Synucleinopathies are neurodegenerative diseases with both central and peripheral immune responses. However, whether the peripheral immune changes occur early in disease and their relation to brain ...events is yet unclear. Isolated rapid-eye-movement (REM) sleep behavior disorder (iRBD) can precede synucleinopathy-related parkinsonism and provides a prodromal phenotype to study early Parkinson's disease events. In this prospective case-control study, we describe monocytic markers in a cohort of iRBD patients that were associated with the brain-imaging markers of inflammation and neuronal dysfunction. Using
C-PK11195 positron emission tomography (PET), we previously showed increased immune activation in the substantia nigra of iRBD patients, while
F-DOPA PET detected reduced putaminal dopaminergic function. Here we describe that patients' blood monocytic cells showed increased expression of CD11b, while HLA-DR expression was decreased compared to healthy controls. The iRBD patients had increased classical monocytes and mature natural killer cells. Remarkably, the levels of expression of Toll-like receptor 4 (TLR4) on blood monocytes in iRBD patients were positively correlated with nigral immune activation measured by
C-PK11195 PET and negatively correlated with putaminal
F-DOPA uptake; the opposite was seen for the percentage of CD163
myeloid cells. This suggesting a deleterious role for TLR4 and, conversely, a protective one for the CD163 expression. We show an association between peripheral blood monocytes and brain immune and dopaminergic changes in a synucleinopathy-related disorder, thus suggesting a cross-talk among periphery and brain during the disease.
OBJECTIVEUnilateral onset of parkinsonism due to nigrostriatal damage of the contralateral hemisphere is frequent in Parkinson disease (PD). There is evidence for a left-hemispheric bias of motor ...asymmetry in right-handed patients with PD indicating a hemispheric dominance. Isolated REM sleep behavior disorder (IRBD) constitutes the prodromal stage of PD and other synucleinopathies. To test the hypothesis that right-handed patients with IRBD exhibit left-hemispheric predominance of subclinical nigrostriatal dysfunction, we evaluated this aspect using neuroimaging instruments.
METHODSIn 167 right-handed patients with IRBD without parkinsonism, we evaluated in each hemisphere the integrity of the striatal dopaminergic terminals by dopamine transporter (DAT)-SPECT and the substantia nigra echogenicity by transcranial sonography.
RESULTSDAT-SPECT showed lower specific binding ratio (SBR) in the left striatum and left caudate nucleus than in the right striatum and right caudate nucleus. The percentage of patients with lower SBR was greater in the left striatum and left caudate nucleus than in the right striatum and right caudate nucleus. In those who developed a synucleinopathy in <5 years from DAT-SPECT, there was a lower SBR in the left putamen and left caudate nucleus than in the right putamen and right caudate nucleus. Substantia nigra echogenic size was greater in the left than in the right side in patients with hyperechogenicity and among individuals who phenoconverted in <5 years from transcranial sonography.
CONCLUSIONRight-handed patients with IRBD exhibit left-hemispheric predominance of subclinical nigrostriatal dysfunction. In premotor PD, the neurodegenerative process begins asymmetrically, initially impairing the nigrostriatal system of the dominant hemisphere.
The validity of α-synuclein (α-Syn) as a biomarker for Parkinson’s disease (PD) is still under investigation. Conventional methods for capture and quantitation of α-Syn protein in human samples are ...primarily based on anti-α-Syn antibodies. Specific and competent antibodies were raised against α-Syn. However, capture by anti-α-Syn antibodies may be limited to specific epitope recognition, attributed to protein structure or post-translational modifications. Hence, antibody-based methods for α-Syn capture raise a concern regarding their efficacy to detect the intracellular, unfolded α-Syn pool. An alternative is α-Syn capture by membrane lipids, i.e., to utilize the biochemical property of α-Syn to specifically bind membrane lipids and acquire a characteristic structure following binding. We determined α-Syn levels in human samples using immobilized lipids for α-Syn capture. The lipids used for α-Syn capture consist of phosphatidyl inositol (PI), phosphatidyl serine (PS), and phosphatidyl ethanolamine (PE). Addition of mono-sialoganglioside, GM1 ganglioside, to the immobilized lipids significantly improved α-Syn detection. Following capture, the lipid-bound α-Syn was detected using an anti-α-Syn antibody. Total α-Syn levels in whole blood cells (WBC), cerebrospinal fluid (CSF), and saliva were determined by the lipid-ELISA method.
Isolated REM sleep behavior disorder (IRBD) represents an early manifestation of the synucleinopathies Parkinson's disease (PD) and dementia with Lewy bodies (DLB). Aggregation of abnormal ...α-synuclein and its increased expression in the brain is crucial in the development of the synucleinopathies. Whereas α-synuclein gene (SNCA) transcripts are overexpressed in brain, a concomitant reduction occurs in blood of DLB patients. We assessed whether this decrease is also detectable in IRBD.
108 IRBD patients and 149 controls were included of which 29 IRBD and 32 control cases were available for expression studies. Expression of SNCAtv1, SNCAtv2, SNCAtv3 and SNCA126 isoforms, and GBA were determined by real-time PCR. Genotype distribution of SNCA SNPs, rs356219 and rs2736990, and correlation with SNCA expression was analyzed.
Expression of all SNCA transcripts was reduced in IRBD blood whereas GBA expression did not change. SNCAtv3 expression correlated inversely with IRBD duration, being lower in patients with longer follow-up. Rs356219-AA genotype frequency was increased in IRBD patients who later developed PD and DLB. Rs2736990-CC frequency was increased among IRBD cases who remained disease-free. No correlation was observed between rs356219 and rs2736990 genotypes and SNCA transcript levels.
SNCA transcript expression is decreased in blood in IRBD, and levels decrease with IRBD duration. Our findings indicate that changes in SNCA expression occur in the earliest stages of the synucleinopathies before motor and cognitive symptoms become apparent.
•SNCA transcript expression is reduced in blood in IRBD patients.•SNCAtv3 levels decrease with increased IRBD duration, especially in younger patients.•Rs356219-AA genotype frequency is increased in IRBD patients who developed PD and DLB.•Rs2736990-CC genotype frequency is increased in IRBD patients who remained disease-free over time.
In Parkinson disease (PD), REM sleep behavior disorder (RBD) and depression may occur before the onset of parkinsonism. Transcranial sonography (TCS) shows that hyperechogenicity of the substantia ...nigra (SN+) and hypoechogenicity of the brainstem raphe (BR+) are frequent in PD, particularly when depression is associated. Combined SN+ and BR+ identify PD subjects in whom depression antedates parkinsonism onset. It can be speculated that SN+ and BR+ may also identify idiopathic RBD (IRBD) subjects with comorbid depression, supporting the clinical diagnosis of this mood disorder. We aimed to study the brainstem raphe and substantia nigra echogenicity and their ability to predict comorbid depression in IRBD. Seventy-two IRBD patients and 71 age and sex-matched controls underwent TCS. Depression was diagnosed by means of DSM-IV criteria. Depression was more frequent in IRBD patients than in controls (44.4 vs. 18.3 %;
p
= 0.001). BR+ was more frequent in depressed than in nondepressed IRBD patients (32.0 vs. 11.4 %;
p
= 0.050). Sensitivity of BR+ to predict depression in IRBD was 32.0 %, specificity was 88.6 %, and relative risk was 1.88. Sensitivity of SN+ to predict depression in IRBD was 72.0 %, specificity was 44.1 %, and relative risk was 1.53. Sensitivity of combined BR+ and SN+ to predict depression in IRBD was 23.1 %, specificity 97.1 %, and relative risk was 2.31. Hypoechogenicity of the brainstem raphe, particularly when combined with hyperechogenicity of the substantia nigra, detects comorbid depression in IRBD. This finding suggests that dysfunction of the serotonergic dorsal raphe may be involved in the pathophysiology of depression in IRBD.
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