Unveiling Parkinson's disease through biomarker research: current insights and future prospects.

Parkinson's disease (PD) is a neurodegenerative condition marked by the gradual depletion of dopaminergic neurons in the substantia nigra. Despite substantial strides in comprehending potential causative mechanisms, the validation of biomarkers with unequivocal evidence for routine clinical application remains elusive. Consequently, the diagnosis heavily relies on patients' clinical assessments and medical backgrounds. The imperative need for diagnostic and prognostic biomarkers arises due to the prevailing limitations of treatments, which predominantly address symptoms without modifying the disease course. This comprehensive review aims to elucidate the existing landscape of diagnostic and prognostic biomarkers for PD, drawing insights from contemporary literature.

A novel mutation in RNF216 gene in a Turkish case with Gordon Holmes syndrome.

BACKGROUND: Gordon Holmes syndrome (GHS) is a rare autosomal recessive disorder characterized by hypogonadotropic hypogonadism, cognitive decline, and cerebellar ataxia. Mutations in the Ring Finger Protein 216 (RNF216) gene have been known to be associated with GHS therewithal RNF216 mutations have been detected in cases with Huntington-like disease, 4H syndrome (hypodontia, hypomyelination, ataxia and hypogonadotropic hypogonadism), and congenital hypogonadotropic hypogonadism. CASE PRESENTATION: Here we report a novel homozygous frameshift mutation in RNF216 gene c.1860_1861dupCT (p.Cys621SerfsTer56) in a patient with hypogonadotropic hypogonadism, ataxia, and cognitive decline diagnosed with GHS also co-occurrence of parkinsonism and dystonia which was not reported before. CONCLUSIONS: We report an extremely rare case of GHS. The core features of GHS are well defined, but genotype-phenotype correlations are still limited. To understand the pathophysiology of different phenotypes, the type and localization of novel mutations need to be defined, and the effect of these different variants on clinical features needs to be determined. Further studies should explain the factors of phenotypic variability present in GHS patients with RNF216 mutations.

Plasma thiol/disulphide homeostasis changes in patients with relapsing-remitting multiple sclerosis.

BACKGROUND: Multiple sclerosis (MS) is a neuroinflammatory disease and inflammation and oxidative stress play important roles in its pathology. Thiol/disulphide homeostasis (TDH) is a special oxidative stress biomarker that has been found to be affected in several disorders including MS. There is no study demonstrating the effects of attack status of the relapsing-remitting multiple sclerosis (RRMS) patients on TDH levels. Our aim was to determine TDH levels in three different periods of RRMS patients and healthy individuals. METHODS: The study was carried out in 29 patients with RRMS without a prior attack in the last twelve months (MS Control), 21 RRMS patients having a clinical acute attack within the last week (MS relapse), 12 of 21 MS relapse patients one month after the onset of attack and following 1000 mg methylprednisolone for 7 days (MS Remission) and 30 age- and sex-matched healthy individuals. TDH status was determined using an automated spectrophotometric analysis method. TDH levels in all patient groups and control subjects were compared with each other. RESULTS: The lowest native thiol, total thiol levels and native thiol/total thiol ratio were found in the MS relapse patients in comparison to the MS control, MS remission groups and healthy controls. In contrast, disulphide levels, disulphide/native thiol and disulphide/total thiol ratios were highest in the MS relapse group compared to the other patient groups and healthy subjects. CONCLUSION: Our findings indicate that increased oxidative stress in RRMS patients is reflected with decreased native and total thiol and increased disulphide levels. Since the formation of disulphide bonds is reversible, the progression of RRMS involving abnormal TDH may be controlled, converting disulphides to thiols. So, we suggest determining the dynamic TDH status as a novel and special biomarker in the diagnosis and prognosis of the RRMS patients.

Plasma thiol/disulphide homeostasis changes in patients with restless legs syndrome.

OBJECTIVES: Restless legs syndrome (RLS) is a common neurological condition. Oxidative stress plays an important role in its pathogenesis. Thiol-disulphide homeostasis (TDH) is a new biomarker of oxidative stress. We studied plasma TDH to determine whether TDH could be used as a new biomarker for RLS and evaluated correlations between TDH and various disease severity rating scales. METHODS: A total of 25 RLS patients and 25 healthy controls were included into the study. TDH status was determined using an automated spectrophotometric analysis method and correlations were analyzed between the TDH status and various disease rating scales in the RLS patients. RESULTS: Plasma total (401±27 µmol/L) and native thiol (354±30 µmol/L) levels were significantly lower, but disulphide level (24±6 µmol/L) was significantly (<0.0001) higher in the RLS patients compared to the controls (455±36, 424±37, 15±5 µmol/L, respectively). The disulphide/native thiol and disulphide/total thiol ratios increased, in contrast, native thiol/total thiol ratio decreased significantly in the RLS patients compared to the healthy controls (<0.0001). The disulphide levels correlated positively with age and various rating scores of the RLS patients. International Restless Legs Syndrome Study Group (IRLSSG) rating score and age correlated negatively with the total and native thiol levels. CONCLUSIONS: Our findings indicate increased oxidative stress in the RLS patients reflected by decreased native and total thiol, and increased disulphide levels and positive correlations between the disulphide levels and various rating scores. We suggest dynamic TDH status to be used as a novel biomarker for the diagnosis and follow-up of the RLS patients.

Plasma copeptin levels in patients with multiple sclerosis.

We compared copeptin levels in relapsing-remitting multiple sclerosis (RRMS) patients with controls and investigated how plasma copeptin levels were changed with the disease period. Thirty patients with RRMS without a prior attack in the last twelve months, and 19 RRMS patients with a clinical acute attack and 30 healthy individuals were included into the study. Copeptin levels were significantly higher in all RRMS patient groups than healthy controls. Plasma copeptin levels were higher in patients in remission period compared with relapse period of 19 RRMS patients with an acute attack. We consider copeptin can be used as a potential biomarker for RRMS.

Evaluation of potential cardiovascular risk protein biomarkers in high severity restless legs syndrome.

Restless legs syndrome (RLS) is a common sensorimotor disorder that, in case of severe symptoms, can be very distressing and negatively interfere with quality of life. Moreover, increasing evidences associate RLS with higher risk of cerebrovascular and cardiovascular disease (CVD). The purpose of this study was to quantify two proteins, previously identified by proteomics and potentially linked with CVD risk, namely kininogen-1 (KNG1) and alpha-1-antitrypsin (A1AT), in primary RLS patients at high severity grade (HS-RLS) in comparison to healthy control subjects. Proteins were quantified through enzyme-linked immunosorbent assay (ELISA) in plasma samples from 14 HS-RLS patients and 15 control individuals. The two groups were closely matched for age and gender. The expression level of KNG1 resulted significantly higher (p < 0.001), while A1AT was significantly decreased (p < 0.05) in HS-RLS patients compared to controls, confirming the relationship between these proteins and the disease severity. Furthermore, in patients group the association between the protein concentrations and the following parameters was further evaluated: age, disease onset and diagnosis, scores obtained from the RLS rating scales (Epworth Sleepiness Scale, Pittsburgh Sleep Quality Index, Beck Depression Inventory) and smoking habit. All the considered variables resulted independent of protein levels, so the disease can be reasonably considered the main cause of protein changes. As emerged from the literature, high levels of KNG1 and low amounts of A1AT seem to be related with a highest probability to develop CVD. Consequently, these proteins may be reliable candidate biomarkers of CVD risk in patients with RLS at high severity grade.

Neuro-inflammation and anti-inflammatory treatment options for Alzheimer's disease.

Alzheimer's disease (AD) is a neurodegenerative disease characterized by progressive memory loss and dementia. The pathological characteristics of AD include the deposition of amyloid beta (Aß), neurofibrillary tangles, and neuronal loss. There is evidence showing the involvement of inflammation in AD, including activated microglia within and surrounding senile plaques. Epidemiological studies suggest the use of anti-inflammatory drugs to reduce incidence of AD. However, clinical trials with anti-inflammatory drugs have not been successful.

Discovery of restless legs syndrome plasmatic biomarkers by proteomic analysis.

OBJECTIVES: Restless legs syndrome (RLS) can lead to severe clinical consequences, thus negatively impacts on patients' overall health and quality of life. Nevertheless, the pathophysiology of RLS is still unclear, resulting in underestimate, incorrect, or ignored diagnosis and in limited management and treatment. The aim of this study was to compare the plasma proteome of RLS patients and healthy controls, in the search of diagnostic biomarkers related to the disease severity. MATERIALS AND METHODS: Two-dimensional gel electrophoresis coupled with liquid chromatography-mass spectrometry was employed to analyze plasma samples of 34 patients with primary RLS, divided into two subgroups according to the disease severity: MMS group (mild-moderate symptoms) and HS group (severe and very severe symptoms), and 17 age- and sex-matched control subjects. Sleep quality, daytime sleepiness, and the level of depression were also evaluated. RESULTS: We identified eight upregulated spots, corresponding to five unique proteins, in both RLS group vs. controls (alpha-1B-glycoprotein, alpha-1-acid glycoprotein 1, haptoglobin, complement C4-A, and immunoglobulin kappa constant); five increased spots, consistent with three unique proteins, only in HS-RLS (kininogen-1, immunoglobulin heavy constant alpha 1, and immunoglobulin lambda constant 2); one downregulated spot in both patient's groups (complement C3) and another one only in HS-RLS (alpha-1-antitrypsin). CONCLUSIONS: The significantly different plasma proteins detected in RLS were mainly associated with inflammation, immune response, and cardiovascular disorders. Particularly, the gradual increasing in immunoglobulins could be indicative of the disease severity and evolution. Accordingly, these proteins may represent a valid set of useful biomarkers for RLS diagnosis, progression and treatment.

Right ventricular geometry and mechanics in patients with obstructive sleep apnea living at high altitude.

PURPOSE: Repetitive obstruction of larynx during sleep can lead to daytime pulmonary hypertension and alterations in right ventricular morphology and function in a small fraction of obstructive sleep apnea syndrome (OSAS) patients. Environmental effects, particularly high altitude, can modify the effects of OSAS on pulmonary circulation, since altitude-related hypoxia is related with pulmonary vasoconstriction. This potential interaction, however, was not investigated in previous studies. METHODS: A total of 41 newly diagnosed OSAS patients were included in this study after pre-enrolment screening. Two-dimensional, three-dimensional, and Doppler echocardiographic data were collected after polysomnographic verification of OSAS. Three-dimensional echocardiograms were analyzed to calculate right ventricular volumes, volume indices, and ejection fraction. RESULTS: Systolic pulmonary artery pressure (38.35 ± 8.60 vs. 30.94 ± 6.47 mmHg; p = 0.002), pulmonary acceleration time (118.36 ± 16.36 vs. 103.13 ± 18.42 ms; p = 0.001), right ventricle (RV) end-diastolic volume index (48.15 ± 11.48 vs. 41.48 ± 6.45 ml; p = 0.009), and RV end-systolic volume index (26.50 ± 8.11 vs. 22.15 ± 3.85; p = 0.01) were significantly higher in OSAS patients, with similar RV ejection fraction (EF) between groups. No significant differences were noted in other two-dimensional, Doppler or speckle-tracking strain, measurements. Both RVEF and pulmonary acceleration time were predictors of disease severity. CONCLUSIONS: A greater degree of RV structural remodeling and higher systolic pulmonary pressure were observed in OSAS patients living at high altitude compared to healthy highlanders. The reversibility of these alterations with treatment remains to be studied.

Increased plasma soluble tumor necrosis factor receptor-1 and myeloperoxidase activity in patients with obstructive sleep apnea syndrome.

PURPOSE/AIM: Obstructive sleep apnea (OSA) is characterized by recurrent respiratory disorders associated with increased cardiovascular morbidity and mortality. The increment of systemic inflammation in OSA has been considered as the major pathogenic mechanism leading to cardiovascular diseases. There is limited and conflicting information in the literature investigating myeloperoxidase (MPO) activity and soluble tumor necrosis factor receptor-1 (sTNF-R1) levels in OSA patients. The aim of our study is to assess the clinical utility of plasma MPO activity and sTNF-R1 levels as risk markers for systemic inflammation and development of cardiovascular diseases in OSA patients. MATERIALS AND METHODS: 59 OSA patients diagnosed with polysomnograhpy for Apnea-Hypopnea index (AHI), and 26 healthy volunteers enrolled into the study. Plasma MPO activity was measured using a spectrophotometric method. An enzyme-linked immunosorbent assay (ELISA) method was used to detect plasma sTNF-R1 levels. RESULTS: Plasma MPO activity and sTNF-R1 levels were significantly higher (43.2 ± 21.65 vs. 30.44 ± 8.05 p = .0046; 2.379 ± 1.2 vs. 1.086 ± 0.86 p < .0001, respectively) in the total OSA patients compared to the control group. There was a significant weak correlation between MPO activity and disease severity indicator AHI (p = .03 r = .27). CONCLUSIONS: Elevated plasma MPO activity and sTNF-R1 levels in the OSA patients indicate increased systemic inflammation and oxidative stress which might contribute to the higher incidence of cardiovascular diseases. Therefore, we recommend measurement of plasma MPO activity and sTNF-R1 levels in the OSA patients as potential risk predictors for cardiovascular diseases.

Advanced oxidation protein products and ischaemia-modified albumin in obstructive sleep apnea.

BACKGROUND: Several studies have shown that obstructive sleep apnea increases incidence of cardiovascular morbidity and mortality. The high systemic oxidative stress in obstructive sleep apnea has been considered as a major pathogenic mechanism leading to cardiovascular disease. Oxidative stress-related lipid and DNA oxidation in obstructive sleep apnea have been reported in the previous studies. In contrast, there is limited and contradictory information regarding protein oxidation in obstructive sleep apnea patients such as ischaemia-modified albumin and advanced oxidation protein products. Therefore, we aimed to investigate plasma ischaemia-modified albumin and advanced oxidation protein products and their correlation with total oxidative status and total antioxidative capacity in the obstructive sleep apnea patients. METHODS: Plasma ischaemia-modified albumin, advanced oxidation protein products, total oxidative status and total antioxidative capacity were measured in 25 healthy volunteers and 59 obstructive sleep apnea patients diagnosed with polysomnography. RESULTS: Plasma total antioxidative capacity was significantly lower (P = 0·012) and total oxidative status was significantly higher (P < 0·001) in the patients compared to the controls demonstrating increased oxidative stress in the patients. Plasma advanced oxidation protein products were significantly higher in the patients than the controls (P = 0·024). Plasma ischaemia-modified albumin levels were not statistically different between the obstructive sleep apnea patients and controls (P = 0·74). CONCLUSIONS: We conclude that high systemic oxidative stress in obstructive sleep apnea is reflected by increased advanced oxidation protein products without causing an increase in ischaemia-modified albumin.

Optic disc and retinal nerve fiber layer parameters as indicators of neurodegenerative brain changes in patients with obstructive sleep apnea syndrome.

PURPOSE: Retina is a unique part of the central nervous system (CNS) for visualizing the processes of axonal and neuronal degeneration. Optical coherence tomography (OCT) allows direct visualization and measurement of retinal nerve fiber layer (RNFL) thickness, macular volume, and optic disc (OD) parameters. One of the disorders associated with atrophy in different brain regions is obstructive sleep apnea syndrome (OSAS). In the present study, we aimed to determine OD and RNFL changes measured by OCT for investigating the progress of neurodegeneration development in OSAS, excluding all the other conditions that can directly affect RNFL thickness and optic nerve parameters. METHODS: Both eyes of 101 patients with OSAS and 20 controls were investigated by OCT. Full-night polysomnography (PSG) and ophthalmologic examination including automated visual field (VF) examination and OCT were performed in all of the patients. RESULTS: According to the OSAS grading, patients were grouped as mild (n=15), moderate (n=27), and severe (n=59). We found significant decrease in RNFL thickness only in the patients with severe OSAS compared with the other groups and decreased macular ganglion cell thickness in the severe OSAS group compared with the control group. VF parameters were significantly worsened in all the OSAS subgroups compared to the control group. We found different data such as normal or increased optic nerve parameters as result of subtle OD edema, which may mask possible peripapillar axonal loss. CONCLUSIONS: We think that evaluation of neurodegeneration in OSAS is not always possible by examining OD and RNFL because there are difficulties due to the confounding issues of cerebral atrophy and OD edema.

Relationship between Structural and Functional Assessment of the Visual System in Mildly Disabled Relapsing-Remitting Multiple Sclerosis Patients.

Studies that explored the anterior visual pathway in the patients with multiple sclerosis (MS) have demonstrated contradictory results about the correlation between structural and functional status of optic nerve and retina. We aimed to investigate the functional and structural findings in our cohort of mildly disabled relapsing-remitting MS patients. A total of 134 eyes (80 eyes of the patients with MS and 54 eyes of the control group) were investigated. Eyes of MS patients were divided into two groups-as eyes with history of optic neuritis (ON group) and without history of optic neuritis (NON group). Ophthalmological investigation including visual evoked potentials, standard automated perimetry, and optical coherence tomography were performed for all participants. Retinal and macular thicknesses were significantly decreased in ON and NON groups compared with controls. Also, visual evoked potential latencies and visual field loss were worse in the both MS groups compared with control group. We did not find any correlation between visual evoked potentials and retinal or macular thickness values but visual field parameters were correlated between retinal and macular layer loss in the NON group. According to our results and some previous studies, although both functional and structural changes were detected in patients with MS, functional status markers do not always show parallelism (or synchrony) with structural changes, especially in eyes with history of optic neuritis.

Relation between Olfactory Dysfunction and Episodic Verbal Memory in Early Parkinson's Disease.

INTRODUCTION: Olfactory dysfunction is an early and common symptom in idiopathic Parkinson's disease (IPD). Recently, the relation between olfactory dysfunction and cognitive loss in IPD has been reported. In our study, we aimed to investigate the relation between olfactory dysfunction and cognitive impairments in early IPD related with this theory. METHODS: In this study, we included 28 patients with stage 1 and stage 2 IPD according to the Hoehn-Yahr (H-Y) scale and 19 healthy participants. The University of Pennsylvania Smell Identification Test (UPSIT) was performed for evaluating olfactory function. For cognitive investigation in participants, the clock drawing test, Stroop test, verbal fluency test, Benton face recognition test (BFR), Benton line judgment orientation test (BLO), and Auditory Verbal Learning Test (AVLT) were performed. RESULTS: We found significantly lower UPSIT scores in the patient group compared to controls (p=.018). In the neuropsychological investigation, only Stroop test and BLOT test scores were significantly lower in the patient group compared to controls (p=.003, p=.002, respectively). We found a negative correlation between UPSIT scores and Stroop time (p=.033) and Stroop error (p=.037) and a positive correlation between UPSIT scores and SBST long-term memory scores (p=.016) in patients. CONCLUSION: In our study, we found mild cognitive impairment related with visuospatial and executive functions in early-stage IPD compared to controls. But, in the patient group, we detected a different impairment pattern of memory and frontal functions that correlated with hyposmia. This different pattern might be indicating a subgroup of IPD characterized by low performance in episodic verbal memory, with accompanying olfactory dysfunction in the early stage.

Relationship of olfactory function with olfactory bulbus volume, disease duration and Unified Parkinson's disease rating scale scores in patients with early stage of idiopathic Parkinson's disease.

We aimed to investigate the relationship between olfactory function and olfactory bulbus (OB) volume, disease duration and Unified Parkinson's disease rating scale (UPDRS) scores in early stage idiopathic Parkinson's disease patients. The University of Pennsylvania Smell Identification Test (UPSIT) was used for the evaluation of olfactory function. UPSIT scores for patients with Parkinson's disease were significantly lower than controls. There was no significant difference between stage 1 and stage 2 patients. OB volumes were higher in stage 1 and 2 patients than controls, but there was no statistical difference between the three groups. No significant correlation was found between UPSIT and UPDRS total scores, nor between UPSIT scores and disease duration in stage 1 and 2 patients. According to our results, we propose UPSIT be used as a screening test to diagnose presymptomatic patients, but not OB volumes.

Ultrasound elastographic evaluation in the diagnosis of carpal tunnel syndrome: initial findings.

The purpose of this study was to investigate ultrasound (US)- and US elastography-detected changes in the median nerve of patients with carpal tunnel syndrome (CTS). Seventy-four wrists of 41 female patients with CTS (mean age, 47.73 ± 11.45 y) and 45 wrists of 24 asymptomatic female controls (mean age, 42.83 ± 10.66 y) were examined with US and US elastography. Electromyography results confirmed the diagnosis of CTS in the patients. The mean median nerve perimeter (MN-P = 15.26 ± 2.18 mm) and median nerve cross-sectional area (MN-CSA = 11.81 ± 4.05 mm²) of patients with CTS were higher than those of controls (12.08 ± 1.54 mm and 7.76 ± 1.40 mm², respectively) (p < 0.05). Mean tissue strain was lower in the patients with CTS (0.094 ± 0.045 than in the controls (0.145 ± 0.068) (p < 0.05). The most sensitive cut-off value for tissue strain was 0.0635, and the most specific was 0.19. US and US elastography, in addition to electromyography, proved to be beneficial in the diagnosis of CTS. US elastography is a new technique that may well find a place in the diagnosis of nerve entrapment syndromes.

Low serum copeptin levels in patients with obstructive sleep apnea.

PURPOSE: Copeptin, the C-terminal fragment of antidiuretic hormone (ADH), is a new biomarker that has been found to be elevated in several cardiovascular disorders and is related with prognosis. Patients with obstructive sleep apnea demonstrate a tendency to develop coronary and cerebral atherosclerotic disease. Our aim was to investigate copeptin levels in untreated new diagnosed obstructive sleep apnea patients without manifest cardiovascular disorders in order to determine whether copeptin could be used as a biomarker in this group. METHODS: A total of 60 patients with obstructive sleep apnea, diagnosed with polysomnography, and 23 healthy volunteers were enrolled into this study. Blood samples were collected after overnight fasting, and copeptin level was measured with an enzyme immunoassay method. RESULTS: Patients with obstructive sleep apnea had a higher incidence of hypertension and body mass index but lower serum copeptin level (0.48 ± 0.24. vs. 0.64 ± 0.28 ng/ml, p = 0.007) compared with the healthy controls. There was no significant difference regarding to serum copeptin levels between the moderate (n = 13) and severe (n = 47) obstructive sleep apnea patients (0.42 ± 0.18 vs. 0.49 ± 0.26 ng/ml, p = 0.409). CONCLUSIONS: Rather than reflecting a reduced risk for cardiovascular disorders, we consider that reduced copeptin level is related with disturbed ADH secretion in obstructive sleep apnea patients. Therefore, it would not be advisable to measure copeptin levels in obstructive sleep apnea patients to determine cardiovascular risk, while this marker could be valuable to demonstrate impairment in ADH regulation in this patient group.

Optical Coherence Tomography in Patients with Relapsing-Remitting Multiple Sclerosis without Optic Neuritis: A 20-Month Longitudinal Study.

Optical coherence tomography is supported and used as a technique for visualisation of neuro-axonal loss in multiple sclerosis, but there are also a few studies expressing the opposite view. The aim of our study was to investigate retinal nerve fibre layer and optic nerve head parameters in patients with multiple sclerosis without a history of prior optic neuritis and symptoms of a new clinical attack during the follow-up for a total of 20-month period. Full ophthalmic evaluation was performed for all of the participants. The baseline retinal nerve fibre layer and macular thicknesses and focal and global loss of macular volume values were significantly lower in the eyes of the patients with multiple sclerosis compared with the healthy controls. No significant change between baseline and follow-up scans were found in all optical coherence tomography parameters in the multiple sclerosis group. Statistical analyses revealed significant retinal nerve fibre layer and macular thickness differences between baseline and second measurements in the controls. No significant difference in percent change between baseline and second measurements was observed between the patient and control groups. We conclude that whereas healthy subjects have an age-related tendency toward a decrease in retinal nerve fibre layer thickness, patients with multiple sclerosis patients are likely to pass through different stages of retinal thinning and thickening due to subclinical optic neuritis and, as a result, we could not detect any statistically significant change between baseline and second measurements in our multiple sclerosis patients.