Iap – phase VI

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IAP – PHASE VI – P6/43


An integrated approach towards understanding the pathogenesis of CNS and PNS neurodegenerative disorders


Network Co-ordinator Christine Van Broeckhoven

Universiteit Antwerpen (UA)




  1. Personnel paid by the IAP-contract (IAP-contract payroll) 2

  2. Personnel working in the frame of the IAP-project 2

(Not paid by the IAP-contract or pro memori personnel)


  1. Description of the research activities 3

Work package 1: Clinical Neurology 3

Work package 2: Pathology 5

Work package 3: Genetics and Genomics 6

Work package 4: Cell Biology 11

Work package 5: Mouse Modelling 12

Work package 6: Small Model Organisms 15

Work package 7: Protein Modelling 15

Work package 8: Therapeutics 17

  1. Organisation and activities of the network 19

Organization of Seminars & meetings 19

Collaboration among the IAP teams 19

Exchange of Personnel 20

Exchange of Material 20

Exchange of Expertise 21

  1. Publications 22

    1. Collaborative Publications acknowledging IAP 22

    2. Partner Publications acknowledging IAP 23

Addendum 1 – Publications relevant to the IAP project 26

  1. Collaborative Publications 26

  2. Partner Publications 26


  1. Personnel paid by the IAP-contract (IAP-contract payroll)

  1. Personnel working in the frame of the IAP-project (not paid by the IAP-contract or pro memori personnel)

See excel file


  1. Description of the research activities

Work package 1: Clinical Neurology - Workpackage leader: P. De Jonghe (P3)

Aim: Recruitment and Characterization of patients

Partner 2: Recruitment and follow-up of Mild Cognitive Impairment (MCI) (n=171) and dementia (n=624) patients was continued. As not all patients included gave consent for lumbar puncture (LP), cerebrospinal fluid (CSF) samples are available from 512 dementia patients and 109 MCI patients. In case an included patient died, an autopsy has been performed. The number of patients with autopsy-confirmed dementia diagnoses now exceeds 100. Actigraphy has been validated as a tool for the standardized and objective evaluation of agitated behavior in dementia, which is one of the most frequently observed behavioral disturbances in dementia. As quantification of agitated behavior nowadays mostly relies on (subjective) caregiver-based information, we set up a study to correlate actigraphic recordings with nurses’ observations of activity in dementia. Based on this study, actigraphy can replace systematic behavioral observation by specialized nursing staff (Nagels et al., International Journal of Geriatric Psychiatry, 2007). An important potential advantage of actigraphy is that it does not require an observer during the recording period. Several publications resulted from the neuropsychological and behavioral characterization of the MCI study population in comparison with AD patients and healthy control subjects (Dierckx et al., Gerontology, 2007). Moreover, studies were set up in order to test whether specific neuropsychological tests like cued recall and the 10-word learning task can help discriminating MCI from AD and/or depression (Dierckx et al., Psychological Medicine, 2007; Dierckx et al., Journal of Geriatric Psychiatry and Neurology, 2008 in press).

Aim: Assessment of CSF biomarkers in patients

Partner 2: To establish diagnostic performance of the cerebrospinal fluid (CSF) biomarkers -amyloid peptide (A1-42), total tau-protein (T-tau) and tau phosphorylated at threonine 181 (P-tau181P) compared to clinical diagnosis, biomarker levels were determined in CSF samples from 100 autopsy-confirmed dementia and 100 control subjects. New biomarker-based models were constructed by means of logistic regression. Using all biomarkers, dementia could be discriminated from controls (sensitivity (S) = 86 %, specificity (Sp) =89 %). T-tau and A1-42 optimally discriminated Alzheimer’s disease (AD) from other dementias (NONAD) and controls (S = 90 %, Sp = 89 %). AD was optimally discriminated from NONAD using P-tau181P and A1-42 (S = 80 %, Sp = 93 %). Diagnostic accuracy of the latter model (82.7 %) was comparable to clinical diagnostic accuracy (81.6 %) that was based on a whole clinical work-up (including imaging). This study has demonstrated the value of a combined assessment of CSF biomarkers in differential dementia diagnosis, using pathological diagnosis as a reference. New biomarker-based models have been developed, achieving sensitivity, specificity, and diagnostic accuracy levels, consistently exceeding 80 % (Engelborghs et al., Neurobiology of Aging, 2007). These findings meanwhile support the original hypothesis that the combined assessment of the CSF biomarkers A1-42, T-tau and P-tau181P reveal S, Sp and diagnostic accuracy levels that are high enough to discriminate AD from other forms of dementia.

The ratio of CSF levels of Aβ1-42 and P-tau181P (Q Aβ1-42/P-tau181P) was recently reported to optimally discriminate between AD and vascular dementia (VaD) with S, Sp, positive (PPV) and negative predictive values (NPV) consistently exceeding 85%. In order to confirm this finding, we set up a study including CSF samples from 85 AD or VaD patients (Le Bastard et al., Journal of Gerontology: Medical Sciences, 2007). Most subjects (76/85) had autopsy-confirmed diagnoses. CSF biomarker levels were determined with commercially available single-parameter ELISA kits (INNOTEST). CSF P-tau181P levels were significantly higher and CSF Aβ1-42 concentrations were significantly lower in AD compared to VaD patients. The ROC curve discriminating AD from VaD by means of Q Aβ1-42/P-tau181P revealed an area under the curve of 0.763 (p<0.001). Applying the Q Aβ1-42/P-tau181P cutoff levels that have been described by de Jong et al. yielded high S (95-97%) levels but low Sp (38-52%) levels with PPV and NPV values varying between 79 and 86%. Moreover, we were not able to determine a single cutoff level with optimal S and Sp values. Our dataset (generated in an age- and sex-matched AD and VaD patient groups of which a majority had neuropathologically confirmed diagnoses) showed that limited specificity might hamper the use of the CSF Aβ1-42/P-tau181P ratio to discriminate AD from VaD(Le Bastard et al., Journal of Gerontology: Medical Sciences, 2007).

Aim: Identification of clinical, behavioral, neuropsychological and genetic correlates of CSF biomarker concentrations

Partner 2 & partner 1: To identify neurochemical correlates of behavioral and psychological signs and symptoms of dementia (BPSD), we set up a prospective study (Engelborghs et al., Neurochemistry International 2007). CSF levels of metabolites of (nor)epinephrine (MHPG), serotonin (5HIAA) and dopamine (DOPAC, HVA) were determined by HPLC and electrochemical detection. Spearman Rank-Order followed by Bonferroni correction was used for calculating correlations. In FTD patients, CSF norepinephrine levels were positively correlated with dementia severity (r=0.539; p=0.021). CSF DOPAC levels were correlated with BPSD in general (r=0.539; p=0.021), associated caregiver burden (r=0.567; p=0.004) and agitated and aggressive behavior (r=0.568; p=0.004). In a subgroup of FTD patients who did not receive psychotropic pharmacological treatment, a strong correlation between CSF HVA/5HIAA ratios (reflecting serotonergic modulation of dopaminergic neurotransmission) and aggressive behavior (r=0.758; p=0.009) was found. In MXD patients, (verbally) agitated behavior was positively associated with the turnover of norepinephrine (r=0.633; p=0.002). No significant correlations were found in AD and DLB groups. In FTD, increased activity of dopaminergic neurotransmission and altered serotonergic modulation of dopaminergic neurotransmission was associated with agitated and aggressive behavior respectively. This study demonstrated that neurochemical mechanisms underlying the pathophysiology of BPSD are both BPSD-specific and disease-specific which might have implications for future development of new and more selective pharmacological treatments of BPSD. The CSF biomarkers Aβ1-42, T-tau, and P-tau181P were determined in autopsy-confirmed AD patients, in order to study possible associations with the 4 allele of APOE and density and spread of plaques (NFT) and tangles (SP) (Engelborghs et al., Brain, 2007). CSF samples from 50 definite AD patients were included. CSF levels of A1-42, T-tau, and P-tau181P were determined with commercially available single parameter ELISA kits. Genomic DNA was extracted from total blood. APOE genotype was determined using standard methods. Tangle burden was assessed by means of Braak’s NFT stages (I to VI). Plaque burden was assessed by means of Braak’s SP stages (A to C). CSF biomarker levels were not different comparing 4 carriers (n=21) and noncarriers (n=29) (p>0.05 for all comparisons). No significant correlations between number of 4 alleles (0, 1 or 2) and CSF levels of A1-42 (Spearman Rank Order: r=-0.057, p=0.695), T-tau (r=0.104, p=0.472), and P-tau181P (r=0.062, p=0.668) were found. Braak’s SP (A1-42: r=-0.060, p=0.679; T-tau: r=-0.002, p=0.986; P-tau181P; r=0.034, p=0.813) and NFT (A1-42: r=-0.115, p=0.423; T-tau: r=0.136, p=0.346; P-tau181P; r=0.164, p=0.253) stages were not significantly correlated with CSF biomarker levels. In conclusion, CSF levels of A1-42, T-tau and P-tau181P were not associated with 4, tangle or plaque burden in 50 autopsy-confirmed AD patients (Engelborghs et al., Brain, 2007). In the light of future biomarker applications like monitoring of disease progression and as allocortical neuropathological changes significantly contribute to the clinical symptoms AD patients display, the concept of in vivo surrogate biomarkers should be further explored.

Aim: Genotype-phenotype correlations

Partner 3: To investigate the clinical and electrophysiologic phenotype of CMT2 in a large number of affected families, we excluded CMT1, hereditary neuropathy with liability to pressure palsies, and CMT due to Cx32 gene mutations by DNA analysis. We performed genetic analysis of the presently known CMT2 genes. We found sixty-one persons from 18 families to be affected. Ninety percent of patients were able to walk with or without the help of aids. Proximal leg muscle weakness was present in 13%. Asymmetrical features were present in 15%. Normal or brisk knee reflexes were present in 36%. Extensor plantar responses without associated spasticity occurred in 10 patients from eight families. Only three causative mutations were identified in the MFN2, BSCL2, and RAB7 genes. No mutations were found in the NEFL, HSPB1, HSPB8, GARS, DNM2, and GDAP1 genes. We concluded that the clinical phenotype of CMT2 is uniform, with symmetric, distal weakness, atrophy and sensory disturbances, more pronounced in the legs than in the arms, notwithstanding the genetic heterogeneity. Brisk reflexes, extensor plantar responses, and asymmetrical muscle involvement can be considered part of the CMT2 phenotype. The causative gene mutation was found in only 17% of the families we studied (Bienfait et al. Neurology, 2007). This work was performed by the IAP partners: P. De Jonghe (P3) and V. Timmerman (P3).

Partner 3: Giant axonal neuropathy (GAN) is a devastating autosomal recessive disorder characterized by an early onset severe peripheral neuropathy, varying central nervous system involvement and strikingly frizzly hair. Giant axonal neuropathy is usually caused by mutations in the gigaxonin gene (GAN) but genetic heterogeneity has been demonstrated for a milder variant of this disease. In collaboration with our German colleagues, we reported ten patients referred for molecular genetic diagnosis. All patients had typical clinical signs suggestive of giant axonal neuropathy. In seven affected individuals, we found disease causing mutations in the gigaxonin gene affecting both alleles: two splice-site and four missense mutations, not reported previously. Gigaxonin binds N-terminally to ubiquitin activating enzyme E1 and C-terminally to various microtubule associated proteins causing their ubiquitin mediated degradation. It was shown for a number of gigaxonin mutations that they impede this process leading to accumulation of microtubule associated proteins and there by impairing cellular functions (Koop et al. Neuromuscular Disorders, 2007). This work was performed by the IAP partners: P. De Jonghe (P3) and V. Timmerman (P3).

Partner 5: Motor neuron diseases: To investigate whether quantitative changes in diffusion tensor images (DTI) of the brain could be used as a biomarker for amyotrophic lateral sclerosis (ALS), we studied patients with clinical evidence of both upper and lower motor neuron findings using DTI NMR. We found that even in those without evidence for frontal dysfunction, widespread white matter abnormalities were found in the frontal and prefrontal regions, and established that signal abnormalities in the descending white matter tracts increase as disease progresses, suggesting that this quantitative marker can be used in longitudinal studies such as therapeutic trials (Sage et al. Neuroimage, 2007). This work was performed by W Robberecht (P5).

Work package 2: Pathology - Workpackage leader: J.-P. Brion (P7)

Aim: Analysis of new gene products expression in pathological tissues from patients with neurodegenerative diseases

Partner 1: Work done over the past decade has led to a molecular understanding of frontotemporal lobar degeneration (FTLD), a deadly disease that afflicts patients in mid-life. It is a common cause of dementia, second only to Alzheimer's disease in the population below 65 years of age. Neuroanatomical and neurobiological substrates have been identified for the three major subtypes of FTLD and these discoveries have broadened the FTLD spectrum to include amyotrophic lateral sclerosis (ALS). Mutations in MAPT were found to cause frontotemporal dementia and Parkinsonism linked to chromosome 17 (FTDP-17), a familial disorder with filamentous tau inclusions in nerve cells and glial cells. FTDP-17 can result in clinical syndromes that closely resemble progressive supranuclear palsy, corticobasal degeneration and Pick's disease. More recently, mutations in three genes (VCP, CHMP2B and PGRN) have been found to cause FTLD with ubiquitin-positive, tau-negative neuronal inclusions (FTLD-U). They explain a large proportion of inherited FTLD-U. It remains to be seen whether dementia lacking distinctive histopathology (DLDH) constitutes a third disease category, as many of these cases are now being reclassified as FTLD-U. Recently, TAR DNA-binding protein-43 (TDP-43) has been identified as a key protein of the ubiquitin inclusions of FTLD-U and ALS. Thus, for familial forms of FTLD and related disorders, we now know the primary etiologies and accumulating proteins. These findings are pivotal for dissecting the pathways by which different etiologies lead to the varied clinicopathological presentations of FTLD (Kumar-Singh and Van Broeckhoven, Brain Pathology, 2007).

Aim: Analysis of new gene products expression in pathological tissues

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