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.

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.

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.

The MMSE should not be the sole indicator of fitness to drive in mild Alzheimer's dementia.

Since Alzheimer's disease may affect driving performance, patients with Alzheimer's disease are assessed on fitness to drive. On-road driving assessments are widely used, and attempts have also been made to develop strategies to assess fitness to drive in a clinical setting. Preferably, a first indication of fitness to drive is obtained quickly after diagnosis using a single test such as the Mini-Mental State Examination (MMSE). The aim of this study is to investigate whether the MMSE can be used to predict whether patients with Alzheimer's disease will pass or fail an on-road driving assessment. Patients with Alzheimer's disease (n = 81) participated in a comprehensive fitness-to-drive assessment which included the MMSE as well as an on-road driving assessment [PLoS One 11(2):e0149566, 2016]. MMSE cutoffs were applied as suggested by Versijpt and colleagues [Acta Neurol Belg 117(4):811-819, 2017]. All patients with Alzheimer's disease who scored below the lower cutoff (MMSE ≤ 19) failed the on-road driving assessment. However, a third of the patients with Alzheimer's disease who scored above the upper cutoff (MMSE ≥ 25) failed the on-road driving assessment as well. We conclude that the MMSE alone has insufficient predictive value to correctly identify fitness to drive in patients with very mild-to-mild Alzheimer's disease implicating the need for comprehensive assessments to determine fitness to drive in a clinical setting.

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.

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.

[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.

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.

Behavioural characterization of AnkyrinG deficient mice, a model for ANK3 related disorders.

ANK3 encodes AnkyrinG (AnkG), a member of the Ankyrin family that is expressed in several different isoforms in many tissues. A unique serine-rich domain and tail domain in the two largest isoforms of AnkG (270 and 480kDa), restrict AnkG to the axon initial segment and nodes of Ranvier of myelinated neurons. At these sites, AnkG is a master regulator, coordinating the strict clustering of components necessary for proper action potential initiation and propagation along the axon. These components include voltage-gated sodium channels, potassium channels and members of the L1 cell adhesion molecule family. Genetic variation in the ANK3 gene has been linked to a range of neuropsychiatric and neurodevelopmental disorders in human, including schizophrenia, bipolar disorder, intellectual disability and autism spectrum disorders. Here, we study the effect of reduced expression of the large isoforms of Ank3 on cognition and behaviour using a heterozygous knockout mouse model. In three independent behavioural tests, being the open field test, elevated plus maze and social interaction test, we found evidence for increased anxiety in our Ank3 mouse model. Besides, we observed specific neuroanatomical defects in heterozygous knockout mice, including a smaller cingulate cortex, granular retrosplenial cortex, primary motor cortex and fimbria of the hippocampus.

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.

Poststroke depression and its multifactorial nature: results from a prospective longitudinal study.

OBJECTIVE: Poststroke depression (PSD) is commonly observed in stroke patients and has a negative impact on functional outcome and quality of life. Therefore, a prospective, longitudinal epidemiological study was conducted aiming to determine prevalence and risk factors for PSD at 1, 3, 6, 12 and 18 months poststroke. METHODS: A total of 222 patients were included in the study and 201 patients entered data analysis. Demographic data, vascular risk factors, stroke characteristics, functional and neurocognitive outcome measures and psychosocial factors were considered as potential risk factors for PSD. 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 (MADRS). RESULTS: PSD was present at 1, 3, 6, 12 and 18 months poststroke in 24.5%, 27.1%, 28.3%, 19.8% and 26.3% of the patients respectively. Univariate regression analyses revealed that PSD was significantly associated with stroke severity, physical disability, cognitive impairment and stroke outcome during the 18 months time frame of the study. Reduced social activities and the presence of apraxia were consistently associated with PSD whereas aphasia was only significantly associated in the first 6 months after stroke. Patients with relational problems had a 3 times greater risk of becoming depressed at 18 months poststroke than patients without relational problems (OR=3.09; 95% CI=1.31-7.26). CONCLUSIONS: Risk factors for PSD seem variable indicating the need for clinicians to consider the dynamic and multifactorial nature of PSD emphasizing the importance of a rigorous and long-term monitoring and support of stroke patients and their caregivers.

Effect of peripartal feeding strategy on colostrum yield and composition in sows.

Research showed a positive association between back fat (BF) change the week before farrowing and colostrum yield (CY). This study tested the causality of this association, hence to optimize CY by altering the sows' peripartal feeding strategy. Sows were randomly divided into 2 treatment groups at d 108 of gestation. The first group (L, n = 28) received 1.5 kg feed·d(-1), the second group (H, n = 22) received 3 times 1.5 kg feed·d(-1) until farrowing. Daily feed intake and CY were measured. Colostrum was analyzed for nutrient composition, AA and fatty acids, IgG and IgA. Sow serum was obtained at d 108 of gestation and d 1 of lactation after overnight fasting and analyzed for NEFA, (iso)butyrylcarnitine (C4), creatinine, urea, 3-OH-butyrylcarnitine (3-OH-C4), IgG, and IgA. Based on BF at d 108, sows were divided into body condition (BC) groups: skinny (<17 mm, n = 15), moderate (17 to 23 mm, n = 21), fat (>23 mm, n = 14). We performed ANOVA with treatment and BC as fixed factors and Scheffé post-hoc test. The week before farrowing, the L group had the lowest daily feed intake (DFI; 1.5 kg), and within the H group, fat sows (3.8 kg) had a lower DFI than skinny sows (4.3 kg; p = 0.006). The H group tended to have a greater total CY (P = 0.074) and had a greater CY/kg liveborn piglet (P = 0.018) than the L group. Compared with sows in moderate BC, fat sows had a lower total CY (P = 0.044) and a lower CY/kg liveborn piglet (P = 0.005). The H group had a greater concentration of lactose (p = 0.009) and n-3 PUFA (p < 0.001) but a lower concentration of protein (p = 0.040) in colostrum than the L group. The concentration of IgG and IgA did not differ between treatment and BC groups. Serum parameters at d 108 were similar between the treatment groups and BC groups. At d 1, the H group mobilized less body fat (NEFA: p = 0.002) and protein (creatinine: p < 0.001, C4: p = 0.016) reserves but had a greater ratio urea:NEFA (p < 0.001) and less ketone bodies (3-OH-C4: p < 0.001) compared with the L group. This indicates a more balanced entry of metabolites in the citric acid cycle and thus a better support of the maternal peripartal metabolism in the H group. Serum parameters did not differ between BC groups. Both CY and composition can be influenced by the peripartal feeding strategy and BC. The highest CY and most beneficial colostrum composition were obtained when sows entered the farrowing unit in a moderate BC and were provided a high peripartal feeding strategy.

Sex-specific associations between Neutrophil Gelatinase-Associated Lipocalin (NGAL) and cognitive domains in late-life depression.

BACKGROUND: Although it is well established that late-life depression is associated with both systemic low-graded inflammation and cognitive impairment, the relation between inflammation and cognition in depressed older persons is still equivocal. The objective of this study is to examine the association between plasma Neutrophil Gelatinase-Associated Lipocalin (NGAL) concentrations and cognitive functioning in late-life depression, including the potentially moderating role of sex. METHODS: A total of 369 depressed older persons (≥60 years) from The Netherlands study of Depression in Older persons (NESDO) were included. Four cognitive domains, i.e. verbal memory, processing speed, interference control and attention were assessed with three cognitive tests (Stroop test, Wais Digit span test, and Rey's verbal learning test). Multiple linear regression analyses were applied with the four cognitive domains as dependent variables adjusted for confounders. RESULTS: The association between NGAL levels and specific cognitive domains were sex-specific. In women, higher NGAL levels were associated with impaired verbal memory and lower processing speed. In men, higher NGAL levels were associated with worse interference control. Higher NGAL levels were not associated with attention. No sex-specific associations of either high sensitivity C-reactive protein (hsCRP) or interleukin-6 (IL-6) with cognitive functioning were found. CONCLUSION: This study shows sex-specific association of NGAL with cognitive functioning in late-life depression.

The squares test as a measure of hand function in multiple sclerosis.

Deterioration of hand function can be important in multiple sclerosis (MS). The standard way of assessing hand function in MS is the 9-hole peg test (9HPT), one of the three components of the MS functional composite measure. In this study we examine the squares test (ST), a test of hand function that is used extensively in handedness research. We evaluated reproducibility of the ST in 49 healthy controls, and both discriminatory power and concurrent validity of the ST in 38 MS patients and 18 age and gender matched controls. The ST proved to be a reliable and easy to administrate paper-and-pencil test of hand function. The ST showed a high and highly significant correlation with the standard 9HPT over a broad range of Expanded Disability Status Scale (EDSS) scores, and had high discriminatory power, also comparable to the 9HPT. Therefore, the ST is a candidate test for use in composite measures of MS related functional deficits for clinical practice and in clinical trials.

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.

Neutrophil gelatinase-associated lipocalin: a novel inflammatory marker associated with late-life depression.

OBJECTIVE: Systemic low graded inflammation has been identified as a possible biological pathway in late-life depression. Identification of inflammatory markers and their association with characteristics of depression is essential with the aim to improve diagnosis and therapeutic approaches. This study examines the determinants of plasma Neutrophil Gelatinase-Associated Lipocalin (NGAL), which is selectively triggered by TNFα receptor 1 signaling within the central nervous system, and its association with late-life depressive disorder. METHODS: Baseline data were obtained from a well-characterized prospective cohort study of 350 depressed and 129 non-depressed older persons (≥60years). Past 6month diagnosis of major depressive disorder (MDD) according to DSM-IV-TR criteria was assessed with the Composite International Diagnostic Interview (CIDI 2.0). Potential determinants of plasma NGAL included sociodemographic characteristics, lifestyle and psychiatric and physical comorbidity. RESULTS: Plasma NGAL concentrations were significantly associated with age, male gender, smoking and waist circumference. Adjusted for these determinants, depressed patients had significantly higher NGAL plasma levels compared to non-depressed comparison group. Depressed patients who did not meet full criteria for MDD in the month before sampling (partially remitted) had lower plasma NGAL levels compared with those who did. Subjects with a recurrent depression had higher plasma NGAL levels compared to those with a first episode. NGAL levels were neither related with specific symptom profiles of depression nor with antidepressant drug use. CONCLUSION: Adjusted for confounders, NGAL plasma levels are increased in depressed older persons, without any effect of antidepressant medication and age of onset.