Cognitive impairment in young adults following cerebellar stroke: Prevalence and longitudinal course.

INTRODUCTION: Cognitive impairment is a well-known result of a stroke, but for cerebellar stroke in young patients detailed knowledge on the nature and extent of cognitive deficits is limited. This study examined the prevalence and course of cognitive impairment in a large cohort of patients with cerebellar stroke. METHODS: Sixty young (18-49 years) cerebellar stroke patients completed extensive neuropsychological assessments in the subacute (<9 months post-stroke) and/or chronic phase (≥9 months post-stroke). Performance and course were assessed using standardized scores and Reliable Change Index analyses. Associations between cognitive deficits and lesion locations were explored using subtraction analyses, and associations with subjective cognitive complaints and fatigue were examined. RESULTS: Sixty patients (52% male) were included with a mean age at event of 43.1 years. Cognitive impairment was observed in 60.3% of patients in the subacute phase and 51.2% during the chronic phase. Deficits were most frequent for visuo-spatial skills and executive functioning (42.5-54.6%). Both improvement and decline were observed over time, in 17.9% and 41.0% of participants, respectively. Cognitive deficits seem to be associated with lesions in certain cerebellar regions, however, no distinct correlation was found for a specific subregion. Subjective cognitive complaints were present in the majority of participants (61-80.5%) and positively correlated with fatigue in both phases (ρ = -.661 and ρ = -.757, p < .001, respectively). DISCUSSION: Cognitive impairment in cerebellar stroke patients is common, with deficits most pronounced for visuo-spatial skills and executive functioning, as in line with the Cerebellar Cognitive Affective Syndrome. The course of cognitive performance was heterogenous, with cognitive decline despite the fact that no recurrent strokes occurred. No clear association between lesion location and cognitive deficits was observed. Subjective cognitive complaints and fatigue were prevalent and positively correlated. Clinicians could use this information to actively screen for and better inform patients about possible cognitive sequalae.

A visual marker for early atrophy of the supraspinatus muscle on conventional MRI: introduction of the blackbird sign.

OBJECTIVES: The aim of this study was to introduce the blackbird sign as a fast, qualitative measure of early supraspinatus (SSP) muscle atrophy and to correlate the sign with quantitatively assessed muscle volume and intramuscular fat fraction (FF) in patients with full-thickness SSP tears. MATERIALS AND METHODS: The blackbird sign describes the asymmetric pattern of early SSP atrophy: on sagittal MR images, the supero-posterior contour of the muscle becomes concave, resembling the shape of a blackbird. MRIs of patients with full-thickness SSP tears were retrospectively reviewed for the presence of the blackbird and tangent signs. Patients were then divided into group 1: negative tangent sign and negative blackbird sign (n = 67), group 2: negative tangent sign and positive blackbird sign (n = 31), and group 3: positive tangent sign (n = 32). A 2-point Dixon sequence was acquired in all patients from which quantitative FF and muscle volumes were calculated. RESULTS: In total 130 patients (mean age 67 ± 11 years) were included. Mean SSP volume was significantly smaller in group 3 (15.8 ± 8.1 cm3) compared to group 2 (23.9 ± 7.0 cm3, p = 0.01) and group 1 (29.7 ± 9.1 cm3, p < 0.01). Significantly lower muscle volumes were also found in group 2 compared to group 1 (p = 0.02), confirming that the blackbird sign is able to identify early SSP atrophy. Mean FF in the SSP was significantly higher in group 3 (18.5 ± 4.4%) compared to group 2 (10.9 ± 4.7%, p < 0.01) and group 1 (6.1 ± 2.6%, p < 0.01). CONCLUSION: Visual assessment of early muscle atrophy of the SSP is feasible and reproducible using the blackbird sign, allowing the diagnosis of early SSP atrophy. CLINICAL RELEVANCE STATEMENT: In routine clinical practice, the blackbird sign may be a useful tool for assessing early muscle degeneration before the risk of postoperative rotator cuff re-tears increases with progressive muscle atrophy and fatty infiltration. KEY POINTS: Quantitative measurements of rotator cuff injuries require time, limiting clinical practicality. The proposed blackbird sign is able to identify early SSP atrophy. Reader agreement for the blackbird sign was substantial, demonstrating reproducibility and ease of implementation in the clinical routine.

Prognostic triad: a novel method for decision-making for adjuvant treatment in stage I-II oral squamous cell carcinoma.

This study proposes a scoring system for adjuvant irradiation for stage I/II oral squamous cell carcinoma (OSCC). Derivation cohort (119 patients, operated between 2011 and 2014) and a validation cohort (204 patients, operated between 2016 and 2019) were included. In derivation cohort, on univariate analysis, tumor size >2 cm [3-year Disease Free Survival (DFS) 72.5% vs 95.6%, P = 0.039], lymphovascular invasion (58.3% vs 83.6%, P = 0.024), perineural invasion (75% vs 85.6%, P = 0.013), and depth of invasion ≥0.5 cm (73.8% vs 97.5%, P = 0.017) predicted 3-year DFS. Tongue lesions and poor differentiation were added as poor prognosticators based on previously published reports. Patients were grouped as low risk (<3 risk factors) and high risk (≥3 risk factors), with only high-risk group receiving adjuvant irradiation in validation cohort. Overall, 47/119 (39.5%) patients in the derivation cohort and 50/204 (24.5%) patients in validation cohort received adjuvant irradiation. In derivation cohort, 3-year DFS was 93% and 72.5% in the low and high-risk group, respectively. 3-year DFS was 90.7% and 85.8% in the low and high-risk group, respectively for validation cohort. The proposed scoring system reduced the use of adjuvant irradiation by 38%, with similar DFS.

Indication and Post-operative Complication of Primary Caesarean Section in Multiparous Women in A Tertiary Level Hospital.

The spectrum of indications for primary caesarean section changes with advancing parity. As parity advances more cesarean section are done for maternal rather than fetal indications. The objective of this study was to determine the indications and complications of caesarean section in multiparous women with history of previous vaginal delivery. This cross-sectional descriptive observational study was conducted in Mymensingh Medical College Hospital from January 2019 to June 2019 among 100 purposively selected multiparous women who underwent primary caesarean section. A well-designed, semi-structured questionnaire was used to collect data by face-to-face interview, clinical examinations and laboratory investigations. Data analysis was conducted in SPSS 20.0 version. Majority (74.0%) of the women in this study were in the age group 21-30 years with mean age of 26.3±5.76 years. Majority of the patients were of second gravida (42.0%) followed by third gravida (33.0%). The highest gravida in this study was 6th. Most of the patients were of para 1(44.0%). Highest para in this study was para 5. The most common indication of caesarean section in this study was foetal distress (26.0%). The next common indications were cephalo-pelvic disproportion (22.0%), antepartum haemorrhage (13.0%), mal-presentaion or mal-position (16.0%). Other causes were PROM (8.0%), prolonged labour (6.0%), cord prolapse (2.0%), post-dated pregnancy (4.0%), severe pre-eclampsia (2.0%) and secondary subfertility (1.0%). There was no case of maternal mortality in this study but 15 mothers suffered from various post-operative complications like wound infection (4.0%), UTI (4.0%), puerperal pyrexia (3.0%), postpartum haemorrhage (3.0%) and paralytic ileus (1.0%). Among the babies delivered 97 were live births. Among the 97 live births 11(11.34%) were preterm babies. Among the babies delivered majority (85.0%) was with good APGAR score (7-10). In conclusion it can say that a multiparous women in labour requires the same attention as that of primigravida. A parous women needs good obstetric care to improve maternal and neonatal outcome and still keeping caesarean section to a lower rate.

Nasal cathelicidin is expressed in early life and is increased during mild, but not severe respiratory syncytial virus infection.

Respiratory syncytial virus is the major cause of acute lower respiratory tract infections in young children, causing extensive mortality and morbidity globally, with limited therapeutic or preventative options. Cathelicidins are innate immune antimicrobial host defence peptides and have antiviral activity against RSV. However, upper respiratory tract cathelicidin expression and the relationship with host and environment factors in early life, are unknown. Infant cohorts were analysed to characterise early life nasal cathelicidin levels, revealing low expression levels in the first week of life, with increased levels at 9 months which are comparable to 2-year-olds and healthy adults. No impact of prematurity on nasal cathelicidin expression was observed, nor were there effects of sex or birth mode, however, nasal cathelicidin expression was lower in the first week-of-life in winter births. Nasal cathelicidin levels were positively associated with specific inflammatory markers and demonstrated to be associated with microbial community composition. Importantly, levels of nasal cathelicidin expression were elevated in infants with mild RSV infection, but, in contrast, were not upregulated in infants hospitalised with severe RSV infection. These data suggest important relationships between nasal cathelicidin, upper airway microbiota, inflammation, and immunity against RSV infection, with interventional potential.

Meso-cortical pathway damage in cognition, apathy and gait in cerebral small vessel disease.

Cerebral small vessel disease (SVD) is known to contribute to cognitive impairment, apathy, and gait dysfunction. Although associations between cognitive impairment and either apathy or gait dysfunction have been shown in SVD, the inter-relations among these three clinical features and their potential common neural basis remains unexplored. The dopaminergic meso-cortical and meso-limbic pathways have been known as the important brain circuits for both cognitive control, emotion regulation and motor function. Here, we investigated the potential inter-relations between cognitive impairment, apathy, and gait dysfunction, with a specific focus on determining whether these clinical features are associated with damage to the meso-cortical and meso-limbic pathways in SVD. In this cross-sectional study, we included 213 participants with SVD in whom MRI scans and comprehensive neurobehavioral assessments were administered. These assessments comprised of six clinical measures: processing speed, executive function, memory, apathy (based on the Apathy Evaluation Scale), and gait function (based on the time and steps in Timed Up and Go test). We reconstructed five tracts connecting ventral tegmental area (VTA) and the dorsolateral prefrontal cortex (dlPFC), ventral lateral PFC (vlPFC), medial orbitofrontal cortex (mOFC), anterior cingulate cortex (ACC) and nucleus accumbens (NAc) within meso-cortical and meso-limbic pathways using diffusion weighted imaging. The damage along the five tracts was quantified using the free water (FW) and FW-corrected mean diffusivity (MD-t) indices. Furthermore, we explored the inter-correlations among the six clinical measures and identified their common components using principal component analysis (PCA). Linear regression analyses showed that higher FW values of tracts within meso-cortical pathways were related to these clinical measures in cognition, apathy, and gait (all P-corrected values < 0.05). PCA showed strong inter-associations among these clinical measures and identified a common component wherein all six clinical measures loaded on. Higher FW values of tracts within meso-cortical pathways were related to the PCA-derived common component (all P-corrected values < 0.05). Moreover, FW values of VTA-ACC tract showed the strongest contribution to the PCA-derived common component over all other neuroimaging features. In conclusion, our study showed that the three clinical features (cognitive impairment, apathy, and gait dysfunction) of SVD are strongly inter-related and that the damage in meso-cortical pathway could be the common neural basis underlying the three features in SVD. These findings advance our understanding of the mechanisms behind these clinical features of SVD and have the potential to inform novel management and intervention strategies for SVD.

Early-Stage Alzheimer's Disease Affects Fast But Not Slow Adaptive Processes in Motor Learning.

Alzheimer's disease (AD) is characterized by an initial decline in declarative memory, while nondeclarative memory processing remains relatively intact. Error-based motor adaptation is traditionally seen as a form of nondeclarative memory, but recent findings suggest that it involves both fast, declarative, and slow, nondeclarative adaptive processes. If the declarative memory system shares resources with the fast process in motor adaptation, it can be hypothesized that the fast, but not the slow, process is disturbed in AD patients. To test this, we studied 20 early-stage AD patients and 21 age-matched controls of both sexes using a reach adaptation paradigm that relies on spontaneous recovery after sequential exposure to opposing force fields. Adaptation was measured using error clamps and expressed as an adaptation index (AI). Although patients with AD showed slightly lower adaptation to the force field than the controls, both groups demonstrated effects of spontaneous recovery. The time course of the AI was fitted by a hierarchical Bayesian two-state model in which each dynamic state is characterized by a retention and learning rate. Compared to controls, the retention rate of the fast process was the only parameter that was significantly different (lower) in the AD patients, confirming that the memory of the declarative, fast process is disturbed by AD. The slow adaptive process was virtually unaffected. Since the slow process learns only weakly from an error, our results provide neurocomputational evidence for the clinical practice of errorless learning of everyday tasks in people with dementia.

Visuospatial working memory in behavioural variant frontotemporal dementia: a comparative analysis with Alzheimer's disease using the box task.

OBJECTIVE: This study investigated the visuospatial working memory profiles of behavioural variant frontotemporal dementia (bvFTD) and Alzheimer's disease (AD) using a novel computerised test of visuospatial working memory: the Box Task. METHODS: Twenty-eight bvFTD and 28 AD patients, as well as 32 age-matched control participants were recruited. All participants completed the Box Task and conventional neuropsychological tests of working memory, episodic memory, and visuospatial function. RESULTS: Both the bvFTD and AD groups exhibited significantly more Box Task between-search errors than the control group across all set sizes. Notably, the AD group demonstrated a significantly higher error rate compared to the bvFTD group. Regression analysis revealed that whilst episodic memory impairment significantly predicted Box Task error performance in AD, this was not the case for bvFTD. Additionally, a noticeable trend was observed for attention in predicting Box Task errors in both bvFTD and AD groups. The Box Task demonstrated high utility in differentiating between bvFTD and AD, with a decision tree correctly classifying 82.1% of bvFTD patients and 75% of AD patients. CONCLUSIONS: Our findings reveal significant visuospatial working memory impairments in bvFTD, albeit of lesser severity compared to disease-matched AD patients. The Box Task, a novel measure of visuospatial working memory, proved effective in differentiating between bvFTD and AD, outperforming many traditional neuropsychological measures. Overall, our findings highlight the utility of assessing visuospatial memory when differentiating between bvFTD and AD in the clinical setting.

FIGO 2023 endometrial staging: a leap of faith into the new "prognostic based' rather than "anatomical based" staging-too fast too furious??

BACKGROUND: In 2023 FIGO revised the endometrial cancer staging system after 13 years. There is a lacuna of data regarding the performance and practicality of the revised 2023 FIGO staging schema for endometrial cancer from Low Middle-Income Countries (LMIC). OBJECTIVE: To estimate the shift of stage and adjuvant management of endometrial cancer based on the FIGO 2023 system compared to the FIGO 2009 system and assess the predictive potential of the FIGO 2023 system. MATERIAL AND METHODS: A retrospective study was conducted from 1st January 2017 to 31st December 2022. All patients with endometrial cancer were staged according to the FIGO 2023 and FIGO 2009 staging system. Follow-up of patients was done to determine recurrence. RESULTS: A total of 152 patients were included. Aggressive histology was seen in 66 (45%) patients. Eighteen (11%) had subserosal involvement. Substantial LVSI was noted in 23 (15%) of patients. Twenty-four (47%) patients of FIGO 2009 Stage IA and 26 patients (63%) of FIGO 2009 Stage IB were upstaged. Eleven (50%) patients of FIGO 2009 Stage IIIA were down staged to IA3. Overall 23 patients (15%) had a shift of stage. Fifteen out of 152 patients (15%) would have had a possible risk stratification change which would imply 23 patients (15%) would have needed a more radical treatment. Molecular classification was done in 32 patients; however, only 2 patients could afford POLE testing. Kaplan-Meier curves showed significant PFS differences in FIGO 2009 Stage IB and Stage IIIA when restaged according to the FIGO 2023 system. CONCLUSION: The FIGO 2023 endometrial staging is a more robust prognosticator; however, the practicality of molecular classification in LMICs is still a distant dream.

The relation of a cerebrospinal fluid profile associated with Alzheimer's disease with cognitive function and neuropsychiatric symptoms in sporadic cerebral amyloid angiopathy.

BACKGROUND: Patients with sporadic cerebral amyloid angiopathy (sCAA) frequently report cognitive or neuropsychiatric symptoms. The aim of this study is to investigate whether in patients with sCAA, cognitive impairment and neuropsychiatric symptoms are associated with a cerebrospinal fluid (CSF) biomarker profile associated with Alzheimer's disease (AD). METHODS: In this cross-sectional study, we included participants with sCAA and dementia- and stroke-free, age- and sex-matched controls, who underwent a lumbar puncture, brain MRI, cognitive assessments, and self-administered and informant-based-questionnaires on neuropsychiatric symptoms. CSF phosphorylated tau, total tau and Aß42 levels were used to divide sCAA patients in two groups: CAA with (CAA-AD+) or without a CSF biomarker profile associated with AD (CAA-AD-). Performance on global cognition, specific cognitive domains (episodic memory, working memory, processing speed, verbal fluency, visuoconstruction, and executive functioning), presence and severity of neuropsychiatric symptoms, were compared between groups. RESULTS: sCAA-AD+ (n=31; mean age: 72 ± 6; 42%, 61% female) and sCAA-AD- (n=23; 70 ± 5; 42% female) participants did not differ with respect to global cognition or type of affected cognitive domain(s). The number or severity of neuropsychiatric symptoms also did not differ between sCAA-AD+ and sCAA-AD- participants. These results did not change after exclusion of patients without prior ICH. CONCLUSIONS: In participants with sCAA, a CSF biomarker profile associated with AD does not impact global cognition or specific cognitive domains, or the presence of neuropsychiatric symptoms.

Demographic and Clinical Characteristics of Functional Dyspepsia and Its Subtypes in Adult Patients: An Experience from a Tertiary Care Centre in Bangladesh.

Functional dyspepsia (FD) is a common gastrointestinal problem in the world. The Rome III consensus subdivided functional dyspepsia into two groups: meal-related postprandial distress syndrome (PDS) and meal-unrelated epigastric pain syndrome (EPS). Limited data are available regarding FD in Bangladesh. The aim of this study was to investigate the demographic and clinical characteristics of FD and its sub-types. This cross-sectional study was conducted in which we recruited patients who attended the outpatient department of Gastroenterology of Bangabandhu Sheikh Mujib Medical University, Bangladesh from March 2017 to February 2018. Patients fulfilling Rome III FD criteria and a negative upper GIT endoscopy were included for this study. The patients were then subdivided into 'pure' PDS (i.e. meeting criteria for PDS without EPS symptoms), 'pure' EPS (i.e., meeting criteria for EPS without PDS symptoms), and overlapping PDS-EPS (i.e., symptoms of both PDS and EPS) groups. Total of 368 FD patients (56.0% females, mean age 32.8±8.6 years, BMI: 22.0±2.7), were included in this study. Out of them, 112(30.4%) patients (57.2% females, mean age 33.9±9.3 years, BMI: 22.0±2.7) fulfilled criteria of pure EPS and 64(17.4%) patients (68.8% females, mean age 33.2±7.8 years, BMI: 22.1±2.4) fulfilled criteria of pure PDS. However, the majority of patients [192(52.2%), 52.1% females, mean age 32.0±8.4 years, BMI: 21.9±2.8] had symptoms of overlapping EPS-PDS. More than 40% of patients in our study presented with 3 or more of the four key symptoms of FD. A longer duration of presenting symptoms was seen among patients with overlapping EPS-PDS in comparison to pure EPS and pure PDS (p<0.001). A significant overlap of symptoms of both EPS and PDS was noticed among patients with FD. The value of dividing functional dyspepsia into the subgroups of PDS and EPS is thus questionable. Further research and modification of the diagnostic criteria for FD subtypes are necessary.

Adaptive immunity and atherosclerosis: aging at its crossroads.

Adaptive immunity plays a profound role in atherosclerosis pathogenesis by regulating antigen-specific responses, inflammatory signaling and antibody production. However, as we age, our immune system undergoes a gradual functional decline, a phenomenon termed "immunosenescence". This decline is characterized by a reduction in proliferative naïve B- and T cells, decreased B- and T cell receptor repertoire and a pro-inflammatory senescence associated secretory profile. Furthermore, aging affects germinal center responses and deteriorates secondary lymphoid organ function and structure, leading to impaired T-B cell dynamics and increased autoantibody production. In this review, we will dissect the impact of aging on adaptive immunity and the role played by age-associated B- and T cells in atherosclerosis pathogenesis, emphasizing the need for interventions that target age-related immune dysfunction to reduce cardiovascular disease risk.

Perivascular Spaces, Diffusivity Along Perivascular Spaces, and Free Water in Cerebral Small Vessel Disease.

BACKGROUND AND OBJECTIVES: Previous studies have linked the MRI measures of perivascular spaces (PVSs), diffusivity along the perivascular spaces (DTI-ALPS), and free water (FW) to cerebral small vessel disease (SVD) and SVD-related cognitive impairments. However, studies on the longitudinal associations between the three MRI measures, SVD progression, and cognitive decline are lacking. This study aimed to explore how PVS, DTI-ALPS, and FW contribute to SVD progression and cognitive decline. METHODS: This is a cohort study that included participants with SVD who underwent neuroimaging and cognitive assessment, specifically measuring Mini-Mental State Examination (MMSE), cognitive index, and processing speed, at 2 time points. Three MRI measures were quantified: PVS in basal ganglia (BG-PVS) volumes, FW fraction, and DTI-ALPS. We performed a latent change score model to test inter-relations between the 3 MRI measures and linear regression mixed models to test their longitudinal associations with the changes of other SVD MRI markers and cognitive performances. RESULTS: In baseline assessment, we included 289 participants with SVD, characterized by a median age of 67.0 years and 42.9% women. Of which, 220 participants underwent the follow-up assessment, with a median follow-up time of 3.4 years. Baseline DTI-ALPS was associated with changes in BG-PVS volumes (ß = -0.09, p = 0.030), but not vice versa (ß = -0.08, p = 0.110). Baseline BG-PVS volumes were associated with changes in white matter hyperintensity (WMH) volumes (ß = 0.33, p-corrected < 0.001) and lacune numbers (ß = 0.28, p-corrected < 0.001); FW fraction was associated with changes in WMH volumes (ß = 0.30, p-corrected < 0.001), lacune numbers (ß = 0.28, p-corrected < 0.001), and brain volumes (ß = -0.45, p-corrected < 0.001); DTI-ALPS was associated with changes in WMH volumes (ß = -0.20, p-corrected = 0.002) and brain volumes (ß = 0.23, p-corrected < 0.001). Furthermore, baseline FW fraction was associated with decline in MMSE score (ß = -0.17, p-corrected = 0.006); baseline FW fraction and DTI-ALPS were associated with changes in cognitive index (FW fraction: ß = -0.25, p-corrected < 0.001; DTI-ALPS: ß = 0.20, p-corrected = 0.001) and processing speed over time (FW fraction: ß = -0.29, p-corrected < 0.001; DTI-ALPS: ß = 0.21, p-corrected < 0.001). DISCUSSION: Our results showed that increased BG-PVS volumes, increased FW fraction, and decreased DTI-ALPS are related to progression of MRI markers of SVD, along with SVD-related cognitive decline over time. These findings may suggest that the glymphatic dysfunction is related to SVD progression, but further studies are needed.

Neuropsychiatric symptoms with focus on apathy and irritability in sporadic and hereditary cerebral amyloid angiopathy.

BACKGROUND: Neuropsychiatric symptoms (NPS) may affect cognition, but their burden in cerebral amyloid angiopathy (CAA), one of the main causes of intracerebral hemorrhage (ICH) and dementia in the elderly, remains unclear. We investigated NPS, with emphasis on apathy and irritability in sporadic (sCAA) and Dutch-type hereditary (D-)CAA. METHODS: We included patients with sCAA and (pre)symptomatic D-CAA, and controls from four prospective cohort studies. We assessed NPS per group, stratified for history of ICH, using the informant-based Neuropsychiatric Inventory (NPI-Q), Starkstein Apathy scale (SAS), and Irritability Scale. We modeled the association of NPS with disease status, executive function, processing speed, and CAA-burden score on MRI and investigated sex-differences. RESULTS: We included 181 participants: 82 with sCAA (mean[SD] age 72[6] years, 44% women, 28% previous ICH), 56 with D-CAA (52[11] years, 54% women, n = 31[55%] presymptomatic), and 43 controls (69[9] years, 44% women). The NPI-Q NPS-count differed between patients and controls (sCAA-ICH+:adj.ß = 1.4[95%CI:0.6-2.3]; sCAA-ICH-:1.3[0.6-2.0]; symptomatic D-CAA:2.0[1.1-2.9]; presymptomatic D-CAA:1.2[0.1-2.2], control median:0[IQR:0-3]), but not between the different CAA-subgroups. Apathy and irritability were reported most frequently: n = 12[31%] sCAA, 19[37%] D-CAA had a high SAS-score; n = 12[29%] sCAA, 14[27%] D-CAA had a high Irritability Scale score. NPS-count was associated with decreased processing speed (adj.ß=-0.6[95%CI:-0.8;-0.4]) and executive function (adj.ß=-0.4[95%CI:-0.6;-0.1]), but not with radiological CAA-burden. Men had NPS more often than women. DISCUSSION: According to informants, one third to half of patients with CAA have NPS, mostly apathy, even in presymptomatic D-CAA and possibly with increased susceptibility in men. Neurologists should inform patients and caregivers of these disease consequences and treat or refer patients with NPS appropriately.

Improved quality of life and psychological symptoms following mindfulness and cognitive rehabilitation in multiple sclerosis and their mediating role for cognition: a randomized controlled trial.

BACKGROUND: Multiple sclerosis (MS) frequently gives rise to depressive and anxiety symptoms, but these are often undertreated. This study investigated the effect of mindfulness-based cognitive therapy (MBCT) and cognitive rehabilitation therapy (CRT) on psychological outcomes and quality of life (QoL), and whether they mediate treatment effects on MS-related cognitive problems. METHODS: This randomized controlled trial included MS patients with cognitive complaints (n = 99) and compared MBCT (n = 32) and CRT (n = 32) to enhanced treatment as usual (n = 35). Baseline, post-treatment and 6-months follow-up assessments included patient-reported outcome measures (PROMS) and cognitive outcomes (self-reported and neuropsychological assessment). PROMS concerned psychological symptoms, well-being, QoL, and daily life function. Linear mixed models indicated intervention effects on PROMS and mediation effects of PROMS on cognitive outcomes. RESULTS: MBCT positively affected depressive symptoms (Cohen's d (d) = -0.46), fatigue (d = -0.39), brooding (d = -0.34), mindfulness skills (d = 0.49), and mental QoL (d = -0.73) at post-treatment. Effects on mindfulness skills remained significant 6 months later (d = 0.42). CRT positively affected depressive symptoms (d = -0.46), mindfulness skills (d = 0.37), and mental QoL (d = -0.45) at post-treatment, but not at 6-month follow-up. No effects on anxiety, well-being, self-compassion, physical QoL, and daily life function were found. Treatment effects on self-reported, but not objective, cognition were mediated by psychological symptoms and mindfulness skills. CONCLUSIONS: MBCT and CRT reduced a wide array of psychological symptoms and improved mental QoL. These improvements seemed to impact self-reported cognitive problems after both treatments, whereas objective cognitive improvements after MBCT seemed independent of improvement in psychological symptoms. Future studies should investigate long-term sustainability of these beneficial effects. TRIAL REGISTRATION: The trial was prospectively registered in the Dutch Trial registry on 31 May 2017 (NL6285; https://trialsearch.who.int/Trial2.aspx?TrialID=NTR6459 ).

A Prospective Randomised Trial to Determine the Effect of a Reduced Versus Standard Dose of Enzalutamide on Side Effects in Frail Patients with Prostate Cancer.

BACKGROUND AND OBJECTIVE: Enzalutamide is a potent androgen receptor signalling inhibitor, effectively used for the treatment of different stages of prostate cancer. Side effects occur frequently at the registered dose, whilst a lower dose might be equally effective. Therefore, the aim of this study is to determine the effect of a reduced dose of enzalutamide on side effects in frail patients with prostate cancer. METHODS: This multicentre randomised trial compared the standard enzalutamide dose of 160 mg once daily (OD) with a reduced dose of 120 mg OD in frail patients with prostate cancer. Fatigue, cognitive side effects, and depressive symptoms were measured by the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) questionnaire, Functional Assessment of Cancer Therapy-Cognitive Function (FACT-Cog) questionnaire, and Geriatric Depression Scale-15 (GDS-15). Linear mixed-effect models were used to study differences in side effects over time between both groups. KEY FINDINGS AND LIMITATIONS: In total, 52 patients were included in the analysis (25 reduced dose and 27 standard dose). Patients treated with the reduced dose had significantly lower fatigue after 24 wk than those with the standard dose (difference FACIT-Fatigue 6.2; 95% confidence interval 1.4-11.0; p = 0.01). Patients treated with the reduced dose showed stable fatigue, cognitive side effects, and depressive symptoms over time, whilst patients with the standard dose showed significantly worse side effects after 24 wk than at baseline. CONCLUSIONS AND CLINICAL IMPLICATIONS: A reduced dose of enzalutamide results in less fatigue, cognitive side effects, and depressive symptoms in frail patients with prostate cancer than the standard dose, without any indication of interference with efficacy endpoints. PATIENT SUMMARY: In this report, we looked at the side effects of enzalutamide at two dose levels. We found that, in frail patients, three tablets a day result in less fatigue than four tablets a day. Patients treated with four tablets a day showed an increase in fatigue, cognitive side effects, and depression. We conclude that a lower dose of three tablets can be used to alleviate side effects without indications for less efficacy.

Carboxyhemoglobin half-life toxicokinetic profiles during and after normobaric oxygen therapy: On a swine model.

Investigations on acute carbon monoxide (CO) poisoning struggle to highlight a relevant discriminant criterion related to CO poisoning severity for predicting complications, such as delayed neurological syndromes. In this context, it remains difficult to demonstrate the superiority of one method of oxygen (O2) administration over others or to identify the optimal duration of normobaric 100% oxygen (NBO) treatment. Myoglobin, as hemoglobin, are a potential binding site for CO, which could be a source of extravascular CO storage that impacts the severity of CO poisoning. It is not possible in routine clinical practice to estimate this potential extravascular CO storage. Indirect means of doing so that are available in the first few hours of poisoning could include, for example, the carboxyhemoglobin half-life (COHbt1/2), which seems to be influenced itself by the level and duration of CO exposure affecting this store of CO within the body. However, before the elimination of CO can be assessed, the COHbt1/2 toxicokinetic model must be confirmed: research still debates whether this model mono- or bi-compartmental. The second indirect mean could be the assessment of a potential COHb rebound after COHb has returned to 5% and NBO treatment has stopped. Moreover, a COHb rebound could be considered to justify the duration of NBO treatment. On an experimental swine model exposed to moderate CO poisoning (940 ppm for ±118 min until COHb reached 30%), we first confirm that the COHb half-life follows a bi-compartmental model. Secondly, we observe for the first time a slight COHb rebound when COHb returns to 5% and oxygen therapy is stopped. On the basis of these two toxicokinetic characteristics in favor of extravascular CO storage, we recommend that COHbt1/2 is considered using the bi-compartmental model in future clinical studies that compare treatment effectiveness as a potential severity criterion to homogenize cohorts of the same severity. Moreover, from a general toxicokinetic point of view, we confirm that a treatment lasting less than 6 hours appears to be insufficient for treating moderate CO poisoning.

Long-Term Longitudinal Course of Cognitive and Motor Symptoms in Patients With Cerebral Small Vessel Disease.

BACKGROUND AND OBJECTIVES: Patients with cerebral small vessel disease (SVD) show a heterogenous clinical course. The aim of the current study was to investigate the longitudinal course of cognitive and motor function in patients who developed parkinsonism, dementia, both, or none. METHODS: Participants were from the Radboud University Nijmegen Diffusion Tensor and Magnetic Resonance Cohort study, a prospective cohort of patients with SVD. Parkinsonism and dementia were, respectively, diagnosed according to the UK Parkinson's Disease Society brain bank criteria and the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, criteria for major neurocognitive disorder. Linear and generalized linear mixed-effect analyses were used to study the longitudinal course of motor and cognitive tasks. RESULTS: After a median follow-up of 12.8 years (interquartile range 10.2-15.3), 132 of 501 (26.3%) participants developed parkinsonism, dementia, or both. Years before diagnosis of these disorders, participants showed distinct clinical trajectories from those who developed none: Participant who developed parkinsonism had an annual percentage of 22% (95% CI 18%-27%) increase in motor part of the Unified Parkinson's Disease Rating Scale score. This was significantly higher than the 16% (95% CI 14%-18%) of controls, mainly because of a steep increase in bradykinesia and posture and gait disturbances. When they developed dementia as well, the increase in Timed Up and Go Test time of 0.73 seconds per year (95% CI 0.58-0.87) was significantly higher than the 0.20 seconds per year increase (95% CI 0.16-0.23) of controls. All groups, including the participants who developed parkinsonism without dementia, showed a faster decline in executive function compared with controls: Annual decline in Z-score was -0.07 (95% CI -0.10 to -0.05), -0.09 (95% CI -0.11 to -0.08), and -0.11 (95% CI -0.14 to -0.08) for participants who developed, respectively, parkinsonism, dementia, and both parkinsonism and dementia. These declines were all significantly faster than the annual decline in Z-score of 0.07 (95% CI -0.10 to -0.05) of controls. DISCUSSION: A distinct pattern in deterioration of clinical markers is visible in patients with SVD, years before the diagnosis of parkinsonism and dementia. This knowledge aids early identification of patients with a high risk of developing these disorders.

Immune regulation and blood-brain barrier permeability in cerebral small vessel disease: study protocol of the INflammation and Small Vessel Disease (INSVD) study - a multicentre prospective cohort study.

INTRODUCTION: The INflammation and Small Vessel Disease (INSVD) study aims to investigate whether peripheral inflammation, immune (dys)regulation and blood-brain barrier (BBB) permeability relate to disease progression in cerebral small vessel disease (SVD). This research aims to pinpoint specific components of the immune response in SVD relating to disease progression. This could identify biomarkers of SVD progression, as well as potential therapeutic targets to inform the development and repurposing of drugs to reduce or prevent SVD, cognitive decline and vascular dementia. METHODS AND ANALYSIS: INSVD is a prospective observational multicentre cohort study in individuals with symptomatic SVD. This longitudinal study combines comprehensive immunophenotyping of the peripheral blood immune compartment with advanced neuroimaging markers of SVD and BBB permeability. The main SVD marker of interest is white matter microstructure as determined by diffusion tensor imaging, a valuable marker of disease progression owing to its sensitivity to early alterations to white matter integrity. The research is being conducted in two sites-in the UK (Cambridge) and the Netherlands (Nijmegen)-with each site recruiting 100 participants (total n=200). Participants undergo clinical and cognitive assessments, blood draws, and brain MRI at baseline and 2-year follow-up. ETHICS AND DISSEMINATION: This study received ethical approval from the local ethics boards (UK: East of England-Cambridge Central Research Ethics Committee (REC) ref: 22/EE/00141, Integrated Research Application System (IRAS) ID: 312 747. Netherlands: Medical Research Ethics Committee (MREC) Oost-Nederland, ref: 2022-13623, NL-number: NL80258.091.22). Written informed consent was obtained from all subjects before the study. Any participant-derived benefits resulting from this research, such as new insights into disease mechanisms or possible novel therapies, will be disseminated to study participants, patient groups and members of the public. TRIAL REGISTRATION NUMBER: NCT05746221.