Christian Eggers

High Prevalence of Pathogenic Mutations in Patients with Early-Onset Dementia Detected by Sequence Analyses of Four Different Genes

Clinical differential diagnosis of early-onset dementia (EOD) includes familial Alzheimer disease (FAD) and hereditary prion disease. In both disease entities, postmortem brain histopathological examination is essential for unambiguous diagnosis. Mutations in the genes encoding the presenilins (PS1 and PS2) and amyloid precursor protein (APP) are associated with FAD, whereas mutations in the prion protein (PrP) gene are associated with prion disease. To investigate the proportion of EOD attributable to known genes, we prospectively (i.e., antemortem) screened these four genes for mutations by sequencing genomic PCR products from patients with EOD before age 60 years. Family history for dementia was positive (PFH) in 16 patients, negative (NFH) in 17 patients, and unknown (UFH) in 3 patients. In 12 patients, we found five novel mutations (in PS1, F105L; in PS2, T122P and M239I; and in PrP, Q160X and T188K) and five previously reported mutations (in APP, in three patients who were most likely unrelated, V717I; in PS1, A79V and M139V; and in PrP, P102L and T183A) that are all considered to be disease causing. Of these 12 patients, 9 had PFH. This indicates a detection rate of 56% (9/16) in patients with PFH. We found two mutations (APP V717I) in two of the three UFH patients, and only one mutation (PrP T188K) in 1 of the 17 patients with NFH. We conclude that because of the lack of specific antemortem diagnostic markers for FAD and hereditary prion disease, all four genes should be included in a molecular diagnostic program in patients with EOD who had PFH.

Elevated levels of neural recognition molecule L1 in the cerebrospinal fluid of patients with Alzheimer disease and other dementia syndromes

In this study we surveyed a total of 218 cerebrospinal fluid (CSF) samples from patients with different neurological diseases including Alzheimer disease, non-Alzheimer forms of dementia, other neurodegenerative diseases without dementia and normal controls to quantitate by capture ELISA the concentrations of the immunoglobulin superfamily adhesion molecules L1 and NCAM, and characterized by immunoblot analysis the molecular forms of L1 and NCAM. We found a significant increase of L1 and a strong tendency for increase of the soluble fragments of NCAM in the CSF of Alzheimer patients compared to the normal control group. The proteolytic fragments of L1, but not NCAM were also elevated in patients with vascular dementia and dementia of mixed type. Higher L1 concentrations were observed irrespective of age and gender. NCAM concentrations were independent of gender, but positively correlated with age and, surprisingly, also with incidence of multiple sclerosis. Thus, there was an influence of Alzheimer and non-Alzheimer dementias and neurodegeneration on L1, whereas age and neurodegeneration influenced NCAM concentrations. These observations point to an abnormal processing and/or shedding of L1 and NCAM in dementia-related neurodegeneration and age, respectively, reflecting changes in adhesion molecule-related cell interactions.

Driving cessation and dementia: results of the prospective registry on dementia in Austria (PRODEM).

Objective To assess the influence of cognitive, functional and behavioral factors, co-morbidities as well as caregiver characteristics on driving cessation in dementia patients. Methods The study cohort consists of those 240 dementia cases of the ongoing prospective registry on dementia in Austria (PRODEM) who were former or current car-drivers (mean age 74.2 (±8.8) years, 39.6% females, 80.8% Alzheimer’s disease). Reasons for driving cessation were assessed with the patients’ caregivers. Standardized questionnaires were used to evaluate patient- and caregiver characteristics. Cognitive functioning was determined by Mini-Mental State Examination (MMSE), the CERAD neuropsychological test battery and Clinical Dementia Rating (CDR), activities of daily living (ADL) by the Disability Assessment for Dementia, behavior by the Neuropsychiatric Inventory (NPI) and caregiver burden by the Zarit burden scale. Results Among subjects who had ceased driving, 136 (93.8%) did so because of “Unacceptable risk” according to caregiver’s judgment. Car accidents and revocation of the driving license were responsible in 8 (5.5%) and 1(0.7%) participant, respectively. Female gender (OR 5.057; 95%CI 1.803–14.180; p = 0.002), constructional abilities (OR 0.611; 95%CI 0.445–0.839; p = 0.002) and impairment in Activities of Daily Living (OR 0.941; 95%CI 0.911–0.973; p<0.001) were the only significant and independent associates of driving cessation. In multivariate analysis none of the currently proposed screening tools for assessment of fitness to drive in elderly subjects including the MMSE and CDR were significantly associated with driving cessation. Conclusion The risk-estimate of caregivers, but not car accidents or revocation of the driving license determines if dementia patients cease driving. Female gender and increasing impairment in constructional abilities and ADL raise the probability for driving cessation. If any of these factors also relates to undesired traffic situations needs to be determined before recommendations for their inclusion into practice parameters for the assessment of driving abilities in the elderly can be derived from our data.

High Frequency of Mutations in Four Different Disease Genes in Early‐Onset Dementia

Abstract: Heterozygous mutations in the genes for amyloid precursor protein (APP), the presenilins (PS1, PS2), prion protein (PrP), neuroserpin, and tau are associated with early‐onset dementia (EOD) with or without neurological signs in the early disease stage. To investigate the proportion of EOD without early neurological signs attributable to known genes we prospectively (i.e., ante mortem) screened these six genes for mutations in 36 patients with EOD before age 60. Family history for dementia was positive (PFH) in 16, negative (NFH) in 17, and unknown (UFH) in 3 patients. In 12 patients, we found 5 novel mutations (PS1: F105L; PS2: T122P, M239I; PrP: Q160X, T188K) and 5 previously reported mutations (APP: in three most likely unrelated patients V717I; PS1: A79V, M139V; PrP: P102L, T183A) that all are considered disease causing. Of these 12 patients, 9 had PFH. This indicates a detection rate of 56% (9/16) in patients with PFH. We found 2 mutations (APP V717I) in 2 of the 3 the UFH‐patients, and only 1 mutation (PrP T188K) in 1 of the 17 patients with NFH. No mutation was found in tau and neuroserpin genes. To date, three patients died and FAD, predicted by PS mutations in two patients, and prion disease, predicted by a PrP mutation in the third one, were histopathologically confirmed at autopsy. Up to now, mutation findings may be the most specific biomarkers for an ante mortem diagnosis of FAD or hereditary prion disease.

Neuromyelitis Optica in Austria in 2011: To Bridge the Gap between Neuroepidemiological Research and Practice in a Study Population of 8.4 Million People

Background In 2008 the Austrian Task Force for Neuromyelitis Optica (NMO) started a nation-wide network for information exchange and multi-centre collaboration. Their aim was to detect all patients with NMO or NMO spectrum disorders (NMO-SD) in Austria and to analyse their disease courses and response to treatment. Methods (1) As of March 2008, 1957 serum samples (of 1557 patients) have been tested with an established cell based immunofluorescence aquaporin-4 antibody (AQP4-ab) assay with a high sensitivity and specificity (both >95%). All tests were performed in a single reference laboratory (Clinical Dept. of Neurology of the Innsbruck Medical University). (2) A nation-wide survey with several calls for participation (via email newsletters, articles in the official journal of the Austrian Society of Neurology, and workshops) was initiated in 2008. All collected data will be presented in a way that allows that every individual patient can be traced back in order to ensure transparency and to avoid any data distortion in future meta-analyses. The careful and detailed presentation allows the visualization and comparison of the different disease courses in real time span. Failure and response to treatment are made visible at one glance. Database closure was 31 December 2011. All co-operators were offered co-authorship. Results All 71 NMO- or NMO-SD patients with AQP4-ab positivity (age range 12.3 to 79.6 years) were analysed in detail. Sex ratio (m:f = 1:7) and the proportion of patients without oligoclonal bands in cerebrospinal fluid (86.6%) were in line with previously published results. All identified patients were Caucasians. Conclusions A nationwide collaboration amongst Austrian neurologists with good network communications made it possible to establish a database of 71 AQP4-ab positive patients with NMO/NMO-SD. This database is presented in detail and provides the basis for further studies and international cooperation in order to investigate this rare disease.

Influence of interferon-beta therapy switching on neutralizing antibody titres: results from the Austrian Switch Study

Neutralizing antibodies against interferon-beta are associated with a reduction of the efficacy of this drug. Continuing treatment leads to a decline or even loss of neutralizing antibodies over years. No strategies are currently available to shorten the period of neutralizing antibody positivity. The objective of this study was to investigate the effect of switching between high and low immunogenic interferon-beta products on neutralising antibody titres. Twenty-four patients treated with the subcutaneously administered interferon-beta 1b or 1a and high titres of neutralizing antibodies were included. At baseline interferon-beta therapy was interrupted for 3 months and two pulses of high dose methylprednisolone were applied. Patients were then randomized to receive either the previous interferon-beta preparation or the low immunogenic intramuscular interferon-beta 1a. The primary end-point was the change of neutralizing antibody titres 12 months after randomization. Twelve patients were switched to interferon-beta 1a intramuscularly and 12 patients remained on previous treatment. Median neutralizing antibody titres were 846 NU at baseline and 196 NU at the end of the study. The median change of neutralizing antibody titres did not differ significantly between therapy switchers and non-switchers. Baseline and final neutralizing antibody titres correlated significantly. In conclusion, neither switching nor continuous therapy with any subcutaneous interferon-beta preparation significantly changed neutralizing antibody titres.

Antibodies to myelin oligodendrocyte glycoprotein in HIV-1 associated neurocognitive disorder: a cross-sectional cohort study

BackgroundNeuroinflammation and demyelination have been suggested as mechanisms causing HIV-1 associated neurocognitive disorder (HAND). This cross-sectional cohort study explores the potential role of antibodies to myelin oligodendrocyte glycoprotein (MOG), a putative autoantigen in multiple sclerosis, in the pathogenesis of HAND.MethodsIgG antibodies against MOG were measured by ELISA in sera and cerebrospinal fluid (CSF) of 65 HIV-positive patients with HAND (n = 14), cerebral opportunistic infections (HIVOI, n = 25), primary HIV infection (HIVM, n = 5) and asymptomatic patients (HIVasy, n = 21). As control group HIV-negative patients with bacterial or viral CNS infections (OIND, n = 18) and other neurological diseases (OND, n = 22) were included. In a subset of HAND patients MOG antibodies were determined before and during antiviral therapy.ResultsIn serum, significantly higher MOG antibody titers were observed in HAND compared to OND patients. In CSF, significantly higher antibody titers were observed in HAND and HIVOI patients compared to HIVasy and OND patients and in OIND compared to OND patients. CSF anti-MOG antibodies showed a high sensitivity and specificity (85.7% and 76.2%) for discriminating patients with active HAND from asymptomatic HIV patients. MOG immunopositive HAND patients performed significantly worse on the HIV dementia scale and showed higher viral load in CSF. In longitudinally studied HAND patients, sustained antibody response was noted despite successful clearance of viral RNA.ConclusionsPersistence of MOG antibodies despite viral clearance in a high percentage of HAND patients suggests ongoing neuroinflammation, possibly preventing recovery from HAND.

Reply to Croes et al.

To the Editor:Croes et al. (2000xCroes, EA, Dermaut, B, van der Cammen, C, van Broeckhove, C, and van Duijn, CM. Genetic testing should not be advocated as a diagnostic tool in familial forms of dementia. 2000; 67: 1033–1035See all References2000 [in this issue]) make the point that genetic testing as a diagnostic tool shows poor performance in differential diagnosis in general medical practice. We fully agree with this comment. Therefore, one of the goals of our study (Finckh et al. 2000xHigh prevalence of pathogenic mutations in patients with early-onset dementia detected by sequence analyses of four different genes. Finckh, U, Muller-Thomsen, T, Mann, U, Eggers, C, Marksteiner, J, Meins, W, Binetti, G, Alberici, A, Hock, C, Nitsch, RM, and Gal, A. Am J Hum Genet. 2000; 66: 110–117Abstract | Full Text | Full Text PDF | PubMed | Scopus (131)See all References2000) was to establish criteria that would increase the chance of identifying a pathogenic mutation in the setting of a specialized clinic. Indeed, among patients who had both onset at an early age and positive family history for early-onset dementia (EOD), diagnostic sequencing identified disease-relevant mutations in >50% of the patients analyzed by us. Another notable result of our study was the finding of four prion mutations among the 36 EOD patients, which suggested that atypical forms of prion disease may remain underdiagnosed. This assumption is supported by independent observations, such as those made by two coauthors of the letter by Croes et al. (2000xCroes, EA, Dermaut, B, van der Cammen, C, van Broeckhove, C, and van Duijn, CM. Genetic testing should not be advocated as a diagnostic tool in familial forms of dementia. 2000; 67: 1033–1035See all References2000), who found a PRNP insertion mutation in a patient with both prion disease and ante mortem diagnosis of familial Alzheimer disease (FAD) (Dermaut et al. 1998xSee all References1998).We agree with Croes et al. that assessment of the relevance of previously unknown mutations is a difficult issue. Nonetheless, in recent screening studies of FAD, 72%–83% of the sequence changes corresponded to pathogenic mutations already reported (Kamimura et al. 1998xFamilial Alzheimers disease genes in Japanese. Kamimura, K, Tanahashi, H, Yamanaka, H, Takahashi, K, Asada, T, and Tabira, T. J Neurol Sci. 1998; 160: 76–81Abstract | Full Text | Full Text PDF | PubMed | Scopus (28)See all References1998; Campion et al. 1999xEarly-onset autosomal dominant Alzheimer disease: prevalence, genetic heterogeneity, and mutation spectrum. Campion, D, Dumanchin, C, Hannequin, D, Dubois, B, Belliard, S, Puel, M, Thomas-Anterion, C, Michon, A, Martin, C, Charbonnier, F, Raux, G, Camuzat, A, Penet, C, Mesnage, V, Martinez, M, Clerget-Darpoux, F, Brice, A, and Frebourg, T. Am J Hum Genet. 1999; 65: 664–670Abstract | Full Text | Full Text PDF | PubMed | Scopus (357)See all References1999). In our study, 58% of the mutations had been previously described by others. Repeated identification of any given rare mutation in a rare disorder, together with the absence of the mutation in control probands, significantly increases the likelihood that it has causative effects.We were pleased to see that Croes et al. agree with our conclusion that E318G in PS1 is a nonpathogenic polymorphism and that they reemphasize the importance of a careful and critical analysis of the literature. The importance of early and disease-specific diagnosis of EOD as a way of identifying treatable forms of dementia is an issue separate from our assertion that diagnostic sequencing of the four known EOD genes may provide important information for proper clinical and genetic counseling in the early phases of the disorder.