Executive, language and fluency dysfunction are markers of localised TDP-43 cerebral pathology in non-demented ALS

ObjectiveApproximately 35% of patients with amyotrophic lateral sclerosis (ALS) exhibit mild cognitive deficits in executive functions, language and fluency, without dementia. The precise pathology of these extramotor symptoms has remained unknown. This study aimed to determine the pathological correlate of cognitive impairment in patients with non-demented ALS.MethodsIn-depth neuropathological analysis of 27 patients with non-demented ALS who had undergone cognitive testing (Edinburgh Cognitive and Behaviour ALS Screen (ECAS)) during life. Analysis involved assessing 43 kDa Tar-DNA binding protein (TDP-43) accumulation in brain regions specifically involved in executive functions, language functions and verbal fluency to ascertain whether functional deficits would relate to a specific regional distribution of pathology.ResultsAll patients with cognitive impairment had TDP-43 pathology in extramotor brain regions (positive predictive value of 100%). The ECAS also predicted TDP-43 pathology with 100% specificity in brain regions associated with executive, language and fluency domains. We also detected a subgroup with no cognitive dysfunction, despite having substantial TDP-43 pathology, so called mismatch cases.ConclusionsCognitive impairment as detected by the ECAS is a valid predictor of TDP-43 pathology in non-demented ALS. The profile of mild cognitive deficits specifically predicts regional cerebral involvement. These findings highlight the utility of the ECAS in accurately assessing the pathological burden of disease.

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Abstract 220: Comparison of 3 Cognitive Exams in Cardiac Arrest Survivors

Circulation ◽

10.1161/circ.130.suppl_2.220 ◽

2014 ◽

Vol 130 (suppl_2) ◽

Author(s):

Allison Koller ◽

Jon Rittenberger ◽

Patrick Morgan ◽

Melissa Repine ◽

Jeffrey Kristan ◽

...

Keyword(s):

Cardiac Arrest ◽

Cognitive Impairment ◽

Cognitive Deficits ◽

Cognitive Testing ◽

Percentile Score ◽

Pairwise Correlations ◽

The Mean ◽

Highly Correlated ◽

Alpha Error

Background: Cognitive deficits may detract from quality of life after cardiac arrest (CA). The pattern and prevalence of these deficits are not well documented. We used the Computer Assessment of Mild Cognitive Impairment (CAMCI), the Montreal Cognitive Assessment (MOCA) and the 41 Cent Test to assess cognitive impairment in survivors of CA. We hypothesized that CAMCI subscales and other scores that were highly correlated could identify specific domains of impairment in CA survivors. Methods: Four researchers administered the CAMCI, MOCA, and/or the 41 Cent Test to CA survivors after discharge from the intensive care unit between 2010 and 2014. Physicians screened patients with the Mini-Mental State Exam to determine when this cognitive testing was feasible. We compared the distribution of scores between patients who presented with coma and those who awoke immediately after CA. Pairwise correlations between the different subscales and tests were considered significant with alpha error of 0.05. Results: Ninety-two participants completed the CAMCI, of which 18 participants completed the CAMCI, MOCA and 41 Cent Test. The mean (SD) percentile score for CAMCI was 32.2 (20.3) out of possible 100, for the MOCA was 20.3 (5.2) out of a possible 30 points and the 41 Cent Test was 5.4 (1.1) out of a possible 7 points. MOCA correlated strongly with the overall CAMCI score (r = 0.82) and with the executive accuracy subscale of the CAMCI (r = 0.75). The executive accuracy subscale and overall CAMCI score correlated with one another (r = 0.81) when all 92 CAMCI exams were considered. The MOCA and 41 Cent Test were correlated with each other (r = 0.63). Conclusion: The CAMCI detects cognitive impairment after CA; the MOCA correlates strongly with the overall CAMCI and the executive function subscale of the CAMCI. The 41 Cent Test may not be as effective as the MOCA in detecting cognitive deficits.

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Neuropathology of Speech Network Distinguishes Bulbar From Nonbulbar Amyotrophic Lateral Sclerosis

Journal of Neuropathology & Experimental Neurology ◽

10.1093/jnen/nlz130 ◽

2019 ◽

Vol 79 (3) ◽

pp. 284-295

Author(s):

Sanjana Shellikeri ◽

Julia Keith ◽

Sandra E Black ◽

Lorne Zinman ◽

Yana Yunusova

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Dna Binding ◽

Cognitive Deficits ◽

Regional Distribution ◽

Neuronal Loss ◽

Dna Binding Protein ◽

Motor Functions ◽

Bulbar Symptoms ◽

Bulbar Onset ◽

Lateral Sclerosis

Abstract Bulbar amyotrophic lateral sclerosis (ALS) is a debilitating neurodegenerative subtype affecting speech and swallowing motor functions as well as associated with the burden of cognitive deficits. The neuroanatomical underpinnings of bulbar ALS are not well understood. The aim of this study was to compare neuropathology of the speech network (SpN) between 3 cases of bulbar-onset ALS (bALS), 3 cases of spinal-onset ALS (sALS) with antemortem bulbar ALS (sALSwB) against 3 sALS without antemortem bulbar ALS (sALSnoB) and 3 controls. Regional distribution and severity of neuronal loss, TDP-43 (transactive response DNA-binding protein of 43 kDa), and tau proteinopathy were examined. All 3 bALS cases showed marked neuronal loss and severe proteinopathy across most SpN regions; sALSwB cases showed no neuronal loss but mild and variable TDP-43 pathology in focal regions; sALSnoB cases demonstrated an absence of pathology. Two bALS cases had coexisting tauopathy in SpN regions, which was not noted in any sALS cases. The findings suggested that bALS may have a distinct neuropathological signature characterized by marked neuronal loss and polypathology in the SpN. Milder TDP-43 pathology in the SpN for sALSwB cases suggested a link between severity of bulbar ALS and SpN damage. Findings support a clinicopathologic link between bulbar symptoms and pathology in the SpN.

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207 - Cognitive deficits in specific settings: challenges for the assessment and disease management

International Psychogeriatrics ◽

10.1017/s1041610220001970 ◽

2020 ◽

Vol 32 (S1) ◽

pp. 45-47

Keyword(s):

Older Adults ◽

Mental Illness ◽

Cognitive Impairment ◽

Cognitive Deficits ◽

Cognitive Assessment ◽

Cognitive Testing ◽

Geriatric Syndrome ◽

Clinical Scenarios ◽

Status Assessment ◽

Global Population

General synopsis of the Symposium: Cognitive impairment is an important geriatric syndrome. As the global population ages exponentially, the prevalence of cognitive impairment and dementia is increasing, and mental status assessment is key in the evaluation of older adults. However, there are several pitfalls during cognitive testing and special clinical situations that demands a more in-depth knowledge and attention from the examiner. The overall objective of this symposium is to show strategies and particularities of cognitive assessment in different settings (in the clinic, inside the hospital) and clinical scenarios (early onset impairment, mental illness comorbidity).

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Cognitive function in elderly patients with Chronic Kidney disease

QJM ◽

10.1093/qjmed/hcab098.003 ◽

2021 ◽

Vol 114 (Supplement_1) ◽

Author(s):

Yumna A Elgazzar ◽

Ramy M Mahmoud ◽

Heba Y Kamel ◽

Tomader T Abdel Rahman ◽

Hala S Sweed

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Chronic Kidney Disease ◽

Cognitive Impairment ◽

Cognitive Function ◽

Kidney Disease ◽

Elderly Patients ◽

Executive Functions ◽

Neuropsychological Battery ◽

Language Functions

Abstract Background Many elderly patients with Chronic Kidney disease (CKD) develop cognitive impairment and dementia. Cognitive impairment impacts CKD patients negatively by functional dependence and recurrent hospitalization. The Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) neuropsychological battery was originally developed to identify early Alzheimer’s disease, but it has become a widely used instrument to assess different levels & domains of cognitive and executive functions. Aim the aim of the study was to assess cognitive function in elderly patients with CKD. Patients and Methods one hundred CKD patients were recruited from outpatient clinics of Ain Shams University hospital. CERAD neuropsychological battery was used to measure cognitive functions in different domains (language functions, verbal learning, visuospatial functions, delayed recall, memory consolidation, recognition memory, and executive functions). Results CKD patients had low mean verbal fluency and mean MMSE while language functions score hadn’t been affected. There was a significant positive correlation (p < 0.001) between the mean eGFR and the CERAD total score. Conclusion This study contributes to the belief that an association exists between renal impairment and cognition, CERAD total score in CKD patients was inversely correlated to eGFR. Age and educational level significantly affect cognitive performance.

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TMEM106B modifies TDP-43 pathology in human ALS brain and cell-based models of TDP-43 proteinopathy

10.1101/2021.05.07.442949 ◽

2021 ◽

Author(s):

Fei Mao ◽

John Robinson ◽

Travis Unger ◽

Marijan Posavi ◽

Defne Amado ◽

...

Keyword(s):

Neurodegenerative Diseases ◽

Regional Distribution ◽

Dna Binding Protein ◽

Brain Regions ◽

Cell System ◽

Hexanucleotide Repeat ◽

Clinical Presentations ◽

Repeat Expansions ◽

The Relationship ◽

Lateral Sclerosis

The neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with TAR DNA-binding protein-43 (TDP-43) inclusions (FTLD-TDP) share the neuropathological hallmark of aggregates of TDP-43. However, factors governing the severity and regional distribution of TDP-43 pathology, which may account for the divergent clinical presentations of ALS and FTLD-TDP, are not well-understood. Here, we investigated the influence of genotypes at TMEM106B, a locus associated with risk for FTLD-TDP, and hexanucleotide repeat expansions in C9orf72, a known genetic cause for both ALS and FTLD-TDP, on global TDP-43 pathology and regional distribution of TDP-43 pathology in 899 postmortem cases from a spectrum of neurodegenerative diseases. We found that, among the 110 ALS cases, minor (C)- allele homozygotes at the TMEM106B locus sentinel SNP rs1990622 had more TDP-43 pathology globally, as well as in select brain regions. C9orf72 expansions similarly associated with greater TDP-43 pathology in ALS. However, adjusting for C9orf72 expansion status did not affect the relationship between TMEM106B genotype and TDP-43 pathology. In order to elucidate the direction of causality for this association, we directly manipulated TMEM106B levels in an inducible cell system that expresses mislocalized TDP-43 protein. We found that partial knockdown of TMEM106B, to levels similar to what would be expected in rs1990622 C allele carriers, led to development of more TDP-43 cytoplasmic aggregates, which were more insoluble, in this system. Taken together, our results support a causal role for TMEM106B in modifying the development of TDP-43 proteinopathy.

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Association Between Cerebral Cortical Microinfarcts and Perilesional Cortical Atrophy on 3T MRI

Neurology ◽

10.1212/wnl.0000000000013140 ◽

2021 ◽

pp. 10.1212/WNL.0000000000013140

Author(s):

Doeschka A. Ferro ◽

Hugo J. Kuijf ◽

Saima Hilal ◽

Susanne J. van Veluw ◽

Daniëlle van Veldhuizen ◽

...

Keyword(s):

Cognitive Impairment ◽

Cognitive Performance ◽

Sex Education ◽

Cortical Thickness ◽

Brain Regions ◽

Primary Objective ◽

Cognitive Testing ◽

Cortical Atrophy ◽

Intracranial Volume ◽

3T Mri

Background and objectives:Cerebral cortical microinfarcts (CMIs) are a novel MRI-marker of cerebrovascular disease (CeVD) that predicts accelerated cognitive decline. Presence of CMIs is known to be associated with global cortical atrophy, although the mechanism linking the two is unclear. Our primary objective was to examine the relation between CMIs and cortical atrophy and establish possible perilesional atrophy surrounding CMIs. Our secondary objective was to examine the role of cortical atrophy in CMI-associated cognitive impairment.Methods:Patients were recruited from two Singapore memory clinics between December 2010 and September 2013 and included if they received the diagnosis no objective cognitive impairment, cognitive impairment (with or without a history of stroke) or Alzheimer’s or vascular dementia. Cortical thickness, chronic cortical microinfarcts and MRI-markers of CeVD were assessed on 3T MRI. Patients underwent cognitive testing. Cortical thickness was compared globally between patients with and without CMIs, regionally within individual patients with CMIs comparing brain regions with CMIs to the corresponding contralateral region without CMIs and locally within individuals patients in a 50 mm radius of CMIs. Global cortical thickness was analyzed as mediator in the relation between CMI and cognitive performance.Results:Of the 238 patients (mean age 72.5 SD 9.1 years) enrolled, 75 had ≥1 CMIs. Patient with CMIs had a 2.1% lower global cortical thickness (B=-.049 mm, 95% CI [.091; -.007] p=.022) compared to patients without CMIs, after correction for age, sex, education and intracranial volume. In patients with CMIs, cortical thickness in brain regions with CMIs was 2.2 % lower than in contralateral regions without CMIs (B=-.048 mm [-.071; -.026] p<.001). In a 20 mm radius area surrounding the CMI-core, cortical thickness was lower than in the area 20-50 mm from the CMI-core (Mean difference -.06 mm 95% CI [-.10; -.02] p=.002). Global cortical thickness was a significant mediator in the relationship between CMI presence and cognitive performance as measure with the Mini-Mental State Examination (B=-.12 [-.22; -.01] p=.025).Discussion:We found cortical atrophy surrounding CMIs, suggesting a perilesional effect in a cortical area many times larger than the CMI-core. Our findings support the notion that CMIs affect brain structure beyond the actual lesion site.

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Cognition and addiction

Dialogues in Clinical Neuroscience ◽

10.31887/dcns.2019.21.3/gdom ◽

2019 ◽

Vol 21 (3) ◽

pp. 281-290 ◽

Cited By ~ 1

Keyword(s):

Decision Making ◽

Executive Functions ◽

Cognitive Training ◽

Cognitive Deficits ◽

Current Knowledge ◽

Cognitive Remediation ◽

Cognitive Testing ◽

Future Research ◽

Reward Expectancy ◽

Individualized Prediction

In this targeted review, we summarize current knowledge on substance-use disorder (SUD)-related cognitive deficits, the link between these deficits and clinical outcomes, and the cognitive training, remediation, and pharmacological approaches that have the potential to rescue cognition. We conclude that: (i) people with SUDs have moderate deficits in memory, attention, executive functions, and decision-making (including reward expectancy, valuation, and learning); (ii) deficits in higher-order executive functions and decision-making are significant predictors of relapse; (iii) cognitive training programs targeting reward-related appetitive biases, cognitive remediation strategies targeting goal-based decision-making, and pharmacotherapies targeting memory, attention, and impulsivity have potential to rescue SUD-related cognitive deficits. We suggest avenues for future research, including developing brief, clinically oriented harmonized cognitive testing suites to improve individualized prediction of treatment outcomes; computational modeling that can achieve deep phenotyping of cognitive subtypes likely to respond to different interventions; and phenotype-targeted cognitive, pharmacological, and combined interventions. We conclude with a tentative model of neuroscience-informed precision medicine.

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Cognitive Impairment In Adult De Novo Acute Leukemia Patients

Blood ◽

10.1182/blood.v116.21.4746.4746 ◽

2010 ◽

Vol 116 (21) ◽

pp. 4746-4746

Author(s):

Stijn Verleden ◽

Kurt Audenaert ◽

Lucien Noens

Keyword(s):

Cognitive Impairment ◽

Executive Functions ◽

Cognitive Deficits ◽

Cognitive Functions ◽

De Novo ◽

Verbal Learning ◽

Cognitive Domains ◽

Motor Dexterity ◽

De Novo Aml

Abstract Abstract 4746 Introduction: A significant percentage of cancer patients develop or have chemotherapy-induced cognitive impairment, during and even long after completion of aggressive treatment. Cognitive deficits are usually subtle and mild, and can occur in various cognitive domains. In AML/MDS patients, impaired cognitive functions, even prior to initiation of chemotherapy, have been described. Objective: To assess baseline cognitive functions and short-term cognitive evolution in de novo acute leukemia patients during induction treatment, and to compare our data with previous research. Methods: Current longitudinal-prospective study of adult de novo AML/ALL patients, treated with induction chemotherapy at the Hematology Department, UZ Ghent, Belgium. Eligible patients are enrolled and investigated with a comprehensive cognitive test battery, within on average five days after admission (pre-induction) and after completion of induction chemotherapy, on average after two months (pre-consolidation). Cognitive functions are assessed across various domains, including attention, executive functions, motor dexterity, and verbal/visual memory. Patients’ psychological functions and quality of life are assessed simultaneously. Results: Twenty adult patients were enrolled between 01/2009 and 06/2010. The median age was 43 years, 50% were male, 80% had AML (20% ALL), and median years of education was 12 years. Baseline hematological values were assessed, with WBC count (mean: 10,4 10E3/uL), RBC count (mean: 3,1 10E6/uL), and HgB (mean: 9,8 g/dL). Adult patients had normal cognitive functions (range: 1,0 SD below normative mean) in different cognitive domains, and mainly in attention and executive functions (COWA letter fluency & semantic fluency, and SCWT mental flexibility), except for mild cognitive deficits in verbal learning (AVLT A1-5), but especially in motor dexterity (PPT left and right hand). These functions were heterogeneous at baseline, ranging from severely impaired to good within a cognitive domain. At follow-up, attention, executive functions, motor dexterity, and verbal learning had all improved significantly (p<0.02). Conclusion: Adult de novo AML/ALL patients exhibit at baseline normal cognitive functions, except for verbal learning and motor dexterity. Cognitive deficits in attention, executive functions, and verbal learning were found similar to previous reported research in AML/MDS. However, our data showed less impaired motor dexterity. Moreover, cognitive functions improved at follow-up. Disclosures: No relevant conflicts of interest to declare.

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Abstract P359: Secondary Thalamic Atrophy Related to Brain Infarction is Associated With Post-Stroke Cognitive Impairment

Stroke ◽

10.1161/str.52.suppl_1.p359 ◽

2021 ◽

Vol 52 (Suppl_1) ◽

Author(s):

Jieli Geng ◽

Kie Honjo ◽

Fuqiang Gao ◽

Joel Ramirez ◽

Melissa Holmes ◽

...

Keyword(s):

Cognitive Impairment ◽

Cognitive Functions ◽

Infarct Volume ◽

Brain Infarction ◽

Brain Mri ◽

Brain Regions ◽

Vascular Lesion ◽

Cognitive Testing ◽

Post Stroke ◽

Brain Infarcts

Background: The thalamus is globally connected to many brain regions. Previous work highlights thalamic contributions to multiple cognitive functions, but few studies have measured thalamic volume changes or explored correlates of such changes with post-stroke cognition. Hence this study investigates possible associations of thalamic volumes with post-stroke cognitive functions. Methods: Participants with brain infarcts (6-42 months) underwent volumetric brain MRI and cognitive testing, including the Montreal Cognitive Assessment (MoCA). Focal Brain infarcts and thalami were traced manually. If the patient had bilateral infarcts, the side of the primary infarct volume defined the hemisphere involved. Brain parcellation and volumetrics used our comprehensive semi-automatic brain region and vascular lesion extraction pipeline (Ramirez, Neuroimage, 2011). MRI in 24 age and gender-matched healthy people provided normal comparative thalamic volumes. Thalamic atrophy was defined by percent thalamic volume loss in the stroke hemisphere compared to the other side. Spearman correlation assessed relationships between thalamic and infarct volumes and MoCA scores. Logistic regression analysis assessed whether thalamic atrophy correlated with MoCA score. Results: Thalami volumes ipsilateral to the infarct in stroke patients (n=55) were smaller than left (4.4 ± 1.4 vs. 5.4 ± 0.8 cc, p = 0.012) and right (4.4 ± 1.4 vs. 5.3 ± 0.7 cc, p = 0.024) thalamic volumes in the controls. Thalamic volumes were inversely correlated with ipsilateral infarct volumes (r = -0.384, p = 0.004). After controlling for head-size and brain atrophy, infarct volume independently correlated with ipsilateral thalamic volume s (β= -0.068, P=0.026), and only frontal infarcts (β = 2.300, p = 0.021) independently contributed to > 15% ipsilateral thalamic atrophy. Left thalamic atrophy of > 10% correlated significantly with poorer MoCA performance (β = 3.139, p = 0.023), after controlling for demographics and infarct volumes. Conclusions: Our results suggest that remote effects of infarction on ipsilateral thalamic volume, presumably related to disrupted thalamic-cortical interconnectivity, is associated with a commonly used metric of post-stroke cognitive impairment.

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Cognitive Impairment Associated With Chemotherapy for Cancer: Report of a Workshop

Journal of Clinical Oncology ◽

10.1200/jco.2004.08.094 ◽

2004 ◽

Vol 22 (11) ◽

pp. 2233-2239 ◽

Cited By ~ 290

Author(s):

Ian F. Tannock ◽

Tim A. Ahles ◽

Patricia A. Ganz ◽

Frits S. van Dam

Keyword(s):

Cognitive Impairment ◽

Cognitive Dysfunction ◽

Cognitive Deficits ◽

Large Scale ◽

Longitudinal Design ◽

Imaging Techniques ◽

Serum Levels ◽

Cognitive Testing ◽

Future Research ◽

Underlying Mechanisms

Cognitive dysfunction may occur in some patients who receive chemotherapy. We provide a summary of an April 2003 workshop on this topic, that included medical oncologists, radiologists, clinical and experimental psychologists, and patient advocates. Current studies indicate that cognitive deficits are often subtle, although they are observed consistently in a proportion of patients, may be durable, and can be disabling. Deficits have been observed in a range of cognitive functions. Underlying mechanisms are unknown, although preliminary studies suggest there may be genetic predisposition and that cognitive impairment may be accompanied by changes in the brain detectable by neuroimaging. The following priorities were established for future research: (1) large-scale clinical studies that use both a longitudinal design and concurrent evaluation of patients with cancer who do not receive chemotherapy—such studies should address the probability and magnitude of cognitive deficits, factors that predict them, and underlying mechanisms; (2) exploration of discrepancies between subjective reports of cognitive dysfunction and the objective results of cognitive testing; (3) studies of cognitive function in patients receiving treatment for diseases other than breast cancer, and in both men and women, to address the hypothesis that underlying mechanisms relate to changes in serum levels of sex hormones and/or to chemotherapy-induced menopause; (4) development of interventions to alleviate these problems; and (5) development of animal models and the use of imaging techniques to address mechanisms that might cause cognitive impairment associated with chemotherapy.

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