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1.
Somatic SNCA Copy Number Variants in Multiple System Atrophy are Related to Pathology and Inclusions
Monica Emili Garcia-Segura Diego Perez-Rodriguez PhD Darren Chambers Zane Jaunmuktane Christos Proukakis PhD FRCP 《Movement disorders》2023,38(2):338-342
Background
Somatic α-synuclein (SNCA) copy number variants (CNVs, specifically gains) occur in multiple system atrophy (MSA) and Parkinson's disease brains.Objective
The aim was to compare somatic SNCA CNVs in MSA subtypes (striatonigral degeneration [SND] and olivopontocerebellar atrophy [OPCA]) and correlate with inclusions.Methods
We combined fluorescent in situ hybridization with immunofluorescence for α-synuclein and in some cases oligodendrocyte marker tubulin polymerization promoting protein (TPPP).Results
We analyzed one to three brain regions from 24 MSA cases (13 SND, 11 OPCA). In a region preferentially affected in one subtype (putamen in SND, cerebellum in OPCA), mosaicism was higher in that subtype, and cells with CNVs were 4.2 times more likely to have inclusions. In the substantia nigra, nonpigmented cells with CNVs and TPPP were about six times more likely to have inclusions.Conclusions
The correlation between SNCA CNVs and pathology (at a regional level) and inclusions (at a single-cell level) suggests a role for somatic SNCA CNVs in MSA pathogenesis. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. 相似文献2.
Alexandra Perez‐Soriano MD Julieta E. Arena MD Katie Dinelle Qing Miao PhD Jessamyn McKenzie Nicole Neilson Andreas Puschmann MD PhD Paul Schaffer PhD Hitoshi Shinotoh MD Jenna Smith‐Forrester MSc Elham Shahinfard PhD Nasim Vafai MSc Daryl Wile MD Zbigniew Wszolek MD PhD Makoto Higuchi MD PhD Vesna Sossi PhD A. Jon Stoessl MD 《Movement disorders》2017,32(7):1016-1024
Background and Objectives : To study selective regional binding for tau pathology in vivo, using PET with [11C]PBB3 in PSP patients, and other conditions not typically associated with tauopathy. Methods : Dynamic PET scans were obtained for 70 minutes after the bolus injection of [11C]PBB3 in 5 PSP subjects, 1 subject with DCTN1 mutation and PSP phenotype, 3 asymptomatic SNCA duplication carriers, 1 MSA subject, and 6 healthy controls of similar age. Tissue reference Logan analysis was applied to each region of interest using a cerebellar white matter reference region. Results : In comparison to the control group, PSP subjects showed specific uptake of [11C]PBB3 in putamen, midbrain, GP, and SN. Longer disease duration and more advanced clinical severity were generally associated with higher tracer retention. A DCTN1/PSP phenotype case showed increased binding in putamen, parietal lobe, and GP. In SNCA duplication carriers, there was a significant increase of [11C] PBB3 binding in GP, putamen, thalamus, ventral striatum, SN, and pedunculopontine nucleus. The MSA case showed increased binding in frontal lobe, GP, midbrain, parietal lobe, putamen, temporal lobe, SN, thalamus, and ventral striatum. Conclusions : All PSP patients showed increased retention of the tracer in the basal ganglia, as expected. Binding was also present in asymptomatic SNCA duplication carriers and in an MSA case, which are not typically associated with pathological tau deposition. This suggests the possibility that [11C]PBB3 binds to alpha‐synuclein. © 2017 International Parkinson and Movement Disorder Society 相似文献
3.
C. A. Guevara C. R. Blain D. Stahl D. J. Lythgoe P. N. Leigh G. J. Barker 《European journal of neurology》2010,17(9):1193-1202
Background and purpose: Magnetic resonance spectroscopy (MRS) allows the measurement of a number of brain tissue metabolites in vivo, including N‐acetylaspartate (NAA), a putative marker of neuronal integrity. Unlike single voxel MRS, magnetic resonance spectroscopic imaging (MRSI) enables quantification of these metabolites simultaneously from multiple anatomically localized voxels. Both single voxel MRS and MRSI allow the absolute quantification of these metabolites and, when combined with tissue segmentation, can give accurate metabolite concentrations even in the presence of partial volume effects from nearby cerebrospinal fluid. Methods: Using MRSI with cubic voxels with a nominal volume of 1.0 cm3, we tested the hypothesis that concentrations of NAA in the basal ganglia in multiple system atrophy (MSA) and progressive supranuclear palsy (PSP) would show differences compared to Parkinson’s disease (IPD). NAA values (in mM) from MRSI voxels centred to the putamen, pallidum and thalamus were obtained from 11 patients with IPD, 11 with MSA‐P, six with MSA‐C, 13 with PSP and 18 controls. The mean concentrations of NAA and its bulk grey and white matter values were also estimated over the whole brain slab. Results: N‐acetylaspartate concentrations in the pallidum, putamen and lentiform nucleus were significantly lower in patients with MSA‐P and PSP compared to IPD and controls. The putaminal values were also significantly reduced in PSP compared to MSA‐P. There were no significant differences between groups in the thalamus and over the whole brain slab. Conclusion: Our findings support the notion that MRSI can potentially quantify basal ganglia cellular pathology in MSA and PSP. 相似文献
4.
Aoife P. Kiely Yasmine T. Asi Eleanna Kara Patricia Limousin Helen Ling Patrick Lewis Christos Proukakis Niall Quinn Andrew J. Lees John Hardy Tamas Revesz Henry Houlden Janice L. Holton 《Acta neuropathologica》2013,125(5):753-769
We report a British family with young-onset Parkinson’s disease (PD) and a G51D SNCA mutation that segregates with the disease. Family history was consistent with autosomal dominant inheritance as both the father and sister of the proband developed levodopa-responsive parkinsonism with onset in their late thirties. Clinical features show similarity to those seen in families with SNCA triplication and to cases of A53T SNCA mutation. Post-mortem brain examination of the proband revealed atrophy affecting frontal and temporal lobes in addition to the caudate, putamen, globus pallidus and amygdala. There was severe loss of pigmentation in the substantia nigra and pallor of the locus coeruleus. Neuronal loss was most marked in frontal and temporal cortices, hippocampal CA2/3 subregions, substantia nigra, locus coeruleus and dorsal motor nucleus of the vagus. The cellular pathology included widespread and frequent neuronal α-synuclein immunoreactive inclusions of variable morphology and oligodendroglial inclusions similar to the glial cytoplasmic inclusions of multiple system atrophy (MSA). Both inclusion types were ubiquitin and p62 positive and were labelled with phosphorylation-dependent anti-α-synuclein antibodies In addition, TDP-43 immunoreactive inclusions were observed in limbic regions and in the striatum. Together the data show clinical and neuropathological similarities to both the A53T SNCA mutation and multiplication cases. The cellular neuropathological features of this case share some characteristics of both PD and MSA with additional unique striatal and neocortical pathology. Greater understanding of the disease mechanism underlying the G51D mutation could aid in understanding of α-synuclein biology and its impact on disease phenotype. 相似文献
5.
Sharma S Bandopadhyay R Lashley T Renton AE Kingsbury AE Kumaran R Kallis C Vilariño-Güell C O'Sullivan SS Lees AJ Revesz T Wood NW Holton JL 《Neuropathology and applied neurobiology》2011,37(7):777-790
S. Sharma, R. Bandopadhyay, T. Lashley, A. E. M. Renton, A. E. Kingsbury, R. Kumaran, C. Kallis, C. Vilariño‐Güell, S. S. O'Sullivan, A. J. Lees, T. Revesz, N. W. Wood and J. L. Holton (2011) Neuropathology and Applied Neurobiology 37, 777–790 LRRK2 expression in idiopathic and G2019S positive Parkinson's disease subjects: a morphological and quantitative study Aims: Mutations in the gene encoding leucine‐rich repeat kinase‐2 (LRRK2) have been established as a common genetic cause of Parkinson's disease (PD). The distribution of LRRK2 mRNA and protein in the human brain has previously been described, although it has not been reported in PD cases with the common LRRK2 G2019S mutation. Methods: To further elucidate the role of LRRK2 in PD, we determined the localization of LRRK2 mRNA and protein in post‐mortem brain tissue from control, idiopathic PD (IPD) and G2019S positive PD cases. Results: Widespread neuronal expression of LRRK2 mRNA and protein was recorded and no difference was observed in the morphological localization of LRRK2 mRNA or protein between control, IPD and G2019S positive PD cases. Using quantitative real‐time polymerase chain reaction, we demonstrated that there is no regional variation in LRRK2 mRNA in normal human brain, but we have identified differential expression of LRRK2 mRNA with significant reductions recorded in limbic and neocortical regions of IPD cases compared with controls. Semi‐quantitative analysis of LRRK2 immunohistochemical staining demonstrated regional variation in staining intensity, with weak LRRK2 immunoreactivity consistently recorded in the striatum and substantia nigra. No clear differences were identified in LRRK2 immunoreactivity between control, IPD and G2019S positive PD cases. LRRK2 protein was identified in a small proportion of Lewy bodies. Conclusions: Our data suggest that widespread dysregulation of LRRK2 mRNA expression may contribute to the pathogenesis of IPD. 相似文献
6.
Multiple system atrophy (MSA) exhibits widespread astrogliosis together with α-synuclein (α-syn) glial cytoplasmic inclusions (GCIs) in mature oligodendrocytes. We quantified astrocyte activation by morphometric analysis of MSA cases, and investigated the correlation to GCI proximity. Using Imaris software, we obtained “skinned” three-dimensional models of GFAP-positive astrocytes in MSA and control tissue (n = 75) from confocal z-stacks and measured the astrocyte process length and thickness and radial distance to the GCI. Astrocytes proximal to GCI-containing oligodendrocytes (r < 25 μm) had significantly (p, 0.05) longer and thicker processes characteristic of activation than distal astrocytes (r > 25 μm), with a reciprocal linear correlation (m, 90 μm2) between mean process length and radial distance to the nearest GCI (R2, 0.7). In primary cell culture studies, α-syn addition caused ERK-dependent activation of rat astrocytes and perinuclear α-syn inclusions in mature (MOSP-positive) rat oligodendrocytes. Activated astrocytes were also observed in close proximity to α-syn deposits in a unilateral rotenone-lesion mouse model. Moreover, unilateral injection of MSA tissue-derived α-syn into the mouse medial forebrain bundle resulted in widespread neuroinflammation in the α-syn-injected, but not sham-injected hemisphere. Taken together, our data suggests that the action of localized concentrations of α-syn may underlie both astrocyte and oligodendrocyte MSA pathological features. 相似文献
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8.
C. A. Davie G. K. Wenning G. J. Barker P. S. Tofts B. E. Kendall N. Quinn W. I. McDonald C. D. Marsden D. H. Miller 《Annals of neurology》1995,37(2):204-210
Proton magnetic resonance spectroscopy, localized to the lentiform nucleus, was carried out in 7 patients with the pure or predominantly striatonigral variant (SND) of multiple system atrophy (MSA), 5 patients with the olivopontocerebellar variant of MSA, 9 patients with a clinical diagnosis of idiopathic Parkinson's disease (IPD), and 9 healthy age-matched controls. The MSA group with predominantly striatonigral involvement showed a significant reduction in the N-acetylaspartate (NAA)/creatine ratio (median, 1.19; range, 0.96–2.0; p < 0.02) compared with the NAA/creatine ratio (median, 1.82; range, 1.19–2.31; p > 0.5). The NAA/creatine ratio was markedly reduced in 6 of the SND patients and in only 1 IPD patient. The choline/creatine ratio was also significantly lower in the SND group (median, 1.02; range, 0.91–1.23; p < 0.04) compared with the control group (median, 1.22; range, 1.05–1.65). The IPD group showed a normal lentiform choline/creatine ratio (median, 1.13; range, 0.89–1.65; p = 0.25) compared with controls. The olivopontocerebellar group also showed a significant reduction in the NAA/creatine ratio from the lentiform nucleus (median, 1.47; range, 1.22–1.68; p < 0.01) compared with the controls as well as a nonsignificant reduction in the choline/creatine ratio (median, 0.93; range, 0.85–1.27; p < 0.4). In vivo quantification of absolute metabolite concentrations was possible in 7 MSA patients and 6 controls and confirmed an absolute reduction of choline-containing compounds and NAA in the MSA group compared with controls with no significant difference in the creatine concentrations between the MSA groups probably reflects neuronal loss, occurring predominantly in the putamen. Proton magnetic resonance spectroscopy is a useful, noninvasive technique to help differentiate MSA from IPD. 相似文献
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10.
Glial cytoplasmic inclusions (GCI) occur characteristically in the cytoplasms of oligodendrocytes of brains with multiple system atrophy. We examined whether proline-directed protein kinases, which have been found in several neuronal inclusion bodies such as neurofibrillary tangles and Lewy bodies, are associated with GCI. We unexpectedly have observed cdk 5 and MAPK in GCI. These kinases were not immunolabeled in coiled bodies which are oligodendroglial inclusion bodies in brains with progressive supsranuclear palsy and Alzheimer's disease. We also found microtubule-associated protein 2 in oligodendrocytes in brains with MSA, which have not been observed in normal controls or neurological disease controls. Cdk 5 and MAP 2 are principally neuronal proteins. MAPK have been found in neuronal somata and some astrocytes, but not in oligodendrocytes. Thus, the present results suggest that oligodendrocytes in MSA harbor an abnormal phenotypic nature in terms of the aberrant expressions of the principally neuronal proteins. 相似文献
11.
Fujishiro H Ahn TB Frigerio R DelleDonne A Josephs KA Parisi JE Eric Ahlskog J Dickson DW 《Acta neuropathologica》2008,116(3):269-275
In this study, we used immunohistochemistry to screen for alpha-synuclein pathology in the brains of 241 individuals without clinical evidence of neurologic disease, and discovered 36 cases (15%) with incidental Lewy bodies (LBs) and one case, a 96-year-old woman (0.4%), with inclusions similar to those seen in multiple system atrophy (MSA), a non-familial neurodegenerative disorder characterized by parkinsonism, cerebellar ataxia and autonomic dysfunction and alpha-synuclein immunoreactive glial cytoplasmic inclusions (GCI). In a routine hospital autopsy series of 125 brains, we detected GCI in a neurologically normal 82-year-old man (0.8%). Both cases showed widespread GCI in the central nervous system, as well as a few neuronal cytoplasmic inclusions, but no neuronal loss or gliosis in vulnerable brain regions, including the substantia nigra, putamen, inferior olive and pontine base. Applying a recently proposed grading scale for MSA, the two cases showed pathology far below that detected in patients with clinically overt MSA, suggesting the possibility that these two individuals had preclinical MSA. The prevalence of clinically overt MSA is estimated to be about 4 per 100,000 persons (0.004%), which is far less than the frequency of GCI in this series (0.4-0.8%). Further studies are needed to determine if GCI in neurologically normal elderly represents prodromal MSA or a rare non-progressive age-related alpha-synucleinopathy. 相似文献
12.
The hypothalamic-pituitary axis (HPA) may be involved early in multiple system atrophy (MSA), whereas in idiopathic Parkinson's
disease (IPD) its impairment seems to be correlated with motor disability. The release of prolactin (PRL) is mediated through
the HPA and an increase in PRL levels is documented during stress. In this study, we investigated basal and erect PRL levels
to assess whether basal PRL or changes in PRL levels after 60° head-up tilt (HUT; orthostatic stress) could distinguish between
MSA and IPD patients.
We studied five patients with MSA on levodopa treatment, five levodopa-naive MSA patients, nine IPD patients on dopaminergic
treatment, six drug-naive IPD patients and six normal individuals. PRL levels were measured in the supine position after 30
minutes rest and during 60° HUT after 5 and 15 minutes.
Baseline PRL values were significantly lower for patients with IPD than for those with MSA, both for levodopa-treated and
naive patients (p < 0.004, estimated decrease 55.1 %, 95 % CI from 29.4 % to 71.52 %). After orthostatic stress PRL levels were increased in
healthy individuals after 15 minutes of HUT (p = 0.044, estimated increase 11.5 %, 95 % CI from 0.4 % to 23.8 %), whereas there was no evidence for a change of PRL levels
in patients with MSA or IPD after 5 and 15 minutes of HUT. We also did not find any evidence for a difference in PRL change
after HUT between MSA and IPD patients.
Baseline PRL levels might differentiate between early MSA and IPD, being higher in MSA. However, orthostatic stress using
HUT appears unable to differentiate between MSA and IPD.
Received: 25 July 2001, Accepted: 14 March 2002
Correspondence to Dr. K Ray Chaudhuri 相似文献
13.
14.
Sonja W. Scholz Henry Houlden Claudia Schulte Manu Sharma Abi Li Daniela Berg Anna Melchers Reema Paudel J. Raphael Gibbs Javier Simon‐Sanchez Coro Paisan‐Ruiz Jose Bras Jinhui Ding Honglei Chen Bryan J. Traynor Sampath Arepalli Ryan R. Zonozi Tamas Revesz Janice Holton Nick Wood Andrew Lees Wolfgang Oertel Ullrich Wüllner Stefano Goldwurm Maria Teresa Pellecchia Thomas Illig Olaf Riess Hubert H. Fernandez Ramon L. Rodriguez Michael S. Okun Werner Poewe Gregor K. Wenning John A. Hardy Andrew B. Singleton Thomas Gasser 《Annals of neurology》2009,65(5):610-614
To test whether the synucleinopathies Parkinson's disease and multiple system atrophy (MSA) share a common genetic etiology, we performed a candidate single nucleotide polymorphism (SNP) association study of the 384 most associated SNPs in a genome‐wide association study of Parkinson's disease in 413 MSA cases and 3,974 control subjects. The 10 most significant SNPs were then replicated in additional 108 MSA cases and 537 controls. SNPs at the SNCA locus were significantly associated with risk for increased risk for the development of MSA (combined p = 5.5 × 1012; odds ratio 6.2). Ann Neurol 2009;65:610–614 相似文献
15.
Kyoko Itoh Takashi Kasai Yukiko Tsuji Kozo Saito Ikuko Mizuta Yoshinori Harada Shinji Sudoh Toshiki Mizuno Masanori Nakagawa Shinji Fushiki 《Neuropathology》2014,34(3):309-313
Multiple system atrophy (MSA) is an oligodendrogliopathy of presumably sporadic origin, characterized by prominent α‐synuclein inclusions with neuronal multisystem degeneration, although a few Mendelian pedigrees have been reported. Here we report two familial cases of MSA of unknown genetic background. One patient was diagnosed as a possible MSA‐C (cerebellar dysfuntion) case, and the other as clinically possible MSA‐P (parkinsonism), which turned out to be definite MSA, based on a detailed autopsy. The neuropathology showed extensive deposition of α‐synuclein in the glia as well as in the neurons located in the cerebral cortices and hippocampal systems, although neither multiplication of the SNCA gene or mutations in COQ2 gene were identified in the family concerned. 相似文献
16.
Huang Y Song YJ Murphy K Holton JL Lashley T Revesz T Gai WP Halliday GM 《Acta neuropathologica》2008,116(6):639-646
Certain genetic defects in LRRK2 and parkin are pathogenic for Parkinson’s disease (PD) and both proteins deposit in the characteristic
Lewy bodies. LRRK2 is thought to be involved in the early initiation of Lewy bodies. The involvement of LRRK2 and parkin in
the similar cellular deposition of fibrillar α-synuclein in glial cytoplasmic inclusions (GCI) in multiple system atrophy
(MSA) has not yet been assessed. To determine whether LRRK2 and parkin may be similarly associated with the abnormal deposition
of α-synuclein in MSA GCI, paraffin-embedded sections from the basal ganglia of 12 patients with MSA, 4 with PD and 4 controls
were immunostained for LRRK2, parkin, α-synuclein and oligodendroglial proteins using triple labelling procedures. The severity
of neuronal loss was graded and the proportion of abnormally enlarged oligodendroglia containing different combinations of
proteins assessed in 80–100 cells per case. Parkin immunoreactivity was observed in only a small proportion of GCI. In contrast,
LRRK2 was found in most of the enlarged oligodendroglia in MSA and colocalised with the majority of α-synuclein-immunopositive
GCI. Degrading myelin sheaths containing LRRK2-immunoreactivity were also observed, showing an association with one of the
earliest oligodendroglial abnormalities observed in MSA. The proportion of LRRK2-immunopositive GCI was negatively associated
with an increase in neuronal loss and α-synuclein-immunopositive dystrophic axons. Our results indicate that an increase in
LRRK2 expression occurs early in association with myelin degradation and GCI formation, and that a reduction in LRRK2 expression
in oligodendroglia is associated with increased neuronal loss in MSA. 相似文献
17.
The origin of α‐synuclein (α‐syn)‐positive glial cytoplasmic inclusions found in oligodendrocytes in multiple system atrophy (MSA) is enigmatic, given the fact that oligodendrocytes do not express α‐syn mRNA. Recently, neuron‐to‐neuron transfer of α‐syn was suggested to contribute to the pathogenesis of Parkinson's disease. In this study, we explored whether a similar transfer of α‐syn might occur from neurons to oligodendrocytes, which conceivably could explain how glial cytoplasmic inclusions are formed. We studied oligodendrocytes in vitro and in vivo and examined their ability to take up different α‐syn assemblies. First, we treated oligodendrocytes with monomeric, oligomeric, and fibrillar forms of α‐syn proteins and investigated whether α‐syn uptake is dynamin‐dependent. Second, we injected the same α‐syn species into the mouse cortex to assess their uptake in vivo. Finally, we monitored the presence of human α‐syn within rat oligodendroglial cells grafted in the striatum of hosts displaying Adeno‐Associated Virus‐mediated overexpression of human α‐syn in the nigro‐striatal pathway. Here , we show that oligodendrocytes take up recombinant α‐syn monomers, oligomers and, to a lesser extent, fibrils in vitro in a concentration and time‐dependent manner, and that this process is inhibited by dynasore. Further, we demonstrate in our injection model that oligodendrocytes also internalize α‐syn in vivo. Finally, we provide the first direct evidence that α‐syn can transfer to grafted oligodendroglial cells from host rat brain neurons overexpressing human α‐syn. Our findings support the hypothesis of a neuron‐to‐oligodendrocyte transfer of α‐syn, a mechanism that may play a crucial role in the progression and pathogenesis of MSA. GLIA 2014;62:387–398 相似文献
18.
Prof. Francesco Federico Isabella L. Simone Vincenzo Lucivero Giovanni Iliceto Michele de Mari Paolo Giannini Domenico M. Mezzapesa Alfredo Tarantino Paolo Lamberti 《Movement disorders》1997,12(6):903-909
Proton magnetic resonance spectroscopy (1H-MRS), localized to the lentiform nucleus, was carried out in 12 patients with idiopathic Parkinson's disease (IPD), seven patients with multiple-system atrophy (MSA), seven patients with progressive supranuclear palsy (PSP), and 10 healthy age matched controls. The study assessed the level of N-acetylaspartate (NAA), creatine–phosphocreatine (Cr), and choline (Cho) in the putamen and globus pallidus of these patients. NAA/Cho and NAA/Cr ratios were significantly reduced in MSA and PSP patients. No significant difference was found between IPD patients and controls. These results suggest an NAA deficit, due to neuronal loss, in the lentiform nucleus of MSA and PSP patients. 1H-MRS is a noninvasive technique that can provide useful information regarding striatal neuronal loss in basal ganglia of patients with atypical parkinsonian disorders and represents a potential tool for diagnosing these disorders. 相似文献
19.
Myhre R Toft M Kachergus J Hulihan MM Aasly JO Klungland H Farrer MJ 《Acta neurologica Scandinavica》2008,118(5):320-327
Objectives – Previous studies have found associations between Parkinson’s disease (PD) and polymorphisms located within both the alpha‐synuclein gene (SNCA) promoter and other gene regions. Our aim was to study SNCA gene markers in a closely matched Norwegian PD population to examine the genetic relationship between different polymorphisms associated with the disease. Methods – We genotyped seven single nucleotide polymorphisms (SNPs) located in the SNCA promoter and two SNPs in the 3′ gene region and seven microsatellite markers located across the gene in a closely matched series of 236 PD patients and 236 controls. Linkage disequilibrium (LD) structure was examined, and association of single markers and gene haplotypes analyzed. Results – Several markers located across the SNCA gene were associated with PD, including marker alleles associated with disease in previous studies (Rep1 263‐bp allele, rs356165 and rs356219). Conclusion – LD between associated marker alleles located across the SNCA gene suggests that a single genetic effect might explain the previous reported association in the promoter and 3′ regions. 相似文献
20.
Lena Kertelge BS Norbert Brüggemann MD Alexander Schmidt MD Vera Tadic MD Claudia Wisse BS Sylwia Dankert Laura Drude BS Joyce van der Vegt MD Hartwig Siebner MD Heike Pawlack BS Peter P. Pramstaller MD Maria Isabel Behrens MD PhD Alfredo Ramirez MD Dirk Reichel MD Carsten Buhmann MD Johann Hagenah MD Christine Klein MD Katja Lohmann PhD Meike Kasten MD 《Movement disorders》2010,25(15):2665-2669
Olfaction is typically impaired in idiopathic Parkinson's disease (IPD), but its role is uncertain in monogenic PD. Diminished color discrimination has been suggested as another early sign of dopaminergic dysfunction but not been systematically studied. Furthermore, it is unknown whether both deficits are linked. We examined 100 patients with IPD, 27 manifesting mutation carriers (MC), 20 nonmanifesting mutation carriers (NMC), and 110 controls. Participants underwent a standardized neurological examination, the University of Pennsylvania Smell Identification Test (UPSIT), the Farnsworth‐Munsell (FM) color discrimination test, and mutation testing in known PD genes. The monogenic group consisted of 15 Parkin (6MC/9NMC), 17 PINK1 (10MC/7NMC), 8 LRRK2 (4MC/4NMC), 3 SNCA (MC), and 4 ATP13A2 (MC) carriers. Olfaction was most impaired in IPD (UPSIT percentiles 10.1 ± 13.5) compared with all other groups (MC 13.8 ± 11.9, NMC 19.6 ± 13.0, controls 33.8 ± 22.4). Within MC, carriers of two mutations in Parkin and PINK1 showed higher UPSIT percentiles than LRRK2 and SNCA carriers. Color discrimination was reduced in IPD (FM total error score 134.8 ± 92.7). In MC (122.4 ± 142.4), the reduction was most pronounced in LRRK2, NMC (80.0 ± 38.8) were comparable with controls (97.2 ± 61.1). UPSIT and FM scores were correlated in the control (r = ?0.305; P = 0.002) and the IPD group (r = ?0.303; P = 0.006) but not among mutation carriers. First, we confirmed olfaction and color discrimination to be impaired in IPD and suggest olfaction to be a premotor sign. Second, olfaction differed between carriers with one and two mutations in Parkin/PINK1‐associated PD. Third, olfaction and color discrimination impairment do not necessarily evolve in parallel. © 2010 Movement Disorder Society 相似文献