Publications by authors named "Jørgen Erik Nielsen"

27 Publications

  • Page 1 of 1

Cortical Frontoparietal Network Dysfunction in -Frontotemporal Dementia.

Front Aging Neurosci 2021 13;13:714220. Epub 2021 Sep 13.

Danish Dementia Research Centre (DDRC), Rigshospitalet and Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark.

A rare cause of inherited frontotemporal dementia (FTD) is a mutation in the gene on chromosome 3 leading to the autosomal dominantly inherited FTD (-FTD). Since -FTD is clinically well-characterized, and patients show a distinct pattern of executive dysfunction, the condition offers possible insight in the early electroencephalographic (EEG) changes in the cortical networks. Specifically, EEG microstate analysis parses the EEG signals into topographies believed to represent discrete network activations. We investigated the EEG dynamics in patients with symptomatic -FTD ( = 5) as well as pre-symptomatic mutation carriers ( = 5) compared to non-carrier family members ( = 6). The data was parsed into four archetypal microstates and global power was calculated. A trend was found for lower occurrence in microstate D in -FTD (value = 0.177, value = 2.036). Patients with recent symptom onset (<1 year) showed an increased duration of microstate D, whereas patients who had been symptomatic for longer periods (>2 years) showed decreased duration. Patients with -FTD present with executive dysfunction, and microstate D has previously been shown to be associated with the fronto-parietal network. The biphasic pattern may represent the pathophysiological changes in brain dynamics during neurodegeneration, which may apply to other neurodegenerative diseases.
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http://dx.doi.org/10.3389/fnagi.2021.714220DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8475188PMC
September 2021

Novel Homozygous Truncating Variant Widens the Spectrum of Early-Onset Multisystemic SYNE1 Ataxia.

Cerebellum 2021 Jul 28. Epub 2021 Jul 28.

Department of Neurology, University of Copenhagen, Rigshospitalet, Inge Lehmanns Vej 8, 2100, Copenhagen, Denmark.

Pathogenic variants in the SYNE1 gene are associated with a phenotypic spectrum spanning from late-onset, slowly progressive, relatively pure ataxia to early-onset, fast progressive multisystemic disease. Since its first description in 2007 as an adult-onset ataxia in French Canadian families, subsequent identification of patients worldwide has widened the clinical spectrum and increased the number of identified pathogenic variants. We report a 20-year-old Faroese female with early-onset progressive gait problems, weakness, dysphagia, slurred speech, orthostatic dizziness, and urge incontinence. Neurological examination revealed mild cognitive deficits, dysarthria, broken slow pursuit, hypometric saccades, weakness with spasticity, hyperreflexia, absent ankle reflexes, ataxia, and wide-based, spastic gait. Magnetic resonance imaging displayed atrophy of the cerebellum, brainstem, and spinal cord. Severely prolonged central motor conduction time and lower motor neuron involvement was demonstrated electrophysiologically. Fluorodeoxyglucose-positron emission tomography (FDG-PET) scan showed hypometabolism of the cerebellum and right frontal lobe. Muscle biopsy revealed chronic neurogenic changes and near-absent immunostaining for Nesprin-1. Next-generation sequencing revealed a previously undescribed homozygous truncating, likely pathogenic variant in the SYNE1 gene. The patient's mother and paternal grandfather were heterozygous carriers of the variant. Her father's genotype was unobtainable. We expand the list of likely pathogenic variants in SYNE1 ataxia with a novel homozygous truncating variant with proximity to the C-terminus and relate it to a phenotype comprising early-onset cerebellar deficits, upper and lower motor neuron involvement and cognitive deficits. Also, we report novel findings of focally reduced frontal lobe FDG-PET uptake and motor evoked potential abnormalities suggestive of central demyelination.
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http://dx.doi.org/10.1007/s12311-021-01308-wDOI Listing
July 2021

Serum Neurofilament Light in Patients with Frontotemporal Dementia Caused by CHMP2B Mutation.

Dement Geriatr Cogn Disord 2020 24;49(6):533-538. Epub 2021 Feb 24.

Neurogenetics Clinic & Research Lab, Danish Dementia Research Centre, Copenhagen, Denmark.

Introduction: The potential of neurofilament light (NfL) as a blood-based biomarker is currently being investigated in autosomal dominant neurodegenerative disease. This study explores the clinical utility of serum-NfL in frontotemporal dementia due to CHMP2B mutation (FTD-3).

Methods: This cross-sectional study included serum and CSF data from 38 members of the Danish FTD-3 family: 12 affected CHMP2B mutation carriers, 10 presymptomatic carriers, and 16 noncarriers. Serum-NfL levels measured by single-molecule array (Simoa) technology were tested for associations with the clinical groups and clinical parameters. Serum and CSF data were compared, and CSF/serum-albumin ratio was included as a measure of blood-brain barrier (BBB) function.

Results: Serum-NfL concentrations were significantly increased in symptomatic CHMP2B mutation carriers compared to presymptomatic carriers and in both groups compared to healthy family controls. Serum-NfL levels appear to increase progressively with age in presymptomatic carriers, and this is perhaps followed by a change in trajectory when patients become symptomatic. Measurements of NfL in serum and CSF were highly correlated and fold-changes in serum and CSF between clinical groups were similar. Increase in serum-NFL levels was correlated with reduced ACE-score. Higher CSF/serum-albumin ratios were demonstrated in FTD-3 patients, but this did not affect the significant associations between serum-NfL and clinical groups.

Conclusion: Serum-NfL could be utilized as an accurate surrogate marker of CSF levels to segregate symptomatic CHMP2B carriers, presymptomatic carriers, and non-carriers. The observed indication of BBB dysfunction in FTD-3 patients did not confound this use of serum-NfL. The results support the occurrence of mutation-related differences in NfL dynamics in familial FTD.
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http://dx.doi.org/10.1159/000513877DOI Listing
October 2021

Enhancement of Autophagy and Solubilization of Ataxin-2 Alleviate Apoptosis in Spinocerebellar Ataxia Type 2 Patient Cells.

Cerebellum 2020 Apr;19(2):165-181

Neurogenetics Clinic & Research Laboratory, Danish Dementia Research Centre, Department of Neurology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.

Spinocerebellar ataxia type 2 (SCA2), a rare polyglutamine neurodegenerative disorder caused by a CAG repeat expansion in the ataxin-2 gene, exhibits common cellular phenotypes with other neurodegenerative disorders, including oxidative stress and mitochondrial dysfunction. Here, we show that SCA2 patient cells exhibit higher levels of caspase-8- and caspase-9-mediated apoptotic activation than control cells, cellular phenotypes that we find to be exacerbated by reactive oxygen species (ROS) and inhibition of autophagy. We also suggest that oligomerization of mutant ataxin-2 protein is likely to be the cause of the observed cellular phenotypes by causing inhibition of autophagy and by inducing ROS generation. Finally, we show that removal of ataxin-2 oligomers, either by increasing autophagic clearance or by oligomer dissolution, appears to alleviate the cellular phenotypes. Our results suggest that oligomerized ataxin-2 and oxidative stress affect autophagic clearance in SCA2 cells, contributing to the pathophysiology, and that activation of autophagy or clearance of oligomers may prove to be effective therapeutic strategies.
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http://dx.doi.org/10.1007/s12311-019-01092-8DOI Listing
April 2020

Quantitative Measurements of Motor Function in Alzheimer's Disease, Frontotemporal Dementia, and Dementia with Lewy Bodies: A Proof-of-Concept Study.

Dement Geriatr Cogn Disord 2018 26;46(3-4):168-179. Epub 2018 Sep 26.

Danish Dementia Research Centre, Department of Neurology, Rigshospitalet, University of Copenhagen, Copenhagen,

Background: This study examines the efficacy of using quantitative measurements of motor dysfunction, compared to clinical ratings, in Alzheimer's disease (AD), frontotemporal dementia (FTD), and dementia with Lewy bodies (DLB).

Methods: In this cross-sectional study, 49 patients with a diagnosis of AD (n = 17), FTD (n = 19), or DLB (n = 13) were included and underwent cognitive testing, clinical motor evaluation, and quantitative motor tests: pronation/supination hand tapping, grasping and lifting, and finger and foot tapping.

Results: Our results revealed significantly higher Q-Motor values in pronation/supination and in grip lift force assessment in AD, FTD, and DLB compared to healthy controls (HC). Q-Motor values detected significant differences between AD and HC, while clinical ratings did not.

Conclusion: Our results suggest that quantitative measurements provide more objective and sensitive measurements of motor dysfunction in dementia.
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http://dx.doi.org/10.1159/000492860DOI Listing
January 2019

Inflammatory markers of CHMP2B-mediated frontotemporal dementia.

J Neuroimmunol 2018 11 17;324:136-142. Epub 2018 Aug 17.

Danish Dementia Research Centre, Department of Neurology, Rigshospitalet, University of Copenhagen, Denmark.

Histopathological studies and animal models have suggested an inflammatory component in the pathomechanism of the CHMP2B associated frontotemporal dementia (FTD-3). In this cross-sectional study, serum and cerebrospinal fluid were analyzed for inflammatory markers in CHMP2B mutation carriers. Serum levels of CCL4 were increased throughout life. Serum levels of IL-15, CXCL10, CCL22 and TNF-α were significantly associated with cognitive decline, suggesting a peripheral inflammatory response to neurodegeneration. CSF levels of sTREM2 appeared to increase more rapidly with age in CHMP2B mutation carriers. The identification of a peripheral inflammatory response to disease progression supports the involvement of an inflammatory component in FTD-3.
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http://dx.doi.org/10.1016/j.jneuroim.2018.08.009DOI Listing
November 2018

Sporadic Creutzfeldt-Jakob Disease in a Woman Married Into a Gerstmann-Sträussler-Scheinker Family: An Investigation of Prions Transmission via Microchimerism.

J Neuropathol Exp Neurol 2018 08;77(8):673-684

Danish Reference Center for Prion Diseases, Department of Pathology, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark.

This is the first report of presumed sporadic Creutzfeldt-Jakob disease (sCJD) and Gerstmann-Sträussler-Scheinker disease (GSS) with the prion protein gene c.305C>T mutation (p.P102L) occurring in one family. The father and son were affected with GSS and the mother had a rapidly progressive form of CJD. Diagnosis of genetic, variant, and iatrogenic CJD was ruled out based on the mother's clinical history, genetic tests, and biochemical investigations, all of which supported the diagnosis of sCJD. However, given the low incidence of sCJD and GSS, their co-occurrence in one family is extraordinary and challenging. Thus, a hypothesis for the transmission of infectious prion proteins (PrPSc) via microchimerism was proposed and investigated. DNA from 15 different brain regions and plasma samples of the CJD patient was subjected to PCR and shallow sequencing for detection of a male sex-determining chromosome Y (chr. Y). However, no trace of chr. Y was found. A long CJD incubation period or presumed small concentrations of chr. Y may explain the obtained results. Further studies of CJD and GSS animal models with controlled genetic and proteomic features are needed to determine whether maternal CJD triggered via microchimerism by a GSS fetus might present a new PrPSc transmission route.
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http://dx.doi.org/10.1093/jnen/nly043DOI Listing
August 2018

Defining active progressive multiple sclerosis.

Mult Scler 2017 Nov 23;23(13):1727-1735. Epub 2017 Aug 23.

Danish Multiple Sclerosis Center, Department of Neurology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.

Background: It is unknown whether disease activity according to consensus criteria (magnetic resonance imaging activity or clinical relapses) associate with cerebrospinal fluid (CSF) changes in progressive multiple sclerosis (MS).

Objective: To compare CSF biomarkers in active and inactive progressive MS according to consensus criteria.

Methods: Neurofilament light chain (NFL), myelin basic protein (MBP), IgG-index, chitinase-3-like-1 (CHI3L1), matrix metalloproteinase-9 (MMP-9), chemokine CXCL13, terminal complement complex, leukocyte counts and nitric oxide metabolites were measured in primary ( n = 26) and secondary progressive MS ( n = 26) and healthy controls ( n = 24).

Results: Progressive MS patients had higher CSF cell counts, IgG-index, CHI3L1, MMP-9, CXCL13, NFL and MBP concentrations. Active patients were younger and had higher NFL, CXCL13 and MMP-9 concentrations than inactive patients. Patients with active disease according to consensus criteria or detectable CXCL13 or MMP-9 in CSF were defined as having combined active progressive MS. These patients had increased CSF cell counts, IgG-index and MBP, NFL and CHI3L1 concentrations. Combined inactive patients only had increased IgG-index and MBP concentrations.

Conclusion: Patients with combined active progressive MS show evidence of inflammation, demyelination and neuronal/axonal damage, whereas the remaining patients mainly show evidence of active demyelination. This challenges the idea that neurodegeneration independent of inflammation is crucial in disease progression.
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http://dx.doi.org/10.1177/1352458517726592DOI Listing
November 2017

Hereditary cerebral small vessel disease and stroke.

Clin Neurol Neurosurg 2017 Apr 22;155:45-57. Epub 2017 Feb 22.

Department of Neurology, Copenhagen University Hospital, Bispebjerg, Denmark.

Cerebral small vessel disease is considered hereditary in about 5% of patients and is characterized by lacunar infarcts and white matter hyperintensities on MRI. Several monogenic hereditary diseases causing cerebral small vessel disease and stroke have been identified. The purpose of this systematic review is to provide a guide for determining when to consider molecular genetic testing in patients presenting with small vessel disease and stroke. CADASIL, CARASIL, collagen type IV mutations (including PADMAL), retinal vasculopathy with cerebral leukodystrophy, Fabry disease, hereditary cerebral hemorrhage with amyloidosis, and forkhead box C1 mutations are described in terms of genetics, pathology, clinical manifestation, imaging, and diagnosis. These monogenic disorders are often characterized by early-age stroke, but also by migraine, mood disturbances, vascular dementia and often gait disturbances. Some also present with extra-cerebral manifestations such as microangiopathy of the eyes and kidneys. Many present with clinically recognizable syndromes. Investigations include a thorough family medical history, medical history, neurological examination, neuroimaging, often supplemented by specific examinations e.g of the of vision, retinal changes, as well as kidney and heart function. However molecular genetic analysis is the final gold standard of diagnosis. There are increasing numbers of reports on new monogenic syndromes causing cerebral small vessel disease. Genetic counseling is important. Enzyme replacement therapy is possible in Fabry disease, but treatment options remain overall very limited.
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http://dx.doi.org/10.1016/j.clineuro.2017.02.015DOI Listing
April 2017

Social Cognition, Executive Functions and Self-Report of Psychological Distress in Huntington's Disease.

PLoS Curr 2016 Dec 28;8. Epub 2016 Dec 28.

Neurogenetics Clinic, Danish Dementia Research Centre, Department of Neurology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark; Denmark Department of Psychology, University of Copenhagen, Copenhagen, Denmark.

Objective: Huntington's disease (HD) is characterized by motor symptoms, psychiatric symptoms and cognitive impairment in, inter alia, executive functions and social cognition. The aim of this study was to investigate the relationship between subjective feeling of psychological distress using a self-report questionnaire and performances on tests of executive functions and social cognition in a large consecutive cohort of HD patients.

Method: 50 manifest HD patients were tested in social cognition and executive functions and each answered a self-report questionnaire about current status of perceived psychological distress (the Symptom Checklist-90-Revised (SCL-90-R)). Correlation analyses of test performance and SCL-90-R scores were made as well as stepwise linear regression analyses with the SCL-90-R GSI score and test performances as dependent variables.

Results: We found that less psychological distress was significantly associated with worse performances on social cognitive tests (mean absolute correlation .34) and that there were no significant correlations between perceived psychological distress and performance on tests of executive functions. The correlations between perceived psychological distress and performance on social cognitive tests remained significant after controlling for age, Unified Huntington's Disease Rating Scale-99 total motor score and performance on tests of executive functions.

Conclusions: Based on previous findings that insight and apathy are closely connected and may be mediated by overlapping neuroanatomical networks involving the prefrontal cortex and frontostriatal circuits, we speculate that apathy/and or impaired insight may offer an explanation for the correlation between self-report of psychological distress and performance on social cognitive tests in this study.
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http://dx.doi.org/10.1371/currents.hd.bba3a680813122013e6d3e8a144c1da8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5234736PMC
December 2016

Personality traits in Huntington's disease: An exploratory study of gene expansion carriers and non-carriers.

Am J Med Genet B Neuropsychiatr Genet 2016 12 7;171(8):1153-1160. Epub 2016 Oct 7.

Neurogenetics Clinic, Danish Dementia Research Center, Department of Neurology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.

Huntington's disease (HD) is associated with risk for developing psychiatric symptoms. Vulnerability or resilience to psychiatric symptoms may be associated with personality traits. This exploratory study, aimed to investigate personality traits in a large cohort of HD carriers and at risk gene-expansion negative individuals (HD non-carriers), exploring whether carrying the HD gene or growing up in an HD family influences personality traits. Forty-seven HD carriers, Thirty-nine HD non-carriers, and 121 healthy controls answered the Danish version of the revised NEO personality inventory. Comparisons between HD carriers and HD non-carriers were mostly non-significant but the combined group of HD carriers and non-carriers showed significantly higher scores on the facets: "hostility," "assertiveness," and "activity" and on the trait "Conscientiousness" relative to controls, "Conscientiousness" have been associated with resilience to psychiatric symptoms. Twelve HD carriers and non-carriers were classified as depressed and showed significantly lower scores on "Extraversion" and "Conscientiousness" and significantly higher scores on "Neuroticism," which are associated with vulnerability to psychiatric symptoms. Our findings suggest that, there is no direct effect of the HD gene on personality traits, but that personality assessment may be relevant to use when identifying individuals from HD families who are vulnerable to develop psychiatric symptoms. © 2016 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/ajmg.b.32501DOI Listing
December 2016

A Novel TTBK2 De Novo Mutation in a Danish Family with Early-Onset Spinocerebellar Ataxia.

Cerebellum 2017 02;16(1):268-271

Danish Dementia Research Centre, Neurogenetics Clinic, Department of Neurology, Rigshospitalet, University of Copenhagen, Blegdamsvej 9, DK-2100, Copenhagen, Denmark.

Spinocerebellar ataxia type 11 (SCA11) is rare and has previously been described in four families worldwide. We report a Danish family with onset of symptoms in early childhood and affected family members in two generations. The proband, a Danish female born in 1968, and family members were examined. Exome sequencing was performed and a "movement disorders" gene panel consisting of approximately 200 genes was used for filtering, while Sanger sequencing was used for subsequent testing for the mutation in the family. Onset of symptoms in affected family members was in early childhood. A novel frameshift mutation (c.1205_1207delinsA) in the tau-tubulin kinase 2 encoding gene, TTBK2, was identified, which was compatible with a diagnosis of SCA11. The mutation was subsequently identified in her two affected sons but not in the unaffected parents or her unaffected brother. This report further delineates the phenotypic spectrum of the rare SCA11 disease. In contrast to previously reported cases, onset of symptoms was in early childhood and the mutation was de novo in the proband.
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http://dx.doi.org/10.1007/s12311-016-0786-9DOI Listing
February 2017

SCA28: Novel Mutation in the AFG3L2 Proteolytic Domain Causes a Mild Cerebellar Syndrome with Selective Type-1 Muscle Fiber Atrophy.

Cerebellum 2017 02;16(1):62-67

Danish Dementia Research Centre, Neurogenetics Clinic, Department of Neurology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.

The spinocerebellar ataxias (SCA) are a group of rare inherited neurodegenerative diseases characterized by slowly progressive cerebellar ataxia, resulting in unsteady gait, clumsiness, and dysarthria. The disorders are predominantly inherited in an autosomal dominant manner. Mutations in the gene AFG3L2 that encodes a subunit of the mitochondrial m-AAA protease have previously been shown to cause spinocerebellar ataxia type 28 (SCA28). Here, we present the clinical phenotypes of three patients from a family with autosomal dominant cerebellar ataxia and show by molecular genetics and in silico modelling that this is caused by a novel missense mutation in the AFG3L2 gene. Furthermore, we show, for the first time, fluorodeoxyglucose-positron emission tomography (FDG-PET) scans of the brain and selective type I fiber atrophy of skeletal muscle of SCA28 patients indicating non-nervous-system involvement in SCA28 as well.
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http://dx.doi.org/10.1007/s12311-016-0765-1DOI Listing
February 2017

Do I misconstrue? Sarcasm detection, emotion recognition, and theory of mind in Huntington disease.

Neuropsychology 2016 Feb;30(2):181-9

Neurogenetics Clinic, Danish Dementia Research Centre, Department of Neurology, Rigshospitalet, University of Copenhagen.

Objective: Emotion recognition has been widely studied in Huntington disease (HD), but only a few studies have investigated more complex social cognition and, when so, exclusively in manifest HD. The present study sought to investigate social-cognitive functions in a large, consecutive cohort of premanifest and manifest HD gene expansion carriers using tests assessing sarcasm detection, theory of mind (ToM), and emotion recognition.

Method: Fifty manifest, 50 premanifest HD gene expansion carriers, and 39 at risk gene expansion negative healthy controls were included. All participants were tested with sarcasm detection, ToM, and emotion recognition tasks. Between-group comparisons of test performances and correlation analyses of test performances and disease burden scores were made.

Results: Group comparisons showed significant differences in performances on the social-cognitive tests between manifest HD gene expansion carriers and healthy controls, but differences in performances between premanifest HD gene expansion carriers and healthy controls were not statistically significant. Correlation analysis showed that the worse test performances were associated with higher disease burden scores in all HD gene expansion carriers.

Conclusion: Our findings support a theory of impaired social-cognitive functions in the early stages of HD. Test performances decreased with increasing disease burden in all HD gene expansion carriers, suggesting that social-cognitive tests may be useful for tracking disease progression. Simple emotion recognition tasks are just as sensitive for measuring social-cognitive deficits as more complex measures, but knowledge of the quality of social-cognitive impairments in HD can be of great importance to both patients and caregivers.
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http://dx.doi.org/10.1037/neu0000224DOI Listing
February 2016

Cerebrospinal Fluid Biomarkers in Familial Forms of Alzheimer's Disease and Frontotemporal Dementia.

Dement Geriatr Cogn Disord 2015 13;40(1-2):54-62. Epub 2015 May 13.

Danish Dementia Research Centre, Department of Neurology, Section 6911, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.

As dementia is a fast-growing health care problem, it is becoming an increasingly urgent need to provide an early diagnosis in order to offer patients the best medical treatment and care. Validated biomarkers which reflect the pathology and disease progression are essential for diagnosis and are important when developing new therapies. Today, the core protein biomarkers amyloid-β42, total tau and phosphorylated tau in the cerebrospinal fluid (CSF) are used to diagnose Alzheimer's disease (AD), because these biomarkers have shown to reflect the underlying amyloid and tau pathology. However, the biomarkers have proved insufficient predictors of dementias with a different pathology, e.g. frontotemporal dementia (FTD); furthermore, the biomarkers are not useful for early AD diagnosis. Familial dementias with a known disease-causing mutation can be extremely valuable to study; yet the biomarker profiles in patients with familial dementias are not clear. This review summarizes CSF biomarker findings from studies on symptomatic and presymptomatic individuals carrying a mutation in one of the genes known to cause early-onset familial AD or FTD. In conclusion, the biomarker profile of inherited AD is quite similar between carriers of different mutations as well as similar to the profile found in sporadic AD, whereas familial FTD does not seem to have a clear biomarker profile. Hence, new biomarkers are needed for FTD.
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http://dx.doi.org/10.1159/000381828DOI Listing
January 2016

Assessing impairment of executive function and psychomotor speed in premanifest and manifest Huntington's disease gene-expansion carriers.

J Int Neuropsychol Soc 2015 Mar 8;21(3):193-202. Epub 2015 Apr 8.

1Neurogenetics Clinic,Danish Dementia Research Centre,Department of Neurology,Rigshospitalet,University of Copenhagen,Copenhagen,Denmark.

Executive functions (EF) and psychomotor speed (PMS) has been widely studied in Huntington's disease (HD). Most studies have focused on finding markers of disease progression by comparing group means at different disease stages. Our aim was to investigate performances on nine measures of EF and PMS in a group of premanifest and manifest HD-gene expansion carriers and to investigate which measures were most sensitive for assessment of individual patients by analyzing frequencies of impaired performances relative to healthy controls. We recruited HD gene-expansion carriers, 48 manifest and 50 premanifest and as controls 39 healthy gene-expansion negative individuals. All participants underwent neurological examination and neuropsychological testing with nine cognitive measures. The frequency of impairment was investigated using cutoff scores. In group comparisons the manifest HD gene-expansion carriers scored significantly worse than controls on all tests and in classification of individual scores the majority of scores were classified as probably impaired (10th percentile) or impaired (5th percentile) with Symbol Digit Modalities Test (SDMT) being the most frequently impaired. Group comparisons of premanifest HD gene-expansion carriers and healthy controls showed significant differences on SDMT and Alternating fluency tests. Nevertheless the frequencies of probably impaired and impaired scores on individual tests were markedly higher for Alternating and Lexical fluency tests than for SDMT. We found distinct group differences in frequency of impairment on measures of EF and PMS in manifest and premanifest HD gene-expansion carriers. Our results indicate to what degree these measures can be expected to be clinically impaired.
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http://dx.doi.org/10.1017/S1355617715000090DOI Listing
March 2015

[Genetic counselling is relevant in familial as well as sporadic cases of amyotrophic lateral sclerosis].

Ugeskr Laeger 2014 Oct;176(43)

Klinisk Genetisk Klinik, Rigshospitalet, Blegdamsvej 9, 2100 København Ø.

Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurodegenerative disease of upper and lower motor neurons which often results in death from respiratory failure within 2-4 years. It has been estimated that 5-10% of ALS patients have a family history with ALS. The genetic background of the disorder is heterogeneous, and recently molecular genetic testing has become increasingly relevant, also in the clinical evaluation. As several genes have been identified in which the pathogenic mutations are characterized by reduced age-dependent penetrance, genetic testing can be relevant to consider, also in isolated cases.
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October 2014

Reduction in mitochondrial DNA copy number in peripheral leukocytes after onset of Huntington's disease.

Mitochondrion 2014 Jul 15;17:14-21. Epub 2014 May 15.

Department of Cellular and Molecular Medicine, University of Copenhagen, Panum Institute, Blegdamsvej 3, DK-2200 Copenhagen N, Denmark. Electronic address:

Huntington's disease (HD) is an inherited neurodegenerative disorder characterised by movement disorder, cognitive symptoms and psychiatric symptoms with predominantly adult-onset. The mutant huntingtin protein leads to mitochondrial dysfunction in blood leukocytes. This discovery led to the investigation of the mitochondrial DNA (mtDNA) copy number relative to nuclear DNA (nDNA) in leukocytes from carriers of the HD mutation compared to healthy individuals. We found significantly reduced mtDNA/nDNA in HD mutation carriers compared to controls. A longitudinal study of archive DNA sample pairs from HD patients revealed a biphasic pattern of increasing mtDNA/nDNA before onset of motor symptoms and decreasing mtDNA/nDNA after.
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http://dx.doi.org/10.1016/j.mito.2014.05.001DOI Listing
July 2014

Intravenous immunoglobulin treatment in a patient with adrenomyeloneuropathy.

BMC Neurol 2012 Sep 26;12:108. Epub 2012 Sep 26.

Kennedy Centre, Copenhagen University Hospital, Rigshospitalet, Gl, Landevej 7, Copenhagen, 2600, Glostrup, Denmark.

Background: Adrenomyeloneuropathy (AMN) is one of several phenotypes of the adrenoleukodystrophy spectrum caused by mutations in the ABCD1 gene on the X chromosome. An inflammatory component is part of the disease complex ranging from severe childhood CNS demyelination to spinal cord and peripheral nerve degeneration.

Case Presentation: We present a patient with clinical progressive AMN and severe lower limb pain. Longitudinal brain magnetic resonance spectroscopy showed a constant slightly elevated myoinositol/total creatine ratio during the five year treatment period, probably reflecting demyelination, microglial activation and gliosis, indicating an inflammatory response. The pain was refractory to conventional therapy but intravenous immunoglobulin (IVIG) treatment was highly efficient.

Conclusion: IVIG may be considered as a last resort for treatment of refractory pain in AMN patients with indications of an inflammatory component.
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http://dx.doi.org/10.1186/1471-2377-12-108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3517486PMC
September 2012

Presymptomatic cerebral blood flow changes in CHMP2B mutation carriers of familial frontotemporal dementia (FTD-3), measured with MRI.

BMJ Open 2012 15;2(2):e000368. Epub 2012 Mar 15.

Center of Functionally Integrative Neuroscience, Aarhus University Hospital, Aarhus, Denmark.

Objectives: To assess functional changes measured by cerebral blood flow (CBF) in the presymptomatic stage of frontotemporal dementia linked to chromosome 3 (FTD-3) caused by a truncating mutation in CHMP2B.

Design: Case-control study.

Setting: A memory clinic and tertiary referrals centre for dementia and inherited neurodegenerative disorders.

Participants: The authors included 11 presymptomatic CHMP2B mutation carriers and seven first-degree-related family non-carriers. Participants were MRI scanned twice with an interval of 15 months.

Primary And Secondary Outcome Measures: Local functional changes in brain tissue perfusion were measured as CBF with two different MR techniques, gradient echo (GRE) and spin echo (SE), focusing on CBF in all cerebral vessels (GRE) and cerebral capillaries (SE), respectively. As planned, data analysis included co-registration of perfusion images to structural T1 images. Perfusion data were then extracted from seven regions-of-interest, normalised to white matter and statistically compared between carriers and non-carriers.

Results: For SE, contrasts between carriers and non-carriers showed significant differences in temporal, occipital and parietal lobes and in hippocampus. There was no evidence of changes from baseline to follow-up. For GRE, there were no significant differences between carriers and non-carriers.

Conclusions: Significantly decreased CBF was found in presymptomatic CHMP2B mutation carriers in occipital-and parietal lobes. Comparing SE with GRE, data indicate that FTD-3 vascular pathology might primarily affect brain capillaries.
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http://dx.doi.org/10.1136/bmjopen-2011-000368DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3307039PMC
October 2012

Huntington's disease: effect of memantine on FDG-PET brain metabolism?

J Neuropsychiatry Clin Neurosci 2011 ;23(2):206-10

Neurogenetics Clinic, Memory Disorders Research Group, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.

In this open-label pilot study, the authors evaluated the effect of memantine on the distribution of brain glucose metabolism in four Huntington's disease (HD) patients as determined by serial 18-fluoro-deoxyglucose [F(18)]FDG-PET scans over a period of 3-4 months (90-129 days, with one patient choosing to continue treatment over the 18-month follow-up period). The treatment regimen was well tolerated. No significant differences on neuropsychological parameters before and after treatment were detected; but the patient who continued treatment did not deteriorate at 18 months' reevaluation, whereas the three patients who had stopped treatment after 3 to 4 months had minor progression in all cognitive domains on re-evaluation 12 months after the end of treatment.
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http://dx.doi.org/10.1176/jnp.23.2.jnp206DOI Listing
September 2011

Novel mutations in EPM2A and NHLRC1 widen the spectrum of Lafora disease.

Epilepsia 2010 Sep 5;51(9):1691-8. Epub 2010 Aug 5.

Service de génétique, hospices civils de Lyon et université Claude Bernard Lyon I, Lyon, France.

Purpose: Lafora disease (LD) is an autosomal recessive form of progressive myoclonus epilepsy with onset in childhood or adolescence and with fatal outcome caused by mutations in two genes: EPM2A and NHLRC1. The aim of this study was to characterize the mutation spectrum in a cohort of unrelated patients with presumed LD.

Methods: Sequencing of the two genes and search for large rearrangements was performed in 46 unrelated patients with suspected LD, 33 originating from France and the others from different countries. Patients were classified into two groups according to the clinical presentation.

Results: Mutations of various types were found in EPM2A in 10 patients and in NHLRC1 in 4 patients. Mutations were found in 14 (93%) of 15 patients with classical clinical and electroencephalography (EEG) presentation of LD and in no patients with an atypical presentation. Ten mutations were novel, including the first substitution reported in a donor splice site of EPM2A, leading to the deletion of exon 2 at the RNA level. Four large deletions, including two deletions of exon 2 with different sizes and breakpoints, were found in EPM2A, corresponding to 20% of the alleles of this gene.

Discussion: We described several novel mutations of EPM2A and NHLRC1 and brought additional data to the genetic epidemiology of LD. This study emphasized the high mutation rate in patients with classical LD as well as the high negativity rate of skin biopsy.
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http://dx.doi.org/10.1111/j.1528-1167.2010.02692.xDOI Listing
September 2010

Proteomic investigations of the ventriculo-lumbar gradient in human CSF.

J Neurosci Methods 2010 Aug 25;191(2):244-8. Epub 2010 Jun 25.

Memory Disorders Research Group, Department of Neurology, Copenhagen University Hospital, Copenhagen, Denmark.

Cerebrospinal fluid (CSF) is an ideal biological material in which to search for new biomarkers for improved diagnosis of neurological diseases. During a lumbar puncture between 5 and 15 mL of CSF are obtained. Previous studies have assessed the ventriculo-lumbar concentration gradient of a number of specific proteins. In the present study we took a proteomics approach to investigate the possible concentration gradient of a panel of proteins and peptides in the CSF of 16 patients with neurodegenerative diseases. Using two different mass spectrometry techniques, matrix assisted laser desorption ionization time of flight (MALDI-TOF) and surface enhanced laser desorption ionization time of flight (SELDI-TOF), we found that only one of the investigated proteins, apolipoprotein CI, was significantly decreased between the 1st and the 10th mL of CSF. Furthermore, we confirmed previous results showing a significant decrease in albumin concentration from the first to the last CSF aliquots. In conclusion, we found a significant gradient effect for only two of the measured proteins. However, a standardized procedure for CSF collection for diagnostic and research purposes is crucial to allow comparisons of results between patient groups and between laboratories. This is especially important since CSF is usually collected at several centres and variation in sampled CSF due to pre-analytical factors could complicate the interpretation of the results.
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http://dx.doi.org/10.1016/j.jneumeth.2010.06.017DOI Listing
August 2010

Atypical early-onset Alzheimer's disease caused by the Iranian APP mutation.

J Neurol Sci 2008 May 9;268(1-2):124-30. Epub 2008 Jan 9.

Memory Disorders Research Group, Department of Neurology, Copenhagen University Hospital Rigshospitalet, Blegdamsvej 9, DK-2100 Copenhagen, Denmark.

Background: Approximately 1% of all cases of Alzheimer's disease are inherited autosomal dominantly, and to date, three causative genes have been found, the Presenilin 1 (PSEN1) gene, the Presenilin 2 (PSEN2) gene and the Amyloid precursor protein (APP) gene. We describe atypical phenotypic features in a family with a pathogenic APP gene mutation and discuss possible explanations for these atypical features.

Methods And Results: We report a family with a history of dementia compatible with autosomal dominant transmission. The disease course in the proband was not typical for Alzheimer's disease as the diagnosis was preceded by 8 years of an isolated amnesia. Further, the proband had epilepsy with complex partial seizures and central degenerative autonomic failure as determined by clinical physiology. Sequencing the three known causative Alzheimer genes revealed a pathogenic missense mutation, APP Thr714Ala (the Iranian mutation).

Conclusions: The atypical clinical phenotype with long prodromal phase, autonomic failure and seizures in this new proband with the APP Thr714Ala mutation illustrates the clinical heterogeneity in families with identical pathogenic mutations.
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http://dx.doi.org/10.1016/j.jns.2007.11.021DOI Listing
May 2008

[Dementia--genetic aspects].

Ugeskr Laeger 2006 Oct;168(40):3405-8

H:S Rigshospitalet, Neurocentret, Neurologisk Klinik, H:S Hukommelsesklinikken.

Several prevalent, sporadic neurodegenerative disorders also occur as rare inherited variants. Mapping of the genes involved in rare variants of the disorders has contributed to elucidating pathogenetic pathways for several dementia disorders, and the increased knowledge creates a possibility for development of new molecular genetic methods for diagnostics and for the treatment of the different types of dementia. Although inherited dementia disorders are generally rare, a genetic basis should always be considered when facing a patient with a recently clinically diagnosed dementia disorder.
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October 2006

Meiotic CAG repeat instability in spinocerebellar ataxia type 6: maternally transmitted elongation in a presumed sporadic case.

J Neurol Sci 2006 Feb 28;241(1-2):95-8. Epub 2005 Nov 28.

Department of Medical Biochemistry and Genetics, Section of Neurogenetics, The Panum Institute, University of Copenhagen, Denmark.

Spinocerebellar ataxia type 6 (SCA6) is an autosomal dominantly inherited disorder characterized by cerebellar ataxia, dysarthria and nystagmus. The molecular background for the disorder is a CAG repeat expansion in the CACNA1A gene located on chromosome 19. The size of SCA6 expanded alleles is usually stable, and variation in repeat size over successive generations is rare. We report a Danish family with one case of SCA6 resembling a sporadic case of spinocerebellar ataxia. Analysis of the CACNA1A gene showed meiotic CAG repeat instability in the transmission from a 70-year-old woman with no subjective symptoms to her symptomatic son. The CAG repeat size expanded from 22 repeats in the mother to 23 repeats in the proband. This case demonstrates maternal repeat instability and clinical anticipation in a family with SCA6.
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http://dx.doi.org/10.1016/j.jns.2005.10.004DOI Listing
February 2006

Dopa-responsive dystonia and early-onset Parkinson's disease in a patient with GTP cyclohydrolase I deficiency?

Mov Disord 2006 May;21(5):679-82

Department of Medical Genetics, The Panum Institute, University of Copenhagen, and Department of Neurology, Rigshospitalet, Copenhagen, Denmark.

We describe a patient with a combination of dystonic and parkinsonian signs. Paraclinical studies revealed a mutation in the GTP cyclohydrolase I gene (GCH1) and a decrease in [123I]-N-omega-fluoropropyl-2beta-carbomethoxy-3beta-(4-iodophenyl) nortropane (123I-FP-CIT) binding ratios indicative of Parkinson's disease. We conclude that the patient probably suffers from a variant of dopa-responsive dystonia (DRD) or two separate movement disorders, normally considered to be differential diagnoses, DRD and early-onset Parkinson's disease with resulting difficulties concerning treatment and prognosis.
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http://dx.doi.org/10.1002/mds.20773DOI Listing
May 2006
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