adjuvant conventional (n = 154) or high-dose chemotherapy (n = 86). Assessments occurred 6 or 12months post-chemotherapy and results were compared with data from 66 women without cancer. MCI was defined by the following: (i) presence of concern regarding a change in cognition, (ii) impairment in one or more cognitive tests (1.5 standard deviation below a normative mean), (iii) preservation of independence in functional abilities, and (iv) the absence of dementia. Twenty percent (n = 49) of breast cancer patients who received chemotherapy (conventional therapy n = 29 (12%), high-dose therapy = 20 (8.3%)) met the criteria for MCI, compared with 7.6% (n = 5) of controls. Prevalence was significantly different between patients and controls (P = 0.020, and corrected for IQ P < 0.001). Patients with MCI had significant lower education levels (P < 0.002) and premorbid IQ (P = 0.001) compared with patients without MCI. Twenty percent of breast cancer patients treated with chemotherapy met NIA-AA criteria for MCI, compared with 7.6% of the controls. These criteria, which include formal test performance as well as a person's symptoms and functional status, can be useful in clinical practice and scientific research.

Cognitive Inflexibility Predicts Negative Symptoms Severity in Patients with First-Episode Psychosis: A 1-Year Follow-Up Study.

Negative symptoms and cognitive deficits play a major role in psychosis and significantly influence the functional outcomes of patients, particularly those with a first episode of psychosis (FEP). However, limited research has explored the predictive capacity of cognitive deficits during FEP for subsequent negative symptomatology. Drawing from the Athens FEP research study, we conducted a retrospective longitudinal study in 80 individuals with FEP. All patients were drug naive at admission. Cognitive tests were administered at 1-month and 1-year post-admission, while negative symptomatology was assessed at the same time points using PANSS by trained raters. We considered confounding factors such as age, gender, duration of untreated psychosis (DUP), treatment received, premorbid social adjustment, and premorbid IQ. Univariate regression analysis identified cognitive domains that correlated with negative symptomatology. These, along with the confounders, were incorporated into a multiple regression, with the 1-year PANSS negative scale serving as the dependent variable. Employing the backward elimination technique, we found a statistically significant inverse relationship between the categories completed in the Wisconsin card sorting test (WCST) and the 1-year PANNS negative scale (p = 0.01), beyond the associations with DUP and the 1-month PANSS negative scale. Our results suggest that cognitive flexibility, a key component of executive functions, predicts negative symptom severity one year after FEP.

Cognitive reserve and the risk of postoperative neurocognitive disorders in older age.

Postoperative delirium (POD) and postoperative cognitive dysfunction (POCD) are postoperative neurocognitive disorders (PNDs) that frequently occur in the aftermath of a surgical intervention. Cognitive reserve (CR) is a concept posited to explain why cognitive health varies between individuals. On this qualitative understanding of cognitive health, factors like IQ, education level, and occupational complexity can affect the impact of neuropathological processes on cognitive outcomes. We investigated the association between CR and POD and CR and POCD on data from 713 patients aged≥65 years with elective surgery. Peak pre-morbid IQ was estimated from vocabulary. Occupational complexity was coded according to the Dictionary of Occupational Titles (DOT). Education level was classed according to the International Standard Classification of Education (ISCED). These three factors were used as proxies of CR. In a series of regression models, age, sex, depression, site of surgery, and several lifestyle and vascular factors were controlled for. Patients with a higher IQ had lower odds of developing POD. We found no significant association between the other two CR markers with POD. None of the CR markers was associated with POCD. The significant association of a higher IQ with lower POD risk allows for the stratification of elderly surgical patients by risk. This knowledge can aid the prevention and/or early detection of POD. Further research should attempt to determine the lack of associations of CR markers with POCD in our study.

Meta-analysis: on average, undergraduate students’ intelligence is merely average

Background: According to a widespread belief, the average IQ of university students is 115 to 130 IQ points, that is, substantially higher than the average IQ of the general population (M = 100, SD = 15). We traced the origin of this belief to obsolete intelligence data collected in 1940s and 1950s when university education was the privilege of a few. Examination of more recent IQ data indicate that IQ of university students and university graduates dropped to the average of the general population. The decline in students’ IQ is a necessary consequence of increasing educational attainment over the last 80 years. Today, graduating from university is more common than completing high school in the 1940s. Method: We conducted a meta-analysis of the mean IQ scores of college and university students samples tested with Wechsler Adult Intelligence Scale between 1939 and 2022. Results: The results show that the average IQ of undergraduate students today is a mere 102 IQ points and declined by approximately 0.2 IQ points per year. The students’ IQ also varies substantially across universities and is correlated with the selectivity of universities (measured by average SAT scores of admitted students). Discussion: These findings have wide-ranging implications. First, universities and professors need to realize that students are no longer extraordinary but merely average, and have to adjust curricula and academic standards. Second, employers can no longer rely on applicants with university degrees to be more capable or smarter than those without degrees. Third, students need to realize that acceptance into university is no longer an invitation to join an elite group. Fourth, the myth of brilliant undergraduate students in scientific and popular literature needs to be dispelled. Fifth, estimating premorbid IQ based on educational attainment is vastly inaccurate, obsolete, not evidence based, and mere wishful thinking. Sixth, obsolete IQ data or tests ought not to be used to make high-stakes decisions about individuals, for example, by clinical psychologists to opine about the intelligence and cognitive abilities of their clients.

Investigating cognitive reserve, symptom resolution and brain connectivity in mild traumatic brain injury

BackgroundA proportion of patients with mild traumatic brain injury (mTBI) suffer long-term consequences, and the reasons behind this are still poorly understood. One factor that may affect outcomes is cognitive reserve, which is the brain's ability to maintain cognitive function despite injury. It is often assessed through educational level or premorbid IQ tests. This study aimed to explore whether there were differences in post-concussion symptoms and symptom resolution between patients with mTBI and minor orthopedic injuries one week and three months after injury. Additional aims were to explore the relationship between cognitive reserve and outcome, as well as functional connectivity according to resting state functional magnetic resonance imaging (rs-fMRI).MethodFifteen patients with mTBI and 15 controls with minor orthopedic injuries were recruited from the emergency department. Assessments, including Rivermead Post-Concussion Questionnaire (RPQ), neuropsychological testing, and rs-fMRI scans, were conducted on average 7 days (SD = 2) and 122 days (SD = 51) after injury.ResultsAt the first time point, significantly higher rates of post-concussion symptoms (U = 40.0, p = 0.003), state fatigue (U = 56.5, p = 0.014), and fatigability (U = 58.5, p = 0.025) were observed among the mTBI group than among the controls. However, after three months, only the difference in post-concussion symptoms remained significant (U = 27.0, p = 0.003). Improvement in post-concussion symptoms was found to be significantly correlated with cognitive reserve, but only in the mTBI group (Spearman’s rho = -0.579, p = .038). Differences in the trajectory of recovery were also observed for fatigability between the two groups (U = 36.5, p = 0.015). Moreover, functional connectivity differences in the frontoparietal network were observed between the groups, and for mTBI patients, functional connectivity differences in an executive control network were observed over time.ConclusionThe findings of this pilot study suggest that mTBI, compared to minor orthopedic trauma, is associated to both functional connectivity changes in the brain and concussion-related symptoms. While there is improvement in these symptoms over time, a small subgroup with lower cognitive reserve appears to experience more persistent and possibly worsening symptoms over time. This, however, needs to be validated in larger studies.Trial registrationNCT05593172. Retrospectively registered.

Relationship between a novel virtual reality test of mild functional difficulties and cerebrovascular disease

AbstractBackgroundIt is well known that mild cognitive impairment (MCI) is associated with subtle functional decline. However, standardized and cost‐effective methods for the objective quantification of mild functional difficulties are lacking. Here we report preliminary validity data for a novel, non‐immersive virtual‐reality task (Virtual Kitchen Challenge [VKC]) against brain markers of cerebrovascular disease and in contrast to a conventional, self‐report measure of function.MethodTwenty (n = 14 healthy control, n = 6 MCI) community‐dwelling older adults aged 60+ completed neuropsychological testing, including the Functional Activities Questionnaire (FAQ), and the VKC, which requires completion of simulated breakfast and lunch tasks on a touch‐screen computer. White matter hyperintensity (WMH) volumes from Fluid Attenuation Inversion Recovery (FLAIR) MRI sequences were derived using the UBO detector, a cluster‐based WMH extraction pipeline based on k‐nearest neighbors (k‐NN) algorithm. WMH volumes were calculated in SPM’s DARTEL space, precluding the need to adjust for intracranial volume (ICV).ResultMCI participants reported significantly more functional difficulties than healthy controls (FAQ U = 76.50 p = .002) and obtained marginally slower completion times on the VKC (U = 60.00, p = .138). VKC completion time was moderately associated with age (r = .441, p = .059) but relations with sex, race, and IQ were weak and not significant (all rs&lt;.195). VKC completion time significantly and strongly correlated with all WMH measures, even after controlling for age, sex, race, and IQ (total WMH r = .649, p = .031; deep WMH r = .615, p = .044; periventricular WMH r = .623, p = .041). By contrast, FAQ was not associated with WMH (rs&lt;.2, p&gt;.05 for all) or VKC completion time (r&lt;.1, p&gt;05) after controlling for age, sex, race, and IQ.ConclusionOur naturalistic, performance‐based measure of function (VKC) was not associated with race, sex, or premorbid IQ, but was strongly associated with neuroimaging markers of cerebrovascular disease (WMH). By contrast, a conventional self‐report measure of everyday functioning (FAQ) was not associated with neuroimaging measures (WMH). These results offer preliminary support for the VKC as a valid measure of early, subtle functional difficulties associated with cerebrovascular pathology that is not vulnerable to bias associated with race, sex, or premorbid IQ.

Relationship between a novel virtual reality test of mild functional difficulties and cerebrovascular disease

AbstractBackgroundIt is well known that mild cognitive impairment (MCI) is associated with subtle functional decline. However, standardized and cost‐effective methods for the objective quantification of mild functional difficulties are lacking. Here we report preliminary validity data for a novel, non‐immersive virtual‐reality task (Virtual Kitchen Challenge [VKC]) against brain markers of cerebrovascular disease and in contrast to a conventional, self‐report measure of function.MethodTwenty (n = 14 healthy control, n = 6 MCI) community‐dwelling older adults aged 60+ completed neuropsychological testing, including the Functional Activities Questionnaire (FAQ), and the VKC, which requires completion of simulated breakfast and lunch tasks on a touch‐screen computer. White matter hyperintensity (WMH) volumes from Fluid Attenuation Inversion Recovery (FLAIR) MRI sequences were derived using the UBO detector, a cluster‐based WMH extraction pipeline based on k‐nearest neighbors (k‐NN) algorithm. WMH volumes were calculated in SPM’s DARTEL space, precluding the need to adjust for intracranial volume (ICV).ResultMCI participants reported significantly more functional difficulties than healthy controls (FAQ U = 76.50 p = .002) and obtained marginally slower completion times on the VKC (U = 60.00, p = .138). VKC completion time was moderately associated with age (r = .441, p = .059) but relations with sex, race, and IQ were weak and not significant (all rs&lt;.195). VKC completion time significantly and strongly correlated with all WMH measures, even after controlling for age, sex, race, and IQ (total WMH r = .649, p = .031; deep WMH r = .615, p = .044; periventricular WMH r = .623, p = .041). By contrast, FAQ was not associated with WMH (rs&lt;.2, p&gt;.05 for all) or VKC completion time (r&lt;.1, p&gt;05) after controlling for age, sex, race, and IQ.ConclusionOur naturalistic, performance‐based measure of function (VKC) was not associated with race, sex, or premorbid IQ, but was strongly associated with neuroimaging markers of cerebrovascular disease (WMH). By contrast, a conventional self‐report measure of everyday functioning (FAQ) was not associated with neuroimaging measures (WMH). These results offer preliminary support for the VKC as a valid measure of early, subtle functional difficulties associated with cerebrovascular pathology that is not vulnerable to bias associated with race, sex, or premorbid IQ.

Does the Timing of Alzheimer’s Disease vary by Severity of Intellectual Disability in Down Syndrome?

AbstractBackgroundTrisomy 21 causes Down syndrome (DS) and is a recognized cause of Alzheimer’s disease (AD). The triplication of the amyloid precursor protein gene leads to an overexpression of amyloid‐beta (Aβ), which accumulates into extracellular plaques, followed by intracellular neurofibrillary tau tangles (Lott &amp; Head, 2019). However, variability in the age of AD onset in DS spans 25+ years (Iulita et al., 2022). As the DS field moves to AD clinical trials, it is important to identify factors related to this variability, such as premorbid severity of intellectual disability (ID). We compared the age‐trajectory of the AD biomarkers Aβ and tau and cognitive decline across premorbid ID levels (mild, moderate, and severe/profound), in models controlling trisomy type (full, mosaic, translocation) and APOE statusMethodAnalyses involved 361 adults with DS (M = 45.22 years, SD = 9.92) from the Alzheimer’s Biomarkers Consortium‐Down Syndrome. Participants completed measures of memory, mental status, and visuospatial ability. Premorbid ID level was recorded. PET was acquired using [11C] PiB for Aβ, and [18F] AV‐1451 for tau in 162 participants. Aβ was quantified using the centiloid method and tau was quantified as SUVR (reference: cerebellar cortex) in a composite region determined as the volume‐weighted average of select FreeSurfer 5.3, T1 MR‐based components.ResultsGeneral linear models controlling for site, age, trisomy type and APOE status indicated no significant effect of premorbid ID level by age on the cognitive outcomes (Figure 1a‐e). There was not a significant effect of premorbid ID by age on PET Aβ or on tau PET (Figure 2a‐b). There was not a significant difference in age of those with mild cognitive impairment‐DS (MCI‐DS) or dementia by premorbid ID level (Figure 3).ConclusionThis study adds to the characterization of the time course of AD pathology and clinical symptomology in DS. Findings provide robust evidence of a similar time course in AD trajectory across severity of ID, laying the groundwork for the inclusion of individuals with DS with a variety of IQ levels in clinical AD trials. Premorbid IQ may have little effect on AD biomarkers in DS in contrast to findings in neurotypical populations.

2 The Contribution of Brain Metastases to Neurocognitive Functioning in Patients with Advanced Metastatic Cancer

Objective:Neurocognitive decline is prevalent in patients with metastatic cancers, attributed to various disease, treatment, and individual factors. Whether the presence of brain metastases (BrMets) contributes to neurocognitive decline is unclear. Aims of this study are to examine neurocognitive performance in BrMets patients and compare findings to patients with advanced metastatic cancer without BrMets. Here, we present baseline findings from an ongoing, prospective longitudinal study.Participants and Methods:English-speaking adults with advanced metastatic cancers were recruited from the brain metastases and lung clinics at the Princess Margaret Cancer Centre. Participants completed standardized tests (WTAR, HVLT-R, BVMT-R, COWAT, Trailmaking test, WAIS-IV Digit Span) and questionnaires (FACT-Cog v3, EORTC-QLQ C30 and BN20, PROMIS Depression(8a) and Anxiety(6a)) prior to cranial radiotherapy for those who required it. Test scores were converted to z-scores based on published normative data and averaged to create a composite neurocognitive performance score and domain scores for memory, attention/working memory, processing speed and executive function. Neurocognitive impairment was defined according to International Cancer and Cognition Task Force criteria. Univariate and multivariate regressions were used to identify individual, disease and treatment variables that predict cognitive performance.Results:76 patients (mean (SD) age: 63.2 (11.7) years; 53% male) with BrMets were included. 61% experienced neurocognitive impairment overall; impairment rates varied across domains (38% memory, 39% executive functioning, 13% attention/working memory, 8% processing speed). BrMets quantity, volume, and location were not associated with neurocognitive performance. Better performance status (ECOG; ß[95%CI];-0.38[-0.70,-0.05], p=0.021), higher premorbid IQ (0.34[0.10,0.58], p=0.005) and greater cognitive concerns (0.02[-3.9e-04,0.04], p=0.051) were associated with better neurocognitive performance in univariate analyses. Only premorbid IQ (0.37[0.14,0.60], p=0.003) and cognitive concerns (0.02[0.0004, 0.03], p=0.05) remained significant in multivariate analysis. We also recruited 31 patients with metastatic non-small cell lung cancer (mNSCLC) with no known BrMets (age: 67.5 (8.3); 32% male) and compared them to the subgroup of BrMets patients in our sample with mNSCLC (N=32; age: 67.8 (11.7); 53% male). We found no differences in impairment rates (BrMets/non-BrMets: Cognitive Composite, 59%/55%; Memory, 31%/32%; Executive Functioning, 35%/29%; Attention/working memory, 16%/13%; Processing speed, 7%/6%; Wilcoxon rank-sum test, all p-value’s &gt; 0.5). The presence or absence of BrMets did not predict neurocognitive performance. Among patients with mNSCLC, higher education (0.11[0.03,0.18], p=0.004) and premorbid IQ (0.36[0.12,0.61], p=0.003), fewer days since primary diagnosis (0.00290[-0.0052,-0.0005], p=0.015) fewer pack-years smoking history (0.01[0.02,-0.001], p=0.027) and greater cognitive concerns (0.02[7e-5,0.04], p=0.045) were associated with better neurocognitive performance in univariate analyses; only premorbid IQ (0.26[0.02,0.51], p=0.04) and cognitive concerns (0.02[0.01,0.04], p=0.02) remained significant in multivariate analysis.Conclusions:Cognitive impairment is prevalent in patients with advanced metastatic cancers, particularly affecting memory and executive functioning. However, 39% of patients in our sample were not impaired in any domain. We found no associations between the presence of BrMets and neurocognitive function in patients with advanced cancers prior to cranial radiation. Premorbid IQ, a proxy for cognitive reserve, was associated with cognitive outcomes in our sample. Our longitudinal study will allow us to identify risk and resilience factors associated with neurocognitive changes in patients with metastatic cancers to better inform therapeutic interventions in this population.

73 Identification of 24-Month Cognitive Trajectories Among Clinical High Risk for Psychosis (CHR-P) Using Latent Class Mixture Modeling

Objective:Cohort studies demonstrate that people who later develop schizophrenia, on average, present with mild cognitive deficits in childhood and endure a decline in adolescence and adulthood. Yet, tremendous heterogeneity exists during the course of psychotic disorders, including the prodromal period. Individuals identified to be in this period (known as CHR-P) are at heightened risk for developing psychosis (~35%) and begin to exhibit cognitive deficits. Cognitive impairments in CHR-P (as a singular group) appear to be relatively stable or ameliorate over time. A sizeable proportion has been described to decline on measures related to processing speed or verbal learning. The purpose of this analysis is to use data-driven approaches to identify latent subgroups among CHR-P based on cognitive trajectories. This will yield a clearer understanding of the timing and presentation of both general and domain-specific deficits.Participants and Methods:Participants included 684 young people at CHR-P (ages 12–35) from the second cohort of the North American Prodromal Longitudinal Study. Performance on the MATRICS Consensus Cognitive Battery (MCCB) and the Wechsler Abbreviated Scale of Intelligence (WASI-I) was assessed at baseline, 12-, and 24-months. Tested MCCB domains include verbal learning, speed of processing, working memory, and reasoning &amp; problem-solving. Sex- and age-based norms were utilized. The Oral Reading subtest on the Wide Range Achievement Test (WRAT4) indexed pre-morbid IQ at baseline. Latent class mixture models were used to identify distinct trajectories of cognitive performance across two years. One- to 5-class solutions were compared to decide the best solution. This determination depended on goodness-of-fit metrics, interpretability of latent trajectories, and proportion of subgroup membership (&gt;5%).Results:A one-class solution was found for WASI-I Full-Scale IQ, as people at CHR-P predominantly demonstrated an average IQ that increased gradually over time. For individual domains, one-class solutions also best fit the trajectories for speed of processing, verbal learning, and working memory domains. Two distinct subgroups were identified on one of the executive functioning domains, reasoning and problem-solving (NAB Mazes). The sample divided into unimpaired performance with mild improvement over time (Class I, 74%) and persistent performance two standard deviations below average (Class II, 26%). Between these classes, no significant differences were found for biological sex, age, years of education, or likelihood of conversion to psychosis (OR = 1.68, 95% CI 0.86 to 3.14). Individuals assigned to Class II did demonstrate a lower WASI-I IQ at baseline (96.3 vs. 106.3) and a lower premorbid IQ (100.8 vs. 106.2).Conclusions:Youth at CHR-P demonstrate relatively homogeneous trajectories across time in terms of general cognition and most individual domains. In contrast, two distinct subgroups were observed with higher cognitive skills involving planning and foresight, and they notably exist independent of conversion outcome. Overall, these findings replicate and extend results from a recently published latent class analysis that examined 12-month trajectories among CHR-P using a different cognitive battery (Allott et al., 2022). Findings inform which individuals at CHR-P may be most likely to benefit from cognitive remediation and can inform about the substrates of deficits by establishing meaningful subtypes.

The relationship between cognitive reserve focused on leisure experiences and cognitive functions in bipolar patients

Bipolar disorder (BP) is characterized by cognitive decline. Individual differences exist in maintaining cognitive function due to daily physical activity and sleep. We examined the relationship between leisure experiences as proxies for cognitive reserve (CR) and cognitive function in patients with bipolar disorder after adjusting for daily physical activity and sleep.The CR of patients with BP (n = 24) and healthy study controls (HC) (n = 24) was assessed using premorbid IQ, years of education, and leisure activity history. Performance-based neuropsychological tests were performed to evaluate cognitive function. A self-reported scale was used to assess resilience. Physical activity and sleep were measured using an activity meter.Verbal fluency, story memory, and verbal memory were significantly positively correlated with the kinds of leisure experiences in patients with BP. A hierarchical regression analysis accounting for confounding factors showed that verbal fluency and memory were associated with the kinds of leisure experiences. Neither years of education nor resilience were significantly associated with neuropsychological scores.Various leisure experiences in patients with BP are associated with higher language-related cognitive functioning. Engaging in various leisure experiences may affect higher cognitive functions related to language.