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Abstract 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 Aβ42 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.

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.

Neuropsychological tests are proliferating in Indonesia. So far, unfortunately, it is not accompanied by the development of a performance validity test (PVT). According to international neuropsychological standards, using PVTs is essential to determine the validity of the neuropsychological test results. To date, there is no single standardized PVT available in Indonesia. In this article, we describe (1) the concept of performance validity testing, (2) the detection strategy, and (3) the procedure of PVT. Furthermore, several factors which affect PVT failure and its implication on the interpretation of a neuropsychological assessment are discussed. Considering the importance of PVTs incorporation and that it has become a standard by some neuropsychological associations, it is crucial to develop PVTs in Indonesia. Finally, the utilization of PVT should be performed cautiously, as many factors might influence the PVT result.

Abstract In stressful or anxiety-provoking situations, most people with Parkinson’s disease (PD) experience a general worsening of motor symptoms, including their gait impairments. However, a proportion of patients actually report benefits from experiencing—or even purposely inducing—stressful or high-arousal situations. Using data from a large-scale international survey study among 4324 people with PD and gait impairments within the online Fox Insight (USA) and ParkinsonNEXT (NL) cohorts, we demonstrate that individuals with PD deploy an array of mental state alteration strategies to cope with their gait impairment. Crucially, these strategies differ along an axis of arousal—some act to heighten, whereas others diminish, overall sympathetic tone. Together, our observations suggest that arousal may act as a double-edged sword for gait control in PD. We propose a theoretical, neurobiological framework to explain why heightened arousal can have detrimental effects on the occurrence and severity of gait impairments in some individuals, while alleviating them in others. Specifically, we postulate that this seemingly contradictory phenomenon is explained by the inherent features of the ascending arousal system: namely, that arousal is related to task performance by an inverted u-shaped curve (the so-called Yerkes and Dodson relationship). We propose that the noradrenergic locus coeruleus plays an important role in modulating PD symptom severity and expression, by regulating arousal and by mediating network-level functional integration across the brain. The ability of the locus coeruleus to facilitate dynamic ‘cross-talk’ between distinct, otherwise largely segregated brain regions may facilitate the necessary cerebral compensation for gait impairments in PD. In the presence of suboptimal arousal, compensatory networks may be too segregated to allow for adequate compensation. Conversely, with supraoptimal arousal, increased cross-talk between competing inputs of these complementary networks may emerge and become dysfunctional. Because the locus coeruleus degenerates with disease progression, finetuning of this delicate balance becomes increasingly difficult, heightening the need for mental strategies to self-modulate arousal and facilitate shifting from a sub- or supraoptimal state of arousal to improve gait performance. Recognition of this underlying mechanism emphasises the importance of PD-specific rehabilitation strategies to alleviate gait disability.

Abstract Heterogeneity in Parkinson’s disease (PD) presents a barrier to understanding disease mechanisms and developing new treatments. This challenge may be partially overcome by stratifying patients into clinically meaningful subtypes. A recent subtyping scheme classifies de novo PD patients into three subtypes: mild-motor predominant, intermediate, or diffuse-malignant, based on motor impairment, cognitive function, rapid eye movement sleep behavior disorder (RBD) symptoms, and autonomic symptoms. We aimed to validate this approach in a large longitudinal cohort of early-to-moderate PD (n = 499) by assessing the influence of subtyping on clinical characteristics at baseline and on two-year progression. Compared to mild-motor predominant patients (42%), diffuse-malignant patients (12%) showed involvement of more clinical domains, more diffuse hypokinetic-rigid motor symptoms (decreased lateralization and hand/foot focality), and faster two-year progression. These findings extend the classification of diffuse-malignant and mild-motor predominant subtypes to early-to-moderate PD and suggest that different pathophysiological mechanisms (focal versus diffuse cerebral propagation) may underlie distinct subtype classifications.

Introduction Many individuals with acquired brain injury tend to experience problems with slowed information processing speed (IPS). A potentially beneficial and cost-effective supplement for cognitive rehabilitation of impaired IPS may be the implementation of serious gaming that focuses on compensatory learning as part of cognitive training. However, most digital platforms used during cognitive rehabilitation focus on restoring cognitive function and evidence for skill transfer from digital practice to everyday life is lacking. This study aims to investigate the efficacy of a game-supported cognitive strategy training. The training combines a well-validated time pressure management cognitive strategy training, targeting slowed IPS, with a novel game and a mobile application. The game-supported training focuses on the generalisation of strategy-use to untrained tasks in everyday life.Methods and analysis The study is designed as a randomised controlled trial in which the experimental group (Karman Line — Tempo module: an 8-week game-supported cognitive strategy training) will be compared with an active control group (CogniPlus training: an 8-week computerised cognitive function training). Data from 60 individuals with acquired brain injury (30 per group, ages between 16 and 75) will be collected at baseline (T0), post-treatment (T1) and at 3-month follow-up (T2). The primary outcome measure is an objective assessment of compensatory strategy use in an untrained experimental task. The secondary outcome is the attainment of trained and untrained treatment goals assessed by goal attainment scaling. Pre-training and post-training data will be analysed using a 2×2 repeated measure analysis of variance.Ethics and dissemination This study has been approved by the medical review ethics committee CMO Region Arnhem and Nijmegen (NL74818.091.20) and is registered in the Netherlands Trial Register. Research findings will be published in peer-reviewed journals and presented at conferences.Trial registration number NL9437; The Netherlands Trial Register.

Enzymatic hydrolysis of lactose is a crucial step to improve the efficiency and selectivity of membrane-based separations toward the recovery of milk oligosaccharides free from simple sugars. Response surface methodology was used to investigate the effects temperature (25.9 to 54.1 °C) and amount of enzyme (0.17 to 0.32% w/w) at 1, 2, and 4 h of reaction on the efficiency of lactose hydrolysis by Aspergillus oryzae β-galactosidase, preservation of major goat whey oligosaccharides, and on the de-novo formation of oligosaccharides. Lactose hydrolysis above 99% was achieved at 1, 2, and 4 h, not being significantly affected by temperature and amount of enzyme within the tested conditions. Formation of 4 Hexose (Hex) and 4 Hex 1 Hex and an increased de-novo formation of 2 Hex 1 N-Acetyl-Neuraminic Acid (NeuAc) and 2 Hex 1 N-Glycolylneuraminic acid (NeuGc) was observed in all treatments. Overall, processing conditions using temperatures ≤40 °C and enzyme concentration ≤0.25% resulted in higher preservation/formation of goat whey oligosaccharides.

Abstract Background With a growing, younger population of head and neck cancer survivors, attention to long-term side-effects of prior, often radiotherapeutic, treatment is warranted. Therefore, we studied the long-term cognitive effects in young adult patients irradiated for head and neck neoplasms (HNN). Methods Young to middle-aged adults with HNN (aged 18-40 years) and treated with unilateral neck irradiation ≥ 5 years before inclusion underwent cardiovascular risk and neuropsychological assessments and answered validated questionnaires regarding subjective cognitive complaints, fatigue, depression, quality of life, and cancer-specific distress. Additionally, magnetic resonance imaging (MRI) of the brain was performed to assess white matter hyperintensities (WMH), infarctions, and atrophy. Results Twenty-nine patients (aged 24–61, 13 men) median 9.2 [7.3–12.9] years post-treatment were included. HNN patients performed worse in episodic memory (Z-score = -1.16 [-1.58–0.34], p

(1) Background: The Wechsler intelligence scales are very popular in clinical practice and for research purposes. However, they are time consuming to administer. Therefore, researchers and psychologists have explored the possibility of shorter test battery compositions. (2) Methods: In this study, we investigated 13 potential short forms of the Indonesian version of the Wechsler Adult Intelligence Scale—Fourth Edition (WAIS-IV-ID). An existing standardization data set of 1745 Indonesian participants collected for the validation of the WAIS-IV-ID was used to examine the short forms’ validity. These ranged from 2-subtest versions to 7-subtest versions. Regression analyses with goodness-of-fit measures were performed, and regression equations were determined for each short form to estimate the Full Scale IQ (FSIQ) score. Discrepancies between the FSIQ and the estimated FSIQ (FSIQEst) scores were examined and classification accuracies were calculated for each short form (% agreement of intelligence classification between the FSIQEst and FSIQ). (3) Results: None of the 13 short form FSIQEst values significantly differed from the FSIQ scores based on the full WAIS-IV-ID, and strong correlations were observed between each of these values. The classification accuracies of the short forms were between 56.8% and 81.0%. The 4-subtest short form of the WAIS-IV-ID consisting of the subtests Matrix Reasoning, Information, Arithmetic, and Coding had the optimal balance between best classification values and a short administration duration. The validity of this short form was demonstrated in a second study in an independent sample (N = 20). (4) Conclusions: Based on the results presented here, the WAIS-IV-ID short forms are able to reliably estimate the FSIQ, with a significant shorter administration duration. The WAIS-IV-ID short form consisting of four subtests, Matrix Reasoning, Information, Arithmetic, and Coding, was the best version according to our criteria.

IntroductionPost-stroke fatigue is frequently present in young adults, but its underlying mechanism is still unclear. The aim of the study was to investigate the association between lesion location, network efficiency and chronic post-stroke fatigue based on voxel-based lesion-symptom mapping and structural network connectivity analysis.Patients and MethodsOne hundred and thirty five young patients, aged 18–50 years, with a first-ever transient ischemic attack or cerebral infarction from the Follow-Up of Transient ischemic attack and stroke patients and Unelucidated Risk factor Evaluation (FUTURE) study, underwent 1.5T MRI and were assessed for fatigue using the self-report Checklist Individual Strength. Stroke lesions were manually segmented, and structural network efficiency was calculated using the diffusion MRI-based brain networks and graph theory for each patient. Univariate and multivariate analyses was performed to study the associations between MRI parameters and chronic post-stroke fatigue. In addition, we used voxel-based lesion-symptom mapping to analyze the relationship between the lesion location and chronic post-stroke fatigue.ResultsMean age at index event was 39.0 years (SD ± 8.2), and mean follow-up duration was 11.0 years (SD ± 8.0). 50 patients (37%) had post-stroke fatigue. Voxel-based lesion-symptom mapping showed no significant relation between stroke lesions and the presence of chronic post-stroke fatigue. Furthermore, there were no significant associations between the lesion size or network efficiency, and the presence of chronic post-stroke fatigue.DiscussionWe did not find any association between stroke characteristics (lesion location and size) and chronic post-stroke fatigue (CIS20-R), nor associations between structural brain network connectivity and post-stroke fatigue on the long term in young stroke patients.

Abstract Background Recent evidence indicates that disrupted sleep could contribute to the development of Alzheimer’s disease by influencing the production and/or clearance of the amyloid-β protein. We set up a case-control study to investigate the association between long-term work-induced sleep disruption, cognitive function, and brain amyloid-β burden. Methods Nineteen male maritime pilots (aged 48–60 years) with chronic work-related sleep disruption and a sex-, age-, and education-matched control sample (n = 16, aged 50–60 years) with normal sleep completed the study. Primary sleep disorders were ruled out with in-lab polysomnography. Additional sleep measurements were obtained at home using actigraphy, sleep-wake logs, and a single-lead EEG device. Cognitive function was assessed with a neuropsychological test battery, sensitive to early symptomatic Alzheimer’s disease. Brain amyloid-β burden was assessed in maritime pilots using 18F-flutemetamol amyloid PET-CT. Results Maritime pilots reported significantly worse sleep quality (Pittsburgh Sleep Quality Index (PSQI) = 8.8 ± 2.9) during work weeks, compared to controls (PSQI = 3.2 ± 1.4; 95% CI 0.01 to 2.57; p = 0.049). This was confirmed with actigraphy-based sleep efficiency (86% ± 3.8 vs. 89.3% ± 4.3; 95% CI 0.43 to 6.03; p = 0.03). Home-EEG recordings showed less total sleep time (TST) and deep sleep time (DST) during work weeks compared to rest weeks (TST 318.56 (250.21–352.93) vs. TST 406.17 (340–425.98); p = 0.001; DST 36.75 (32.30–58.58) vs. DST 51.34 (48.37–69.30); p = 0.005)). There were no differences in any of the cognitive domains between the groups. For brain amyloid-β levels, mean global cortical standard uptake value ratios of 18F-flutemetamol were all in the normal range (1.009 ± 0.059; 95% CI 0.980 to 1.037), confirmed by visual reads. Conclusions Capitalizing on the particular work-rest schedule of maritime pilots, this study with a small sample size observed that long-term intermittent sleep disruption had no effects on global brain amyloid-β levels or cognitive function.

Abstract Background To develop a Korsakoff-specific measure of quality of life (QoL), to be rated by professional caregivers, and to field-test its psychometric properties in a sample of patients with Korsakoff’s syndrome (KS) living in a specialized nursing home. Methods A research version of the QUALIKO was developed based on an existing instrument for dementia (the QUALIDEM), literature review and two rounds of surveys among expert professionals involved in the care for patients with KS. Next, QoL was independently rated using the preliminary QUALIKO for 77 patients with KS by two primary caregivers. Results The research QUALIKO consisted of 48 items describing observable behaviors across ten aspects of QoL relevant to patients with KS. Six items demonstrated poor scalability in the field test. The remaining 42 items all formed subscales with moderate to strong scalability according to Mokken scale analysis. Reliability was acceptable to good across both raters for all subscales (Mokken rho’s = 0.70–0.90), except for the two 2-item subscales of negative affect and positive self-image (Mokken rho’s = 0.47–0.71). Inter-observer agreement was excellent for five subscales (ICCs = 0.75–0.89) and fair to moderate for the other five subscales (ICCs = 0.59–0.72). The multidimensional internal structure was confirmed and all subscales were significantly correlated with primary caregivers’ global ratings of QoL except for positive self-image. Missing item values were low and floor and ceiling effects acceptable for most subscales. Conclusions The QUALIKO holds promise as a feasible, reliable, and valid measure of QoL in residential KS patients. Future research in larger samples is needed to confirm the psychometric dimensionality of the instrument, to gather normative data and to examine its test-retest reliability.

Abstract Background Primary aim of this study was to compare cognitive performance of patients with chronic Q fever or Q fever fatigue syndrome (QFS) to matched controls from the general population, while taking performance validity into account. Second, we investigated whether objective cognitive performance was related to subjective cognitive complaints or psychological wellbeing. Methods Cognitive functioning was assessed with a neuropsychological test battery measuring the domains of processing speed, episodic memory, working memory and executive functioning. Tests for performance validity and premorbid intelligence were also included. Validated questionnaires were administered to assess self-reported fatigue, depressive symptoms and cognitive complaints. Results In total, 30 patients with chronic Q fever, 32 with QFS and 35 controls were included. A high percentage of chronic Q fever patients showed poor performance validity (38%) compared to controls (14%, p = 0.066). After exclusion of participants showing poor performance validity, no significant differences between patients and controls were found in the cognitive domains. QFS patients reported a high level of cognitive complaints compared to controls (41.2 vs 30.4, p = 0.023). Cognitive complaints were not significantly related to cognitive performance in any of the domains for this patient group. Conclusions The high level of self-reported cognitive complaints in QFS patients does not indicate cognitive impairment. A large proportion of the chronic Q fever patients showed suboptimal mental effort during neuropsychological assessment. More research into the underlying explanations is needed. Our findings stress the importance of assessing cognitive functioning by neuropsychological examination including performance validity, rather than only measuring subjective cognitive complaints.

Abstract Background Sedentary behaviour might be a potential risk factor for cognitive decline. However, the short-term effects of sedentary behaviour on (cerebro) vascular and cognitive performance in older people are unknown. Methods We used a cross-over design with 22 older adults (78 years, 9 females) to assess the short-term hemodynamic and cognitive effects of three hours uninterrupted sitting and explored if these effects can be counteracted with regular (every 30 min) two-minute walking breaks. In addition, we investigated if low versus high mental activity during the three hours of sitting modified these effects. Before and after each condition, alertness, executive functioning, and working memory were assessed with the Test of Attentional Performance battery. Additionally, cerebral blood flow velocity (Transcranial Doppler) and blood pressure (Finapres) were measured in rest, and during sit-to-stand and CO2 challenges to assess baroreflex sensitivity, cerebral autoregulation, and cerebral vasomotor reactivity. Results No short-term differences were observed in cognitive performance, cerebral blood flow velocity, baroreflex sensitivity, cerebral autoregulation, or cerebral vasomotor reactivity across time, or between conditions. Blood pressure and cerebrovascular resistance increased over time (8.6 mmHg (5.0;12.1), p