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To evaluate the contribution of an imbalance between coagulation activation and fibinolysis activation and inhibition to morbidity and mortality in sepsis, we determined in medical hospitalized patients at inclusion (day 0) for fever... more
To evaluate the contribution of an imbalance between coagulation activation and fibinolysis activation and inhibition to morbidity and mortality in sepsis, we determined in medical hospitalized patients at inclusion (day 0) for fever (temperature above 38.0 degrees C axillary or 38.3 degrees C rectally), and daily thereafter for two days, circulating thrombin-antithrombin III (TAT) complexes, plasmin-alpha2-antiplasmin (PAP) complexes (day 0 only), tissue-type plasminogen activator (t-PA), plasminogen activator inhibitor-1 (PAI-1) and interleukin (IL)-6, the latter as a marker of the inflammatory host response. Study variables were 1) positive microbiological results for specimens from local sites associated with a clinical infection, positive blood cultures (including parasitemia) or both, within 7 days after inclusion, 2) development of shock, i.e. systolic blood pressure <90 mmHg or a reduction of 40 mmHg from baseline within 7 days after inclusion, and 3) death related to feb...
Research Interests: Inflammation, Adolescent, Humans, Septic Shock, Female, and 17 moreInfection, Male, Sepsis, Haemostasis and Thrombosis, Anticoagulants, Clinical Sciences, Aged, Middle Aged, Adult, Fever, Prognosis, Thrombosis, Tissue Plasminogen Activator, Predictive value of tests, Plasminogen Activator Inhibitor, Cohort Studies, and Interleukin
Research Interests:
To evaluate the contribution of an imbalance between coagulation activation and fibinolysis activation and inhibition to morbidity and mortality in sepsis, we determined in medical hospitalized patients at inclusion (day 0) for fever... more
To evaluate the contribution of an imbalance between coagulation activation and fibinolysis activation and inhibition to morbidity and mortality in sepsis, we determined in medical hospitalized patients at inclusion (day 0) for fever (temperature above 38.0 degrees C axillary or 38.3 degrees C rectally), and daily thereafter for two days, circulating thrombin-antithrombin III (TAT) complexes, plasmin-alpha2-antiplasmin (PAP) complexes (day 0 only), tissue-type plasminogen activator (t-PA), plasminogen activator inhibitor-1 (PAI-1) and interleukin (IL)-6, the latter as a marker of the inflammatory host response. Study variables were 1) positive microbiological results for specimens from local sites associated with a clinical infection, positive blood cultures (including parasitemia) or both, within 7 days after inclusion, 2) development of shock, i.e. systolic blood pressure <90 mmHg or a reduction of 40 mmHg from baseline within 7 days after inclusion, and 3) death related to feb...
Research Interests: Inflammation, Adolescent, Humans, Septic Shock, Female, and 17 moreInfection, Male, Sepsis, Haemostasis and Thrombosis, Anticoagulants, Clinical Sciences, Aged, Middle Aged, Adult, Fever, Prognosis, Thrombosis, Tissue Plasminogen Activator, Predictive value of tests, Plasminogen Activator Inhibitor, Cohort Studies, and Interleukin
There is an overlap between amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Some 5-10% of ALS patients show changes in their behaviour and personality that are characteristic of FTD and about 10% of FTD patients... more
There is an overlap between amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Some 5-10% of ALS patients show changes in their behaviour and personality that are characteristic of FTD and about 10% of FTD patients develop ALS. Mild cognitive impairment occurs in 30% of ALS patients. The progressive decline of muscle strength in ALS patients and social skills in FTD patients places severe demands on the patient and his or her contacts. In some ALS and FTD patients, ubiquitin-positive inclusions have been found in the hippocampus and anterior horn cells. In patients with familial FTD who have ubiquitin-positive inclusions, mutations have been found in the progranulin (PGRN) gene. TAR-DNA-binding protein-43, encoded by the TARDBP gene, has recently been identified as a constituent of the ubiquitin inclusions. TARDBP and PGRN mutations are found in patients with ALS. The overlapping characteristics provide clues for further research into the pathogenesis of ALS and FTD
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Research Interests:
Research Interests:
Research Interests: Immunohistochemistry, Tissue Banks, In Situ Hybridization, Amyotrophic Lateral Sclerosis, Brain, and 18 moreHumans, Female, Male, Polymerase Chain Reaction, Netherlands, Proteins, Pedigree, Neurons, Aged, Middle Aged, Autopsy, Genotype, Adult, Frontotemporal Dementia, DNA binding proteins, Age of Onset, Cohort Studies, and Neuropsychological Tests
and primary lateral sclerosis (PLS), the lower and upper motor neuron variants of MND, respectively (7,9). The frequency and characteristics of behav-ioural symptoms however, which are the hallmark of bvFTD, have not been fi rmly... more
and primary lateral sclerosis (PLS), the lower and upper motor neuron variants of MND, respectively (7,9). The frequency and characteristics of behav-ioural symptoms however, which are the hallmark of bvFTD, have not been fi rmly determined in MND. There is ongoing debate about the prevalence of behavioural changes (both bvFTD and mild behavioural changes) and the association of bvFTD with clinical variables of MND, i.e. bulbar onset and survival (10 13). Our aim was to systematically review the literature on MND and behaviour in order to 1) estimate the prevalence of bvFTD and of mild behavioural changes in MND; 2) calculate prevalence rates of bvFTD symptoms (behavioural, cognitive and psychiatric symptoms) in MND-bvFTD patients; and 3) determine the site of MND onset, survival and age of onset in MND-bvFTD patients.
All since 1951, it is now a weekly with 48 issues per year.
Research Interests: Cancer and Cancer Biology
Objective: To examine brain activation patterns during verbal fluency performance in patients with progressive muscular atrophy (PMA) and amyotrophic lateral sclerosis (ALS). Methods: fMRI was used to examine the blood oxygen... more
Objective: To examine brain activation patterns during verbal fluency performance in patients with progressive muscular atrophy (PMA) and amyotrophic lateral sclerosis (ALS). Methods: fMRI was used to examine the blood oxygen level–dependent response during letter and category fluency performance in 18 patients with PMA, 21 patients with ALS, and 17 healthy control subjects, matched for age and education. fMRI results are reported at p , 0.05, family-wise error (FWE)-corrected for multiple comparisons. We analyzed effects of performance, age-related white matter changes (ARWMC), and regional brain volumes; all participants underwent neuropsychological investigation. Results: Disease duration of patients with PMA (mean 26.0 months, SD 13.6) and ALS (22.2 months, SD 11.4) was comparable. Patients with PMA and ALS had mild to moderate disease severity and showed impaired letter fluency compared with controls. Between-group analysis showed a main effect of group in the left inferior frontal gyrus (IFG, Brodmann area 45) during letter fluency, which was unaffected by performance, ARWMC, and IFG volume: patients with PMA showed lower activation than controls but higher than that of patients with ALS (ALS , PMA , healthy controls; p FWE 5 0.035; z score 4.11; cluster size 5 11). A more caudal region in the IFG showed lower activation in patients with PMA than controls during letter fluency performance (post hoc test; p FWE 5 0.026). No activation differences were observed during the category fluency task.
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Background and purpose: We assessed the first evaluation at a large ventilation clinic in the Netherlands to: (i) determine what proportion of patients with motor neuron disease would benefit from earlier referral; and (ii) examine the... more
Background and purpose: We assessed the first evaluation at a large ventilation clinic in the Netherlands to: (i) determine what proportion of patients with motor neuron disease would benefit from earlier referral; and (ii) examine the patient preferences regarding ventilatory support. Methods: Observational study at a single centre with a catchment area of 7.6 million inhabitants. Data on disease status, the referral process and patients' preferences regarding ventilatory support were collected during the first home ventilation services (HVS) assessment and analysed for correlation with the presence of daytime hypercapnia and suspected nocturnal hypoventilation. The latter conditions require immediate (within 48 h) or subacute (within 3 weeks) initiation of ventilatory support. Results: Vital capacity (in percentage of predicted value, VC%pred) was assessed by referring physicians in 84% of the 217 referred patients; the mean VC%pred was 69% (SD 16). One-hundred and ninety-one patients attended the first HVS assessment without ventilatory support, at a median of 21 days following referral: 18% had respiratory failure (daytime hypercapnia), 19% had normocapnia but were suspected of nocturnal hypoventilation, and 63% had normocapnia without symptoms. Following the HVS assessment, 25 patients (13%) declined home mechanical ventilation ; this occurred more often in patients with (14/70) compared with patients without respiratory impairment (11/121; P < 0.05). Conclusion: A meaningful proportion of patients who desire ventilatory support are referred to a ventilation clinic after already developing respiratory failure. Future studies could examine means, including more sensitive respiratory measures, to detect those patients who could benefit from earlier referral.
Research Interests:
Sum m a ry To evaluate the contribution of an imbalance between coagulation activation and fibinolysis activation and inhibition to morbidity and mortality in sepsis, we determined in medical hospitalized patients at inclusion (day 0) for... more
Sum m a ry To evaluate the contribution of an imbalance between coagulation activation and fibinolysis activation and inhibition to morbidity and mortality in sepsis, we determined in medical hospitalized patients at inclusion (day 0) for fever (temperature above 38.0° C axillary or 38.3° C rectally), and daily thereafter for two days, circulating thrombin-antithrombin III (TAT) complexes, plasmin-2-antiplasmin (PAP) complexes (day 0 only), tissue-type plasminogen activator (t-PA), plasminogen activator inhibitor-1 (PAI-1) and interleukin (IL)-6, the latter as a marker of the inflammatory host response. Study variables were 1) positive microbiological results for specimens from local sites associated with a clinical infection, positive blood cultures (including parasitemia) or both, within 7 days after inclusion, 2) development of shock, i.e. systolic blood pressure <90 mmHg or a reduction of 40 mmHg from baseline within 7 days after inclusion, and 3) death related to febrile illness within 28 days after inclusion. The peak plasma levels of TAT complexes were elevated in 44% and the PAP complexes in all patients. The t-PA and PAI-1 levels were elevated in 74 and 94% of patients, respectively. Values for TAT and PAP did not differ among subgroups, while peak t-PA and IL-6 levels were higher in patients with positive microbiological results, developing shock or ultimately dying than in those without the complications (p <0.005). Peak PAI-1 levels were elevated in patients developing shock and ultimate death versus those with an uncomplicated course (p <0.05). Peak IL-6 related to PAI-1 and t-PA levels, which interrelated. Patients with elevated TAT levels had increased plasma levels of IL-6, PAP, PAI-1 and t-PA versus those with normal TAT (p <0.05). Our data indicate that inhibition of activated fibrinolysis, which may partly depend on both cytokinemia and activation of coagulation, predicts microbial infection, septic shock and mortality of febrile medical patients. This suggests an early pathogenic role of inhibition of activated fibrinolysis in the downhill course of serious microbial infection.
Cognitive impairment is present in approximately 30% of patients with amyotrophic lateral sclerosis (ALS) and, especially when severe, has a negative impact on survival and caregiver burden. Our 2010 meta-analysis of the cognitive profile... more
Cognitive impairment is present in approximately 30% of patients with amyotrophic lateral sclerosis (ALS) and, especially when severe, has a negative impact on survival and caregiver burden. Our 2010 meta-analysis of the cognitive profile of ALS showed impairment of fluency, executive function, language and memory. However, the limited number of studies resulted in large confidence intervals. To obtain a more valid assessment, we updated the meta-analysis and included methodological improvements (controlled data extraction, risk of bias analysis and effect size calculation of individual neuropsychological tests). Embase, Medline and PsycInfo were searched for neuropsychological studies of non-demented patients with ALS and age-matched and education-matched healthy controls. Neuropsychological tests were categorised in 13 cognitive domains and effect sizes (Hedges' g) were calculated for each domain and for individual tests administered in ≥5 studies. Subgroup analyses were performed to assess the influence of clinical and demographic variables. Forty-four studies were included comprising 1287 patients and 1130 healthy controls. All cognitive domains, except visuoperceptive functions, showed significant effect sizes compared to controls. Cognitive domains without bias due to motor impairment showed medium effect sizes (95% CI): fluency (0.56 (0.43 to 0.70)), language (0.56 (0.40 to 0.72)), social cognition (0.55 (0.34 to 0.76)), or small effect sizes: delayed verbal memory 0.47 (0.27 to 0.68)) and executive functions (0.41 (0.27 to 0.55)). Individual neuropsychological tests showed diverging effect sizes, which could be explained by bias due to motor impairment. Subgroup analyses showed no influence of bulbar disease onset and depression and anxiety on the cognitive outcomes. The cognitive profile of ALS consists of deficits in fluency, language, social cognition, executive functions and verbal memory. Social cognition is a new cognitive domain with a relatively large effect size, highlighting the overlap between ALS and frontotemporal dementia. The diverging effect sizes for individual neuropsychological tests show the importance of correction for motor impairment in patients with ALS. These findings have implications for bedside testing, the design of cognitive screening measures and full neuropsychological examinations.
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Aim In contrast with findings in amyotrophic lateral sclerosis (ALS), cognitive impairments have as yet not been shown in the lower motor neuron variant of motor neuron disease, progressive spinal muscular atrophy (PMA). The objective of... more
Aim In contrast with findings in amyotrophic lateral sclerosis (ALS), cognitive impairments have as yet not been shown in the lower motor neuron variant of motor neuron disease, progressive spinal muscular atrophy (PMA). The objective of this study was to investigate cognitive function in PMA and to compare the cognitive profile with that of ALS. In addition, visuospatial functions were assessed comprehensively; these tests are underrepresented in earlier neuropsychological investigations in ALS. Methods 23 PMA and 30 ALS patients (vital capacity >70% of predicted value) underwent a neuropsychological assessment adapted to motor impairments: global cognitive and executive functioning, psychomotor speed, memory, language, attention and visuospatial skills. The results were compared with age, education and sex matched controls and with normative data. Results Compared with controls, PMA patients performed worse on attention/working memory (digit span backward), category fluency and the Mini-Mental State Examination. Compared with normative data, PMA patients most frequently showed impairment on three measures: letterenumber sequencing, and immediate and delayed story recall. 17% of PMA patients showed cognitive impairment, defined as performance below 2 SDs from the mean of normative data on at least three neuropsychological tests. In ALS, similar but more extensive cognitive deficits were found. Visuospatial dysfunction was not found in PMA and ALS. Conclusions 17% of PMA patients have executive and memory impairments. PMA with cognitive impairment adds a formerly unknown phenotype to the existing classification of motor neuron diseases.
Background and purpose: Thirty per cent of amyotrophic lateral sclerosis (ALS) patients have non-motor symptoms, including executive and memory deficits. The in vivo anatomical basis of memory deficits in ALS has not been elucidated. In... more
Background and purpose: Thirty per cent of amyotrophic lateral sclerosis (ALS) patients have non-motor symptoms, including executive and memory deficits. The in vivo anatomical basis of memory deficits in ALS has not been elucidated. In this observational study, brain atrophy in relation to memory function was investigated in ALS patients and controls. Methods: Twenty-six ALS patients without dementia and 21 healthy volunteers matched for gender, age and education level underwent comprehensive neuropsychological evaluation and T1-and T2-weighted 3 T magnetic resonance imaging scanning of the brain. Grey and white matter brain volumes were analysed using voxel-based morphometry and age related white matter changes were assessed. The most frequently abnormal memory test (<2 SD below normative data corrected for age, gender and education) was correlated with regional brain volume variations by multiple regression analyses with age, gender and total grey matter volumes as covariates. Results: Immediate and delayed story recall scores were abnormal in 23% of ALS patients and correlated to bilateral hippocampus grey matter volume (r = 0.52 for both memory tests; P < 0.05; corrected for age, gender and total grey matter volume). This correlation was not found in healthy controls with similar age, education, anxiety and depression levels and white matter changes. Conclusions: Prose memory impairment is a frequent finding in this cohort and is associated with hippocampus volume in ALS patients without demen-tia. These findings complement previous hippocampus changes in imaging studies in ALS and suggest involvement of the hippocampus in cognitive dys-function of ALS.
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) share common clinical, genetic and neu-ropathological features. Some ALS patients have behavioral/personality changes, which could result in significant obstacles in... more
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) share common clinical, genetic and neu-ropathological features. Some ALS patients have behavioral/personality changes, which could result in significant obstacles in the care provided by family members and caregivers. An easy screening tool would contribute greatly to the evaluation of these symptoms. We translated the ALS-FTD-Questionnaire, developed in the Netherlands, into Japanese (ALS-FTD-Q-J) and examined the clinimetric properties (internal consistency, construct and clinical validity). Patients with ALS and/or be-havioral variant FTD (bvFTD) were evaluated alongside healthy controls in this multicenter study. All ALS patients, regardless of bvFTD status, were further evaluated by the frontal behavioral inventory (FBI) and for fron-tal/executive function, cognition, anxiety/depression, and motor functions. Data from 146 subjects were analyzed: ALS (92), ALS-bvFTD (6), bvFTD (16), and healthy controls (32). The internal consistency of the ALS-FTD-Q-J was good (Cronbach α = 0.92). The ALS-FTD-Q-J showed construct validity as it exhibited a high correlation with the FBI (r = 0.79). However, correlations were moderate with anxiety/de-pression and low with cognitive scales, in contrast to the original report, i.e. a moderate correlation with cognition and a low correlation with anxiety/depression. The ALS-FTD-Q-J discriminated ALS patients from (ALS-)bvFTD patients and controls. Thus, the ALS-FTD-Q-J is useful for evaluating Japanese ALS/FTD patients.
The current literature shows no consensus on the localization and number of characteristic neuronal inclusions (p62 and dipeptide repeat proteins (DRP) positive, TDP-43-negative and TDP-43 positive) in the brain and spinal cord of... more
The current literature shows no consensus on the localization and number of characteristic neuronal inclusions (p62 and dipeptide repeat proteins (DRP) positive, TDP-43-negative and TDP-43 positive) in the brain and spinal cord of patients with the hexanucleotide repeat expansion on chromosome 9 (C9ORF72-positive patients). This may be due to small size of the studies. A valid brain map of the inclusions in C9ORF72-positive patients may improve clinicopathological correlations and may serve as a reference for neuropathologists. We performed a systematic review on 42 pathological studies to assess the pooled prevalence rates and density (a measure of the number of inclusions per brain region) of (phosphorylated)-TDP-43, p62 and DRP neuronal inclusions in seven brain regions and the spinal cord of 261 C9ORF72-positive patients with amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD) and ALS-FTD. In the cerebellum and hippocampus the pooled prevalence rates of TDP-43 neu...
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The current literature shows no consensus on the localization and number of characteristic neuronal inclusions (p62 and dipeptide repeat proteins (DRP) positive, TDP-43-negative and TDP-43 positive) in the brain and spinal cord of... more
The current literature shows no consensus on the localization and number of characteristic neuronal inclusions (p62 and dipeptide repeat proteins (DRP) positive, TDP-43-negative and TDP-43 positive) in the brain and spinal cord of patients with the hexanucleotide repeat expansion on chromosome 9 (C9ORF72-positive patients). This may be due to small size of the studies. A valid brain map of the inclusions in C9ORF72-positive patients may improve clinicopathological correlations and may serve as a reference for neuropathologists. We performed a systematic review on 42 pathological studies to assess the pooled prevalence rates and density (a measure of the number of inclusions per brain region) of (phosphorylated)-TDP-43, p62 and DRP neuronal inclusions in seven brain regions and the spinal cord of 261 C9ORF72-positive patients with amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD) and ALS-FTD. In the cerebellum and hippocampus the pooled prevalence rates of TDP-43 neuronal cytoplasmic inclusions (NCI; cerebellum: 3.9%; hippocampus: 68.3%) were lower than those of DRP (cerebellum: 97.2%; hippocampus 97.1%). Moreover, TDP-43 inclusion density was lower compared to p62 inclusion density in these regions. The pooled prevalence rates of TDP-43 NCI in the substantia nigra was high (94.4%). The findings of this systematic review largely confirm findings of previous smaller studies on the localization and prevalence of inclusions in the central nervous system of C9ORF72-positive patients. The high prevalence of TDP-43 inclusions in the substantia nigra is a relatively new finding and is probably related to the relatively high prevalence of parkinsonism in C9ORF72-positive patients.
Research Interests:
There is an overlap between amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Some 5-10% of ALS patients show changes in their behaviour and personality that are characteristic of FTD and about 10% of FTD patients... more
There is an overlap between amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Some 5-10% of ALS patients show changes in their behaviour and personality that are characteristic of FTD and about 10% of FTD patients develop ALS. Mild cognitive impairment occurs in 30% of ALS patients. The progressive decline of muscle strength in ALS patients and social skills in FTD patients places severe demands on the patient and his or her contacts. In some ALS and FTD patients, ubiquitin-positive inclusions have been found in the hippocampus and anterior horn cells. In patients with familial FTD who have ubiquitin-positive inclusions, mutations have been found in the progranulin (PGRN) gene. TAR-DNA-binding protein-43, encoded by the TARDBP gene, has recently been identified as a constituent of the ubiquitin inclusions. TARDBP and PGRN mutations are found in patients with ALS. The overlapping characteristics provide clues for further research into the pathogenesis of ALS and ...
Thirty per cent of amyotrophic lateral sclerosis (ALS) patients have non-motor symptoms, including executive and memory deficits. The in vivo anatomical basis of memory deficits in ALS has not been elucidated. In this observational study,... more
Thirty per cent of amyotrophic lateral sclerosis (ALS) patients have non-motor symptoms, including executive and memory deficits. The in vivo anatomical basis of memory deficits in ALS has not been elucidated. In this observational study, brain atrophy in relation to memory function was investigated in ALS patients and controls. Twenty-six ALS patients without dementia and 21 healthy volunteers matched for gender, age and education level underwent comprehensive neuropsychological evaluation and T1- and T2-weighted 3 T magnetic resonance imaging scanning of the brain. Grey and white matter brain volumes were analysed using voxel-based morphometry and age related white matter changes were assessed. The most frequently abnormal memory test (<2 SD below normative data corrected for age, gender and education) was correlated with regional brain volume variations by multiple regression analyses with age, gender and total grey matter volumes as covariates. Immediate and delayed story rec...
Research Interests:
To examine brain activation patterns during verbal fluency performance in patients with progressive muscular atrophy (PMA) and amyotrophic lateral sclerosis (ALS). fMRI was used to examine the blood oxygen level-dependent response during... more
To examine brain activation patterns during verbal fluency performance in patients with progressive muscular atrophy (PMA) and amyotrophic lateral sclerosis (ALS). fMRI was used to examine the blood oxygen level-dependent response during letter and category fluency performance in 18 patients with PMA, 21 patients with ALS, and 17 healthy control subjects, matched for age and education. fMRI results are reported at p<0.05, family-wise error (FWE)-corrected for multiple comparisons. We analyzed effects of performance, age-related white matter changes (ARWMC), and regional brain volumes; all participants underwent neuropsychological investigation. Disease duration of patients with PMA (mean 26.0 months, SD 13.6) and ALS (22.2 months, SD 11.4) was comparable. Patients with PMA and ALS had mild to moderate disease severity and showed impaired letter fluency compared with controls. Between-group analysis showed a main effect of group in the left inferior frontal gyrus (IFG, Brodmann ar...