Impaired Executive Function Research Articles

Executive control training for adolescents with ADHD: Study protocol for a randomised controlled trial

BackgroundAttention-Deficit/Hyperactivity Disorder (ADHD) is one of the most prevalent neurodevelopmental conditions diagnosed during childhood and adolescence. In addition to the commonly observed symptoms of inattention, hyperactivity, and impulsivity, individuals with ADHD often experience impairments in executive functions (EFs). Goal management training (GMT) is a cognitive remediation intervention targeting EFs, with empirical support from studies with adult populations, including ADHD. The objective of the upcoming trial is to assess the effectiveness of GMT for adolescents with ADHD. MethodsThis pre-registered protocol outlines a multi-centre randomised controlled trial (RCT) comparing GMT to treatment as usual (TAU) to improve EFs. We aim to recruit 120 participants, aged 12 to 18 years, recently diagnosed with ADHD. Participants will be randomly allocated to the group-based GMT intervention in addition to TAU, or the TAU condition, through block randomisation with site stratification. GMT will be delivered in groups of four to six participants, with weekly two-hour sessions for seven weeks, complemented by separate parent and teacher sessions. TAU is standard community mental health treatment. The primary outcome measure will be parent-reported EF assessed with the Behaviour Rating Inventory of Executive Function 2 (BRIEF-2). Secondary outcomes will include ADHD symptom measures, social functioning, quality of life, and neuropsychological tests (attention span, inhibition, working memory, and visuo-motor speed). The outcome assessments will be conducted at baseline, 12 weeks, 12 months, and 24 months post-treatment. ConclusionThe study findings will contribute to determine the effectiveness of a non-pharmacological ADHD treatment, including outcome trajectories up to 24 months post-treatment.

Exploring language performance in people with mild cognitive impairment and Alzheimer's disease: a prospective longitudinal study

Background/Aims Language changes are the earliest signs and symptoms of mild cognitive impairment and Alzheimer's disease. The aim of this study was to explore the language difference performance between people with mild cognitive impairment, people with Alzheimer's disease and healthy individuals as a control group. To accomplish this aim, the language profile of both mild cognitive impairment and Alzheimer's disease needs to be characterised to determine which feature is more affected by both mild cognitive impairment and Alzheimer's disease among expressive language, receptive language, executive function and memory performance. Methods This case-control prospective study involved 90 participants. The Mini-Mental Status Examination and the Functional Assessment Staging Tool were used to classify the participants into three groups: people with mild cognitive impairment, people with Alzheimer's disease and healthy individuals as a control group. Then, the language performance of patients in the mild cognitive impairment and Alzheimer's disease groups was investigated and compared with those of the control group by using the Barnes Language Assessment. The groups were reassessed 6 months later to see if there was any change in language ability. Results The results showed that the mild cognitive impairment group and Alzheimer's disease group had significant decreases in expressive language (P>0.01), executive function (P>0.01), receptive language (P>0.01) and memory skills (P>0.01) from baseline to the reassessment at 6 months. Conclusions Language deficits, especially expressive language deficits, could appear before impairment in executive function, receptive language and verbal episodic memory in participants with mild cognitive impairment or Alzheimer's disease. Speech and language therapists can use the findings of this study to design and implement treatment programmes.

Evaluating cognitive phenotypes and associations with neuroimaging biomarkers of dementia in a sample of aging individuals using unsupervised machine learning

AbstractBackgroundOtherwise cognitively normal individuals can experience age‐related cognitive dysfunction and may present with heterogenous patterns of cognitive impairment. There is limited knowledge regarding the presence and stability of cognitive subtypes observed in individuals with mild cognitive impairment and dementia (e.g., dysexecutive, non‐amnestic). Further, the extent to which cognitive subtypes related to age‐ and dementia‐related neuroimaging biomarkers is uncertain.MethodThis study sought to evaluate the presence and composition of cognitive subtypes in a large diverse community sample of aging individuals without dementia (NC; Baseline N = 337; Table 1). Participants enrolled in the Wake Forest ADRC and completed an annual battery of cognitive assessments (Uniform Data Set; NACC), the Mini‐Mental State Exam (MMSE), and Clinical Diagnostic Rating Scale (CDR). Unsupervised machine learning (e.g., clustering: hierarchical, k‐means, and k‐medoids algorithms; 1000 bootstrap iterations; majority voting rule) was applied to the battery of cognitive assessments. Demographic characteristics and neuroimaging measures of amyloid deposition (global PiB PET SUVr; Aβ‐PET), total brain volume (BVOL), diffusion‐weighted fractional anisotropy (FA), and NODDI freewater (FW) were compared across prospective clusters using general linear models. Highly correlated cognitive metrics (r>.85) were removed prior to analysis.ResultCluster analyses using baseline cognitive scores suggested NC participants could be partitioned into two to eight clusters; two primary clusters representing one large homogenous group of relatively unimpaired individuals and another heterogenous cluster composed of 4‐7 possible cognitive subgroups (Figure 1). The two‐cluster solution partitioned NC participants into higher and lower cognitive performers. Across cluster solutions, lower performing individuals were older, had higher Aβ‐PET, and lower total brain volume on average (p<.05; Figure 2).ConclusionWe did not observe well‐defined clusters representing distinct cognitive subtypes reported in previous studies (e.g., dysexecutive, amnestic, visuospatial). However, a heterogenous subset of NC participants exhibited substantial variability across assessments. Three‐ and four‐cluster solutions identified individuals with greater impairment in executive functioning, and verbal learning and memory respectively. Findings highlight the need to model complex patterns of cognitive abilities in otherwise healthy older adults. Future longitudinal work will assess how health information and neuroimaging biomarkers of dementia contribute to the composition and stability of cognitively defined subgroups.

P133: Impairment of Executive Functions in Dialysis Patients. Necessity of Evaluation Cognitive State in Advanced Chronic Kidney Disease

Introduction:Cognitive impairment is common and underdiagnosed in patients in hemodialysis (HD) can be moderate and severe. About 38% of patients in Dialysis has serious deficits in executive function and this affects patients of all ages.Material and methods:Based on the case of an 82-year-old patient in a HD program who enters from Nephrology to the Convalescence Unit for miscontrol of pain due to ganglion and liver recidivism after years of cystectomy by bladder neoplasia and having acute confusional syndrome (ACS) subsequently presented after treatmet with morphine MST and Tramadol. We performed an integral geriatric evaluation that showed a deterioration of the executive functions. Through medical literature we analyze this find of atypical pattern and its possible relationship to renal disease.Results:BI 100/100. No known history of cognitive impairment. Despite optimal pain control with fentanyl patch, pregabalin, paracetamol, metamizol and dexamethasone, without new episodes of ACS, we saw high difficulties in comprehension time schedule, spatial location, bad understanding of medical treatment, etc. Neuropsychological study showed MMSE 24/30; SKT subtest of immediate memory 1/12, null recognition without understanding the task. Memory Imparily Screen 5/8, Test clock 3/7. In summary there were deficits in executive functions such as complex attention, mental control, fluency and reasoning. Fluctuating memory abilities. Mild multiple cognitive impairment executive domain. Atypical Profile.Conclusions:There is a strong correlation between the decrease in GF and the degree of cognitive impairment. This worsens with the Dialysis due to hemodynamic changes. It is essential to evaluate the cognitive situation in all patients with CKD. Being the most affected cognitive domain, the function executive,it can avoid in these patients the correct assesment of established medications and dietary restrictions that are so important in the control of potassium, phosphorus and liquids that cause greater complications and even more mortality.

Mild cognitive impairment in novel SPG4/SPAST mutation‐related sporadic late onset hereditary spastic paraplegia: case series

AbstractBackgroundMutations and deletions in the SPG4/SPAST gene cause for up to 50% of the autosomal dominant forms of hereditary spastic paraplegia (HSP) and for up to 15% of the sporadic cases. Affected individuals have pyramidal signs in the lower limbs and some present additional features. Cognitive impairment is common in late‐onset forms of HSPs.MethodsThis study examined the cognitive abilities of 20 sporadic late‐onset patients with HSP using next‐generation sequencing. We also used a combination of the Mini‐Mental State Examination (MMSE) and the Montreal Cognitive Assessment (MoCA) to assess their cognition.ResultsThe present study led to the discovery of three new pathogenic mutations of the SPG4 gene through evolutionary conservation and analysis of structural models. We also confirmed mild cognitive impairment (MCI) with normal MMSE scores (≥27) and reduced MoCA scores (<26) in these HSP‐SPG4 mutant patients. Such individuals mainly present with impaired executive function, delayed memory, abstraction and language.ConclusionsThe results broaden the mutational space of SPG4‐associated HSP with sporadic late‐onset modality and indicate a combination of reduced MoCA and normal MMSE for diagnosis, indicating that clinicians should consider performing a MoCA to detect MCI in patients with HSP, particularly those with sporadic onset SPG4/SPAST‐HSP.

Low-dose PLX5622 treatment prevents neuroinflammatory and neurocognitive sequelae after sepsis

BackgroundSepsis-associated encephalopathy (SAE) is characterized by symptoms of delirium including hallucinations, impaired concentration, agitation, or coma and is associated with poor outcome in the early phase of sepsis. In addition, sepsis survivors often suffer from persisting memory deficits and impaired executive functions. Recent studies provide evidence that microglia are involved in the pathophysiology of SAE.MethodsHere, we investigated whether pharmacological depletion of microglia using PLX5622 (1200 ppm or 300 ppm) in the acute phase of sepsis is able to prevent long-term neurocognitive decline in a male mouse model of polymicrobial sepsis or lipopolysaccharide-induced sterile neuroinflammation. Therefore, we performed the novel object recognition test at different time points after sepsis to address hippocampus-dependent learning. To further assess synapse engulfment in microglia, colocalization analysis was performed using high-resolution 3D Airyscan imaging of Iba1 and Homer1. We also investigated the effect of PLX5622 on acute astrocyte and chronic microglia proliferation in the hippocampus after sepsis induction using immunofluorescence staining.ResultsHigh-dose application of the colony stimulating factor 1 receptor (CSF1R) inhibitor PLX5622 (1200 ppm) seven days prior to sepsis induction lead to 70–80% microglia reduction but resulted in fatal outcome of bacterial sepsis or LPS induced inflammation. This is likely caused by severely compromised host immune response upon PLX5622-induced depletion of peripheral monocytes and macrophages. We therefore tested partial microglia depletion using a low-dose of PLX5622 (300 ppm) for seven days prior to sepsis which resulted in an increased survival in comparison to littermates subjected to high-dose CSF1R inhibiton and to a stable microglia reduction of ~ 40%. This partial microglia depletion in the acute stage of sepsis largely prevented the engulfment and microglia-induced stripping of postsynaptic terminals. In addition, PLX5622 low-dose microglia depletion attenuated acute astrogliosis as well as long-term microgliosis and prevented long-term neurocognitive decline after experimental sepsis.ConclusionsWe conclude that partial microglia depletion before the induction of sepsis may be sufficient to attenuate long-term neurocognitive dysfunction. Application of PLX5622 (300 ppm) acts by reducing microglia-induced synaptic attachement/engulfment and preventing chronic microgliosis.

Novel quantitative method for characterization of hippocampal sclerosis and its association with other neuropathologies and cognitive deficits

AbstractBackgroundHippocampal sclerosis of aging (HS) is characterized by neuronal loss and astrogliosis in subiculum and/or CA1 subfield of hippocampus. Using a novel quantitative approach, we studied the prevalence and localization of HS pathology in a well‐characterized oldest‐old cohort and examined its association with other neuropathologic changes and cognitive impairment.MethodsWe studied 409 consecutive autopsied participants of The 90+ Study with longitudinal assessments. In those with HS by traditional method (presence/absence), we used digitized hematoxylin and eosin and luxol fast blue hippocampal slides for further quantitative analysis. Using QuPath, we measured the length of each hippocampal subfield partitioned into three subregions (Figure1). We then calculated the proportion affected by HS for each subregion. Both traditional (presence/absence) and quantitative (subfield‐specific proportions) measures were used to study the relationship between HS and other neuropathologic changes and cognitive outcomes using regression models adjusted for sex, age at death, and education with all neuropathologic changes as covariates.ResultsHS was present in 11% of participants and was always focal, mostly affecting CA1 (89%), followed by subiculum (27%). Overlapping CA1/subiculum pathology was seen in 16% (Figure2). Left‐sided HS was more frequent (75%) than right‐sided (18%). Bilateral cases were the least frequent (7%). HS presence (traditional measure) was only associated with Limbic‐predominant age‐related TDP‐43 encephalopathy (LATE) (OR = 3.45, p<0.001). Quantitative measures revealed that HS proportion in subiculum and CA1 was associated with arteriolosclerosis (t36 = 4.11, p = 0.001) and LATE (t35 = 2.98, p = 0.005). HS proportion in subiculum alone was inversely associated with microvascular lesions (t41 = ‐3.16, p = 0.003) (Table1). HS proportion in subiculum and CA1 was associated with dementia at death and impairment of memory, language, calculation, and orientation. HS proportion in subiculum was additionally associated with impaired executive function. HS traditional measure was only associated with impaired orientation (Table1).ConclusionBased on our novel quantitative analysis, HS pathology was always focal, mostly unilateral, and associated with dementia and impairment in major cognitive domains. We found associations between HS and vascular pathologies that were not detected using traditional measure. The associations of HS with dementia and impaired memory, language, and calculation, identified with our quantitative method, were not detected using traditional measure.

Cell‐Based Genetic Subtypes Predict Neuroimaging Biomarkers and Clinical Conversion to Alzheimer’s Disease

AbstractBackgroundThe complex etiology and slow progression of AD have complicated efforts to establish robust patient subtypes resulting in high attrition rates among late‐stage clinical trials. We developed a novel procedure to stratify at risk individuals to develop AD using network‐based polygenic risk scores from brain cell‐type specific transcriptome signatures.MethodWe previously computed cell‐based polygenic risk scores (cbPRSs) in the Alzheimer’s Disease Neuroimaging Initiative (Sahelijo et al. 2022). Recently, we computed cbPRSs in 8,481 Framingham Heart Study (FHS) participants using the same genetic markers used in ADNI. We defined low‐ and high‐risk genetic subtypes using the first and the fourth quartiles of the cbPRS distributions, respectively. We conducted association tests with domain specific cognitive tests and neuroimaging biomarkers using subtype risk status as a binary outcome in cognitively normal (CN), mild cognitive impairment (MCI), AD, and all subjects from ADNI. We compared conversion rates from CN and MCI to AD between subtypes using a Cox proportional hazard regression in ADNI and FHS. Using brain‐wide gray matter volume maps with voxel‐based morphometry we compared brain atrophy patterns between subtypes in ADNI corrected for multiple comparisons using Standard FDR at q = 0.05.ResultGenetic subtypes for astrocytes (Ast‐M2) and oligodendrocytes (Oli‐M45) showed significant association with memory and executive function impairment, decreased hippocampal volume, increased amyloid deposition, and decreased glucose metabolism using all subjects from ADNI (P<1.39E‐3). These associations for memory impairment, global amyloid deposition, and decreased glucose metabolism remained significant only in MCI subjects (best P<7.23E‐09). Conversion rates for Ast‐M2 and Oli‐M45 genetic subtypes were significantly different in both ADNI (P<8.67E‐5) and FHS (P<3.90E‐9). These differential conversion rates for Ast‐M2 and Oli‐M45 in FHS were not fully explained by presence of APOE ɛ4 allele (P<0.05 in ɛ4 non‐carriers). Voxel‐wise whole brain analysis identified significant atrophy in bilateral hippocampi, entorhinal cortex, and amygdala for Ast‐M2 (P = 0.0007) and Oli‐M45 (P = 0.001).ConclusionWe demonstrate that polygenic risk scores informed by cell type specific brain transcriptomic networks can stratify at risk subjects with AD related changes in imaging biomarkers and higher chance of progression to AD. These findings provide insight into early detection of cell‐type specific at‐risk individuals for AD.

Characterization of a R493X progranulin haploinsufficient knockin mouse model of frontotemporal dementia

AbstractBackgroundFrontotemporal dementia (FTD) is the second most common form of dementia in young individuals, characterized by impairments in social cognition, language processing and executive function. Heterozygous loss‐of‐function mutations in the progranulin gene (GRN) are well known as a major genetic cause of a TDP‐43‐positive subtype of FTD (FTD‐GRN). The role of progranulin in the pathogenesis of FTD is not fully understood but has been shown to be associated with lysosomal dysfunction, impaired neuronal survival, and neuroinflammation. Rodent models of FTD‐GRN have been extensively used to model disease pathophysiology, but most studies utilize mice null for GRN. Our lab recently published a comprehensive neuropathological and behavioural assessment of a GRN R493X homozygous mouse model, confirming several phenotypes relevant to human FTD.To our knowledge, haploinsufficient R493X mice have not previously been studied. Here we assessed whether haploinsufficient GRN 493X mice would demonstrate relevant phenotypes for FTD pathophysiologic studies and drug screening.MethodWe characterized behavioural and neuropathological phenotypes of aged GRN R493X+/‐, GRN R493X‐/‐ and age‐matched C57BL/6J wildtype mice. The open‐field test was used to assess anxiety phenotype. Brain lysosomal dysfunction was assessed by western blot, and neuroinflammation, including astrogliosis and microgliosis, as well as hippocampal and thalamic synaptic dysfunction were analyzed by immunohistochemistry.ResultAs expected, our preliminary data show a higher progranulin level in GRN R493X+/‐ mice in comparison with the homozygous GRN R493X mice. Behavioural data, as well as analysis of neuroinflammation, lysosomal dysfunction and brain excitatory and inhibitory synaptic function, are being analyzed and will be presented.ConclusionHeterozygous GRN R493X mice more closely resemble the human genetic condition. Our characterization and comparison of neuropathologic phenotypes in aged GRN R493X+/‐ and GRN R493X‐/‐ mice provide insights into the molecular mechanisms underlying the effects of GRN haploinsufficiency and the suitability of this model for drug screening studies in FTD‐GRN.

Proteome Analysis in Plasma and Brain Reveals a Novel Plasma Biomarker Linked to Antemortem Cognitive Impairment and Postmortem Neuropathological Traits for Alzheimer Disease

AbstractBackgroundIdentification of blood‐based biomarkers that are indicative of Alzheimer’s disease (AD) pathology may help with early detection.MethodsWe generated proteome data for ∼7,000 proteins in both antemortem plasma and postmortem brain tissue from 103 participants of the Boston University Alzheimer’s Disease Research Center. All participants completed comprehensive neuropsychological evaluations and dementia severity was measured by global cognitive dementia rating (CDR) scores. A pathological AD diagnosis was established using NIA Reagan criteria. We conducted association tests with dementia (i.e., CDR ≥1 for dementia, CDR <1 for control) and autopsy‐confirmed AD status as binary outcomes. Plasma proteins significantly associated with clinical or pathological AD (P<0.05) were tested for association with quantitative cognitive tests and AD‐related neuropathological traits in which outcomes were rank‐transformed after adjusting for sex and either age at last antemortem exam or death.ResultsOf the 103 brain donors, 43 were diagnosed with dementia and 55 had autopsy‐confirmed AD. Five proteins (ACES, AURKB, CBARP, G45IP, and MMP‐8) measured in plasma were significantly associated with both pathological AD and dementia, while 252 plasma proteins were associated with either diagnosis (P<0.05). MMP‐8 was the only protein that was significantly associated in both plasma and brain with autopsy‐confirmed AD (Pplasma = 0.005, Pbrain = 0.001) and dementia (Pplasma = 0.01, Pbrain = 9×10−5). ACES and AURKB levels in plasma and brain were significantly associated with dementia (P<0.05). Levels of these. Increased MMP‐8 level in plasma was associated with decreased animals (P = 0.03) and scores (P = 0.04), which both assess verbal fluency. Dementia and pathologically confirmed AD were associated with lower AURKB and elevated ACES levels in plasma. Decreased plasma ACES level was associated with executive function (TrailsB: P = 0.01) and language (Boston Naming Test: P = 0.02) impairment, and the reduced plasma AURKB level was associated with memory impairment (Logical Memory Immediate Recall score: P = 0.03).ConclusionMMP‐8, a neutrophil collagenase and member of the matrix metalloproteinase family, is a potential blood‐based biomarker for dementia and underlying AD pathology and is associated predominantly with impaired verbal fluency.

Sporadic behavioral phenotype of Right Temporal Variant of Frontotemporal Dementia: a case report

AbstractBackgroundThere are two subtypes of the right Temporal Variant of Frontotemporal Dementia (rtv‐FTD). Semantic dementia (SMD) phenotype is defined by negative familiar history, word‐finding, anomia, comprehension difficulties, prosopagnosia, and topographagnosia. The behavioral frontotemporal dementia (bvFTD) phenotype is defined by personality changes, inappropriate behaviors, positive family history, and relatively poor performance on neurobehavioral testing with better performance on confrontational naming tests. (1) We present a rare interesting case.MethodWe describe the clinical and imaging features of a man who presented a sporadic behavioral phenotype of rtv‐FTD, showing negative genetic results.ResultA 62‐year‐old man with 8 years of progressive behavioral impairment. He showed personality changes, and compulsive‐like / ritualistic behaviors such as excessive unpurposed accumulation of items, washing hands repeatedly every five minutes, and walking and wandering repeatedly in circles. He also had hiperorality, cravings for sweet foods, social cognition impairment, associated with loss of empathy, and inappropriate social behavior (hypersexuality, verbal aggressivity to unrelated people, and talking bad words to neighbors with no reason). After years he followed with mild to moderate apathy. The neuropsychological evaluation showed impairment of executive functioning, episodic memory impairment, and MMSE 19/30. The neurological exam was unremarkable, and the familiar history was negative. Brain MRI revealed frontotemporal atrophy with a marked asymmetry in the right temporal lobe. The genetic testing was negative, illustrating and sporadic case.ConclusionTheoretically, rtv‐FTD is considered a right variant of semantic phenotype, and the general assumption is that is also a sporadic disorder. Although the behavioral phenotype of rtv‐FTD normally has a genetic basis, showing positive family history, It can be presented as a sporadic disorder with non‐familial variants of FTD, as in this case. (2)

Slowly progressive Right Temporal Variant of Frontotemporal Dementia with ALS2 mutation: A case report

AbstractBackgroundBehavioral variant frontotemporal dementia (bvFTD) is a neurodegenerative disorder characterized by behavioral and personality changes. Findings show variation in the disease progression. Some patients show a rapid progression over a few years, and others show little or no changes over a decade (1) Mutations in the amyotrophic lateral sclerosis 2 (ALS2) gene cause autosomal recessive motor neuron diseases, including juvenile‐onset amyotrophic lateral sclerosis (JALS), and other associated disorders. (2) We present a rare case.MethodWe describe the clinical and imaging features of a man who presented a rare case of Slowly progressive Right Temporal Variant of Frontotemporal Dementia with ALS2 mutation.ResultA 63‐year‐old man presented a 10‐year history of insidious and slowly progressive behavioral changes. He showed reduced emotional responsiveness, with no concern since his wife had received a diagnosis of a malignancy. He followed with disinhibition, and impulsive actions such as excessive shopping with no payment, overspending, and socially inappropriate behavior. He also had a compulsive/ritualized behavior with stereotyped speech, and counting repeatedly steps. His medical family history was unremarkable. The neuropsychological evaluation showed impairment of executive functioning, MMSE 27/30. Neurological examination was normal. Brain MRI frontotemporal atrophy with a marked asymmetry in the right temporal lobe in sagittal, axial, and coronal sequences. CSF biomarkers showed elevated t‐tau with no other changes, and the genetic test showed an ALS2 heterozygous mutation., also counting repeatedly steps.ConclusionThe presence of the C9ORF72 mutation has been shown in slowly progressive FTD, however, other mutations such as ALS2 have not yet been reported with the following phenotype, as in this case (3)

Metabolic Syndrome‐Associated Oligodendrocyte Dysfunction and Cognitive Impairment

AbstractBackgroundOne in nine people aged 65 and older in the United States suffer from cognitive decline, including dementias such as Alzheimer’s disease (AD) and AD‐related Dementias (ADRD). A major risk factor for cognitive impairment is midlife metabolic syndrome (MetS). MetS‐associated cognitive impairment progresses in a non‐cell autonomous manner and implicates a breakdown in metabolic support. This breakdown in metabolic support is likely due to disruption of metabolic crosstalk between neurons and glia, especially oligodendrocytes. Our aim was therefore to elucidate midlife MetS effects on oligodendrocytes and subsequent impact on oligodendrocyte metabolism and cognition.MethodTo accomplish this aim, middle‐aged mice (12‐month old) were fed either standard diet (SD, 10% fat) or high‐fat diet (HFD, 60% fat) for 13 weeks, followed by full assessment of metabolic parameters and cognitive function. Oligodendrocytes were then isolated for single cell RNA‐sequencing (scRNA‐seq), and protein expression of monocarboxylate transporters (MCTs).ResultWe observed that, as expected, HFD mice gained more weight and had higher blood glucose and fat mass versus SD controls. Middle‐aged HFD mice also performed worse in puzzle box and social recognition tests, reflecting impaired executive function and impaired short‐ and long‐term memory responses. scRNA‐seq analysis identified multiple oligodendrocyte clusters. One cluster of interest contained genes involved in cognition (Fam171a2, Nrsn1, Dlgap4) and metabolism (Ldhb, Slc25a5, Cox7c, Cox17), which were differentially expressed in HFD versus SD mice. This was coupled with downregulated MCT1 protein expression in HFD mouse oligodendrocytes versus oligodendrocytes from their SD counterparts. In vitro, human oligodendrocytes treated with palmitate to mimic MetS developed insulin resistance and had downregulated MCT1 protein expression.ConclusionCollectively, these results suggest that midlife MetS impairs oligodendrocyte metabolic function, suggesting a novel mechanism underlying MetS‐associated cognitive impairment.

Maternal major depression during early pregnancy is associated with impaired child executive functioning at 4.5 years of age

BackgroundMaternal depression is a serious condition that effects up to 1 in 7 pregnancies. Despite evidence linking maternal depression to pregnancy complications and adverse fetal outcomes, there remain significant gaps in its identification and treatment. More work is needed to define the specific timing and severity of depression that most urgently requires intervention, where feasible, to protect maternal health and the developing fetus. ObjectiveTo examine whether the timing and severity of maternal depression and/or anxiety during pregnancy effects child executive functioning at age 4.5 years. Executive functioning in the pre-school years is a strong predictor of both school readiness and long term quality of life. Study DesignThis longitudinal observational pregnancy cohort study included a sample of 323 mother-child dyads taking part in the Ontario Birth Study, an open pregnancy cohort in Toronto, Ontario, Canada. Maternal symptoms of depression and anxiety were assessed at 12-16 and 28-32 weeks of pregnancy, and at the time of child testing at age 4.5 years, using the 4-item Patient Health Questionnaire. Child executive functioning was measured during a home visit using standardized computerized administration of the Flanker test (a measure of attention) and the Dimensional Change Card Sort (a measure of cognitive flexibility). Stepwise linear regressions, controlling for possible confounding variables, were used to assess the predictive value of continuous measures of maternal depression and/or anxiety symptoms at each assessment time on the Flanker and Dimensional Change Card Sort. Post-hoc general linear models assessed whether maternal depression severity categories (no symptoms, mild symptoms, probable major depressive disorder) were helpful in identifying children-at-risk. ResultsAcross all children, after controlling for potential confounds, greater maternal depressive symptoms at weeks 12-16 of pregnancy predicted worse performance on both the Flanker test (ΔR2=0.058, p < .001) and the Dimensional Change Card Sort (ΔR2 = 0.017, p = 0.018). Post-hoc general linear modelling further demonstrated that the children of mothers meeting screening criteria for major depression in early pregnancy scored 11.3 % lower on the Flanker test, and 9.8 % lower on the Dimensional Change Card Sort, than did children exposed to no maternal depressive symptoms in early pregnancy. Mild depressive symptoms had no significant effect on executive function scores. There was no significant effect of anxiety symptoms or maternal anti-depressant use in early pregnancy, nor of pandemic conditions or maternal symptoms in later pregnancy or at the time of child testing on either the Flanker or Dimensional Change Card Sort results. ConclusionThis is the first study to demonstrate that during weeks 12-16 of pregnancy, fetal exposure to maternal major depression, but not milder forms of depression, associates with impaired executive functioning in the pre-school years. Child executive functioning is critical for school readiness and predicts long-term quality of life. This emphasizes an urgent need to improve the recognition and treatment of maternal major depression, particularly in early pregnancy, to limit its negative effects on the patient and on child cognitive development.

REM Sleep Behavior Disorder and Cognitive Functions in Parkinson’s Patients: A Systematic Review

Sleep disorders, such as REM sleep behavior disorder (RBD) and excessive daytime sleepiness, are among the most common non-motor symptoms in subjects with Parkinson’s disease (PD). Sleep disorders have a major negative impact on the quality of life of patients and their caregivers. In addition, REM sleep behavior disorder is an important risk factor for cognitive impairment in PD. This systematic review was conducted on studies investigating the influence of RBD on cognitive performance in PD subjects. We searched the PubMed and Scopus databases, screened the references of the studies included, and reviewed articles for additional citations. From the first 244 publications, we included only 11 studies that met the search criteria. The results showed that sleep disorders in PD were associated with impaired executive functions, visual-constructive abilities, reduced attention, and episodic verbal memory, and could predict the possible risk of developing dementia.

Mind, brain and education: neuropsychological contributions to executive function training in the classroom with students with ADHD

Attention Deficit Hyperactivity Disorder (ADHD) is one of the neurodevelopmental disorders with the highest incidence in children and adolescents. With multifactorial characteristics, ADHD leads to impairments in executive functioning, for example, in skills related to Executive Functions (EFs) such as behavior control, sustaining attention and mastering activity levels or impulses, usually leading to impairments in learning. The aim of this article was to carry out a literature review as a contribution of neuropsychology to training EFs in the classroom with students with ADHD. An exploratory study was carried out, followed by descriptive or experimental research. Searches were carried out in the Scientific Electronic Library Online (SCIELO), Biblioteca Virtual em Saúde-Psicologia Brasil (BVSPSI), Periódicos Eletrônicos de Psicologia (PEPSIC) databases, in the journals available in the Brazilian Digital Library of Theses and Dissertations (BDTD), in PUBMED and in textbooks. Covering publications from 2017 to 2023, 8 articles were selected for analysis. The bibliographic survey showed the importance of studies on ADHD related to EFs, and it is important for teachers to stimulate these functions, as studies have shown that they have minimized the impact on learning deficits in students with ADHD, and that they can consequently bring about better emotional regulation. This review provided evidence showing that EF training improves executive functioning, reducing ADHD symptoms and leading to improvements in academic functioning. It is suggested that further empirical research into EF intervention by educators for students with ADHD with greater breadth and sampling needs to be carried out.

Association of genetic and sulcal traits with executive function in congenital heart disease.

Persons with congenital heart disease (CHD) are at increased risk of neurodevelopmental disabilities, including impairments to executive function. Sulcal pattern features correlate with executive function in adolescents with single-ventricle heart disease and tetralogy of Fallot. However, the interaction of sulcal pattern features with genetic and participant factors in predicting executive dysfunction is unknown. We studied sulcal pattern features, participant factors, and genetic risk for executive function impairment in a cohort with multiple CHD types using stepwise linear regression and machine learning. Genetic factors, including predicted damaging de novo or rare inherited variants in neurodevelopmental disabilitiesrisk genes, apolipoprotein E genotype, and principal components of sulcal pattern features were associated with executive function measures after adjusting for age at testing, sex, mother's education, and biventricular versus single-ventricle CHD in a linear regression model. Using regression trees and bootstrap validation, younger participant age and larger alterations in sulcal pattern features were consistently identified as important predictors of decreased cognitive flexibility with left hemisphere graph topology often selected as the most important predictor. Inclusion of both sulcal pattern and genetic factors improved model fit compared to either alone. We conclude that sulcal measures remain important predictors of cognitive flexibility, and the model predicting executive outcomes is improved by inclusion of potential genetic sources of neurodevelopmental risk. If confirmed, measures of sulcal patterning may serve as early imaging biomarkers to identify those at heightened risk for future neurodevelopmental disabilities.

Immune proteins C1q and CD47 may contribute to aberrant microglia-mediated synapse loss in the aging monkey brain that is associated with cognitive impairment.

Cognitive impairment in learning, memory, and executive function occurs in normal aging even in the absence of Alzheimer's disease (AD). While neurons do not degenerate in humans or monkeys free of AD, there are structural changes including synapse loss and dendritic atrophy, especially in the dorsolateral prefrontal cortex (dlPFC), and these correlate with cognitive age-related impairment. Developmental studies revealed activity-dependent neuronal properties that lead to synapse remodeling by microglia. Microglia-mediated phagocytosis that may eliminate synapses is regulated by immune "eat me" and "don't eat me" signaling proteins in an activity-dependent manner, so that less active synapses are eliminated. Whether this process contributes to age-related synapse loss remains unknown. The present study used a rhesus monkey model of normal aging to investigate the balance between the "eat me" signal, complement component C1q, and the "don't eat me" signal, transmembrane glycoprotein CD47, relative to age-related synapse loss in dlPFC Area 46. Results showed an age-related elevation of C1q and reduction of CD47 at PSD95+ synapses that is associated with cognitive impairment. Additionally, reduced neuronal CD47 RNA expression was found, indicating that aged neurons were less able to produce the protective signal CD47. Interestingly, microglia do not show the hypertrophic morphology indicative of phagocytic activity. These findings suggest that in the aging brain, changes in the balance of immunologic proteins give microglia instructions favoring synapse elimination of less active synapses, but this may occur by a process other than classic phagocytosis such as trogocytosis.

An Evaluation of the Use of the Child and Adolescent Scale of Participation (CASP) to Measure Social Participation After Pediatric ABI in a Specialist Service in East Anglia

ABSTRACT Pediatric acquired brain injury (ABI) can lead to lifelong challenges restricting social participation, which is an important goal for rehabilitation due to associations with improved wellbeing. This evaluation considered the utility of the Child Adolescent Scale of Participation (CASP) in ABI rehabilitation services. The 20-item measure is rated on a Likert scale with reference to what the rater would expect of their child at that age, including ”not applicable” (N/A). It showed high internal consistency (α = 0.954–0.968). Two-step cluster analysis indicated greater difficulties in children with lower participation, including more impairments of executive function and higher staff involvement. Between-group analysis indicated higher rates of N/A answers for younger children and those of ethnic minorities. Overall, the CASP is reliable and clinically useful on an individual level, helping identify people who may need prioritizing for neurorehabilitation; however, group-level analyses were more challenging due to high frequency of N/A responses.

Do ADHD and SLD children differ in executive functions and behavioural problems? A comparative study

AbstractIt is well‐known that children with attention‐deficit/hyperactivity disorder (ADHD) and specific learning disorder (SLD) often exhibit behavioural and emotional problems. However, little is known about how these problems compare between the two groups of children. This study sought to fill this gap in knowledge by comparing the executive functions and behavioural–emotional problems of children with ADHD, SLD and typically developing children. For this study, 94 children were recruited through purposeful sampling (ADHD = 23, SLD = 30 and TD = 41). All participants were screened based on WISC‐IV. Subsequently, participants were administered executive functions and behavioural problems questionnaires. The analysis of the data using MANOVA and Scheffe post hoc pairwise shows that children with ADHD and SLD had significantly higher scores on measures of executive function impairment than typically developing children. Our study revealed that children in the ADHD group scored significantly higher in social problems, aggressive behaviours, AD/HD problems, ODD, conduct problems and externalizing problems sub‐tests. Conversely, the LD group demonstrated higher scores in the anxiety problems sub‐test. Furthermore, Our study demonstrated that children in the ADHD group scored significantly higher in the following sub‐tests: metacognition, inhibit, shift, bri, shift and emotion control. In contrast, the LD group exhibited higher scores in the initiate sub‐test. In addition, the two groups of children with disorders also exhibited more behavioural–emotional problems than typically developing children. These findings suggest that ADHD and SLD are associated with impaired executive function and increased behavioural–emotional problems. These findings have implications for the assessment and treatment of these disorders.