Postganglionic Sudomotor Assessment in Early Stage of Multiple System Atrophy and Parkinson Disease: A Morpho-functional Study

Background and Objectives:Sudomotor impairment has been recognized as a key feature in differentiating Parkinson disease (PD) and multiple system atrophy-parkinsonian type (MSA-P) with the latter been characterized by diffuse anhidrosis in prospective study including patients in late stage of disease.We aimed to evaluate morphological and functional postganglionic sudomotor involvement in patients with new diagnosis MSA-P and PD to identify possible biomarkers that might be of help in differentiating the two conditions in early stage.Methods:One hundred patients with parkinsonism within 2 years from onset of motor symptoms were included in the study. At time of recruitment, questionnaires to assess non-motor, autonomic and small fiber symptoms were administered and patients underwent post-ganglionic sudomotor function assessment by the dynamic sweat test and punch skin biopsy from distal leg. Skin samples were processed for indirect immunofluorescence with a panel of antibodies including noradrenergic and cholinergic markers. The density of intraepidermal, sudomotor and pilomotor nerve fibers was measured on confocal images using dedicated software. A follow-up visit twelve months after recruitment was performed to confirm the diagnosis.Results:We recruited 57 patients with PD (M/F=36/21; age 63.5±9.4years) and 43 patients with MSA-P (M/F=27/16; age 62.3±9.0 years). Clinical scales and questionnaires showed a more severe clinical picture in MSA-P compared to PD patients. Sweating output and intraepidermal, pilomotor and sudomotor nerve densities, compared to controls, were lower in both groups but with a greater impairment in MSA-P patients. Pilomotor and sudomotor nerve density correlated with sweating function and with non-motor clinical symptoms. A composite sudomotor parameter defined as the arithmetic product of sweat production multiplied by the density of sudomotor fibers, efficiently separated the two populations, the receiver operating characteristics showing an area under the curve of 0.83.Discussion:Dynamic sweat test and the quantification of cutaneous autonomic nerves provided to be a sensitive morpho-functional approach to assess postganglionic component of the sudomotor pathway, revealing a more severe involvement in MSA-P than in PD early in the disease course. This approach can be applied to early differentiate the two conditions.Classification of Evidence:This study provides Class II evidence that post ganglionic sudomotor morpho-functional assessment accurately distinguish PD from MSA-P patients.

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P1.3 Thermal sweat test for the differential diagnosis of Parkinson disease and multiple system atrophy in human patients

Autonomic Neuroscience ◽

10.1016/j.autneu.2009.05.099 ◽

2009 ◽

Vol 149 (1-2) ◽

pp. 60

Author(s):

Y. Nagashima ◽

M. Kunimoto ◽

M. Saito ◽

T. Kudeken ◽

Y. Kasai ◽

...

Keyword(s):

Differential Diagnosis ◽

Multiple System Atrophy ◽

Parkinson Disease ◽

Sweat Test

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Substantia nigra neuromelanin magnetic resonance imaging in patients with different subtypes of Parkinson disease

Journal of Neural Transmission ◽

10.1007/s00702-020-02295-8 ◽

2021 ◽

Author(s):

Lu Wang ◽

Yayun Yan ◽

Liyao Zhang ◽

Yan Liu ◽

Ruirui Luo ◽

...

Keyword(s):

Magnetic Resonance Imaging ◽

Magnetic Resonance ◽

Substantia Nigra ◽

Parkinson Disease ◽

Clinical Symptoms ◽

Dopamine Neurons ◽

Substantia Nigra Pars Compacta ◽

Resonance Imaging ◽

Mean Values

AbstractNeuromelanin (NM) is a dark pigment that mainly exists in neurons of the substantia nigra pars compacta (SNc). In Parkinson disease (PD) patients, NM concentration decreases gradually with degeneration and necrosis of dopamine neurons, suggesting potential use as a PD biomarker. We aimed to evaluate associations between NM concentration in in vivo SN and PD progression and different motor subtypes using NM magnetic resonance imaging (NM-MRI). Fifty-four patients with idiopathic PD were enrolled. Patients were divided into groups by subtypes with different clinical symptoms: tremor dominant (TD) group and postural instability and gait difficulty (PIGD) group. Fifteen healthy age-matched volunteers were enrolled as controls. All subjects underwent clinical assessment and NM-MRI examination. PD patients showed significantly decreased contrast-to-noise ratio (CNR) values in medial and lateral SN (P < 0.05) compared to controls. CNR values in lateral SN region decreased linearly with PD progression (P = 0.001). PIGD patients showed significant decreases in CNR mean values in lateral SN compared to TD patients (P = 0.004). Diagnostic accuracy of using lateral substantia nigra (SN) in TD and PIGD groups was 79% (sensitivity 76.5%, specificity 78.6%). NM concentration in PD patients decreases gradually during disease progression and differs significantly between PD subtypes. NM may be a reliable biomarker for PD severity and subtype identification.

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Patterns of striatal dopamine depletion in early Parkinson disease

Neurology ◽

10.1212/wnl.0000000000009878 ◽

2020 ◽

Vol 95 (3) ◽

pp. e280-e290 ◽

Cited By ~ 2

Author(s):

Seok Jong Chung ◽

Hye Sun Lee ◽

Han Soo Yoo ◽

Yang Hyun Lee ◽

Phil Hyu Lee ◽

...

Keyword(s):

Factor Analysis ◽

Parkinson Disease ◽

Cox Regression ◽

Early Stage ◽

Freezing Of Gait ◽

Striatal Dopamine ◽

Dopamine Depletion ◽

Wearing Off ◽

Striatal Dopamine Depletion ◽

Selective Dopamine

ObjectiveTo investigate whether the patterns of striatal dopamine depletion on dopamine transporter (DAT) scans could provide information on the long-term prognosis in Parkinson disease (PD).MethodsWe enrolled 205 drug-naive patients with early-stage PD, who underwent 18F-FP-CIT PET scans at initial assessment and received PD medications for 3 or more years. After quantifying the DAT availability in each striatal subregion, factor analysis was conducted to simplify the identification of striatal dopamine depletion patterns and to yield 4 striatal subregion factors. We assessed the effect of these factors on the development of levodopa-induced dyskinesia (LID), wearing-off, freezing of gait (FOG), and dementia during the follow-up period (6.84 ± 1.80 years).ResultsThe 4 factors indicated which striatal subregions were relatively preserved: factor 1 (caudate), factor 2 (more-affected sensorimotor striatum), factor 3 (less-affected sensorimotor striatum), and factor 4 (anterior putamen). Cox regression analyses using the composite scores of these striatal subregion factors as covariates demonstrated that selective dopamine depletion in the sensorimotor striatum was associated with a higher risk for developing LID. Selective dopamine loss in the putamen, particularly in the anterior putamen, was associated with early development of wearing-off. Selective involvement of the anterior putamen was associated with a higher risk for dementia conversion. However, the patterns of striatal dopamine depletion did not affect the risk of FOG.ConclusionsThese findings suggested that the patterns of striatal dopaminergic denervation, which were estimated by the equation derived from the factor analysis, have a prognostic implication in patients with early-stage PD.

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FGF23, a novel muscle biomarker detected in the early stages of ALS

Scientific Reports ◽

10.1038/s41598-021-91496-6 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Ying Si ◽

Mohamed Kazamel ◽

Michael Benatar ◽

Joanne Wuu ◽

Yuri Kwon ◽

...

Keyword(s):

Biomarker Discovery ◽

Clinical Symptoms ◽

Early Stage ◽

Fold Increase ◽

Progressive Increase ◽

Molecular Signature ◽

Muscle Membrane ◽

Sequencing Project ◽

Progressive Muscle Weakness ◽

End Stage

AbstractAmyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive muscle weakness. Skeletal muscle is a prime source for biomarker discovery since it is one of the earliest sites to manifest disease pathology. From a prior RNA sequencing project, we identified FGF23 as a potential muscle biomarker in ALS. Here, we validate this finding with a large collection of ALS muscle samples and found a 13-fold increase over normal controls. FGF23 was also increased in the SOD1G93A mouse, beginning at a very early stage and well before the onset of clinical symptoms. FGF23 levels progressively increased through end-stage in the mouse. Immunohistochemistry of ALS muscle showed prominent FGF23 immunoreactivity in the endomysial connective tissue and along the muscle membrane and was significantly higher around grouped atrophic fibers compared to non-atrophic fibers. ELISA of plasma samples from the SOD1G93A mouse showed an increase in FGF23 at end-stage whereas no increase was detected in a large cohort of ALS patients. In conclusion, FGF23 is a novel muscle biomarker in ALS and joins a molecular signature that emerges in very early preclinical stages. The early appearance of FGF23 and its progressive increase with disease progression offers a new direction for exploring the molecular basis and response to the underlying pathology of ALS.

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Whole brain atlas-based diffusion kurtosis imaging parameters for evaluation of minimal hepatic encephalopathy

The Neuroradiology Journal ◽

10.1177/19714009211026924 ◽

2021 ◽

pp. 197140092110269

Author(s):

Prateek Gupta ◽

Sameer Vyas ◽

Teddy Salan ◽

Chirag Jain ◽

Sunil Taneja ◽

...

Keyword(s):

Hepatic Encephalopathy ◽

Clinical Symptoms ◽

Early Stage ◽

Imaging Techniques ◽

Clinical Stage ◽

Minimal Hepatic Encephalopathy ◽

Brain Atlas ◽

Diffusion Kurtosis Imaging ◽

Whole Brain ◽

Diffusion Kurtosis

Background and purposes Minimal hepatic encephalopathy (MHE) has no recognizable clinical symptoms, but patients have cognitive and psychomotor deficits. Hyperammonemia along with neuroinflammation lead to microstructural changes in cerebral parenchyma. Changes at conventional imaging are detected usually at the overt clinical stage, but microstructural alterations by advanced magnetic resonance imaging techniques can be detected at an early stage. Materials and methods Whole brain diffusion kurtosis imaging (DKI) data acquired at 3T was analyzed to investigate microstructural parenchymal changes in 15 patients with MHE and compared with 15 age- and sex-matched controls. DKI parametric maps, namely kurtosis fractional anisotropy (kFA), mean kurtosis (MK), axial kurtosis (AK) and radial kurtosis (RK), were evaluated at 64 white matter (WM) and gray matter (GM) regions of interest (ROIs) in the whole brain and correlated with the psychometric hepatic encephalopathy score (PHES). Results The MHE group showed a decrease in kFA and AK across the whole brain, whereas MK and RK decreased in WM ROIs but increased in several cortical and deep GM ROIs. These alterations were consistent with brain regions involved in cognitive function. Significant moderate to strong correlations (–0.52 to –0.66; 0.56) between RK, MK and kFA kurtosis metrics and PHES were observed. Conclusion DKI parameters show extensive microstructural brain abnormalities in MHE with minor correlation between the severity of tissue damage and psychometric scores.

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Abdominal irradiation increases inflammatory cytokine expression and activates NF-κB in rat ileal muscularis layer

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00094.2003 ◽

2003 ◽

Vol 285 (3) ◽

pp. G556-G565 ◽

Cited By ~ 56

Author(s):

C. Linard ◽

A. Ropenga ◽

M. C. Vozenin-Brotons ◽

A. Chapel ◽

D. Mathe

Keyword(s):

Inflammatory Cytokine ◽

Intestinal Inflammation ◽

Clinical Symptoms ◽

Early Stage ◽

Cytokine Expression ◽

Mrna Levels ◽

Activator Protein 1 ◽

Γ Irradiation ◽

Control Tissue ◽

Anti Inflammatory

The small bowel is an important dose-limiting organ in abdominal radiotherapy because irradiation can cause acute enteritis that, in turn, leads to progressively reduced motility and finally, in a later phase, to fibrosis. Because these clinical symptoms may be caused by the early stage of an inflammatory process, we characterized the radiation-induced intestinal inflammation in rats. Abdominal γ-irradiation (10-Gy) induced a cascade of inflammatory events characterized by an early (6 h after exposure) increase in IL-1β, TNF-α, and IL-6 mRNA levels in the rat ileal muscularis layer. IL-8 [a cytokine-induced neutrophil chemoattractant (CINC)] mRNA appeared later (at 3 days). The expression of TGF-β (a profibrotic cytokine) was higher in irradiated than control tissue at day 1, whereas IL-10 (an anti-inflammatory cytokine) expression vanished completely. Despite strong IL-1ra expression, the IL-1ra/IL-1β ratio, which is an indicator of inflammatory balance, was -41% at day 1 in irradiated compared with control tissue. The nuclear transcription factors NF-κB and activator protein-1 (AP-1) govern transcription of these genes, directly or indirectly. Although expression of the subunits of NF-κB (p65, p50) and AP-1 (c- fos, c- jun) did not increase, irradiation caused a rapid and persistent translocation of p65 and p50. An imbalance between proinflammatory and anti-inflammatory mediators may contribute to perpetuating intestinal inflammation, thus making it chronic.

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Experimental pain sensitivity in multiple system atrophy and Parkinson's disease at an early stage

European Journal of Pain ◽

10.1002/ejp.846 ◽

2016 ◽

Vol 20 (8) ◽

pp. 1223-1228 ◽

Cited By ~ 10

Author(s):

V. Mylius ◽

S. Pee ◽

H. Pape ◽

M. Teepker ◽

M. Stamelou ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Multiple System Atrophy ◽

Pain Sensitivity ◽

Early Stage ◽

Experimental Pain ◽

Experimental Pain Sensitivity

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Fatigue in Patients With Multiple System Atrophy

Neurology ◽

10.1212/wnl.0000000000012968 ◽

2021 ◽

Vol 98 (1) ◽

pp. e73-e82

Author(s):

Lingyu Zhang ◽

Bei Cao ◽

Yanbing Hou ◽

Xiaojing Gu ◽

Qian-Qian Wei ◽

...

Keyword(s):

Multiple System Atrophy ◽

Regression Model ◽

Rating Scale ◽

Early Stage ◽

Progression Rate ◽

Nonmotor Symptoms ◽

Binary Logistic Regression Model ◽

Neurofilament Light Chain ◽

Neurofilament Light

Background and ObjectivesNonmotor symptoms are common in patients with multiple system atrophy (MSA), but there is limited knowledge regarding fatigue in MSA. This study aimed to investigate the frequency and evolution of fatigue and the factors related to fatigue and its progression in patients with MSA at an early stage.MethodsPatients with probable MSA were comprehensively evaluated at both baseline and the 1-year follow-up, including their motor and nonmotor symptoms. Fatigue and anxiety were assessed using the Fatigue Severity Scale (FSS) and Hamilton Anxiety Rating Scale (HARS), respectively. Orthostatic hypotension (OH) was defined as a decrease in the systolic or diastolic blood pressure by at least 30 and 15 mm Hg, respectively. The binary logistic regression model and linear regression model were used to analyze the factors related to fatigue and its progression, respectively.ResultsThis study enrolled 146 patients with MSA. The frequency of fatigue was 60.3%, 55.1%, and 64.9% in MSA, MSA with predominant parkinsonism (MSA-P), and MSA with predominant cerebellar ataxia (MSA-C), respectively. The frequency of fatigue and the FSS score in patients with MSA increased from baseline to the 1-year follow-up (p < 0.05). Young age (odds ratio [OR] 0.939, 95% confidence interval [CI] 0.894–0.987), OH (OR 2.806, 95% CI 1.253–6.286), and high HARS score (OR 1.014, 95% CI 1.035–1.177) were associated with fatigue in MSA. OH was associated with fatigue in MSA-P (OR 3.391, 95% CI 1.066–10.788), while high HARS score was associated with fatigue in MSA-C (OR 1.159, 95% CI 1.043–1.287). In addition, only low FSS scores at baseline were associated with the annual progression rate of FSS scores in MSA, MSA-P, and MSA-C (p < 0.05). Neurofilament light chain, α-synuclein, glial fibrillary acidic protein, brain-derived neurotrophic factor, and triggering receptor expressed on myeloid cell-2 were not significantly associated with fatigue and its progression in MSA.DiscussionFatigue was prevalent in early-stage MSA, and it increased and remained persistent over time. This study demonstrated that OH and anxiety were associated with fatigue in patients with MSA.

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