Cognitive performance changes in chronic kidney disease patients related to cardiovascular risc factors and diseases over a 2-year-follow-up

Einleitung. Viele Patienten mit einer chronischen Nierenerkrankung (CKD) weisen kognitive Defizite und gleichzeitig kardiovaskuläre Risikofaktoren und Erkrankungen auf. Wie sich die kognitive Leistung bei CKD-Patienten im zeitlichen Verlauf ändert und welche Rolle dabei kardiovaskuläre Risikofaktoren und Erkrankungen spielen, ist bislang unklar. Methode. In unserer Studie wurden 120 Probanden (73 Patienten mit CKD, Stadium 3-5D, Alter 64,3 ± 13,6 Jahre und 47 Kontrollpatienten mit vergleichbaren kardiovaskulären Risikofaktoren und Erkrankungen, Alter 62,6 ± 10,2 Jahre) im Rahmen der Studie „New Tools for the Prevention of Cardiovascular Disease in Chronic Kidney Disease“ (NTCVD) bei Baseline und nach 2 Jahren untersucht. Die Nierenfunktion wurde anhand von eGFR beurteilt. Die neuropsychologische Untersuchung bestand aus zehn Tests, die fünf kognitive Bereiche erfassten. Ergebnisse. Die Nierenfunktion, kardiovaskuläre Risikofaktoren und Erkrankungen sowie kognitive Leistungen blieben innerhalb von 2 Jahren in den beiden Patientengruppen sehr stabil. Der Summenwert für globale kognitive Leistung veränderte sich von Baseline (BL) zum Follow-up (FU) in den beiden Patientengruppen nahezu nicht (z = -0,63 ± 0,76 bei BL vs. z = -0,54 ± 0,79 bei FU, p = 0,113 für CKD-Patienten; z = -0,01 ± 0,59 bei BL vs. z = 0,01 ± 0,70 bei FU, p = 0,862 für Kontrollpatienten). Es gab eine signifikante Verbesserung im kognitiven Bereich „Sprache“ bei CKD-Patienten (z = -0,61 ± 0,85 bei BL vs. z = 0,41 ± 0,94 bei FU, p = 0,008). Das Gesamtcholesterin verringerte sich in den beiden Patientengruppen innerhalb des Untersuchungszeitraums signifikant, die Intima-Media-Dicke nahm in der CKD-Gruppe signifikant ab. Die wichtigsten Prädiktoren für eine Verschlechterung bzw. geringere Verbesserung der globalen kognitiven Leistung in multivariablen Regressionsanalysen waren hohes Alter und hohe kognitive Leistung zum Zeitpunkt der Baseline. Diskussion. In der NTCVD-Kohorte, die engmaschig untersucht und optimal behandelt wurde, trat keine kognitive Verschlechterung innerhalb von 2 Jahren auf. Unsere Daten betonten die Bedeutung der Auswahl einer geeigneten Kontrollgruppe mit kardiovaskulären Risikofaktoren. Außerdem erlaubten unsere Ergebnisse anzunehmen, dass bei einer optimalen medizinischen Behandlung von CKD-Patienten eine kognitive Verschlechterung im Erkrankungsverlauf vermieden werden könnte

Evolution of Neuropsychological Deficits in First-Ever Isolated Ischemic Thalamic Stroke and Their Association With Stroke Topography: A Case-Control Study.

BACKGROUND The thalamus plays an essential role in cognition. Cognitive deficits have to date mostly been studied retrospectively in chronic thalamic stroke in small cohorts. Studies prospectively evaluating the evolution of cognitive deficits and their association with thalamic stroke topography are lacking. This knowledge is relevant for targeted patient diagnostics and rehabilitation. METHODS Thirty-seven patients (57.5±17.5 [mean±SD] years, 57% men) with first-ever acute isolated ischemic stroke covering the anterior (n=5), paramedian (n=12), or inferolateral (n=20) thalamus and 37 in-patient controls without stroke with similar vascular risk factors matched for age and sex were prospectively studied. Cognition was evaluated using predefined tests at 1, 6, 12, and 24 months. Voxel-based lesion-symptom mapping was used to determine associations between neuropsychological deficits and stroke topography. RESULTS Patients with anterior thalamic stroke revealed severe deficits in verbal memory (median T score [Q1-Q3]: 39.1 [36.1-44.1]), language (31.8 [31.0-43.8]), and executive functions (43.8 [35.5-48.1]) at 1 month compared with controls (verbal memory: 48.5 [43.6-61.0], language: 55.7 [42.3-61.1], executive functions: 51.3 [50.1-56.8]). Patients with paramedian thalamic stroke showed moderate language (44.7 [42.8-55.9]) and executive (49.5 [44.3-55.1]) deficits and no verbal memory deficits (48.1 [42.5-54.7]) at 1 month compared with controls (59.0 [47.0-64.5]; 59.6 [51.1-61.3]; 52.5 [44.2-55.3]). The language and executive deficits in paramedian thalamic stroke patients almost completely recovered during follow-up. Intriguingly, significant deficits in verbal memory (44.7 [41.5-51.9]), language (47.5 [41.8-54.1]), and executive functions (48.2 [46.2-59.7]) were found in inferolateral thalamic stroke patients at 1 month compared with controls (50.5 [46.7-59.9]; 57.0 [51.2-62.9]; 57.4 [51.2-60.7]). Language, but not executive deficits persisted during follow-up. Voxel-based lesion-symptom mapping revealed an association of verbal memory deficits with anterior thalamus lesions and an association of non-verbal memory, language, and executive deficits with lesions at the anterior/paramedian/inferolateral border. CONCLUSIONS All 3 stroke topographies exhibited significant deficits in diverse cognitive domains, which recovered to a different degree depending on the stroke localization. Our study emphasizes the need for comprehensive neuropsychological diagnostics to secure adequate patient rehabilitation

Depression and anxiety in acute ischemic stroke involving the anterior but not paramedian or inferolateral thalamus

Background and objectivesEmotional and cognitive deficits are prevalent in strokes involving the thalamus. In contrast to cognitive deficits, emotional deficits have not been studied prospectively in isolated thalamic stroke.MethodsIn 37 ischemic thalamic stroke patients (57.0 [50.0; 69.5] years [median (Q1; Q3)], 21 males, 5 anterior, 12 paramedian, 20 inferolateral vascular territory), and 37 non-stroke control patients matched for age and sex, we prospectively examined depression, anxiety, activities of daily living, and quality of life at 1, 6, 12, and 24 months post-stroke using the Hospital-Anxiety-and-Depression Scale (HADS), Nürnberger-Alters-Alltagsaktivitäten scale (NAA), and Short Form-36 (SF36) questionnaire. Voxel-based lesion-symptom mapping (VLSM) and lesion-subtraction analyzes were performed to determine associations between questionnaire scores and thalamic stroke topography.ResultsAt 1 month post-stroke, anterior thalamic stroke patients had higher depression scores [8.0 (7.5; 10.5)] than paramedian [4.5 (1.0; 5.8)] and inferolateral [4.0 (1.0; 7.0)] thalamic stroke patients. Furthermore, anterior thalamic stroke patients had higher anxiety scores [11.0 (8.0; 14.5)] than their matched controls [2.5 (2.0; 2.5)], paramedian [4.5 (1.0; 5.8)] and inferior [4.0 (1.0; 7.0)] thalamic stroke patients. Depression and anxiety scores in anterior thalamic stroke patients remained high across the follow-up [depression: 9.0 (3.5; 13,8); anxiety:10.05 (2.8, 14.5)].Physical health assessed by SF36 was intact in anterior [1 month post-stroke: T-score = 55.9 (37.0; 57.6)] but reduced in inferolateral [44.5(32.4; 53.1)] thalamic stroke, whereas mental health was reduced in anterior thalamic stroke [32.0 (29.8; 47.3)].VLSM confirmed that voxels in the anterior thalamus around Montreal Neurological Institute (MNI) coordinates X = −8, Y = −12, Z = 2 were more often affected by the stroke in depressed (HADS-score ≥ 8) than non-depressed (HADS-score < 8) patients and voxels around coordinates X = −10, Y = −12, Z = 2 were more often affected in anxious (HADS-score ≥ 8) than non-anxious (HADS-score < 8) patients.ConclusionAnterior, but not paramedian or inferolateral thalamic stroke was associated with depression and anxiety. Even though our results are mostly significant in the left thalamus, this observation on stroke laterality might be confounded by the fact that the right hemisphere was underrepresented in our study

18F–FDG-PET/CT and diffusion-weighted MRI for monitoring a BRAF and CDK 4/6 inhibitor combination therapy in a murine model of human melanoma

Background: The purpose of the study was to investigate a novel BRAF and CDK 4/6 inhibitor combination therapy in a murine model of BRAF-V600-mutant human melanoma monitored by F-18-FDG-PET/CT and diffusionweighted MRI (DW-MRI). Methods: Human BRAF-V600-mutant melanoma (A375) xenograft-bearing balb/c nude mice (n = 21) were imaged by 18F-FDG-PET/CT and DW-MRI before (day 0) and after (day 7) a 1-week BRAF and CDK 4/6 inhibitor combination therapy (n = 12;dabrafenib, 20 mg/kg/d;ribociclib, 100 mg/kg/d) or placebo (n = 9). Animals were scanned on a small animal PET after intravenous administration of 20 MBq F-18-FDG. Tumor glucose uptake was calculated as the tumor-to-liver-ratio (TTL). Unenhanced CT data sets were subsequently acquired for anatomic coregistration. Tumor diffusivity was assessed by DW-MRI using the apparent diffusion coefficient (ADC). Anti-tumor therapy effects were assessed by ex vivo immunohistochemistry for validation purposes (microvascular density -CD31;tumor cell proliferation -Ki-67). Results: Tumor glucose uptake was significantly suppressed under therapy (Delta TTLTherapy -1.00 +/- 0.53 vs.Delta TTLControl 0.85 +/- 1.21;p < 0.001). In addition, tumor diffusivity was significantly elevated following the BRAF and CDK 4/6 inhibitor combination therapy (Delta ADC(Therapy) 0.12 +/- 0.14 x 10(-3) mm(2)/s;Delta ADCControl -0.12 +/- 0.06 x 10(-3) mm(2)/s;p < 0.001). Immunohistochemistry revealed a significant suppression of microvascular density (CD31, 147 +/- 48 vs. 287 +/- 92;p = 0.001) and proliferation (Ki-67, 3718 +/- 998 vs. 5389 +/- 1332;p = 0.007) in the therapy compared to the control group. Conclusion: A novel BRAF and CDK 4/6 inhibitor combination therapy exhibited significant anti-angiogenic and anti-proliferative effects in experimental human melanomas, monitored by F-18-FDG-PET/CT and DW-MRI

Physical, cognitive and emotional factors contributing to quality of life, functional health and participation in community dwelling in chronic kidney disease.

Quality of life (QoL) impairment is a well-known consequence of chronic kidney disease (CKD). The factors influencing QoL and late life functional health are poorly examined.Using questionnaires combined with neuropsychological examinations, we prospectively evaluated physical, cognitive, and emotional factors influencing QoL, functional health and participation in community dwelling in 119 patients with CKD stages 3-5 including hemodialysis (61.5±15.7years; 63% men) and 54 control patients of the same age without CKD but with similar cardiovascular risk profile.Compared with control patients, CKD patients showed impairment of the physical component of QoL and overall function, assessed by the SF-36 and LLFDI, whereas disability, assessed by LLFDI, was selectively impaired in CKD patients on hemodialysis. Multivariable linear regressions (forced entry) confirmed earlier findings that CKD stage (β = -0.24; p = 0.012) and depression (β = -0.30; p = 0.009) predicted the QoL physical component. Hitherto unknown, CKD stage (β = -0.23; p = 0.007), cognition (β = 0.20; p = 0.018), and depression (β = -0.51; <0.001) predicted disability assessed by the LLFDI, while age (β = -0.20; p = 0.023), male gender (B = 5.01; p = 0.004), CKD stage (β = -0.23; p = 0.005), stroke history (B = -9.00; p = 0.034), and depression (β = -0.41; p<0.001) predicted overall function. Interestingly, functional health deficits, cognitive disturbances, depression, and anxiety were evident almost only in CKD patients with coronary heart disease (found in 34.2% of CKD patients). The physical component of QoL and functional health decreased with age and depressive symptoms, and increased with cognitive abilities.In CKD, QoL, functional health, and participation in community dwelling are influenced by physical, cognitive, and emotional factors, most prominently in coronary heart disease patients

Cognitive Performance Is Highly Stable over a 2-Year-Follow-Up in Chronic Kidney Disease Patients in a Dedicated Medical Environment.

As kidney and brain functions decline with aging, chronic kidney disease (CKD) and dementia are becoming increasing health burdens worldwide. Among the risk factors for cognitive impairment, CKD is increasingly recognized. The precise impact of CKD on the development of cognitive impairment is poorly understood.In the New Tools for the Prevention of Cardiovascular Disease in Chronic Kidney Disease (NTCVD) cohort, which was recruited in a dedicated nephrology department, we examined the 2-year course of cognitive performance in 120 patients (73 patients with CKD stages 3-5D, 47 control patients without CKD with similar vascular risk profile) using a comprehensive battery of 10 neuropsychological tests.Kidney function, vascular risk factors and cognitive performance were highly stable both in CKD and control patients. The summary score of cognitive performance in CKD patients was very similar at baseline (z = -0.63±0.76) and follow-up (z = -0.54±0.79, p = 0.113), as was cognitive performance in control patients (z = -0.01±0.59 and 0.01±0.70, p = 0.862, at baseline and follow-up, respectively). Total serum cholesterol (199.6±36.0 and 186.0±32.9, p = 0.005 in controls; 194.4±46.1 and 181.2±41.2, p = 0.008 in CKD) and common carotid intima-media thickness (0.87±0.18 and 0.84±0.17, p = 0.351 in controls; 0.88±0.21 and 0.82±0.16, p = 0.002 in CKD) moderately but significantly decreased during the follow-up. In multivariable regression analyses, high age (β = -0.28, 95%CI = -0.48 to 0.08, p = 0.007) predicted decrease in cognitive performance.In this well-defined cohort receiving state-of-the-art therapy, cognitive performance did not decrease over 2 years. Our data emphasize the aspect of risk factor control, suggesting that dedicated medical care might prevent cognitive decline in CKD patients

Neuropsychological disturbances in frontal lobe epilepsy due to mutated nicotinic receptors

Mutations in nicotinic receptor subunits have been identified in some families with autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE). Normal intelligence has currently been considered the rule, although anecdotal cases with intellectual disability have been reported. We aimed to evaluate the frequency and degree of neuropsychological disorders in ADNFLE associated with nicotinic receptor mutations by testing 11 subjects from four families with a comprehensive neuropsychological assessment. General intellectual function was below the normal range in 45% of the subjects. All were abnormal in one or more executive task. Memory was either more affected than executive functions or equally affected in two thirds of subjects, suggesting a frontotemporal pattern of cognitive impairment. Cognitive dysfunction appears to be an integral part of the broad phenotype of ADNFLE with nicotinic receptor mutations, a fact that has been underestimated until now. The cognitive disorder affects executive functions as well as memory in most subjects

Characteristics of control patients and CKD patients, the latter also split into patients not requiring and requiring hemodialysis.

<p>Data are means ± SD for normally distributed continuous data or median (Q1;Q3) for non-normally distributed continuous data, categorical data are presented as n (%). Continuous data were evaluated by unpaired two-tailed t-tests for comparisons between control patients and all CKD patients. Continuous data were evaluated by oneway ANOVA followed by Bonferroni or Games-Howell (in case of non-equal variances) tests (normally distributed data) or Kruskall-Wallis followed by Mann-Whitney tests (non-normally distributed data) for comparisons between control patients, CKD patients requiring hemodialysis and CKD patients not requiring hemodialysis. Categorical data were evaluated by chi-square or Fisher exact tests.</p><p>*p<0.05 compared with control patients,</p>†<p>p<0.05 compared with CKD patients not requiring hemodialysis. CHD, coronary heart disease; CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; ESRD, end stage renal disease; HADS, Hospital Anxiety and Depression Scale; PAD, peripheral artery disease; TIA, transient ischemic attack.</p

Baseline Predictors for Change of Global Cognitive Performance from Baseline to Follow-up in the Total Cohort: More Complex Multivariable Models.

<p>Baseline Predictors for Change of Global Cognitive Performance from Baseline to Follow-up in the Total Cohort: More Complex Multivariable Models.</p

Disease relevant predictors for depressive symptoms in all patients.

<p>For the adjusted models, linear regressions were calculated using a forced entry strategy. Model 1: Age, gender, education, CKD stage, hemoglobin. Model 2: Age, gender, education CKD stage, hemoglobin, CHD or myocardial infarct, stroke or TIA, PAD. Model 3: Age, gender, education, CKD stage, CHD or myocardial infarct, stroke or TIA, PAD, global cognitive performance. CHD, coronary heart disease; CKD, chronic kidney disease; HADS, Hospital Anxiety and Depression Scale; PAD, peripheral artery disease; TIA, transient ischemic attack.</p