NPC1 encodes a lysosomal protein involved in cholesterol transport. Biallelic mutations in this gene may lead to Niemann-Pick disease type C (NPC), a lysosomal storage disorder. The role of NPC1 in alpha synucleinopathies is still unclear, as different genetic, clinical, and pathological studies have reported contradictory results. This study aimed to evaluate the association of NPC1 variants with the synucleinopathies Parkinson's disease (PD), dementia with Lewy bodies (DLB), and rapid eye movement-sleep behavior disorder (RBD). We analyzed common and rare variants from 3 cohorts of European descent: 1084 RBD cases and 2945 controls, 2852 PD cases and 1686 controls, and 2610 DLB cases and 1920 controls. Logistic regression models were used to assess common variants while optimal sequence Kernel association tests were used to assess rare variants, both adjusted for sex, age, and principal components. No variants were associated with any of the synucleinopathies, supporting that common and rare NPC1 variants do not play an important role in alpha synucleinopathies.
Rapid-eye movement (REM) sleep behavior disorder (RBD), enactment of dreams during REM sleep, is an early clinical symptom of alpha-synucleinopathies and defines a more severe subtype. The genetic background of RBD and its underlying mechanisms are not well understood. Here, we perform a genome-wide association study of RBD, identifying five RBD risk loci near SNCA, GBA, TMEM175, INPP5F, and SCARB2. Expression analyses highlight SNCA-AS1 and potentially SCARB2 differential expression in different brain regions in RBD, with SNCA-AS1 further supported by colocalization analyses. Polygenic risk score, pathway analysis, and genetic correlations provide further insights into RBD genetics, highlighting RBD as a unique alpha-synucleinopathy subpopulation that will allow future early intervention.
Patients with isolated rapid-eye-movement sleep behaviour disorder (RBD) are commonly regarded as being in the early stages of a progressive neurodegenerative disease involving α-synuclein pathology, such as Parkinson's disease, dementia with Lewy bodies, or multiple system atrophy. Abnormal α-synuclein deposition occurs early in the neurodegenerative process across the central and peripheral nervous systems and might precede the appearance of motor symptoms and cognitive decline by several decades. These findings provide the rationale to develop reliable biomarkers that can better predict conversion to clinically manifest α-synucleinopathies. In addition, biomarkers of disease progression will be essential to monitor treatment response once disease-modifying therapies become available, and biomarkers of disease subtype will be essential to enable prediction of which subtype of α-synucleinopathy patients with isolated RBD might develop.
- MeSH
- alpha-Synuclein MeSH
- Biomarkers * MeSH
- Humans MeSH
- REM Sleep Behavior Disorder complications diagnosis MeSH
- Prognosis MeSH
- Disease Progression MeSH
- Synucleinopathies diagnosis etiology MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Review MeSH
- Research Support, N.I.H., Extramural MeSH
- MeSH
- Humans MeSH
- REM Sleep Behavior Disorder * etiology MeSH
- Primary Dysautonomias * MeSH
- Synucleinopathies * MeSH
- Check Tag
- Humans MeSH
- Publication type
- Editorial MeSH
Neurodegenerativní onemocnění tvoří širokou a heterogenní skupinu nemocí. Jejich společnou vlastností je ukládání určitého patologického proteinu v mozkové tkáni. U synukleinopatií je tímto proteinem α-synuklein, jehož abnormálně složená depozita v centrálním i periferním nervovém systému definují na základě své lokalizace a struktury jednotlivá onemocnění. V současné době jsou mezi synukleinopatie řazeny Parkinsonova nemoc, Parkinsonova nemoc s demencí, demence s Lewyho tělísky, multisystémová atrofie, čisté autonomní selhání a idiopatická porucha chování v REM spánku. Průkaz samotného α-synukleinu u těchto nemocí má efekt v odlišení od jiných neurodegenerativních onemocnění, nicméně jeho specificita v diferenciální diagnostice jednotlivých synukleinopatií je poměrně nízká. Proto je třeba hledat další diagnostické biomarkery, které by přispěly k časné a přesné diagnóze jednotlivých onemocnění. Zároveň nejde jen o to pátrat po nových markerech, ale hledat i dostupnější biologické vzorky nebo tělesné tekutiny, v nichž lze tyto biomarkery účinně detekovat. V této práci jsou v úvodu velmi stručně shrnuta jednotlivá onemocnění a následně je uveden stručný přehled převážně diagnostických laboratorních biomarkerů. Uvádíme nejprve biomarkery mozkomíšního moku, které odrážejí přímé neuropatologické změny, dále několik biomarkerů nacházejících se v periferních tkáních.
Neurodegenerative diseases represent a large and heterogeneous group of disorders. Their common feature is the deposition of a certain pathological protein in brain tissue. The location and distribution of abnormally constituted α-synuclein deposits in central and peripheral nervous system define each respective disorder. The location and distribution of a-synuclein deposits define each respective disorder. Synucleinopathies currently include Parkinson‘s disease, Parkinson‘s disease with dementia, Lewy body dementia, multiple system atrophy, pure autonomic failure, and idiopathic REM sleep disorder. The detection of α-synuclein alone in these diseases has the effect in differentiating them from other neurodegenerative diseases; however, its specificity in the differential diagnosis of individual synucleinopathies is relatively low. Therefore, it is necessary to look for other diagnostic biomarkers that would contribute to the early and accurate diagnosis of individual diseases. At the same time, it is not just a matter of looking for new markers, but also of looking for more available biological samples or body fluids in which these biomarkers can be effectively detected. In the introduction of this review there is a brief description of each disorder and subsequently there is a brief overview of mostly diagnostic laboratory biomarkers. We first present the cerebrospinal fluid biomarkers that reflect the direct neuropathological changes, and then several biomarkers found in peripheral tissues.
- MeSH
- alpha-Synuclein analysis MeSH
- Biomarkers MeSH
- Lewy Body Disease diagnosis pathology therapy MeSH
- Humans MeSH
- Multiple System Atrophy diagnosis pathology MeSH
- Parkinson Disease diagnosis pathology MeSH
- Synucleinopathies * diagnosis pathology MeSH
- Check Tag
- Humans MeSH
- Publication type
- Research Support, Non-U.S. Gov't MeSH
- Review MeSH
- MeSH
- Humans MeSH
- Parkinson Disease, Secondary MeSH
- REM Sleep Behavior Disorder * diagnosis physiopathology MeSH
- Risk Factors MeSH
- Synucleinopathies MeSH
- Check Tag
- Humans MeSH
- Publication type
- Research Support, Non-U.S. Gov't MeSH
- Review MeSH
Isolated REM sleep behavior disorder (iRBD) is an early stage of synucleinopathy with most patients progressing to Parkinson's disease (PD) or related conditions. Quantitative susceptibility mapping (QSM) in PD has identified pathological iron accumulation in the substantia nigra (SN) and variably also in basal ganglia and cortex. Analyzing whole-brain QSM across iRBD, PD, and healthy controls (HC) may help to ascertain the extent of neurodegeneration in prodromal synucleinopathy. 70 de novo PD patients, 70 iRBD patients, and 60 HCs underwent 3 T MRI. T1 and susceptibility-weighted images were acquired and processed to space standardized QSM. Voxel-based analyses of grey matter magnetic susceptibility differences comparing all groups were performed on the whole brain and upper brainstem levels with the statistical threshold set at family-wise error-corrected p-values <.05. Whole-brain analysis showed increased susceptibility in the bilateral fronto-parietal cortex of iRBD patients compared to both PD and HC. This was not associated with cortical thinning according to the cortical thickness analysis. Compared to iRBD, PD patients had increased susceptibility in the left amygdala and hippocampal region. Upper brainstem analysis revealed increased susceptibility within the bilateral SN for both PD and iRBD compared to HC; changes were located predominantly in nigrosome 1 in the former and nigrosome 2 in the latter group. In the iRBD group, abnormal dopamine transporter SPECT was associated with increased susceptibility in nigrosome 1. iRBD patients display greater fronto-parietal cortex involvement than incidental early-stage PD cohort indicating more widespread subclinical neuropathology. Dopaminergic degeneration in the substantia nigra is paralleled by susceptibility increase, mainly in nigrosome 1.
- MeSH
- Humans MeSH
- Brain diagnostic imaging pathology MeSH
- Parkinson Disease * complications MeSH
- REM Sleep Behavior Disorder * diagnostic imaging MeSH
- Substantia Nigra diagnostic imaging pathology MeSH
- Synucleinopathies * complications pathology MeSH
- Iron MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
Synucleinopathies-related disorders such as Lewy body dementia (LBD) and isolated/idiopathic REM sleep behavior disorder (iRBD) have been associated with neuroinflammation. In this study, we examined whether the human leukocyte antigen (HLA) locus plays a role in iRBD and LBD. In iRBD, HLA-DRB1*11:01 was the only allele passing FDR correction (OR = 1.57, 95% CI = 1.27-1.93, p = 2.70e-05). We also discovered associations between iRBD and HLA-DRB1 70D (OR = 1.26, 95%CI = 1.12-1.41, p = 8.76e-05), 70Q (OR = 0.81, 95%CI = 0.72-0.91, p = 3.65e-04) and 71R (OR = 1.21, 95%CI = 1.08-1.35, p = 1.35e-03). Position 71 (pomnibus = 0.00102) and 70 (pomnibus = 0.00125) were associated with iRBD. Our results suggest that the HLA locus may have different roles across synucleinopathies.
OBJECTIVE: Rapid eye movement sleep behavior disorder (RBD) is a prodromal synucleinopathy, as >80% will eventually convert to overt synucleinopathy. We performed an in-depth analysis of the SNCA locus to identify RBD-specific risk variants. METHODS: Full sequencing and genotyping of SNCA was performed in isolated/idiopathic RBD (iRBD, n = 1,076), Parkinson disease (PD, n = 1,013), dementia with Lewy bodies (DLB, n = 415), and control subjects (n = 6,155). The iRBD cases were diagnosed with RBD prior to neurodegeneration, although some have since converted. A replication cohort from 23andMe of PD patients with probable RBD (pRBD) was also analyzed (n = 1,782 cases; n = 131,250 controls). Adjusted logistic regression models and meta-analyses were performed. Effects on conversion rate were analyzed in 432 RBD patients with available data using Kaplan-Meier survival analysis. RESULTS: A 5'-region SNCA variant (rs10005233) was associated with iRBD (odds ratio [OR] = 1.43, p = 1.1E-08), which was replicated in pRBD. This variant is in linkage disequilibrium (LD) with other 5' risk variants across the different synucleinopathies. An independent iRBD-specific suggestive association (rs11732740) was detected at the 3' of SNCA (OR = 1.32, p = 4.7E-04, not statistically significant after Bonferroni correction). Homozygous carriers of both iRBD-specific SNPs were at highly increased risk for iRBD (OR = 5.74, p = 2E-06). The known top PD-associated variant (3' variant rs356182) had an opposite direction of effect in iRBD compared to PD. INTERPRETATION: There is a distinct pattern of association at the SNCA locus in RBD as compared to PD, with an opposite direction of effect at the 3' of SNCA. Several 5' SNCA variants are associated with iRBD and with pRBD in overt synucleinopathies. ANN NEUROL 2020;87:584-598.
- MeSH
- alpha-Synuclein genetics MeSH
- Lewy Body Disease genetics MeSH
- Adult MeSH
- Genetic Predisposition to Disease MeSH
- Polymorphism, Single Nucleotide MeSH
- Middle Aged MeSH
- Humans MeSH
- Logistic Models MeSH
- Odds Ratio MeSH
- Parkinson Disease genetics MeSH
- REM Sleep Behavior Disorder genetics MeSH
- Prodromal Symptoms * MeSH
- Aged MeSH
- Case-Control Studies MeSH
- Synucleinopathies genetics MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
Cíl: Porucha chování v REM (rapid eye movement) spánku (REM sleep behavior disorder; RBD) je parasomnie charakterizovaná nepřítomností fyziologické atonie a chováním uskutečňování snu v REM spánku. Jako idiopatická RBD (iRBD) je RBD označena v nepřítomnosti jiné nemoci, která RBD obvykle vyvolává. Idiopatická RBD je známkou prodromální fáze synukleinopatie a má vysokou míru fenokonverze do neurodegenerativních nemocí ze skupiny synukleinopatií. Cílem této průřezové studie bylo zjistit stav čichové funkce u pacientů s iRBD a její vztah k jiným symptomům. Materiál a metody: Do studie bylo zahrnuto 54 pacientů s iRBD s mediánem věku 67 (IQR 63–72) let a 37 kontrolních subjektů s mediánem věku 67 (57,5–70,0) let, které byly spárovány podle věku a pohlaví. Všichni účastníci studie absolvovali komplexní vyšetření, které obsahovalo Identifikační čichový test Pensylvánské univerzity (University of Pennsylvania Identifaction Test; UPSIT). Výsledky: Úplnou ztrátu čichu anebo jeho těžkou dysfunkci mělo 62,9 % pacientů s iRBD, přitom u kontrolních subjektů to bylo pouze 8,1 %. Porucha atonie v REM spánku v polysomnografi i nepřímo korelovala se skóre UPSIT (p < 0,01). Závěr: Studie prokázala významně horší čich u pacientů s iRBD než u kontrolních osob.
Aim: Rapid eye movement (REM) sleep behaviour disorder (RBD) is a sleep abnormality heralded by the absence of physiological atonia in REM sleep and dream enactment behaviour. Idiopathic RBD (iRBD), diagnosed when no primary RBD cause can be identified, is a marker of prodromal synucleinopathy with a high conversion rate to overt neurodegenerative disorders from the synucleinopathy group. The aim of this cross-sectional study was to investigate olfactory function in iRBD patients and its relation to other symptoms. Patients and methods: This study included 54 iRBD patients with a median age of 67 (IQR 63–72) years; the 37 control subjects, matched by gender and age, had a median age of 67 (57.5–70.0) years. All subjects underwent a complex examination, which included olfactory testing using the University of Pennsylvania Smell Identification Test (UPSIT). Results: In total, 62.9% of iRBD patients had either total loss of olfactory function or severe hyposmia. In contrast, only 8.1% of controls showed such a degree of olfactory dysfunction. Furthermore, we found that the percentage of REM sleep without atonia on polysomnography negatively correlates with the UPSIT score (P < 0.01). Conclusion: This study demonstrated a significantly lower olfactory function in the iRBD group compared to controls.
- Keywords
- fenokonverze,
- MeSH
- Clinical Studies as Topic MeSH
- Middle Aged MeSH
- Humans MeSH
- Parkinson Disease physiopathology MeSH
- REM Sleep Behavior Disorder * MeSH
- Olfaction Disorders MeSH
- Aged MeSH
- Synucleinopathies MeSH
- Check Tag
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Research Support, Non-U.S. Gov't MeSH
