Repeatable Battery For The Assessment Of Neuropsychological Status Research Articles

Cognitive Deficits among Individuals Admitted to a Post-Acute Pneumological Rehabilitation Unit in Southern Italy after COVID-19 Infection.

(1) Background: We investigated the differences in the neuropsychological profile as well as the pneumological and motor functions in two groups of patients admitted to rehabilitation who received different respiratory support during their COVID-19 infection. (2) Methods: Group-1 (n = 18; 15 male, median age 67.5) consisted of patients who received non-invasive mechanical ventilation; Group-2 (n = 19; 16 male, median age 63) consisted of patients who received invasive mechanical ventilation. All patients underwent a neuropsychological assessment including Mini-Mental State Examination (MMSE), Frontal Assessment Battery (FAB), and the Repeatable Battery for the Assessment of Neuropsychological Status (R-BANS) to evaluate the patients' cognition. Depression and anxiety were also measured at admission and discharge to rehabilitation. (3) Results: At admission, patients impaired at MMSE were 44% in Group-1 and 5% in Group-2, while patients impaired at FAB were 88% in Group-1 and 26% in Group-2. Wilcoxon's effect size revealed meaningful differences between groups for FAB, R-BANS global score, immediate and delayed memory, and attention-coding task, with Group-2 performing better than Group-1 across all measures. At discharge, 52% of the 25 patients re-assessed still had mild to moderate cognitive deficits, while 19% had depression and 35% had anxiety. (4) Conclusions: Patients who received oxygen therapy experienced higher levels of acute and chronic stress compared to those who benefitted from invasive mechanical ventilation. Despite patients showing a meaningful improvement at discharge, cognitive impairment persisted in a great number of patients; therefore, long-term neuropsychological follow-up and treatment for COVID-19 patients are recommended.

Insomnia in Chinese patients with chronic schizophrenia: prevalence, clinical correlates and relationship with cognitive impairment.

Insomnia is a major public health concern thatoften occurs in patients with schizophrenia, complicating the treatment and prognosis of patients. This study aimed to investigate the prevalence of insomnia and its relationship with cognitive function in Chinese patients with chronic schizophrenia. We recruited patients with schizophrenia and collected their clinical and demographic data. Insomnia data were collected through a self-reported questionnaire consisting of three questions. The positive and negative syndrome scale (PANSS) was used to measure psychopathological symptoms, while the repeatable battery for the assessment of neuropsychological status (RBANS) was used to measure cognitive performance. Of 957Chinese patients with chronic schizophrenia 20.2%reported having insomnia (193/957). Male patients (107/630, 17.0%) had a lower rate of insomnia than female patients (86/327, 26.3%) (x2 = 11.60, p = 0.001). Patients with insomniaexhibited significantly higher PANSS total score and positive symptom, negative symptom, and general psychopathology scores, but significantly lower RBANS total score, language, attention and delayed memory scores compared to patients without insomnia (all p < 0.05). Logistic regression analysis showed that femalesex, high PANSS total score and the use of diazepam were independently associated with insomnia (all p < 0.05). Insomnia is relatively commonin Chinese patients with chronic schizophrenia. Some demographic dataand clinical symptoms are associated with insomnia. Patients with schizophrenia andinsomnia perform poorlyon cognition tests suggesting that insomnia and cognitive function are closely related in patientswith schizophrenia.

Longitudinal post-shunt outcomes in idiopathic normal pressure hydrocephalus with and without comorbid Alzheimer's disease.

Alzheimer's disease (AD) is highly comorbid with idiopathic normal pressure hydrocephalus (iNPH) and may diminish the benefits of shunting; however, findings in this area are mixed. We examined postoperative outcomes, with emphases on cognition and utilization of novel scoring procedures to enhance sensitivity. Using participant data from an iNPH outcome study at Butler Hospital, a mixed effect model examined main and interaction effects of time since surgery (baseline, 3 months, 12 months, and 24-60 months) and AD comorbidity (20 iNPH and 11 iNPH+AD) on activities of daily living (ADLs) and iNPH symptoms. Regression modeling explored whether baseline variables predicted improvements 3 months postoperatively. There were no group differences in gait, incontinence, and global cognition over time, and neither group showed changes in ADLs. Cognitive differences were observed postoperatively; iNPH patients showed stable improvements in working memory (p = 0.012) and response inhibition (p = 0.010), while iNPH + AD patients failed to maintain initial gains. Regarding predicting postoperative outcomes, baseline AD biomarkers did not predict shunt response at 3 months; however, older age at surgery predicted poorer cognitive outcomes (p = 0.04), and presurgical Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) (p = 0.035) and Mini-Mental Status Examination (MMSE) scores (p = 0.009) predicted improvements incontinence. iNPH + AD may be linked with greater declines in aspects of executive functioning postoperatively relative to iNPH alone. While baseline AD pathology may not prognosticate shunt response, younger age appears linked with postsurgical cognitive improvement, and utilizing both brief and comprehensive cognitive measures may help predict improved incontinence. These results illustrate the potential benefits of surgery and inform postoperative expectations for those with iNPH + AD.

Mediterranean diet score is associated with greater allocentric processing in the EPAD LCS cohort: A comparative analysis by biogeographical region.

Background: Adherence to the Mediterranean diet (MedDiet), a primarily plant-based eating pattern, has been associated with lower dementia incidence. Much of the research has focused on Alzheimer's disease (AD) dementia and mild cognitive impairment (MCI), with less research looking at the preclinical symptomatically silent stages that pre-empt MCI and AD dementia. Although there is evidence from studies conducted globally, no studies have compared the effects of the MedDiet within and outside of the Mediterranean region in one cohort. Methods: Our study explored cross-sectional and longitudinal associations between MedDiet and cognition in the pan-European EPAD LCS, comparing those living within and outside of the Mediterranean region (as classified by European Union biogeographical definitions). After deriving MEDAS scores to quantify adherence to the MedDiet, we used linear regression and linear mixed effects models to test for associations between the MEDAS score and cognitive function measured by the Four Mountains Test (FMT) and the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). We additionally calculated MEDAS continuous and PYRAMID scores to provide alternative measures of MedDiet adherence. Results: We included 1826 participants, mean age 65.69 (±7.42) years, majority female (56.2%) with family history (65.8%) and minority APOEε4 carriers (38.9%). Higher MEDAS scores were associated with better performance on the FMT both cross-sectionally (n = 1,144, ß: -0.11, SE: 0.04, p = 0.007) and longitudinally (slope: 0.10, 95% CI: 0.04-0.17, p: 0.002). The effect was marginally greater in the Mediterranean region in the cross-sectional analysis, with a stronger effect emerging longitudinally. In exploratory analyses, the association between MEDAS and FMT scores was only seen in female participants. A sensitivity analysis excluding Toulouse and Perugia, as cities near, but not within, the biogeographical region, found significant associations between higher MEDAS and MEDAS continuous scores, and a number of RBANS total and index scores. Conclusion: MedDiet adherence is associated with better FMT scores, with effects seen most strongly in the Mediterranean region from longitudinal data. Our sensitivity analysis suggested a more global cognitive benefit of MedDiet adherence. This study highlights the need to further explore for whom and for what brain health outcomes the MedDiet confers benefit. This evidence would identify a window of opportunity in the life-course to maximise the benefit and better inform public health campaigns and patient-level interventions.

Change in Plasma ATN Biomarkers Over a 12‐Week Physical Activity Intervention Among Older African Americans: Program for African American Cognition and Exercise (PAACE)

AbstractBackgroundPlasma markers of amyloid, tau, and neurodegeneration (ATN) are promising as correlates of AD biological and clinical features, but data from older African Americans, and data on change during non‐pharmacological interventions, is limited.MethodThe Program for African American Cognition and Exercise (PAACE) randomized older cognitively normal African American adults into a 12‐week successful aging group (SAG) to attend educational sessions or a 12‐week physical activity group (PAG) to complete supervised and in‐home physical activity. The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and cardiometabolic risks were assessed pre‐ and post‐intervention. The Quanterix Simoa® Neuro 4‐Plex E and pTau‐181 Advantage Kits were used to measure plasma concentrations of amyloid beta (ABeta) 1‐40 and 1‐42, glial fibrillary acidic protein (GFAP), neurofilament light (NfL), and tau protein phosphorylated at threonine 181 (pTau‐181). Linear mixed effects regression models assessed modifiers of change in plasma and RBANS measures.ResultA set of 54 PAACE completers aged 69.3 +/‐ 3.4 years (40 female, 14 male) provided non‐outlier measurements. ABeta 1‐40 decreased (p=.027), and RBANS global cognition, visuospatial, and delayed memory scores increased, over the intervention (maximum p value: .040). Plasma ATN biomarkers did not differ between SAG and PAG at baseline, but SAG did have greater declines in pTau‐181 than PAG did (p=.003, Figures 1‐2), and women had greater declines in pTau‐181 than men did (p= .045, Figure 3). Greater age was associated with greater ABeta 1‐40, ABeta 1‐42, GFAP, and NFL (maximum p= .008). Greater diastolic blood pressure was associated with lesser NFL (p= .021) and ABeta 1‐40 (p= .041). Greater GFAP, NfL, and pTau‐181, suggestive of greater burden of tau and neurodegeneration, were associated with lesser RBANS language score (maximum p= 0495). Greater pTau‐181 was associated with lesser RBANS immediate memory score (p= .035). Plasma ATN markers did not modify pre‐to‐post‐intervention change in any RBANS summary score (minimum p=.10).ConclusionAmong cognitively normal older African Americans, change in plasma ATN biomarkers over the course of a nonpharmacological intervention differed by study group and gender. The markers differed by cardiometabolic risks and associated with cognitive function in an intuitive fashion.

Effect of SUPERBRAIN program in Amyloid PET positive mild dementia patient: Cognitive outcome, EEG and stool microbiome

AbstractBackgroundThe effect of SUPERBRAIN (multi‐domain lifestyle intervention program), on the mild stage of AD positive mild stage of dementia for an 8‐week treatment in the cognitive function, EEG and stool microbiom outcome.MethodA total of 58 amnestic MCI or early stage of mild dementia patient (CDR 0.5‐1) with amyloid PET positive, were recruited. Patients were randomized to either three group of 1) Superbrain with Memory pack group, 2) Memory pack only group, 3) control group. Memory Pack is nutritional support that is supplied by Daesang Yuup that is specially designed for brain reinforcing formula such as choline, serine, glycine, etc. Cognitive training programs and exercise programs were conducted two persons in a group session twice in a week for the 8 week in the hospital. The primary outcome was the change in the total scale of index score of the Repeatable Battery for the Assessment of Neuropsychological Status (RBARNS) after 2 months of training. Analysis of covariance was used to compare the index score of the RBANS between the three groups.ResultThe age was 75.70 (5.26) in treatment group, 75.75 (5.80) for Memory pack only group, 75.00 (6.50) for control group (P value. 0.967). The baseline MMSE scores were 22. 38 (3.50) in treatment group, 20.75 (1.75) for Memory pack only group, 21.63(2.50) for control group (P value. 0.492). RBARNS score showed improvements in the total RBARNS scale index score (72(15.78) in Baseline to Fup 78.88(16.51) in the treatment group (P value 0.05) compared to Memory pack only (75.38(9.02) in Baseline to Fup 79.00(8.68) (P value 0.045) and control group (75.38(11.90) in Baseline to Fup 75.75(18.79) (0.970). The MMSE were significantly improved in both treatment group (22.38, 24.13; p = 0.013) and Memory pack only group(20.75,22.57, P = 0.045) as well but worsened in control group (21.63, 20.00 P = 0.142) compared to baseline. The CDR sum of box statistically worsened in the control group compared to treatment group and memory pack group.ConclusionCognitive improvement was evident even in this short term 8 weeks of multi‐domain intervention program of for AD dementia which needs further study for the long‐term outcome.

Electrophysiological markers of early Alzheimer’s Disease proteinopathy in the human brain

AbstractBackgroundAlzheimer's Disease (AD) is characterized by the pathological accumulation of amyloid‐beta (Aβ) and hyperphosphorylated tau proteins in the brain. Animal models have demonstrated that early Aβ accumulation induces neuronal hyperexcitability (Stargardt et al., 2015), whereas later additive effects of Aβ and tau lead to suppression of neuronal activity that parallels disease severity (Busche et al., 2020). Although neural hypo‐excitability has been reported in the later stages of AD, it remains unknow if such a shift from hyper‐ to hypo‐excitability exists at the macroscopic level in the human brain of asymptomatic individuals (Figure 1).MethodsWe used Positron Emission Tomography to measure the deposition of whole‐brain Aβ ([18F] NAV4694) and medial temporal tau ([18F] Flortaucipir) and resting‐state Magnetoencephalography (MEG) to capture the neurophysiological changes related to AD pathology in a group of clinically unimpaired older adults with family history of AD (PREVENT‐AD cohort; McSweeney et al., 2020). We used linear mixed effects models to test the association between MEG spectral power and Aβ across cortical regions, and the interactive effect of tau accumulation on this relationship. We then used linear regressions to test if the observed associations between MEG spectral power and AD pathology related to longitudinal cognitive performance, evaluated annually using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS).ResultsAβ deposition was associated with neural hyper‐activity, as reflected by a positive association between Aβ SUVR values and MEG spectral power in higher frequencies (alpha [8 ‐ 12 Hz]) and a negative association in slow frequencies (delta [2 – 4 Hz]; Figure 2). The accumulation of medial temporal tau predicted a shift in these associations towards a hypo‐activation pattern (increased neural slowing), which was related to longitudinal decreases in attention scores (Figure 3).ConclusionOur results support the hypothesis that Aβ induces neural hyper‐activity in asymptomatic individuals, while the additive effects of Aβ and tau accumulation lead to a shift towards neural slowing that relates to cognitive deficits. These early detectable electrophysiological changes may represent novel non‐invasive biomarkers of the preclinical stages of AD and may potentially help predicting cognitive trajectories and disease progression in the AD continuum.

The role of IGFBP2 in pre‐symptomatic Alzheimer's disease: a multimodal longitudinal study of cognitively unaffected individuals with a family history of sporadic Alzheimer’s disease

AbstractBackgroundInsulin‐like growth factors (IGF) play pivotal roles in neurogenesis, neuronal survival, synaptogenesis and compensatory repair mechanisms following injury. Insulin‐like growth factor binding proteins (IGFBP) bind to IGFs, and regulate interactions between IGFs and their cell surface receptors. In the brain, IGFBP2 is the most abundant IGFBP. Several studies have observed altered IGFBP2 levels in Alzheimer’s disease (AD) patients. However, the role of IGFBP2 during pre‐symptomatic AD remains unknown. Thus, we used longitudinal data acquired from the pre‐symptomatic PREVENT‐AD cohort to examine its possible contributions to AD pathophysiology.MethodFor initial cross‐sectional analyses, the Mini‐Mental State Examination was used to stage the participants (PREVENT‐AD, CCNA and Douglas cohorts) across the AD spectrum. Olink’s primer extension assay was used to measure cerebrospinal fluid (CSF) IGFBP2 levels. PREVENT‐AD participants were followed longitudinally for 6‐8 years. Annual visits included cognitive performance assessments, lumbar punctures and neuroimaging. The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) evaluated five cognitive domains (immediate memory, delayed memory, attention, language and visuospatial abilities) and included a total summary score.ResultCSF IGFBP2 levels were significantly reduced in MCI (p &lt; 0.001) and AD participants (p = 0.027 and p &lt; 0.001 respectively), relative to controls (Figure 1). In the PREVENT‐AD cohort, baseline CSF IGFBP2 levels were negatively correlated with RBANS cognitive performance trajectory slopes estimated over the course of 6 to 8 years, for the delayed memory (p = 0.003), visuospatial (p = 0.008) and total scale indices (p = 0.021) (Figure 2). However, baseline CSF IGFBP2 levels were not associated with cognitive decline for the immediate memory (p = 0.162), attention (p = 0.890) and language (p = 0.841) indices (Figure 3). Finally, in the PREVENT‐AD cohort, baseline CSF IGFBP2 levels were negatively correlated with baseline left entorhinal cortex volume (p = 0.011), but were not correlated with right entorhinal cortex volume (p = 0.868)(Figure 4).ConclusionOur results suggest that IGFBP2 may exhibit a bi‐directional association with AD stage pathology. Our findings revealed that IGFBP2 is strongly correlated with early cognitive decline in the delayed memory and visuospatial domains, in pre‐symptomatic individuals.

Prognostic utility of baseline [18F]GTP1 tau PET signal for subsequent cognitive and functional decline in prodromal‐to‐mild Alzheimer's disease

AbstractBackgroundPrior studies of tau PET tracers in participants with normal cognition and/or a broad range of Alzheimer’s disease (AD) severity suggest baseline tau PET signal is associated with subsequent rates of cognitive decline. However, the prognostic utility of tau PET imaging is less well‐established within more homogenous cohorts limited to specific AD stages and for cognitive versus functional decline. We addressed these questions by analyzing baseline [18F]GTP1 tau PET signal and longitudinal changes in cognitive and functional measures in the Phase 2 Tauriel study of semorinemab in prodromal‐to‐mild AD.MethodsWe analyzed data from a subset of Tauriel participants with prodromal AD (pAD; n=127) or mild AD (mAD; n=233) who underwent baseline [18F]GTP1 tau PET and longitudinal assessments with the Clinical Dementia Rating‐Sum of Boxes (CDR‐SB), Alzheimer’s Disease Assessment Scale‐Cognitive Subscale (ADAS‐Cog13), Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), and/or Alzheimer’s Disease Cooperative Study‐Activities of Daily Living (ADCS‐ADL). As no treatment effects were observed with semorinemab in Tauriel, data were pooled across semorinemab and placebo arms. Associations between baseline [18F]GTP1 SUVRs and annualized longitudinal change on each measure were explored using Pearson correlations and multiple linear mixed effects regression models adjusting for relevant baseline covariates.ResultsBaseline cortical [18F]GTP1 SUVRs and longitudinal decline on clinical measures were significantly greater in mAD relative to pAD cohort. Prognostic associations with baseline cortical [18F]GTP1 were similar in pAD and mAD and more robust for predominantly cognitive measures (ADAS‐Cog13: pAD rs=0.37, mAD rs=0.35; RBANS Total Index: pAD rs=‐0.40, mAD rs=‐0.41) than measures incorporating functional status (CDR‐SB: pAD rs=0.27, mAD rs=0.29; ADCS‐ADL: pAD rs=‐0.12, mAD rs=‐0.26). Analogous results were seen using temporal or Braak stage regions of interest. [18F]GTP1 associations with cognitive decline generally remained significant after adjusting for baseline cognitive score, age, hippocampal volume, and education.ConclusionsHigher baseline [18F]GTP1 tau PET signal was associated with faster subsequent clinical decline in both prodromal and mild AD. More robust associations were seen with cognitive relative to functional measures. These results bolster prior work that suggests a role for tau PET in patient selection/stratification in AD clinical trials.

Gender Difference in Cognitive Function Among Stable Schizophrenia: A Network Perspective.

To investigate the gender differences and influencing factors of cognitive function in stable schizophrenic patients, and to explore the cognitive characteristics of male and female patients. A total of 298 patients with chronic schizophrenia were divided into two groups according to gender. The differences of demographic and clinical characteristics between the two groups were firstly analyzed. Then the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) was used to measure their cognitive function, and the correlation between cognitive function and demographic characteristics and clinical characteristics was analyzed. Finally, the gender-based cognitive characteristics were explored through network analysis. There was no significant difference in the RBANS total score and sub-item score between the male schizophrenia and female schizophrenia patients. Correlation analysis showed that RBANS total score was inversely proportional with age, duration and Positive and Negative Syndrome Scale (PANSS) score in male schizophrenia, while being directly proportional with age at onset and inversely proportional with PANSS score in female schizophrenia. Network analysis showed that language was the core of cognitive function for male schizophrenia, and the delayed memory was the core of cognitive function for female schizophrenia. There was no significant gender difference in cognitive function score among patients with stable schizophrenia. The core cognitive functions of male and female schizophrenia are language and delayed memory, respectively.

Functional fitness predicts global cognition scores

AbstractBackgroundAlzheimer’s disease (AD) is the 5th leading cause of death and the 6th most burdensome disease among US older adults. Given the concern with public health, understanding modifiable risk factors contributing to cognitive decline is imperative. With preliminary symptoms of cognitive decline occurring long before diagnosis, the ability to identify modifiable risk factors is key to primary prevention and maintenance of cognition. Often among individuals with AD, physical function is concurrently impaired. Thus, the primary aim of the present investigation is to determine the ability to predict global cognition scores from commonly used physical function assessments.MethodCommunity‐dwelling adults 60 years and older completed all assessments. Global cognition (percentile score) was assessed using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). All participants were free from mild cognitive impairment, dementia, and probable dementia. Physical function variables included maximal hand grip strength (average of right and left hands), lower‐body peak force development during a sit‐to‐stand task, and 10‐mfast walking time. Linear regression analysis was performed to determine the proportion of variance accounted for by the independent variables (sex, hand grip strength, peak force, 10‐meter walk time). Semi‐partial correlations were performed to determine the unique contribution from each independent variable.Result27% of the variance in global cognition was accounted for when including all independent variables. Semi‐partial correlations revealed the largest unique contribution was from the 10‐meter fast walking time, accounting for 19% of the variance (p &lt; .001). Lower‐body peak force production accounted for 9% (p &lt; .001). Sex accounted for 2.6% (p =.04) and hand grip strength accounted for 2% (p = .055).ConclusionThe current investigation provides support for the predictive capabilities of physical function assessments on cognitive ability—in particular, the time to complete a 10‐meter walk. This is paramount to future efficacious treatments with the inconsistent nature of current cognitive testing and implementation, primarily because of difficulties accessing qualified neuropsychological professionals. The physical function assessments presented here are cost effective and may serve as an early warning sign to cognitive decline.

Prognostic utility of baseline [18F]GTP1 tau PET signal for subsequent cognitive and functional decline in prodromal‐to‐mild Alzheimer's disease

AbstractBackgroundPrior studies of tau PET tracers in participants with normal cognition and/or a broad range of Alzheimer’s disease (AD) severity suggest baseline tau PET signal is associated with subsequent rates of cognitive decline. However, the prognostic utility of tau PET imaging is less well‐established within more homogenous cohorts limited to specific AD stages and for cognitive versus functional decline. We addressed these questions by analyzing baseline [18F]GTP1 tau PET signal and longitudinal changes in cognitive and functional measures in the Phase 2 Tauriel study of semorinemab in prodromal‐to‐mild AD.MethodsWe analyzed data from a subset of Tauriel participants with prodromal AD (pAD; n=127) or mild AD (mAD; n=233) who underwent baseline [18F]GTP1 tau PET and longitudinal assessments with the Clinical Dementia Rating‐Sum of Boxes (CDR‐SB), Alzheimer’s Disease Assessment Scale‐Cognitive Subscale (ADAS‐Cog13), Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), and/or Alzheimer’s Disease Cooperative Study‐Activities of Daily Living (ADCS‐ADL). As no treatment effects were observed with semorinemab in Tauriel, data were pooled across semorinemab and placebo arms. Associations between baseline [18F]GTP1 SUVRs and annualized longitudinal change on each measure were explored using Pearson correlations and multiple linear mixed effects regression models adjusting for relevant baseline covariates.ResultsBaseline cortical [18F]GTP1 SUVRs and longitudinal decline on clinical measures were significantly greater in mAD relative to pAD cohort. Prognostic associations with baseline cortical [18F]GTP1 were similar in pAD and mAD and more robust for predominantly cognitive measures (ADAS‐Cog13: pAD rs=0.37, mAD rs=0.35; RBANS Total Index: pAD rs=‐0.40, mAD rs=‐0.41) than measures incorporating functional status (CDR‐SB: pAD rs=0.27, mAD rs=0.29; ADCS‐ADL: pAD rs=‐0.12, mAD rs=‐0.26). Analogous results were seen using temporal or Braak stage regions of interest. [18F]GTP1 associations with cognitive decline generally remained significant after adjusting for baseline cognitive score, age, hippocampal volume, and education.ConclusionsHigher baseline [18F]GTP1 tau PET signal was associated with faster subsequent clinical decline in both prodromal and mild AD. More robust associations were seen with cognitive relative to functional measures. These results bolster prior work that suggests a role for tau PET in patient selection/stratification in AD clinical trials.

Update on the TOGETHER study: a patient‐ and investigator‐blind, randomized, placebo‐controlled study evaluating the efficacy, safety and tolerability of bepranemab, UCB0107, in prodromal‐to‐mild Alzheimer’s disease

AbstractBackgroundBepranemab is a recombinant, humanized, full‐length IgG4 monoclonal antibody that binds to a central tau epitope (amino acids 235‐250). Here, we update on the progress of the TOGETHER study (AH0003; NCT04867616) with bepranemab in early Alzheimer’s disease (AD).MethodTOGETHER is a global, multicenter, double‐blind, placebo‐controlled, parallel‐group study investigating the efficacy, safety and tolerability of bepranemab versus placebo. Patients with prodromal (National Institute on Aging‐Alzheimer’s Association [NIA‐AA] Stage 3) or mild (NIA‐AA Stage 4) AD (target N = 450) will be randomized (1:1:1) to receive one of two doses of bepranemab or placebo (intravenous, every 4 weeks), over an 80‐week treatment period, followed by an optional 48‐week open‐label‐extension period. Participants will have a global Clinical Dementia Rating (CDR) score of 0.5 (prodromal AD) or 0.5–1.0 (mild AD) and a CDR‐Memory Box score ≥0.5 at screening and baseline, a score of ≤85 for the delayed recall domain of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), mini‐mental state examination (MMSE) ≥20 at screening and must meet the NIA‐AA 2018 definition of cerebral beta‐amyloid (Aβ) accumulation, by either a positive centrally read positron emission tomography (PET) scan or a positive cerebrospinal fluid (CSF) pTau181/Aβ1‐42 ratio. The primary endpoint is change from baseline to Week 80 in CDR scale Sum of Boxes total score. Secondary endpoints include: pharmacokinetics; safety and tolerability; tau PET imaging and change from baseline in AD Assessment Scale‐Cognitive Subscale 14, Amsterdam Instrumental Activities of Daily Living questionnaire and MMSE at Weeks 56 and 80.ResultAs of March 1, 2022, 56/125 planned centers have enrolled participants across 8 countries: Belgium, Canada, France, Netherlands, Poland, Spain, UK and USA. Of the 538 participants who entered screening, 62 have been randomized so far and 334 failed screening. Predominant reasons for screen failure include not meeting RBANS, MMSE or Aβ positivity (CSF or PET) criteria.ConclusionThis proof‐of‐concept study employs clinical outcome measures, imaging, pharmacokinetics, and biomarkers to assess the ability of bepranemab to slow progression of AD when administered in the early stages of disease. Enrollment and randomization are underway with nearly half of the study centers active.

Clusterin is associated with Alzheimer’s disease biomarkers and cognitive scores in the pre‐symptomatic phase of the disease.

AbstractBackgroundClusterin (CLU) is one of the main genetic risk factors of late onset Alzheimer’s disease (AD), and different polymorphisms have been associated with the disease. A GWAS performed in a population isolate from eastern Canada has found the polymorphism rs11136000 of the CLU gene to be associated with increased risk for AD. For the present work, we used two different cohorts (the “at‐risk” pre‐symptomatic PREVENT‐AD and the symptomatic ROSMAP cohort) with the objective of exploring how the rs11136000 polymorphism is associated with clinical manifestations, biomarkers and neuropathology of AD at different disease stages.MethodIn the PREVENT‐AD cohort, ELISAs were used for Tau, phospho(181) Tau (p‐tau), and Aß CSF levels. Cognition was assessed with the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Participants were followed for at least 4 years. In the autopsied‐confirmed ROSMAP cohort, Aß load and NFT density in the cortex were measured with immunocytochemistry, and cognition was assessed with the Mini‐Mental State Examination (MMSE). Participants were followed throughout their adult life, until death.ResultIn the cognitively unimpaired PREVENT‐AD cohort, participants who are APOE4 positive and non‐carriers for the rs11136000 T variant had lower CSF Aß1‐42 (p=0.01) and higher CSF p‐tau (p=0.027) (Fig 1). Additionally, participants who are APOE4 positive and have 2 copies of the CLU rs11136000 T variant display significantly higher coding scores (p=0.003), attention scores (p=0.015) and visuospatial/constructional score (p= 0.026) (Fig 2). However, participants who are APOE4 negative and are homozygous for the rs11136000 T variant have lower semantic fluency score (p=0.001), list recall score (p=0.038) and language score (p=0.007) (fig 2). In the ROSMAP cohort, there was no association of the CLU rs11136000 variant with risk of developing dementia, MMSE scores or Braak or CERAD scores.ConclusionOur results confirm the role of the CLU rs11136000 variant in the pathology of AD, particularly in the pre‐symptomatic phase of the disease when pathology begins to unfold.

Declining Gait Speed is associated with Deteriorating Executive Performance in people with Mild Cognitive Impairment

AbstractBackgroundThe Motoric Cognitive Risk Syndrome has highlighted the link between cognitive and motor performance, and the associated incremental higher risk of developing dementia. There is considerable debate regarding what aspects of cognition (working memory, executive function, attention) are most associated with gait changes. This study investigates the relationship between mobility scores and cognitive profiles in individuals with Mild Cognitive Impairment (MCI) specifically with regard to executive performance and amnestic/non‐amnestic profiles.MethodParticipants diagnosed with MCI, (Clinical Dementia Rating scale global score of ≤0.5, sum of boxes score ≤4.0), attending a regional specialist memory service had a three‐meter Timed Up and Go (TUG) gait assessment and multi‐domain neuropsychiatric assessment undertaken. Amnestic neuropsychiatric profile was defined as Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) delayed memory subset score &lt;1SD i.e. ≤16th centile below norm for age/ education. Executive function performance was assessed using the Executive Interview (EXIT‐25) where higher scores reflect poorer executive performance.ResultData was reviewed for 161 patients with MCI; 53% (86/161) women. 80% (129/161) had an amnestic neuropsychiatric profile, mean age 73.8 ±7.2 (51‐94). 20% (32/161) had non‐amnestic MCI, mean age 74 ±7.07 (60‐87). There was no significant difference in TUG results between amnestic and non‐amnestic MCI patients (11.2 ±3.3 vs 10.7 ±3.1 p = NS). There was a significant increase in TUG values with worsening executive function performance [EXIT‐25 score 0–9 (88/161) mean TUG = 10.5 ±3.3 seconds vs EXIT‐25 score 10–14 (43/161) mean TUG = 11.9 ±2.8 seconds vs EXIT‐25 score 15–25 (30/161) mean TUG = 12.1 ±3.9 seconds; p = 0.021] which persisted after controlling for age, gender and other relevant cofactors.ConclusionReflective of the importance of frontal lobe integration to the respective tasks, subtle differences in gait performance are associated with executive function performance regardless of predominant amnestic or non‐amnestic MCI profile.

Diffusion MRI subnetwork efficiency is associated with cognitive resilience to AD pathology in cognitively unimpaired older adults at risk of AD dementia

AbstractBackgroundWhile higher levels of Aβ and tau pathology are typically associated with more pronounced cognitive decline in Alzheimer’s disease (AD), some older adults exhibit normal cognition even with a substantial burden of AD pathology. This phenomenon is known as ‘cognitive resilience’. The potential role of structural connectivity in cognitive resilience remains inconclusive. The present study tested whether higher global efficiency in structural brain networks moderate the relationship between AD pathology and cognitive performance in the preclinical phase of AD.MethodWe studied 118 cognitively normal older adults from the family history enriched Prevent‐AD cohort. Diffusion‐weighted MRI was used to measure the structural connectome, PET to measure global Aβ (18F‐NAV4694) and entorhinal tau (18F‐Flortaucipir) pathology, and the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) to evaluate cognitive performance. We first used graph theory analyses to calculate global efficiency of networks known to be affected in early AD (i.e., limbic and default mode network (DMN)). Then multiple linear regressions were performed to examine relationships between Aβ / tau pathology, cognitive performance, and global efficiency of the two subnetworks. Interaction analyses were used to examine whether network efficiency attenuates the relationships between AD pathology and cognitive performance.ResultAs expected, higher levels of Aβ and tau pathology in the brain were associated with worse cognitive performance in individuals at risk of AD (Figure 1). Higher entorhinal tau pathology was also associated with lower global efficiency in the limbic network (Figure 2). Subsequent interaction analyses showed that global efficiency in the limbic moderated the relationships between AD pathology and cognitive performance. Specifically, higher global efficiency was associated with an attenuated effect of both amyloid and tau pathology on delayed memory performance (Figure 3).ConclusionIndividuals with higher global efficiency in the limbic structural network exhibit better memory performance at a given level of AD pathology in preclinical stages of the disease. Structural network properties of the brain may play an important role in maintaining cognitive performance in the face of AD pathology, and could serve as a potential biomarker for cognitive resilience.

Alternations of vitamin D and cognitive function in first-diagnosed and drug-naïve BD patients: Physical activity as a moderator

BackgroundThe pathophysiological mechanism of cognitive impairments of bipolar disorder (BD) has not yet been completely revealed. It is well known that Vitamin D and physical activity (PA) are associated with BD. However, specific links between Vitamin D and cognitive deficits in BD are still unclear. MethodThe serum levels of vitamin D were measured. The cognitive performances of 102 first-diagnosed and drug-naïve BD patients were evaluated for analysis. The repeatable battery for the assessment of neuropsychological status (RBANS) and the Stroop Color-Word test was used in this study. PA was collected by international physical activity questionnaire. ResultPatients with BD had high levels of serum vitamin D. Furthermore, immediate and delayed memory was negatively associated with vitamin D levels in patients' group. The serum levels of vitamin D in patients with low PA were positively associated with memory. However, increased PA attenuated the protective effect of vitamin D on executive cognition. ConclusionIt is concluded that the increased levels of vitamin D were observed in the serum of patients with BD. Thus, it is found that more PA is less beneficial to cognition of patients with BD than longer resting.

The Use of Episodic Memory Tests for Screening in Clinical Trials for Early Alzheimer’s Disease: A Comparison of the Free and Cued Selective Reminding Test (FCSRT) and the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS)

BackgroundScreening procedures for early Alzheimer’s disease (AD) trials seek to efficiently identify participants who fulfill clinical and biomarker criteria for AD and enrich for those most likely to experience significant clinical progression during the study. Episodic memory performance is often assessed in screening, but the utility of different memory tests for optimizing screening efficiency and/or rates of clinical progression remains uncertain.ObjectivesCross-study comparisons of the effects of inclusion criteria based on performance on the Free and Cued Selective Reminding Test (FCSRT) or the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) on screen-failure rates for episodic memory and β-amyloid (Aβ) positivity (by CSF or PET) and on subsequent rates of clinical disease progression in randomized participants across three clinical trials in early (prodromal-to-mild) AD.DesignSecondary analyses of cross-sectional and longitudinal clinical trial data.SettingMulti-center international clinical trials.ParticipantsIndividuals with prodromal-to-mild AD screened and/or randomized in clinical trials for crenezumab (CREAD, CREAD2) or semorinemab (Tauriel). Cross-sectional analyses of screening data for episodic memory impairment included participants from CREAD2 (n=2897) and Tauriel (n=887) and for Aβ positivity included participants from CREAD (n=1138), CREAD2 (n=1119), and Tauriel (n=483). Longitudinal analyses of rates of clinical progression included participants from CREAD (n=779), CREAD2 (n=773), and Tauriel (n=331).MeasurementsCross-sectional analyses examined eligibility rates per cutoffs defined for the FCSRT (CREAD, CREAD2) or RBANS (Tauriel) and per Aβ positivity using CSF and/or PET biomarkers. Longitudinal analyses examined rates of clinical progression on the Clinical Dementia Rating-Sum of Boxes (CDR-SB), the 13-item version of the Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog13), and Alzheimer’s Disease Cooperative Study-Activities of Daily Living Scale (ADCS-ADL).ResultsLower rates of study eligibility per episodic memory criteria were seen with the FCSRT (CREAD2) relative to the RBANS (Tauriel), but similar rates of eligibility per Aβ positivity criteria were seen amongst participants with episodic memory impairment per the cutoffs used on either assessment. Similar rates of clinical decline over 18 months on the CDR-SB, ADAS-Cog13, and ADCS-ADL were observed in study populations enriched using the FCSRT (CREAD, CREAD2) or the RBANS (Tauriel).ConclusionsCutoffs for episodic memory impairment on the FCSRT used in the CREAD and CREAD2 studies are more stringent than those on the RBANS used in the Tauriel study, resulting in lower rates of eligibility. However, given that study enrichment with either test yields similar rates of Aβ positivity and clinical progression, considerations beyond these factors may drive the decision of which assessment to use for screening in early AD clinical trials.

Differences of resting fMRI and cognitive function between drug-naïve bipolar disorder and schizophrenia

Background:Bipolar disorder (BD) and schizophrenia (SC) have many similarities in clinical manifestations. The acute phase of BD has psychotic symptoms, while SC also has emotional symptoms during the onset, which suggests that there is some uncertainty in distinguishing BD and SC through clinical symptoms.Aim:To explore the characteristics of brain functional activities and cognitive impairment between BD and SC.Methods:Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) test was performed on patients in drug-naïve BD and SC (50 subjects in each group), and resting-state functional magnetic resonance imaging (rs-fMRI) scanning was performed meanwhile. Rs-fMRI data were routinely preprocessed, and the value of the fractional amplitude of low-frequency fluctuation (fALFF) was calculated. Then each part of the scores of the RBANS and the characteristics of brain function activities were compared between the two groups. Finally used Pearson correlation to analyze the correlation between cognition and brain function.Results:(1) Compared with BD group, all parts of RBANS scores in SC group decreased; (2) The left inferior occipital gyrus (IOG, peak coordinates − 30, -87, -15; t = 4.78, voxel size = 31, Alphasim correction) and the right superior temporal gyrus (STG, peak coordinates 51, -12, 0; t = 5.08, voxel size = 17, AlphaSim correction) were the brain areas with significant difference in fALFF values between BD and SC. Compared with SC group, the fALFF values of the left IOG and the right STG in BD group were increased (p < 0.05); (3) Pearson correlation analysis showed that the visuospatial construction score was positively correlated with the fALFF values of the left IOG and the right STG (rleft IOG = 0.304, p = 0.003; rright STG = 0.340, p = 0.001); The delayed memory (figure recall) score was positively correlated with the fALFF value of the left IOG (rleft IOG = 0.207, p = 0.044).Discussion:The cognitive impairment of SC was more serious than BD. The abnormal activities of the left IOG and the right STG may be the core brain region to distinguish BD and SC, and are closely related to cognitive impairment, which provide neuroimaging basis for clinical differential diagnosis and explore the pathological mechanism of cognitive impairment.

Differences in inflammatory marker profiles and cognitive functioning between deficit and nondeficit schizophrenia.

Deficit schizophrenia (DS) patient is a homogenous subtype of schizophrenia that includes primary and enduring negative symptoms. This study aimed to compare the differences in cognitive functioning and plasma levels of C-reactive protein (CRP) and inflammatory cytokines among DS patients, nondeficit schizophrenia (NDS) patients, and healthy controls (HCs). A total of 141 schizophrenia patients and 67 HCs were included in this study. The schizophrenia patients were divided into DS (N= 51) and NDS (N=90) groups based on the Proxy for the Deficit Syndrome Scale (PDS). The Positive and Negative Syndrome Scale (PANSS) and the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) were used to evaluate the clinical symptoms and cognitive performances, respectively. The plasma level of CRP, IL-1β, Il-2, IL-4, IL-6, IL-8, IL-10, IL-12, IL-17, TNF-α, and IFN-γ were measured using enzyme-linked immunosorbent assays (ELISAs). Our results showed that DS patients had the worst cognitive performance, especially in the immediate memory, attention, and language dimensions, compared to the NDS and HC groups. Compared to the HCs group, DS patients had higher levels of CRP, IL-1β, IL-6, IL-8, IFN-γ, and total proinflammatory cytokines, and NDS patients had higher levels of IL-1β, IFN-γ, and proinflammatory cytokines. We also found that CRP levels were significantly increased in DS patients compared to NDS patients. Moreover, stepwise logistic regression analysis revealed that CRP is an independent risk factor for DS. Sex stratification analysis showed significant differences in almost all cytokines in female samples but not in male samples. The significant differences in cognitive performance and inflammatory components among groups suggest that deficit syndrome is an independent endophenotype of schizophrenia patients with unique immune-inflammatory features, but may have sex characteristics.