Peer Review History: PLOS recognizes the benefits of transparency in the peer review process; the... more Peer Review History: PLOS recognizes the benefits of transparency in the peer review process; therefore, we enable the publication of all of the content of peer review and author responses alongside final, published articles. The editorial history of this article is available here:
The objective was to compare predictive values of clinical and CT findings, co-existing cerebrova... more The objective was to compare predictive values of clinical and CT findings, co-existing cerebrovascular disease (CVD) and CSF outflow resistance (Rcsf) for outcome of shunting in NPH. A group of 95 NPH patients was shunted and followed for one year. Gait disturbance and dementia were quantified by an NPH scale (NPHS) and handicap by the modified Rankin scale (MRS). Improvement was defined as a change of at least 15% in NPHS and one grade in MRS at last follow-up. Clinical and CT findings at entry were classified as typical or not typical for NPH. CVD was defined as a history of stroke or CT-scans showing infarcts or moderate to severe white matter hypodense lesions. Clinical and CT findings typical for NPH, absence of CVD and Rcsf> 18 mmHg/ml/min were positive tests and the reciprocal outcomes negative tests. Typical clinical and CT findings were found in 69% and 68%, CVD (history of stroke n = 14, infarcts on CT n = 13, leucoaraiosis n = 32) in 47% and Rcsf> 18 in 38% of patients. The ratio of patients classified as improved in both scales was significantly greater for those with positive than negative tests. Mean improvement differed the most between patients with and without CVD. Using logistic regression analysis Rcsf > 18 was the only significant predictor of improvement in NPHS (OR 4.4, 95% CI 1.3-16.7) and typical CT findings in MRS (OR 5.6, 95% CI \.8-17.9). We conclude that CVD is an important predictor of poor outcome. The best strategy is to shunt NPH patients if Rcsf is > 18 mmHg/ml/min or, when Rcsf is lower, if CT findings are typical for NPH and there is no or limited CVD.
We describe the neurological, electrophysiological, and genetic features of autosomal dominant di... more We describe the neurological, electrophysiological, and genetic features of autosomal dominant distal hereditary motor neuronopathy (HMN) in a threegeneration Dutch family, including 12 patients with distal muscle weakness and atrophy. The severity of disease ranged from disabling muscle weakness to a subclinical phenotype. Neurologic exams of nine patients and nerve conduction studies (NCS) and myography in five endorsed the variable presentations of HMN in this family, including patients with only lower (four), upper (one), or both upper and lower extremities involvement (four). Asymmetrical or strictly unilateral disease was noted in three patients. Three also showed pyramidal features. A genome-wide search combining SNP arrays (250K) with parametric linkage analysis identified a novel locus on chromosome 16p (mLOD=3.28) spanning 6 Mb (rs6500882-rs7192086). Direct sequencing excluded mutations in the SIMPLE/ LITAF gene (mapping to the 16p locus) and identified a pathogenic mutation (p.N88S) in BCLS2 (11q12-q14). All 12 affected relatives had the BSCL2 mutation and the chromosome 16p haplotype and showed features of motor neuron degeneration. One patient had a very mild phenotype with bilateral pes cavus, normal concentric needle electromyography but signs of motor neuron involvement at electrophysiological muscle scan (EMS). Similar EMS abnormalities in addition to abnormal NCS and myography were observed in a clinically unaffected person (carrying only the 16p haplotype). These results expand the clinical spectrum of HMN and suggest a digenic inheritance of HMN in this family with a BSCL2 mutation and a chromosome 16 locus likely contributing to the phenotype.
A BS T RA C T : Background: The most common genetic risk factor for Parkinson's disease known is ... more A BS T RA C T : Background: The most common genetic risk factor for Parkinson's disease known is a damaging variant in the GBA1 gene. The entire GBA1 gene has rarely been studied in a large cohort from a single population. The objective of this study was to assess the entire GBA1 gene in Parkinson's disease from a single large population. Methods: The GBA1 gene was assessed in 3402 Dutch Parkinson's disease patients using nextgeneration sequencing. Frequencies were compared with Dutch controls (n = 655). Family history of Parkinson's disease was compared in carriers and noncarriers. Results: Fifteen percent of patients had a GBA1 nonsynonymous variant (including missense, frameshift, and recombinant alleles), compared with 6.4% of controls (OR, 2.6; P < 0.001). Eighteen novel variants were detected. Variants previously associated with Gaucher's disease were identified in 5.0% of patients compared with 1.5% of controls (OR, 3.4; P < 0.001). The rarely reported complex allele p.D140H + p.E326K appears to likely be a Dutch founder variant, found in 2.4% of patients and 0.9% of controls (OR, 2.7; P = 0.012). The number of first-degree relatives (excluding children) with Parkinson's disease was higher in p.D140H + p.E326K carriers (5.6%, 21 of 376) compared with p.E326K carriers (2.9%, 29 of 1014); OR, 2.0; P = 0.022, suggestive of a dose effect for different GBA1 variants. Conclusions: Dutch Parkinson's disease patients display one of the largest frequencies of GBA1 variants reported so far, consisting in large part of the mild p.E326K variant and the more severe Dutch p.D140H + p.E326K founder allele.
Nederlands Tijdschrift voor Geneeskunde, Mar 13, 2004
Progressive supranuclear palsy is a neurodegenerative disorder accompanied by parkinsonism, distu... more Progressive supranuclear palsy is a neurodegenerative disorder accompanied by parkinsonism, disturbances of eye movements, pseudobulbar palsy and often cognitive decline. Onset of disease is usually between 50-70 years of age and mean survival is 5-8 years. The prevalence of PSP has been estimated at around 5 per 100,000, although exact figures for the population of the Netherlands are not yet available. International consensus criteria differentiate between possible, probable and definite PSP; the latter requiring neuropathological confirmation. An extensive differential diagnosis may be made early in the course of the disease, but at a later stage development of the characteristic symptoms will make diagnosis easier. Imaging techniques can lend support to the clinical diagnosis to a limited extent, although they lack sufficient specificity to confirm it. PSP is a &amp;amp;#39;tauopathy&amp;amp;#39; characterized by aggregates of abnormal tau protein in the basal ganglia and brainstem. Some mutations in the tau gene can cause a clinical and pathological picture similar to that of PSP, although most patients with sporadic and familial PSP do not have tau mutations. Various studies have found a strong association between PSP and a specific tau haplotype (H1 haplotype), but its role in the pathophysiological mechanism of PSP is still unclear and needs further research.
Introduction: The diagnosis aceruloplasminemia is usually made in patients with advanced neurolog... more Introduction: The diagnosis aceruloplasminemia is usually made in patients with advanced neurological manifestations of the disease. In these patients prognosis is poor, disabilities are severe and patients often die young. The aim of our study was to facilitate recognition of aceruloplasminemia at a disease stage at which treatment can positively influence outcome. Currently, the neurological phenotype of aceruloplasminemia has been mainly described in Japanese patients. This 'classical' phenotype consists of cerebellar ataxia, hyperkinetic movement disorders and cognitive decline. In this study we describe the spectrum of neurological disease in Caucasian patients. Methods: Data on neurological presentation and follow-up were gathered from both our patients, homozygous for the G631R mutation in the CP gene, and other published Caucasian cases. Neurological features of aceruloplasminemia in Caucasian patients were compared to those summarized in Japanese patients. Results: 21 Caucasian patients, both ours and the described cases, displayed a wide range of movement disorders with predominant chorea, parkinsonism and ataxia, and also tremor and dystonia. In addition to cognitive decline, nearly half of the Caucasian patients presented with psychiatric changes, including depression, anxiety and behavioral changes. In one-third of the neurologically symptomatic Caucasian patients, cognitive-or psychiatric changes were the first neurological manifestations of aceruloplasminemia. Conclusions: Aceruloplasminemia in Caucasian patients can present with a wider range and a different order of neurological symptoms than previously described in Japanese patients. Psychiatric changes and parkinsonism can be added to the spectrum of neurological disease. Cognitive-or psychiatric changes may be the first neurological manifestations of aceruloplasminemia.
Background: Progressive supranuclear palsy (PSP) is a progressive neurodegenerative disorder char... more Background: Progressive supranuclear palsy (PSP) is a progressive neurodegenerative disorder characterized by aggregates of the microtubule-associated protein tau (MAPT). A nonsignificant trend for positive family history has been observed in two case-control studies and several pedigrees with familial clustering of parkinsonism have been described. Occasionally, mutations in MAPT are found in patients with a clinical phenotype similar to PSP. In this case-control study, we compared the occurrence of dementia and parkinsonism among first-degree relatives of patients with PSP with an age-and sex-matched control group. Methods: Family history of dementia and parkinsonism was collected from all first-degree relatives of patients with PSP who fulfilled the international National Institute of Neurological Disorders and Stroke criteria for PSP. Age-and sex-matched controls were selected from the Rotterdam Study. Genetic testing and pathologic examination was performed in a subset of familial PSP cases. Results: Fifty-seven (33%) of the 172 patients with PSP had at least one first-degree relative who had dementia or parkinsonism compared to 131 (25%) of the control subjects (odds ratio [OR] 1.5, 95% confidence interval [CI] 1.01-2.13). In patients with PSP, more first-degree relatives with parkinsonism were observed compared to controls, with an OR 3.9 (95% CI 1.99-7.61). Twelve patients with PSP (7%) fulfilled the criteria for an autosomal dominant mode of transmission. The intrafamilial phenotype within these pedigrees varied among PSP, dementia, tremor, and parkinsonism. Genetic studies revealed one patient with a P301L mutation in MAPT. Pathologic examination of five familial cases confirmed the clinical diagnosis of PSP, with predominant four repeat tau pathology in affected brain areas. Conclusion: This study demonstrates familial aggregation of parkinsonism in progressive supranuclear palsy. Neurology ® 2009;73:98-105 GLOSSARY CB ϭ coiled bodies; CI ϭ confidence interval; FTD ϭ frontotemporal dementia; GRN ϭ progranulin; LRRK2 ϭ leucine-rich repeat kinase 2; MAPT ϭ microtubule-associated protein tau; NFT ϭ neurofibrillary tangles; NINDS-SPSP ϭ National Institute for Neurological Diseases and Stroke-Society for Progressive Supranuclear Palsy; OR ϭ odds ratio; PD ϭ Parkinson disease; PSP ϭ progressive supranuclear palsy; STN ϭ subthalamic nucleus; TA ϭ tufted astrocytes; Thr ϭ threads.
Progressive Supranuclear Palsy (PSP) has been used to denote a unifying disorder with progressive... more Progressive Supranuclear Palsy (PSP) has been used to denote a unifying disorder with progressive parkinsonism with early falls, vertical supranuclear gaze palsy, pseudobulbar dysfunction and cognitive decline. Over the last decade, heterogeneity of the disease into different clinical subtypes has been recognized in clinicopathological studies. Although neuroimaging features and laboratory findings may support the diagnosis, true biomarkers are still lacking in the clinical setting. Neuronal and glial tau positive aggregates are predominantly found in basal ganglia and brainstem, and the significant association of PSP with the common H1 tau haplotype likely points to a pathophysiological role of the tau protein in the disease process. Future genetic studies of familial cases and an ongoing genome-wide association study of large series of pathological-proven cases may reveal additional genetic factors in the near future.
Background: Progressive supranuclear palsy (PSP) with a frontal presentation, characterized by co... more Background: Progressive supranuclear palsy (PSP) with a frontal presentation, characterized by cognitive deficits and behavioral changes, has been recognized as an early clinical picture, distinct from the classical so-called Richardson and parkinsonism presentations. The midcingulate cortex is associated with executive and attention tasks and has consistently been found to be impaired in imaging studies of patients with PSP. The aim of the present study was to determine alterations in neurotransmission underlying the pathophysiology of PSP, as well as their significance for clinically identifiable PSP subgroups. Methods: In vitro receptor autoradiography was used to quantify densities of 20 different receptors in the caudate nucleus and midcingulate area 24' of patients with PSP (n = 16) and age-and sex-matched control subjects (n = 14). Results: Densities of γ-aminobutyric acid type B, peripheral benzodiazepine, serotonin receptor type 2, and Nmethyl-D-aspartate receptors were significantly higher in area 24′ of patients with PSP, where tau impairment was stronger than in the caudate nucleus. Kainate and nicotinic cholinergic receptor densities were significantly lower, and adenosine receptor type 1 (A 1) receptors significantly higher, in the caudate nucleus of patients with PSP. Receptor fingerprints also segregated PSP subgroups when clinical parameters such as occurrence of frontal presentation and tau pathology severity were taken into consideration. Conclusions: We demonstrate, for the first time to our knowledge, that kainate and A 1 receptors are altered in PSP and that clinically identifiable PSP subgroups differ at the neurochemical level. Numerous receptors were altered in the midcingulate cortex, further suggesting that it may prove to be a key region in PSP. Finally, we add to the evidence that nondopaminergic systems play a role in the pathophysiology of PSP, thus highlighting potential novel treatment strategies.
Autoimmune encephalitis can be classified into antibody-defined subtypes, which can manifest with... more Autoimmune encephalitis can be classified into antibody-defined subtypes, which can manifest with immunotherapy-responsive movement disorders sometimes mimicking non-inflammatory aetiologies. In the elderly, anti-LGI1 and contactin associated protein like 2 (CASPR2) antibody-associated diseases compose a relevant fraction of autoimmune encephalitis. Patients with LGI1 autoantibodies are known to present with limbic encephalitis and additionally faciobrachial dystonic seizures may occur. However, the clinical spectrum of CASPR2 autoantibody-associated disorders is more diverse including limbic encephalitis, Morvan’s syndrome, peripheral nerve hyperexcitability syndrome, ataxia, pain and sleep disorders. Reports on unusual, sometimes isolated and immunotherapy-responsive movement disorders in CASPR2 autoantibody-associated syndromes have caused substantial concern regarding necessity of autoantibody testing in patients with movement disorders. Therefore, we aimed to systematically assess their prevalence and manifestation in patients with CASPR2 autoimmunity. This international, retrospective cohort study included patients with CASPR2 autoimmunity from participating expert centres in Europe. Patients with ataxia and/or movement disorders were analysed in detail using questionnaires and video recordings. We recruited a comparator group with anti-LGI1 encephalitis from the GENERATE network. Characteristics were compared according to serostatus. We identified 164 patients with CASPR2 autoantibodies. Of these, 149 (90.8%) had only CASPR2 and 15 (9.1%) both CASPR2 and LGI1 autoantibodies. Compared to 105 patients with LGI1 encephalitis, patients with CASPR2 autoantibodies more often had movement disorders and/or ataxia (35.6 versus 3.8%; P &lt; 0.001). This was evident in all subgroups: ataxia 22.6 versus 0.0%, myoclonus 14.6 versus 0.0%, tremor 11.0 versus 1.9%, or combinations thereof 9.8 versus 0.0% (all P &lt; 0.001). The small group of patients double-positive for LGI1/CASPR2 autoantibodies (15/164) significantly more frequently had myoclonus, tremor, ‘mixed movement disorders’, Morvan’s syndrome and underlying tumours. We observed distinct movement disorders in CASPR2 autoimmunity (14.6%): episodic ataxia (6.7%), paroxysmal orthostatic segmental myoclonus of the legs (3.7%) and continuous segmental spinal myoclonus (4.3%). These occurred together with further associated symptoms or signs suggestive of CASPR2 autoimmunity. However, 2/164 patients (1.2%) had isolated segmental spinal myoclonus. Movement disorders and ataxia are highly prevalent in CASPR2 autoimmunity. Paroxysmal orthostatic segmental myoclonus of the legs is a novel albeit rare manifestation. Further distinct movement disorders include isolated and combined segmental spinal myoclonus and autoimmune episodic ataxia.
Recentelijk zijn rasagiline en rotigotine geregistreerd voor de behandeling van de ziekte van Par... more Recentelijk zijn rasagiline en rotigotine geregistreerd voor de behandeling van de ziekte van Parkinson en is tolcapon opnieuw beschikbaar gekomen, zij het onder strikte voorwaarden. Rasagiline heeft een bescheiden effect als monotherapie bij de de-novoparkinsonpatient en is voor de behandeling van ‘wearing off’ te vergelijken met entacapon, in combinatie met levodopa. Rotigotine wordt via een pleister transdermaal toegediend, een veelbelovende methode. De resultaten vallen echter tegen en zijn minder dan verwacht. In Nederland wordt rasagiline alleen bij zogeheten pluspakketten vergoed, maar in Belgie volledig. Rotigotine wordt in Nederland niet vergoed, terwijl het in Belgie niet is geregistreerd. Tolcapon ten slotte kan en mag alleen worden voorgeschreven indien alternatieve behandelingen niet tot het gewenste resultaat leiden en dan alleen onder de voorwaarde dat zeer frequent de leverfuncties worden bepaald.
An optimized clinically feasible neuromelanin-MRI imaging protocol for visualising the SN and LC ... more An optimized clinically feasible neuromelanin-MRI imaging protocol for visualising the SN and LC simultaneously using deep learning reconstruction is presented. We optimize flip-angle for optimal combined SN and LC depiction. We also experimented with combinations of anisotropic and isotropic in-plane resolution, partial vs full echoes and the number of averages. Phantom and in-vivo experiments on three healthy volunteers illustrate that high-resolution imaging combined with deep-learning denoising shows good depiction of the SN and LC with a clinically feasible sequence of around 7 minutes.
BackgroundAs gene‐targeted therapies are increasingly being developed for Parkinson's disease... more BackgroundAs gene‐targeted therapies are increasingly being developed for Parkinson's disease (PD), identifying and characterizing carriers of specific genetic pathogenic variants is imperative. Only a small fraction of the estimated number of subjects with monogenic PD worldwide are currently represented in the literature and availability of clinical data and clinical trial‐ready cohorts is limited.ObjectiveThe objectives are to (1) establish an international cohort of affected and unaffected individuals with PD‐linked variants; (2) provide harmonized and quality‐controlled clinical characterization data for each included individual; and (3) further promote collaboration of researchers in the field of monogenic PD.MethodsWe conducted a worldwide, systematic online survey to collect individual‐level data on individuals with PD‐linked variants in SNCA, LRRK2, VPS35, PRKN, PINK1, DJ‐1, as well as selected pathogenic and risk variants in GBA and corresponding demographic, clinical,...
The protein phosphatase 2A complex (PP2A), the major Ser/Thr phosphatase in the brain, is involve... more The protein phosphatase 2A complex (PP2A), the major Ser/Thr phosphatase in the brain, is involved in a number of signalling pathways and functions, including the regulation of crucial proteins for neurodegeneration, such as alpha-synuclein, tau and LRRK2. Here, we report the identification of variants in the PTPA/PPP2R4 gene, encoding a major PP2A activator, in two families with early-onset parkinsonism and intellectual disability. We carried out clinical studies and genetic analyses, including genome-wide linkage analysis, whole-exome sequencing, and Sanger sequencing of candidate variants. We next performed functional studies on the disease-associated variants in cultured cells and knock-down of ptpa in Drosophila melanogaster. We first identified a homozygous PTPA variant, c.893T>G (p.Met298Arg), in patients from a South African family with early-onset parkinsonism and intellectual disability. Screening of a large series of additional families yielded a second homozygous vari...
Parkinson's disease covers a wide spectrum of symptoms, ranging from early non-motor symptoms... more Parkinson's disease covers a wide spectrum of symptoms, ranging from early non-motor symptoms to the characteristic bradykinesia, tremor and rigidity. Although differences in the symptomatology of Parkinson's disease are increasingly recognized, there is still a lack of insight into the heterogeneity of the pre-diagnostic phase of Parkinson's disease. In this perspective, we highlight three aspects regarding the role of population-based studies in providing new insights into the heterogeneity of pre-diagnostic Parkinson's disease. First we describe several specific advantages of population-based cohort studies, including the design which overcomes some common biases, the broad data collection and the high external validity. Second, we draw a parallel with the field of Alzheimer's disease to provide future directions to uncover the heterogeneity of pre-diagnostic Parkinson's disease. Finally, we anticipate on the emergence of prevention and disease-modificatio...
Peer Review History: PLOS recognizes the benefits of transparency in the peer review process; the... more Peer Review History: PLOS recognizes the benefits of transparency in the peer review process; therefore, we enable the publication of all of the content of peer review and author responses alongside final, published articles. The editorial history of this article is available here:
The objective was to compare predictive values of clinical and CT findings, co-existing cerebrova... more The objective was to compare predictive values of clinical and CT findings, co-existing cerebrovascular disease (CVD) and CSF outflow resistance (Rcsf) for outcome of shunting in NPH. A group of 95 NPH patients was shunted and followed for one year. Gait disturbance and dementia were quantified by an NPH scale (NPHS) and handicap by the modified Rankin scale (MRS). Improvement was defined as a change of at least 15% in NPHS and one grade in MRS at last follow-up. Clinical and CT findings at entry were classified as typical or not typical for NPH. CVD was defined as a history of stroke or CT-scans showing infarcts or moderate to severe white matter hypodense lesions. Clinical and CT findings typical for NPH, absence of CVD and Rcsf> 18 mmHg/ml/min were positive tests and the reciprocal outcomes negative tests. Typical clinical and CT findings were found in 69% and 68%, CVD (history of stroke n = 14, infarcts on CT n = 13, leucoaraiosis n = 32) in 47% and Rcsf> 18 in 38% of patients. The ratio of patients classified as improved in both scales was significantly greater for those with positive than negative tests. Mean improvement differed the most between patients with and without CVD. Using logistic regression analysis Rcsf > 18 was the only significant predictor of improvement in NPHS (OR 4.4, 95% CI 1.3-16.7) and typical CT findings in MRS (OR 5.6, 95% CI \.8-17.9). We conclude that CVD is an important predictor of poor outcome. The best strategy is to shunt NPH patients if Rcsf is > 18 mmHg/ml/min or, when Rcsf is lower, if CT findings are typical for NPH and there is no or limited CVD.
We describe the neurological, electrophysiological, and genetic features of autosomal dominant di... more We describe the neurological, electrophysiological, and genetic features of autosomal dominant distal hereditary motor neuronopathy (HMN) in a threegeneration Dutch family, including 12 patients with distal muscle weakness and atrophy. The severity of disease ranged from disabling muscle weakness to a subclinical phenotype. Neurologic exams of nine patients and nerve conduction studies (NCS) and myography in five endorsed the variable presentations of HMN in this family, including patients with only lower (four), upper (one), or both upper and lower extremities involvement (four). Asymmetrical or strictly unilateral disease was noted in three patients. Three also showed pyramidal features. A genome-wide search combining SNP arrays (250K) with parametric linkage analysis identified a novel locus on chromosome 16p (mLOD=3.28) spanning 6 Mb (rs6500882-rs7192086). Direct sequencing excluded mutations in the SIMPLE/ LITAF gene (mapping to the 16p locus) and identified a pathogenic mutation (p.N88S) in BCLS2 (11q12-q14). All 12 affected relatives had the BSCL2 mutation and the chromosome 16p haplotype and showed features of motor neuron degeneration. One patient had a very mild phenotype with bilateral pes cavus, normal concentric needle electromyography but signs of motor neuron involvement at electrophysiological muscle scan (EMS). Similar EMS abnormalities in addition to abnormal NCS and myography were observed in a clinically unaffected person (carrying only the 16p haplotype). These results expand the clinical spectrum of HMN and suggest a digenic inheritance of HMN in this family with a BSCL2 mutation and a chromosome 16 locus likely contributing to the phenotype.
A BS T RA C T : Background: The most common genetic risk factor for Parkinson's disease known is ... more A BS T RA C T : Background: The most common genetic risk factor for Parkinson's disease known is a damaging variant in the GBA1 gene. The entire GBA1 gene has rarely been studied in a large cohort from a single population. The objective of this study was to assess the entire GBA1 gene in Parkinson's disease from a single large population. Methods: The GBA1 gene was assessed in 3402 Dutch Parkinson's disease patients using nextgeneration sequencing. Frequencies were compared with Dutch controls (n = 655). Family history of Parkinson's disease was compared in carriers and noncarriers. Results: Fifteen percent of patients had a GBA1 nonsynonymous variant (including missense, frameshift, and recombinant alleles), compared with 6.4% of controls (OR, 2.6; P < 0.001). Eighteen novel variants were detected. Variants previously associated with Gaucher's disease were identified in 5.0% of patients compared with 1.5% of controls (OR, 3.4; P < 0.001). The rarely reported complex allele p.D140H + p.E326K appears to likely be a Dutch founder variant, found in 2.4% of patients and 0.9% of controls (OR, 2.7; P = 0.012). The number of first-degree relatives (excluding children) with Parkinson's disease was higher in p.D140H + p.E326K carriers (5.6%, 21 of 376) compared with p.E326K carriers (2.9%, 29 of 1014); OR, 2.0; P = 0.022, suggestive of a dose effect for different GBA1 variants. Conclusions: Dutch Parkinson's disease patients display one of the largest frequencies of GBA1 variants reported so far, consisting in large part of the mild p.E326K variant and the more severe Dutch p.D140H + p.E326K founder allele.
Nederlands Tijdschrift voor Geneeskunde, Mar 13, 2004
Progressive supranuclear palsy is a neurodegenerative disorder accompanied by parkinsonism, distu... more Progressive supranuclear palsy is a neurodegenerative disorder accompanied by parkinsonism, disturbances of eye movements, pseudobulbar palsy and often cognitive decline. Onset of disease is usually between 50-70 years of age and mean survival is 5-8 years. The prevalence of PSP has been estimated at around 5 per 100,000, although exact figures for the population of the Netherlands are not yet available. International consensus criteria differentiate between possible, probable and definite PSP; the latter requiring neuropathological confirmation. An extensive differential diagnosis may be made early in the course of the disease, but at a later stage development of the characteristic symptoms will make diagnosis easier. Imaging techniques can lend support to the clinical diagnosis to a limited extent, although they lack sufficient specificity to confirm it. PSP is a &amp;amp;#39;tauopathy&amp;amp;#39; characterized by aggregates of abnormal tau protein in the basal ganglia and brainstem. Some mutations in the tau gene can cause a clinical and pathological picture similar to that of PSP, although most patients with sporadic and familial PSP do not have tau mutations. Various studies have found a strong association between PSP and a specific tau haplotype (H1 haplotype), but its role in the pathophysiological mechanism of PSP is still unclear and needs further research.
Introduction: The diagnosis aceruloplasminemia is usually made in patients with advanced neurolog... more Introduction: The diagnosis aceruloplasminemia is usually made in patients with advanced neurological manifestations of the disease. In these patients prognosis is poor, disabilities are severe and patients often die young. The aim of our study was to facilitate recognition of aceruloplasminemia at a disease stage at which treatment can positively influence outcome. Currently, the neurological phenotype of aceruloplasminemia has been mainly described in Japanese patients. This 'classical' phenotype consists of cerebellar ataxia, hyperkinetic movement disorders and cognitive decline. In this study we describe the spectrum of neurological disease in Caucasian patients. Methods: Data on neurological presentation and follow-up were gathered from both our patients, homozygous for the G631R mutation in the CP gene, and other published Caucasian cases. Neurological features of aceruloplasminemia in Caucasian patients were compared to those summarized in Japanese patients. Results: 21 Caucasian patients, both ours and the described cases, displayed a wide range of movement disorders with predominant chorea, parkinsonism and ataxia, and also tremor and dystonia. In addition to cognitive decline, nearly half of the Caucasian patients presented with psychiatric changes, including depression, anxiety and behavioral changes. In one-third of the neurologically symptomatic Caucasian patients, cognitive-or psychiatric changes were the first neurological manifestations of aceruloplasminemia. Conclusions: Aceruloplasminemia in Caucasian patients can present with a wider range and a different order of neurological symptoms than previously described in Japanese patients. Psychiatric changes and parkinsonism can be added to the spectrum of neurological disease. Cognitive-or psychiatric changes may be the first neurological manifestations of aceruloplasminemia.
Background: Progressive supranuclear palsy (PSP) is a progressive neurodegenerative disorder char... more Background: Progressive supranuclear palsy (PSP) is a progressive neurodegenerative disorder characterized by aggregates of the microtubule-associated protein tau (MAPT). A nonsignificant trend for positive family history has been observed in two case-control studies and several pedigrees with familial clustering of parkinsonism have been described. Occasionally, mutations in MAPT are found in patients with a clinical phenotype similar to PSP. In this case-control study, we compared the occurrence of dementia and parkinsonism among first-degree relatives of patients with PSP with an age-and sex-matched control group. Methods: Family history of dementia and parkinsonism was collected from all first-degree relatives of patients with PSP who fulfilled the international National Institute of Neurological Disorders and Stroke criteria for PSP. Age-and sex-matched controls were selected from the Rotterdam Study. Genetic testing and pathologic examination was performed in a subset of familial PSP cases. Results: Fifty-seven (33%) of the 172 patients with PSP had at least one first-degree relative who had dementia or parkinsonism compared to 131 (25%) of the control subjects (odds ratio [OR] 1.5, 95% confidence interval [CI] 1.01-2.13). In patients with PSP, more first-degree relatives with parkinsonism were observed compared to controls, with an OR 3.9 (95% CI 1.99-7.61). Twelve patients with PSP (7%) fulfilled the criteria for an autosomal dominant mode of transmission. The intrafamilial phenotype within these pedigrees varied among PSP, dementia, tremor, and parkinsonism. Genetic studies revealed one patient with a P301L mutation in MAPT. Pathologic examination of five familial cases confirmed the clinical diagnosis of PSP, with predominant four repeat tau pathology in affected brain areas. Conclusion: This study demonstrates familial aggregation of parkinsonism in progressive supranuclear palsy. Neurology ® 2009;73:98-105 GLOSSARY CB ϭ coiled bodies; CI ϭ confidence interval; FTD ϭ frontotemporal dementia; GRN ϭ progranulin; LRRK2 ϭ leucine-rich repeat kinase 2; MAPT ϭ microtubule-associated protein tau; NFT ϭ neurofibrillary tangles; NINDS-SPSP ϭ National Institute for Neurological Diseases and Stroke-Society for Progressive Supranuclear Palsy; OR ϭ odds ratio; PD ϭ Parkinson disease; PSP ϭ progressive supranuclear palsy; STN ϭ subthalamic nucleus; TA ϭ tufted astrocytes; Thr ϭ threads.
Progressive Supranuclear Palsy (PSP) has been used to denote a unifying disorder with progressive... more Progressive Supranuclear Palsy (PSP) has been used to denote a unifying disorder with progressive parkinsonism with early falls, vertical supranuclear gaze palsy, pseudobulbar dysfunction and cognitive decline. Over the last decade, heterogeneity of the disease into different clinical subtypes has been recognized in clinicopathological studies. Although neuroimaging features and laboratory findings may support the diagnosis, true biomarkers are still lacking in the clinical setting. Neuronal and glial tau positive aggregates are predominantly found in basal ganglia and brainstem, and the significant association of PSP with the common H1 tau haplotype likely points to a pathophysiological role of the tau protein in the disease process. Future genetic studies of familial cases and an ongoing genome-wide association study of large series of pathological-proven cases may reveal additional genetic factors in the near future.
Background: Progressive supranuclear palsy (PSP) with a frontal presentation, characterized by co... more Background: Progressive supranuclear palsy (PSP) with a frontal presentation, characterized by cognitive deficits and behavioral changes, has been recognized as an early clinical picture, distinct from the classical so-called Richardson and parkinsonism presentations. The midcingulate cortex is associated with executive and attention tasks and has consistently been found to be impaired in imaging studies of patients with PSP. The aim of the present study was to determine alterations in neurotransmission underlying the pathophysiology of PSP, as well as their significance for clinically identifiable PSP subgroups. Methods: In vitro receptor autoradiography was used to quantify densities of 20 different receptors in the caudate nucleus and midcingulate area 24' of patients with PSP (n = 16) and age-and sex-matched control subjects (n = 14). Results: Densities of γ-aminobutyric acid type B, peripheral benzodiazepine, serotonin receptor type 2, and Nmethyl-D-aspartate receptors were significantly higher in area 24′ of patients with PSP, where tau impairment was stronger than in the caudate nucleus. Kainate and nicotinic cholinergic receptor densities were significantly lower, and adenosine receptor type 1 (A 1) receptors significantly higher, in the caudate nucleus of patients with PSP. Receptor fingerprints also segregated PSP subgroups when clinical parameters such as occurrence of frontal presentation and tau pathology severity were taken into consideration. Conclusions: We demonstrate, for the first time to our knowledge, that kainate and A 1 receptors are altered in PSP and that clinically identifiable PSP subgroups differ at the neurochemical level. Numerous receptors were altered in the midcingulate cortex, further suggesting that it may prove to be a key region in PSP. Finally, we add to the evidence that nondopaminergic systems play a role in the pathophysiology of PSP, thus highlighting potential novel treatment strategies.
Autoimmune encephalitis can be classified into antibody-defined subtypes, which can manifest with... more Autoimmune encephalitis can be classified into antibody-defined subtypes, which can manifest with immunotherapy-responsive movement disorders sometimes mimicking non-inflammatory aetiologies. In the elderly, anti-LGI1 and contactin associated protein like 2 (CASPR2) antibody-associated diseases compose a relevant fraction of autoimmune encephalitis. Patients with LGI1 autoantibodies are known to present with limbic encephalitis and additionally faciobrachial dystonic seizures may occur. However, the clinical spectrum of CASPR2 autoantibody-associated disorders is more diverse including limbic encephalitis, Morvan’s syndrome, peripheral nerve hyperexcitability syndrome, ataxia, pain and sleep disorders. Reports on unusual, sometimes isolated and immunotherapy-responsive movement disorders in CASPR2 autoantibody-associated syndromes have caused substantial concern regarding necessity of autoantibody testing in patients with movement disorders. Therefore, we aimed to systematically assess their prevalence and manifestation in patients with CASPR2 autoimmunity. This international, retrospective cohort study included patients with CASPR2 autoimmunity from participating expert centres in Europe. Patients with ataxia and/or movement disorders were analysed in detail using questionnaires and video recordings. We recruited a comparator group with anti-LGI1 encephalitis from the GENERATE network. Characteristics were compared according to serostatus. We identified 164 patients with CASPR2 autoantibodies. Of these, 149 (90.8%) had only CASPR2 and 15 (9.1%) both CASPR2 and LGI1 autoantibodies. Compared to 105 patients with LGI1 encephalitis, patients with CASPR2 autoantibodies more often had movement disorders and/or ataxia (35.6 versus 3.8%; P &lt; 0.001). This was evident in all subgroups: ataxia 22.6 versus 0.0%, myoclonus 14.6 versus 0.0%, tremor 11.0 versus 1.9%, or combinations thereof 9.8 versus 0.0% (all P &lt; 0.001). The small group of patients double-positive for LGI1/CASPR2 autoantibodies (15/164) significantly more frequently had myoclonus, tremor, ‘mixed movement disorders’, Morvan’s syndrome and underlying tumours. We observed distinct movement disorders in CASPR2 autoimmunity (14.6%): episodic ataxia (6.7%), paroxysmal orthostatic segmental myoclonus of the legs (3.7%) and continuous segmental spinal myoclonus (4.3%). These occurred together with further associated symptoms or signs suggestive of CASPR2 autoimmunity. However, 2/164 patients (1.2%) had isolated segmental spinal myoclonus. Movement disorders and ataxia are highly prevalent in CASPR2 autoimmunity. Paroxysmal orthostatic segmental myoclonus of the legs is a novel albeit rare manifestation. Further distinct movement disorders include isolated and combined segmental spinal myoclonus and autoimmune episodic ataxia.
Recentelijk zijn rasagiline en rotigotine geregistreerd voor de behandeling van de ziekte van Par... more Recentelijk zijn rasagiline en rotigotine geregistreerd voor de behandeling van de ziekte van Parkinson en is tolcapon opnieuw beschikbaar gekomen, zij het onder strikte voorwaarden. Rasagiline heeft een bescheiden effect als monotherapie bij de de-novoparkinsonpatient en is voor de behandeling van ‘wearing off’ te vergelijken met entacapon, in combinatie met levodopa. Rotigotine wordt via een pleister transdermaal toegediend, een veelbelovende methode. De resultaten vallen echter tegen en zijn minder dan verwacht. In Nederland wordt rasagiline alleen bij zogeheten pluspakketten vergoed, maar in Belgie volledig. Rotigotine wordt in Nederland niet vergoed, terwijl het in Belgie niet is geregistreerd. Tolcapon ten slotte kan en mag alleen worden voorgeschreven indien alternatieve behandelingen niet tot het gewenste resultaat leiden en dan alleen onder de voorwaarde dat zeer frequent de leverfuncties worden bepaald.
An optimized clinically feasible neuromelanin-MRI imaging protocol for visualising the SN and LC ... more An optimized clinically feasible neuromelanin-MRI imaging protocol for visualising the SN and LC simultaneously using deep learning reconstruction is presented. We optimize flip-angle for optimal combined SN and LC depiction. We also experimented with combinations of anisotropic and isotropic in-plane resolution, partial vs full echoes and the number of averages. Phantom and in-vivo experiments on three healthy volunteers illustrate that high-resolution imaging combined with deep-learning denoising shows good depiction of the SN and LC with a clinically feasible sequence of around 7 minutes.
BackgroundAs gene‐targeted therapies are increasingly being developed for Parkinson's disease... more BackgroundAs gene‐targeted therapies are increasingly being developed for Parkinson's disease (PD), identifying and characterizing carriers of specific genetic pathogenic variants is imperative. Only a small fraction of the estimated number of subjects with monogenic PD worldwide are currently represented in the literature and availability of clinical data and clinical trial‐ready cohorts is limited.ObjectiveThe objectives are to (1) establish an international cohort of affected and unaffected individuals with PD‐linked variants; (2) provide harmonized and quality‐controlled clinical characterization data for each included individual; and (3) further promote collaboration of researchers in the field of monogenic PD.MethodsWe conducted a worldwide, systematic online survey to collect individual‐level data on individuals with PD‐linked variants in SNCA, LRRK2, VPS35, PRKN, PINK1, DJ‐1, as well as selected pathogenic and risk variants in GBA and corresponding demographic, clinical,...
The protein phosphatase 2A complex (PP2A), the major Ser/Thr phosphatase in the brain, is involve... more The protein phosphatase 2A complex (PP2A), the major Ser/Thr phosphatase in the brain, is involved in a number of signalling pathways and functions, including the regulation of crucial proteins for neurodegeneration, such as alpha-synuclein, tau and LRRK2. Here, we report the identification of variants in the PTPA/PPP2R4 gene, encoding a major PP2A activator, in two families with early-onset parkinsonism and intellectual disability. We carried out clinical studies and genetic analyses, including genome-wide linkage analysis, whole-exome sequencing, and Sanger sequencing of candidate variants. We next performed functional studies on the disease-associated variants in cultured cells and knock-down of ptpa in Drosophila melanogaster. We first identified a homozygous PTPA variant, c.893T>G (p.Met298Arg), in patients from a South African family with early-onset parkinsonism and intellectual disability. Screening of a large series of additional families yielded a second homozygous vari...
Parkinson's disease covers a wide spectrum of symptoms, ranging from early non-motor symptoms... more Parkinson's disease covers a wide spectrum of symptoms, ranging from early non-motor symptoms to the characteristic bradykinesia, tremor and rigidity. Although differences in the symptomatology of Parkinson's disease are increasingly recognized, there is still a lack of insight into the heterogeneity of the pre-diagnostic phase of Parkinson's disease. In this perspective, we highlight three aspects regarding the role of population-based studies in providing new insights into the heterogeneity of pre-diagnostic Parkinson's disease. First we describe several specific advantages of population-based cohort studies, including the design which overcomes some common biases, the broad data collection and the high external validity. Second, we draw a parallel with the field of Alzheimer's disease to provide future directions to uncover the heterogeneity of pre-diagnostic Parkinson's disease. Finally, we anticipate on the emergence of prevention and disease-modificatio...
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Papers by Agnita Boon