Knowledge, health beliefs and attitudes towards dementia and dementia risk reduction among descendants of people with dementia: a qualitative study using focus group discussions.

BACKGROUND: Individuals with a parental family history of dementia have an increased risk of developing dementia because they share their genes as well as their psychosocial behaviour. Due to this increased risk and their experience with dementia, they may be particularly eager to receive information regarding dementia risk reduction (DRR). This study evaluated the knowledge, beliefs and attitudes towards dementia and DRR among descendants of people with dementia. METHOD: Using a semi-structured topic guide, three focus group discussions were conducted consisting of 12 female (80%) and 3 male (20%) descendants of people with dementia with a mean (± SD) age of 48.8 (± 12) years. Focus group discussions were audio recorded and transcribed. Each transcript was analysed thoroughly, and where appropriate, a code was generated and assigned by two researchers independently. Then, similar codes were grouped together and categorized into themes. RESULTS: The items in the topic guide could only be addressed after participants had been given the opportunity to share their experiences of having a parent with dementia. Participants were unaware or uncertain about the possibility of reducing the risk of developing dementia and therefore hesitant to assess their dementia risk without treatment options in sight. Moreover, participants indicated that their general practitioner only gave some information on heritability, not on DRR. Although participants identified a large number of modifiable risk factors as a group during the group discussions, they were eager to receive more information on dementia and DRR. In the end, participants adopted a more positive attitude towards a DRR programme and provided suggestions for the development of future DRR programmes. CONCLUSIONS: Although the research aim was to evaluate the knowledge, beliefs and attitudes towards dementia and DRR, sharing experiences of having a parent with dementia seemed a prerequisite for considering participants' own risk of developing dementia and participating in a DRR programme. Knowledge of dementia and DRR was limited. Due to unawareness of the possibility of reducing dementia risk, participants were hesitant about assessing their dementia risk. Group discussions positively changed the perception of dementia risk assessment and participants' willingness to participate in a DRR programme.

[Detection and prevention in later life: risk profiles for physical, psychological, social and environmental frailty.] / Detectie en preventie van kwetsbaarheid: Op zoek naar risicoprofielen voor fysieke, psychische, sociale en omgevingskwetsbaarheid.

In order to provide proactive care and support for older people attention is needed for the prevention of frailty among older adults. Subsequently, accurate case finding of those who are more at risk of becoming frail is crucial to undertake specific preventive actions. This study investigates frailty and risk profiles of frailty among older people in order to support proactive detection. Hereby, frailty is conceived not only as a physical problem, but also refers to emotional, social, and environmental hazards. Using data generated from the Belgian Ageing Studies (N = 21,664 home-dwelling older people), a multinomial logistic regression model was tested which included socio-demographic and socio-economic indicators as well as the four dimensions of frailty (physical, social, psychological and environmental). Findings indicate that for both men and women having moved in the previous 10 years and having a lower household income are risk factors of becoming multidimensional frail. However, studying the different frailty domains, several risk profiles arise (e. g. marital status is important for psychological frailty), and gender-specific risk groups are detected (e. g. non-married men). This paper elaborates on practical implications and formulates a number of future research recommendations to tackle frailty in an ageing society.

The C9orf72 repeat size correlates with onset age of disease, DNA methylation and transcriptional downregulation of the promoter.

Pathological expansion of a G4C2 repeat, located in the 5' regulatory region of C9orf72, is the most common genetic cause of frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). C9orf72 patients have highly variable onset ages suggesting the presence of modifying factors and/or anticipation. We studied 72 Belgian index patients with FTLD, FTLD-ALS or ALS and 61 relatives with a C9orf72 repeat expansion. We assessed the effect of G4C2 expansion size on onset age, the role of anticipation and the effect of repeat size on methylation and C9orf72 promoter activity. G4C2 expansion sizes varied in blood between 45 and over 2100 repeat units with short expansions (45-78 units) present in 5.6% of 72 index patients with an expansion. Short expansions co-segregated with disease in two families. The subject with a short expansion in blood but an indication of mosaicism in brain showed the same pathology as those with a long expansion. Further, we provided evidence for an association of G4C2 expansion size with onset age (P<0.05) most likely explained by an association of methylation state of the 5' flanking CpG island and expansion size in blood (P<0.0001) and brain (P<0.05). In several informative C9orf72 parent-child transmissions, we identified earlier onset ages, increasing expansion sizes and/or increasing methylation states (P=0.0034) of the 5' CpG island, reminiscent of disease anticipation. Also, intermediate repeats (7-24 units) showed a slightly higher methylation degree (P<0.0001) and a decrease of C9orf72 promoter activity (P<0.0001) compared with normal short repeats (2-6 units). Decrease of transcriptional activity was even more prominent in the presence of small deletions flanking G4C2 (P<0.0001). Here we showed that increased methylation of CpGs in the C9orf72 promoter may explain how an increasing G4C2 size lead to loss-of-function without excluding repeat length-dependent toxic gain-of-function. These data provide insights into disease mechanisms and have important implications for diagnostic counseling and potential therapeutic approaches.

Weight loss and undernutrition in community-dwelling patients with Alzheimer's dementia: From population based studies to clinical management.

Weight loss and undernutrition are commonly described in patients with Alzheimer's disease (AD) and have been associated with various adverse outcomes. Therefore, it is important to know what the best approach is to community-dwelling AD patients with a risk of developing a poor nutritional status; however, there is currently no evidence on which to base nutritional recommendations. Expert based recommendations are that the nutritional status should be part of the work-up of all AD patients. If weight loss of 5% or more has occurred in 3-6 months or if the mini-nutritional assessment (MNA) classifies a patient as undernourished, a nutritional intervention should be started. The intervention should be multifactorial and encompass treatment of the underlying proposed causes and risk factors of weight loss and undernutrition as well as improvement of the nutritional status by increasing energy and protein intake combined with daily physical activity.

Increased expression of BIN1 mediates Alzheimer genetic risk by modulating tau pathology.

Genome-wide association studies (GWAS) have identified a region upstream the BIN1 gene as the most important genetic susceptibility locus in Alzheimer's disease (AD) after APOE. We report that BIN1 transcript levels were increased in AD brains and identified a novel 3 bp insertion allele ∼28 kb upstream of BIN1, which increased (i) transcriptional activity in vitro, (ii) BIN1 expression levels in human brain and (iii) AD risk in three independent case-control cohorts (Meta-analysed Odds ratio of 1.20 (1.14-1.26) (P=3.8 × 10(-11))). Interestingly, decreased expression of the Drosophila BIN1 ortholog Amph suppressed Tau-mediated neurotoxicity in three different assays. Accordingly, Tau and BIN1 colocalized and interacted in human neuroblastoma cells and in mouse brain. Finally, the 3 bp insertion was associated with Tau but not Amyloid loads in AD brains. We propose that BIN1 mediates AD risk by modulating Tau pathology.

Psychosocial problems associated with depression at 18 months poststroke.

OBJECTIVE: With a prevalence that varies between 20% and 65%, poststroke depression (PSD) is a frequent sequel of stroke. The aim of this study was to determine incidence and risk factors for PSD 18 months after stroke. METHODS: As part of the Middelheim Interdisciplinary Stroke Study, patients were followed up for 18 months in this prospective and longitudinal epidemiological study. Clinically significant signs and symptoms of PSD were quantified by means of the Cornell Scale for Depression (CSD) and the Montgomery and Åsberg Depression Rating Scale. Activities, including social activities, were measured with the Stroke Impact Scale (SIS). Relational problems since stroke onset were defined by a questionnaire. RESULTS: Data analysis was performed on 125 patients who completed follow-up assessments. Depression (CSD score ≥8) was diagnosed in 28% of the patients. Patients with PSD were more dependent for activities of daily living and displayed more physical and cognitive impairment than patients without PSD. The risk to become depressed decreased with 5% when the patient's activities increased with one unit on the SIS (odds ratio (OR) = 0.95; 95% confidence interval (CI) = 0.93-0.97). Patients with persistent relational problems since stroke onset had approximately four and a half times greater risk of becoming depressed than patients without (OR = 4.48; 95%CI = 1.17-16.87). CONCLUSIONS: Multiple regression models indicated that the most determining features for developing PSD at 18 months poststroke include reduced activity and relationship problems due to stroke. Further studies on risk factors for PSD are essential, including psychosocial aspects, given its negative impact on rehabilitation and quality of life.

Plasma proteome profiling identifies changes associated to AD but not to FTD.

BACKGROUND: Frontotemporal dementia (FTD) is caused by frontotemporal lobar degeneration (FTLD), characterized mainly by inclusions of Tau (FTLD-Tau) or TAR DNA binding43 (FTLD-TDP) proteins. Plasma biomarkers are strongly needed for specific diagnosis and potential treatment monitoring of FTD. We aimed to identify specific FTD plasma biomarker profiles discriminating FTD from AD and controls, and between FTD pathological subtypes. In addition, we compared plasma results with results in post-mortem frontal cortex of FTD cases to understand the underlying process. METHODS: Plasma proteins (n = 1303) from pathologically and/or genetically confirmed FTD patients (n = 56; FTLD-Tau n = 16; age = 58.2 ± 6.2; 44% female, FTLD-TDP n = 40; age = 59.8 ± 7.9; 45% female), AD patients (n = 57; age = 65.5 ± 8.0; 39% female), and non-demented controls (n = 148; 61.3 ± 7.9; 41% female) were measured using an aptamer-based proteomic technology (SomaScan). In addition, exploratory analysis in post-mortem frontal brain cortex of FTD (n = 10; FTLD-Tau n = 5; age = 56.2 ± 6.9, 60% female, and FTLD-TDP n = 5; age = 64.0 ± 7.7, 60% female) and non-demented controls (n = 4; age = 61.3 ± 8.1; 75% female) were also performed. Differentially regulated plasma and tissue proteins were identified by global testing adjusting for demographic variables and multiple testing. Logistic lasso regression was used to identify plasma protein panels discriminating FTD from non-demented controls and AD, or FTLD-Tau from FTLD-TDP. Performance of the discriminatory plasma protein panels was based on predictions obtained from bootstrapping with 1000 resampled analysis. RESULTS: Overall plasma protein expression profiles differed between FTD, AD and controls (6 proteins; p = 0.005), but none of the plasma proteins was specifically associated to FTD. The overall tissue protein expression profile differed between FTD and controls (7-proteins; p = 0.003). There was no difference in overall plasma or tissue expression profile between FTD subtypes. Regression analysis revealed a panel of 12-plasma proteins discriminating FTD from AD with high accuracy (AUC: 0.99). No plasma protein panels discriminating FTD from controls or FTD pathological subtypes were identified. CONCLUSIONS: We identified a promising plasma protein panel as a minimally-invasive tool to aid in the differential diagnosis of FTD from AD, which was primarily associated to AD pathophysiology. The lack of plasma profiles specifically associated to FTD or its pathological subtypes might be explained by FTD heterogeneity, calling for FTD studies using large and well-characterize cohorts.

iPSC-derived cortical neurons to study sporadic Alzheimer disease: A transcriptome comparison with post-mortem brain samples.

Alzheimer's disease (AD) is the most common cause of dementia, characterized by the progressive impairment of cognition and memory loss. Sporadic AD (sAD) represents approximately 95 % of the AD cases and is induced by a complex interplay between genetic and environmental factors called "Alzheimerogens". Heavy metals (e.g. copper) and pesticides (e.g. fipronil) can affect many AD-related processes, including neuroinflammation (considered as AD-inducing factor). Research would benefit from in vitro models to investigate effects of Alzheimerogens. We compared transcriptomics changes in sAD induced pluripotent stem cell (iPSC) derived cortical neurons to differentially expressed genes (DEGs) identified in post-mortem AD brain tissue. These analyses showed that many AD-related processes could be identified in the sAD iPSC-derived neurons, and furthermore, could even identify more DEGs functioning in these processes than post-mortem AD-brain tissue. Thereafter, we exposed the iPSCs to AD-inducing factors (copper(II)chloride, fipronil sulfone and an inflammatory cytokine cocktail). Cytokine exposure induced expression of immune related genes while copper-exposure affected genes involved in lipid and cholesterol metabolism, which are known AD-related processes. Fipronil-exposure did not result in significant transcriptomic changes, although prolonged exposures or higher doses may be necessary. Overall, we show that iPSC-derived cortical neurons can be beneficial in vitro models to identify Alzheimerogens and AD-related molecular mechanisms.

The Effect of Tryptophan 2,3-Dioxygenase Inhibition on Kynurenine Metabolism and Cognitive Function in the APP23 Mouse Model of Alzheimer's Disease.

Alzheimer's disease (AD) is associated with progressive endogenous neurotoxicity and hampered inflammatory regulation. The kynurenine (Kyn) pathway, which is controlled by tryptophan 2,3-dioxygenase (TDO), produces neuroactive and anti-inflammatory metabolites. Age-related Kyn pathway activation might contribute to AD pathology in humans, and inhibition of TDO was found to reduce AD-related cellular toxicity and behavioral deficits in animal models. To further explore the effect of aging on the Kyn pathway in the context of AD, we analyzed Kyn metabolite profiles in serum and brain tissue of the APP23 amyloidosis mouse model. We found that aging had genotype-independent effects on Kyn metabolite profiles in serum, cortex, hippocampus and cerebellum, whereas serum concentrations of many Kyn metabolites were reduced in APP23 mice. Next, to further establish the role of TDO in AD-related behavioral deficits, we investigated the effect of long-term pharmacological TDO inhibition on cognitive performance in APP23 mice. Our results indicated that TDO inhibition reversed recognition memory deficits without producing measurable changes in cerebral Kyn metabolites. TDO inhibition did not affect spatial learning and memory or anxiety-related behavior. These data indicate that age-related Kyn pathway activation is not specific for humans and could represent a cross-species phenotype of aging. These data warrant further investigation on the role of peripheral Kyn pathway disturbances and cerebral TDO activity in AD pathophysiology.

Fabry disease in a patient with Turner syndrome.

We report a unique case with co-occurrence of Turner syndrome and Fabry disease (OMIM #301500). The latter is a rare X-linked lysosomal storage disease that is characterized by partial or complete deficiency of alpha-galactosidase A (GLA; EC 3.2.1.22) following mutations in the gene (GLA) localized at Xq22.1. Accumulation of metabolic intermediates can occur in many tissues and leads to severe morbidity, especially due to renal failure, cardiac involvement and stroke. It is well established that hemizygous male mutation carriers with Fabry disease are generally more severely affected than heterozygous female mutation carriers, but disabling clinical features and disease progression often occur in female Fabry patients as well. The majority of this patient's cells are of the 45,X type, making her a hemizygous GLA mutation carrier displaying a very severe Fabry disease phenotype.

The normal phenotype of Pmm1-deficient mice suggests that Pmm1 is not essential for normal mouse development.

Phosphomannomutases (PMMs) are crucial for the glycosylation of glycoproteins. In humans, two highly conserved PMMs exist: PMM1 and PMM2. In vitro both enzymes are able to convert mannose-6-phosphate (mannose-6-P) into mannose-1-P, the key starting compound for glycan biosynthesis. However, only mutations causing a deficiency in PMM2 cause hypoglycosylation, leading to the most frequent type of the congenital disorders of glycosylation (CDG): CDG-Ia. PMM1 is as yet not associated with any disease, and its physiological role has remained unclear. We generated a mouse deficient in Pmm1 activity and documented the expression pattern of murine Pmm1 to unravel its biological role. The expression pattern suggested an involvement of Pmm1 in (neural) development and endocrine regulation. Surprisingly, Pmm1 knockout mice were viable, developed normally, and did not reveal any obvious phenotypic alteration up to adulthood. The macroscopic and microscopic anatomy of all major organs, as well as animal behavior, appeared to be normal. Likewise, lectin histochemistry did not demonstrate an altered glycosylation pattern in tissues. It is especially striking that Pmm1, despite an almost complete overlap of its expression with Pmm2, e.g., in the developing brain, is apparently unable to compensate for deficient Pmm2 activity in CDG-Ia patients. Together, these data point to a (developmental) function independent of mannose-1-P synthesis, whereby the normal knockout phenotype, despite the stringent conservation in phylogeny, could be explained by a critical function under as-yet-unidentified challenge conditions.

Verbal cued recall as a predictor of conversion to Alzheimer's disease in Mild Cognitive Impairment.

OBJECTIVE: This study was set up to investigate whether neuropsychological tests are able to predict conversion to AD among Mild Cognitive Impairment (MCI) patients. METHODS: At baseline the cognitive part of the Cambridge Examination for Mental Disorders of the Elderly (CAMCOG), the Mini Mental Status Examination (MMSE), the Geriatric Depression Scale (GDS), a Dutch variation of Rey's Auditory Verbal Learning Test, the Memory Impairment Screen plus (MISplus) and the Visual Association Test (VAT) were administered to 40 patients diagnosed with MCI. After 18 months, MCI-patients were reassessed and a follow-up diagnosis was established. Of those who were seen for follow-up (n = 31), seven fulfilled (NINCDS-ADRDA) criteria of probable AD, while 24 did not convert. RESULTS: A binary logistic regression analysis showed that the MISplus contributed most to the prediction of conversion (OR = 0.28, 95% CI 0.099-0.790). With a cut-off of 2 out of 6, a positive predictive value of 71.5%, a negative predictive value of 91.5% and an overall diagnostic accuracy of 87.0% were achieved. CONCLUSIONS: This prospective, longitudinal study shows that a score of 0 or 1 out of 6 on the MISplus may be a good indicator of future (within 18 months) progression to AD among MCI-patients.

A worldwide multicentre comparison of assays for cerebrospinal fluid biomarkers in Alzheimer's disease.

BACKGROUND: Different cerebrospinal fluid (CSF) amyloid-beta 1-42 (Abeta(1-42)), total Tau (Tau) and Tau phosphorylated at threonine 181 (P-Tau) levels are reported, but currently there is a lack of quality control programmes. The aim of this study was to compare the measurements of these CSF biomarkers, between and within centres. METHODS: Three CSF-pool samples were distributed to 13 laboratories in 2004 and the same samples were again distributed to 18 laboratories in 2008. In 2004 six laboratories measured Abeta(1-42), Tau and P-Tau and seven laboratories measured one or two of these marker(s) by enzyme-linked immunosorbent assays (ELISAs). In 2008, 12 laboratories measured all three markers, three laboratories measured one or two marker(s) by ELISAs and three laboratories measured the markers by Luminex. RESULTS: In 2004, the ELISA intercentre coefficients of variance (interCV) were 31%, 21% and 13% for Abeta(1-42), Tau and P-Tau, respectively. These were 37%, 16% and 15%, respectively, in 2008. When we restricted the analysis to the Innotest (N = 13) for Abeta(1-42), lower interCV were calculated (22%). The centres that participated in both years (N = 9) showed interCVs of 21%, 15% and 9% and intra-centre coefficients (intraCV) of variance of 25%,18% and 7% in 2008. CONCLUSIONS: The highest variability was found for Abeta(1-42). The variabilities for Tau and P-Tau were lower in both years. The centres that participated in both years showed a high intraCV comparable to their interCV, indicating that there is not only a high variation between but also within centres. Besides a uniform standardization of (pre)analytical procedures, the same assay should be used to decrease the inter/intracentre variation.

Organisation of inhospital acute stroke care and minimum criteria for stroke care units. Recommendations of the Belgian Stroke Council.

There is ample evidence from randomized trials that for patients with stroke, stroke unit care is superior to care in general medical or neurological wards. This evidence, which has been adopted by international guidelines has to be implemented into daily stroke care. This consensus document prepared by the Belgian Stroke Council provides a set of minimum criteria to meet international standards for stroke care. It is intended to provide help in the creation of stroke units in centers who do not currently have one and to provide a benchmark for centres already having organised stroke care.

Progranulin locus deletion in frontotemporal dementia.

Ubiquitin-positive, tau-negative, frontotemporal dementia (FTD) is caused by null mutations in progranulin (PGRN; HUGO gene symbol GRN), suggesting a haploinsufficiency mechanism. Since whole gene deletions also lead to the loss of a functional allele, we performed systematic quantitative analyses of PGRN in a series of 103 Belgian FTD patients. We identified in one patient (1%) a genomic deletion that was absent in 267 control individuals. The deleted segment was between 54 and 69 kb in length and comprised PGRN and two centromeric neighboring genes RPIP8 (HUGO gene symbol RUNDC3A) and SLC25A39. The patient presented clinically with typical FTD without additional symptoms, consistent with haploinsufficiency of PGRN being the only gene contributing to the disease phenotype. This study demonstrates that reduced PGRN in absence of mutant protein is sufficient to cause neurodegeneration and that previously reported PGRN mutation frequencies are underestimated.

Development of screening guidelines and clinical criteria for predementia Alzheimer's disease. The DESCRIPA Study.

BACKGROUND: There is an urgent need to identify subjects with Alzheimer's disease (AD) in the predementia phase, but validated diagnostic approaches are currently lacking. In this paper, we present the background, design and methods of a study, which aims to develop clinical criteria for predementia AD. We also present baseline characteristics of the subjects included. The study was part of the multicentre DESCRIPA project, which is being conducted within the network of the European Alzheimer's Disease Consortium. METHODS: Clinical criteria will be based on a prospective cohort study of non-demented subjects older than 55 years and referred to a memory clinic. At baseline, a number of markers and risk factors for AD were collected, including demographic variables, measures of performance in activities of daily living, cognitive, neuroimaging and genetic markers, and serum and cerebrospinal fluid markers. Subjects will be reassessed annually for 2-3 years, and we will evaluate which combination of variables best predicts AD-type dementia at follow-up. RESULTS: Between 2003 and 2005, 881 subjects were included from 20 memory clinics. Subjects were on average 70.3 years old, and had 10.4 years of education. The average score on the Mini-Mental State Examination was 27.4.

Actigraphic measurement of motor deficits in acute ischemic stroke.

BACKGROUND: This study aimed to investigate the use of actigraphy (accelerometry) to measure disuse of the impaired arm in acute stroke patients. We correlated the National Institute of Health Stroke Scale (NIHSS) and the Fugl-Meyer Assessment arm section (FMA) findings with actigraphic data as a measure of validity. METHODS: Thirty-nine acute ischemic stroke patients were included within 1 week after stroke onset. At inclusion, motor deficits were assessed by the NIHSS, FMA and 48-hour actigraphic recordings of both wrists were performed. RESULTS: Moderate but highly significant correlations (Spearman's rho) between actigraphic recordings and total NIHSS (ratio r = -0.59 and activity of impaired arm r = -0.75; p < 0.001) and FMA (ratio r = 0.54 and activity of impaired arm r = 0.69; p < 0.001) scores were found. Based on actigraphic motor activity scores, ROC curves were calculated following dichotomization of the population based on NIHSS = 7 and FMA = 45, showing good sensitivity and specificity, with negative predictive value of 100% and positive predictive value of 91% for the ratio variable. CONCLUSIONS: Moderate but highly significant correlations were found between actigraphy and the stroke scales NIHSS and FMA. Actigraphy was able to reliably discriminate less impaired from more impaired stroke patients with excellent sensitivity and specificity values. Actigraphy is a simple, valid, objective and reliable clinical research tool that can be used to determine motor impairment of the upper limb in stroke patients.

Procarboxypeptidase U (proCPU, TAFI, proCPB2) in cerebrospinal fluid during ischemic stroke is associated with stroke progression, outcome and blood-brain barrier dysfunction.

Essentials Little is known of procarboxypeptidase U (proCPU) in cerebrospinal fluid (CSF) of stroke patients. ProCPU levels were studied in CSF of controls and non-thrombolyzed acute ischemic stroke patients. ProCPU is elevated in CSF of stroke patients compared with controls. ProCPU in CSF correlates with stroke progression, outcome, and blood-brain barrier dysfunction. SUMMARY: Background Procarboxypeptidase U (proCPU, TAFI, proCPB2), the zymogen of CPU, which is a potent antifibrinolytic enzyme and a modulator of inflammation, has previously been investigated in plasma of stroke patients, but so far, no information on the proCPU levels in cerebrospinal fluid (CSF) during acute ischemic stroke (AIS) is available. Objectives This case-control observational study investigates proCPU in CSF of AIS patients compared with controls with an intact blood-brain barrier (BBB) and evaluates the relationship of CSF/plasma proCPU ratios with stroke parameters. Methods A sensitive HPLC-based enzymatic assay was used to determine proCPU levels in CSF of non-thrombolyzed patients in the hyperacute phase (< 24 h after onset) of AIS (n = 72). Individuals (n = 32) without stroke, an intact BBB and no apparent abnormalities in biochemical and microbiological tests, served as controls. Relations between the CSF/plasma proCPU ratio and (i) stroke severity, (ii) stroke progression/recurrence, (iii) stroke outcome and (iv) BBB dysfunction (CSF/serum albumin ratio) were assessed. Results Mean (SEM) proCPU levels were elevated in the CSF of stroke patients compared with controls (4.36 (0.23) U L-1 vs. 3.50 (0.23) U L-1 ). Higher median [IQR] CSF/plasma proCPU ratios were found in patients with stroke progression ((6.0 [4.2-6.9]) × 10-3 ) and poor outcome ((6.4 [3.9-7.0]) × 10-3 ) after 3 months (modified Rankin Scale; mRS > 3) compared with patients without progression ((3.9 [2.7-5.4]) × 10-3 ) or better outcome ((4.0 [2.8-5.0]) × 10-3 ). In stroke patients with a disrupted BBB, proCPU ratios were higher compared with stroke patients with an intact BBB ((6.4 [5.8-9.0]) × 10-3 vs. (3.7 [2.8-5.0]) × 10-3 ). Conclusions ProCPU is increased in CSF during hyperacute ischemic stroke and is associated with stroke progression and outcome after 3 months, most likely due to BBB dysfunction in the hyperacute phase of ischemic stroke.

Burrowing as a novel voluntary strength training method for mice: A comparison of various voluntary strength or resistance exercise methods.

BACKGROUND: Voluntary strength training methods for rodents are necessary to investigate the effects of strength training on cognition and the brain. However, few voluntary methods are available. NEW METHOD: The current study tested functional and muscular effects of two novel voluntary strength training methods, burrowing (digging a substrate out of a tube) and unloaded tower climbing, in male C57Bl6 mice. To compare these two novel methods with existing exercise methods, resistance running and (non-resistance) running were included. Motor coordination, grip strength and muscle fatigue were measured at baseline, halfway through and near the end of a fourteen week exercise intervention. Endurance was measured by an incremental treadmill test after twelve weeks. RESULTS: Both burrowing and resistance running improved forelimb grip strength as compared to controls. Running and resistance running increased endurance in the treadmill test and improved motor skills as measured by the balance beam test. Post-mortem tissue analyses revealed that running and resistance running induced Soleus muscle hypertrophy and reduced epididymal fat mass. Tower climbing elicited no functional or muscular changes. COMPARISON WITH EXISTING METHODS: As a voluntary strength exercise method, burrowing avoids the confounding effects of stress and positive reinforcers elicited in forced strength exercise methods. Compared to voluntary resistance running, burrowing likely reduces the contribution of aerobic exercise components. CONCLUSIONS: Burrowing qualifies as a suitable voluntary strength training method in mice. Furthermore, resistance running shares features of strength training and endurance (aerobic) exercise and should be considered a multi-modal aerobic-strength exercise method in mice.

Crossed Cerebellar Diaschisis in Alzheimer's Disease.

BACKGROUND: We describe the phenomenon of crossed cerebellar diaschisis (CCD) in four subjects diagnosed with Alzheimer's disease (AD) according to the National Institute on Aging - Alzheimer Association (NIA-AA) criteria, in combination with 18F-FDG PET and 11C-PiB PET imaging. METHODS: 18F-FDG PET showed a pattern of cerebral metabolism with relative decrease most prominent in the frontal-parietal cortex of the left hemisphere and crossed hypometabolism of the right cerebellum. 11C-PiB PET showed symmetrical amyloid accumulation, but a lower relative tracer delivery (a surrogate of relative cerebral blood flow) in the left hemisphere. CCD is the phenomenon of unilateral cerebellar hypometabolism as a remote effect of supratentorial dysfunction of the brain in the contralateral hemisphere. The mechanism implies the involvement of the cortico-ponto-cerebellar fibers. The pathophysiology is thought to have a functional or reversible basis but can also reflect in secondary morphologic change. CCD is a well-recognized phenomenon, since the development of new imaging techniques, although scarcely described in neurodegenerative dementias. RESULTS: To our knowledge this is the first report describing CCD in AD subjects with documentation of both 18F-FDG PET and 11C-PiB PET imaging. CCD in our subjects was explained on a functional basis due to neurodegenerative pathology in the left hemisphere. There was no structural lesion and the symmetric amyloid accumulation did not correspond with the unilateral metabolic impairment. CONCLUSION: This suggests that CCD might be caused by non-amyloid neurodegeneration. The pathophysiological mechanism, clinical relevance and therapeutic implications of CCD and the role of the cerebellum in AD need further investigation.