Neurodegeneration in Parkinson’s disease (PD) is accompanied by a local immune reaction in the affected brain regions. It is well established that α‐synuclein is directly implicated in the ...pathogenesis of PD. Development of the disease is often associated with changes of expression and cellular compartmentalisation of this protein; moreover, its oligomers or protofibrils are often released to the CSF and plasma of patients. Aggregated α‐synuclein can trigger the activation of microglia; however, its capacity to induce production of specific autoantibodies (AAb) has not been assessed. In this study, we examined the presence of AAb against synuclein family members in the peripheral blood serum of PD patients and control individuals. Presence of AAb against β‐synuclein or γ‐synuclein showed no association with PD. Multi‐epitopic AAb against α‐synuclein were detected in 65% of all patients tested and their presence strongly correlated with an inherited mode of the disease but not with other disease‐related factors. The frequency of the presence of AAb in the studied group of patients with sporadic form of PD was not significantly different from the frequency in the control group but very high proportion (90%) of patients with familial form of the disease were positive for AAb against α‐synuclein. We hypothesise that these AAb could be involved in pathogenesis of the inherited form of PD.
Abstract
The advent of next generation sequencing has revolutionized diagnostic approaches to hereditary polyneuropathies. Recently, mutations on the membrane metallo-endopeptidase (MME) gene, ...encoding neprilysin, have been related to the development of late-onset Charcot-Marie-Tooth disease type 2 (CMT2). Here, we report the first Greek patient presenting with a slowly progressive late-onset axonal polyneuropathy and a novel, likely pathogenic, heterozygous variant in the MME gene. In addition, we have performed a systematic review of all published case reports of patients with MME mutations. The results of the studies show that MME variants can be inherited as both fully penetrant autosomal-recessive and incompletely penetrant autosomal-dominant traits. A number of heterozygous variants characterized as incompletely penetrant impose an increased risk of developing a CMT2-like phenotype late in life, identical to the case study described here. Greater mutation numbers in different populations and mutation-specific functional studies will be essential to identify the pathogenicity and inheritance of more MME variants.
Parkinson’s disease (PD) is a neurodegenerative disease, mostly presenting with characteristic motor symptoms. Organochlorines (OC) are a class of widely-used pesticides that have been included among ...the list of environmental factors incriminated in PD pathogenesis. However, most studies reporting this association are based on questionnaires, and few have reported exposure data.
To examine the relationship between OC blood concentrations and PD risk.
In the present study, we studied the concentrations of 8 OC compounds (hexachlorobenzene, heptachlor, hepachlor epoxide, c-chlordane, a-chlordane, p,p’-DDE, DDD, DDT) in 104 Greek PD patients and 110 healthy controls.
All substances studied were present in at least one sample. The most frequently detected (above the level of quantification) pesticides were p,p’-DDE (n = 214, 100 % of both groups) and hexachlorobenzene, HCB (n = 189, cases 46.5 %, controls 53.5 %). Higher levels of DDE were detected among PD patients in comparison to controls by using logistic regression analysis to control for confounders Odds Ratio, OR (95 % confidence interval, C.I.): 2.592,(1.29–5.21), whilst lower levels of HCB were detect among PD patients OR,95 %CI:0.176(0.09−0.35).
Our data suggest that exposure to specific OCs is related to the risk of PD. Further studies, using real exposure data, are needed in order to confirm and extend these findings.
The Greek Society of Migraine and Headache Patients conducted its third in-line population web-based survey in 2023 to ascertain if the burden of the disease and the patients' satisfaction with ...conventional and novel migraine therapies are changing compared to our previous findings from 2018 and 2020.
The sampling process was based on a random call to participants to reply to a specific migraine-focused self-administered questionnaire, including 83 questions in Greek, which was distributed nationwide through the online research software SurveyMonkey.
We eventually enrolled 2565 patients, the majority of which were females. Our findings clearly demonstrate that migraine is still a burdensome condition. The degree of its impact on all aspects of productivity depends on the monthly frequency of migraine and the response rates to acute and prophylactic treatments. A total of 1029 (42.4%) of the patients had visited the emergency room mainly for unresponsiveness to acute treatments or aura-related symptoms. Triptans seem to be partly effective as acute therapies. OnabotulinumtoxinA seems to be effective for almost half of chronic migraine patients (43.9%) to report adequate satisfaction with this treatment (27.8% were "fairly happy", 10.6% were "very happy", and 5.5% were "extremely happy"). Due to their high rates of preventative effectiveness, most respondents treated with anti-CGRP Mabs expressed their optimism concerning their future while living with their migraine (88.25%), as well as towards further improvements in their quality of life (82.8%) status, mostly with fremanezumab.
The patients recognize the usefulness of anti-CGRP Mabs in migraine prevention and consequently seem to be more optimistic than before about living with migraine. Considering the market change that is anticipated with the use of gepants and ditans, larger longitudinal population-based studies are warranted to further explore if the new era of migraine therapeutics might further lessen the burden of the disease.
this post hoc analysis aimed to evaluate the efficacy of fremanezumab in difficult-to-treat chronic migraine (CM) patients with and without psychiatric comorbidities (PCs), mainly anxiety and/or ...depression.
We assessed data from CM patients with and without PCs who failed at least 3 preventives and eventually received at least 3 consecutive monthly doses of fremanezumab 225 mg. Outcomes included the crude response (≥50% reduction in monthly headache days (MHDs)) rates to fremanezumab from the baseline to the last clinical follow-up. The changes in MHDs; MHDs of moderate/greater severity; monthly days with intake of abortive medication; and the proportion of patients' changing status from with PCs to decreased/without PCs were also compared. Disability and quality of life (QOL) outcomes were also assessed.
Of 107 patients enrolled, 65 (60.7%) had baseline PCs. The percentage of patients with (
= 38/65; 58.5%) and without (
= 28/42; 66.6%) PCs that achieved a ≥50% reduction in MHDs with fremanezumab was comparable (
= 0.41), whereas MHDs were significantly reduced (difference vs. baseline) in both patients with PCs (mean -8.9 (standard error: 6.8);
< 0.001) and without PCs (-9.8 (7.5);
< 0.001). Both groups experienced significant improvements in all other efficacy, disability, and QOL outcomes at comparable rates, including in MHD reduction. A significant proportion of fremanezumab-treated patients with baseline PCs de-escalated in corresponding severities or even reverted to no PCs (28/65; 43.1%) post-fremanezumab.
fremanezumab appears to be effective as a preventive treatment in difficult-to-treat CM patients with and without PCs while also being beneficial in reducing the severity of comorbid anxiety and/or depression.
To investigate whether the incidence of triggers, prodromal symptoms, hypersensitivity symptoms accompanying headache and responses to triptans were modified during a continuous 9-month fremanezumab ...therapy for migraine prophylaxis.
We studied 63 patients with high-frequency episodic migraine (HFEM). Enrolled patients received fremanezumab for nine consecutive months before defining the response rates and being stratified into treatment responders (≥50-74% reduction in monthly headache days (MHDs)), super responders (≥75%), partial non-responders (<50%) and super non-responders (<30%). Through headache diaries, patients provided data in order to document the impact of fremanezumab on the incidence of triggers, associated symptoms followed by headache and response to triptans (the use of the migraine treatment optimization questionnaire-4 (mTOQ-4)) during the 9-month treatment period.
Fremanezumab had early (after 3 monthly cycles) beneficial effects on the response to triptans in the majority of responders with relevant increases in mTOQ-4 scoring, but also in half of partial non-responders. A significant reduction in median days with migraine-associated symptoms was seen in responders after 6 months of therapy with fremanezumab, mostly for osmophobia, photophobia, phonophobia and nausea/vomiting, but partial non-responders also benefited. Likewise, the incidence of self-reported prodromal symptoms was significantly reduced in responders and was modestly diminished in partial non-responders. Triggers remained unaffected in both responders and non-responders.
Fremanezumab given for at least 6-9 months may exert neuromodulatory effects in the migraine brain. These effects could result both in the inhibition of migraine chronification, but also in the diminishing of the magnitude of migraine-associated symptoms, mostly in responders and in partial non-responders.
Rare diseases (RDs) are life-threatening or chronically impairing conditions that affect about 6% of the world's population. RDs are often called 'orphan' diseases, since people suffering from them ...attract little support from national health systems.
The aim of this study is to describe the clinical characteristics of, and the available laboratory examinations for, patients who were hospitalized in a tertiary referral center and finally received a diagnosis associated with a Rare Neurological Disease (RND).
Patients that were hospitalized in our clinic from 1 January 2014 to 31 March 2022 and were finally diagnosed with an RND were consecutively included. The RND classification was performed according to the ORPHAcode system.
A total of 342 out of 11.850 (2.9%) adult patients admitted to our department during this period received a diagnosis associated with an RND. The most common diagnosis (N = 80, 23%) involved an RND presenting with dementia, followed by a motor neuron disease spectrum disorder (N = 64, 18.7%). Family history indicative of an RND was present in only 21 patients (6.1%). Fifty-five (16%) people had previously been misdiagnosed with another neurological condition. The mean time delay between disease onset and diagnosis was 4.24 ± 0.41 years.
Our data indicate that a broad spectrum of RNDs may reach a tertiary Neurological Center after a significant delay. Moreover, our data underline the need for a network of reference centers, both at a national and international level, expected to support research on the diagnosis and treatment of RND.
Autosomal recessive hereditary spastic paraplegia (HSP) due to AP4M1 mutations is a very rare neurodevelopmental disorder reported for only a few patients.
We investigated a Greek HSP family using ...whole exome sequencing (WES).
A novel AP4M1A frameshift insertion, and a very rare missense variant were identified in all three affected siblings in the compound heterozygous state (p.V174fs and p.C319R); the unaffected parents were carriers of only one variant. Patients were affected with a combination of: (a) febrile seizures with onset in the first year of life (followed by epileptic non-febrile seizures); (b) distinctive facial appearance (e.g., coarse features, bulbous nose and hypomimia); (c) developmental delay and intellectual disability; (d) early-onset spastic weakness of the lower limbs; and (e) cerebellar hypoplasia/atrophy on brain MRI.
We review genotype-phenotype correlations and discuss clinical overlaps between different AP4-related diseases. The AP4M1 belongs to a complex that mediates vesicle trafficking of glutamate receptors, being likely involved in brain development and neurotransmission.
Several studies have investigated the association of the Parkinson's disease (PD) polygenic risk score (PRS) with several aspects of well-established PD. We sought to evaluate the association of PRS ...with the prodromal stage of PD. We calculated PRS in a longitudinal sample (
= 1120) of community dwelling individuals ≥ 65 years from the HELIAD (The Hellenic Longitudinal Investigation of Aging and Diet) study in order to evaluate the association of this score with the probability of prodromal PD or any of the established risk and prodromal markers in MDS research criteria, using regression multi-adjusted models. Increases in PRS estimated from GWAS summary statistics' ninety top SNPS with
< 5 × 10
was associated with increased odds of having probable/possible prodromal PD (i.e., ≥ 30% probability, OR = 1.033, 95%CI: 1.009-1.057
= 0.006). From the prodromal PD risk markers, significant association was found between PRS and global cognitive deficit exclusively (
= 0.003). To our knowledge, our study is the first population based study investigating the association between PRS scores and prodromal markers of Parkinson's disease. Our results suggest a strong relationship between the accumulation of many common genetic variants, as measured by PRS, and cognitive deficits.
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