Autonomic nervous system education in Europe: EAN/EFAS/INUS survey on curricula and skills in autonomic medicine of European neurology residents and consultants.

BACKGROUND AND PURPOSE: Centers for training in autonomic nervous system (ANS) disorders are not widely available and the recent coronavirus 2019 pandemic temporarily reduced training opportunities in autonomic medicine across European countries. Here we evaluated the current state of education, clinical skills and postgraduate educational preferences on ANS disorders of European neurology residents and consultants. METHODS: A 23-item questionnaire was developed and distributed online amongst European neurology residents and consultants via mailing lists of the European Academy of Neurology. The questions assessed demographics, current training opportunities and learning preferences in ANS disorders. Six multiple-choice questions were used to self-evaluate knowledge of ANS disorders. RESULTS: In all, 285 individuals answered the survey (60% female, mostly 25-34 years of age). All respondents considered clinical autonomic skills necessary for good clinical neurological practice, and 92% would like to increase their ANS knowledge. Female respondents and those who trained in Southern/Eastern/Greater Europe more frequently judged ANS skills important for clinical practice than male respondents (p = 0.012) and respondents from Northern/Western Europe (p = 0.011). Female and younger respondents felt less confident in managing ANS disorders (p = 0.001 and p < 0.001, respectively). Respondents below 45 years of age (p < 0.001) and those with lower confidence in managing ANS disorders (p = 0.004) were more likely to recommend that ANS education is embedded in the residency curriculum. CONCLUSIONS: Most European neurology residents and consultants reported a need for more autonomic education, with additional gender, age and regional differences. These findings underscore the importance of increasing the educational content on autonomic medicine in European medical and postgraduate curricula.

Agrypnia excitata: a human model to explore the derailment of sleep-wake cycle integrated control.

The commemoration of the 70th anniversary of rapid eye movement sleep discovery offers a unique possibility to reassess the peculiar organic condition of agrypnia excitata. Agrypnia excitata is characterized by a severe loss of sleep leading to a complete derangement of physiological sleep-wake cycle and body homeostasis. Agrypnia excitata is a definite clinico-neurophysiological condition characterized by: (1) slow-wave sleep loss with disruption of sleepwake cycle; (2) a 24-hr motor and autonomic overactivity; and (3) peculiar episodes of oneiric stupor. Agrypnia excitata may happen within different pathophysiologies, such as delirium tremens, Morvan's syndrome and fatal familial insomnia, suggesting some general reflections on the composition and function of the cerebral neuronal network generating wake and sleep behaviour and regulating body homeostasis, with a focus on rapid eye movement sleep.

Intrasubject reproducibility of supine norepinephrine plasma concentrations in patients with cardiovascular sympathetic failure.

BACKGROUND: Plasma levels of the catecholamine norepinephrine (NE) has emerged as a useful tool to help differentiate pre- and post-ganglionic disorders in patients with cardiovascular autonomic failure (AF). However, data on intrasubject reliability in individuals with these conditions are limited. We evaluated the intrasubject reproducibility of supine plasma NE levels drawn across two consecutive time points under controlled conditions during head-up table testing in a large cohort of patients with alpha-synucleinopathies and both pre- and post-ganglionic cardiovascular AF. METHODS: Antecubital venous blood drawn via an indwelling cannula with the subject supine was assayed for plasma level of catecholamines. We collected two consecutive samples, the first after 20 min of supine rest (NE1) and the second 5 min later (NE2), from a group of 279 participants including 57 with Parkinson's disease/Lewy body dementia (44 M; 65.5 ± 11.1 y), 131 with multiple system atrophy (81 M; 63.2 ± 8.5 y), 41 with pure autonomic failure (25 M, 65.1 ± 9.3 y), and 50 healthy controls (27 M; 46.7 ± 19.4 y). RESULTS: We found no difference between NE1 and NE2 (p = 0.645), with a mean intrasubject reproducibility (NE maximum - NE minimum) × 100 / NE maximum) of 11.5 % ± 10.64. This finding was confirmed when controlling for diagnosis (p = 0.669), gender (p = 0.493), age (p = 0.865), disease duration (p = 0.596) or considering all factors together (p = 0.527). CONCLUSIONS: We found excellent test-retest reliability of consecutive supine NE measurements in patients with alpha-synucleinopathies and cardiovascular AF, independent of age, gender and disease duration. This lends evidence to support the use of a single supine NE measurement in these conditions.

How Accurate Is Frameless Fiducial-Free Deep Brain Stimulation?

BACKGROUND AND OBJECTIVES: Frameless deep brain stimulation (DBS) offers advantages in terms of patient comfort and reduced operative time. However, the need for bony fiducial markers for localization remains a drawback due to the time-consuming and uncomfortable procedure. An alternative localization method involves the direct tracking of an intraoperative 3-dimensional scanner. This study aims to assess the accuracy of the NexFrame frameless DBS system in conjunction with the O-Arm (Medtronic Inc.), both with and without fiducial markers. METHODS: The locations of 100 DBS leads were determined, with 50 cases using fiducial-free localization and 50 involving fiducial markers. The coordinates were compared with the expected intraoperative targets. Absolute errors in the X, Y, and Z coordinates (ΔX, ΔY, and ΔZ) were calculated, along with the vector error (Euclidean) (vector error ). RESULTS: The vector error averaged 1.61 ± 0.49 mm (right) and 1.52 ± 0.60 mm (left) for the group without fiducial bone markers and 1.66 ± 0.69 (right) and 1.44 ± 0.65 mm (left) for the other cohort (P = .76 right; P = .67 left). Absolute errors in the X, Y, and Z coordinates for the fiducial-free group were 0.88 ± 0.55, 0.79 ± 0.45, and 0.79 ± 0.57 mm (right) and 0.72 ± 0.37, 0.78 ± 0.56, and 0.77 ± 0.71 mm (left). For the group with fiducial markers, these errors were 0.87 ± 0.72, 0.92 ± 0.39, and 0.86 ± 0.50 mm (right) and 0.75 ± 0.33, 0.80 ± 0.51, and 0.73 ± 0.64 mm (left) with no statistically significant difference. CONCLUSION: Our analysis of the accuracy of NexFrame DBS, both with and without fiducial markers, using an intraoperative navigable cone-beam computed tomography, demonstrates that both techniques provide sufficient and equivalent 3-dimensional accuracy.

Neurotoxic effects of coronavirus: Potential implications in Alzheimer's onset and progression.

The COVID-19, caused by SARS-CoV-2, first affects the respiratory tract but evidence is emerging that the virus, reaching the central nervous system (CNS), can lead to severe neurological disorders. In particular, CoV infection could cause an acceleration of the neurodegenerative process. On the other hand, patients diagnosed with Alzheimer's disease (AD) develop more serious forms of COVID-19 with worse relapses. Therefore, understanding the connection between the two pathologies, AD and infection by coronavirus, could help in the development of new therapeutic approaches to counter them. We used the SH-SY5Y cell line differentiated into neurons, as widely used in studies of AD if supplemented with exogenous fibrillary ß-amyloid (Aß). As a glial counterpart, human microglia (HMC3) and astrocytic (D54MG) cell lines were used to create co-cultures with neurons via transwell systems. In these experimental models, we generated infection with the Human Coronavirus OC43 (HCoV-OC43), a low-risk model of SARS-CoV-2. Our results suggest that the infection by HCoV-OC43 leads to a neurotoxic effect not depending on an already present event of Aß deposition. Indeed, unlike microglia, neurons and even more astrocytes are susceptible to CoV infection and, although the infection does not show a cytotoxic effect in the neurons in the first few days, significant alterations at a biochemical and morphological level have been observed, suggesting that the neurons are reacting to a stressful condition, including the prodromal and neurodegenerative features of AD. Interestingly, the interaction of infected astrocytes with the neurons resulted in the manifestation of signs of neurodegeneration, such as amyloid-beta deposition. By using exogenous fibrillary Aß, as an AD in vitro model, our data suggest that there is an aggravating effect both on the infection itself and on the neurological disease progression. In conclusion, the results of this study suggest a causal interplay between HCoV-OC43 and neurological diseases and demonstrate that the co-presence of different CNS cell populations is the necessary condition to study the pathogenic effects in vitro as a whole.

A method for the synchronization of inertial sensor signals and local field potentials from deep brain stimulation systems.

Objective. Recent innovative neurostimulators allow recording local field potentials (LFPs) while performing motor tasks monitored by wearable sensors. Inertial sensors can provide quantitative measures of motor impairment in people with subthalamic nucleus deep brain stimulation. To the best of our knowledge, there is no validated method to synchronize inertial sensors and neurostimulators without an additional device. This study aims to define a new synchronization method to analyze disease-related brain activity patterns during specific motor tasks and evaluate how LFPs are affected by stimulation and medication.Approach. Fourteen male subjects treated with subthalamic nucleus deep brain stimulation were recruited to perform motor tasks in four different medication and stimulation conditions. In each condition, a synchronization protocol was performed consisting of taps on the implanted neurostimulator, which produces artifacts in the LFPs that a nearby inertial sensor can simultaneously record.Main results. In 64% of the recruited subjects, induced artifacts were detected at least in one condition. Among those subjects, 83% of the recordings could be synchronized offline analyzing LFPs and wearables data. The remaining recordings were synchronized by video analysis.Significance. The proposed synchronization method does not require an external system (e.g., TENS electrodes) and can be easily integrated into clinical practice. The procedure is simple and can be carried out in a short time. A proper and simple synchronization will also be useful to analyze subthalamic neural activity in the presence of specific events (e.g., freezing of gait events) to identify predictive biomarkers.

Structural Variants at the LMNB1 Locus: Deciphering Pathomechanisms in Autosomal Dominant Adult-Onset Demyelinating Leukodystrophy.

OBJECTIVE: We aimed to elucidate the pathogenic mechanisms underlying autosomal dominant adult-onset demyelinating leukodystrophy (ADLD), and to understand the genotype/phenotype correlation of structural variants (SVs) in the LMNB1 locus. BACKGROUND: Since the discovery of 3D genome architectures and topologically associating domains (TADs), new pathomechanisms have been postulated for SVs, regardless of gene dosage changes. ADLD is a rare genetic disease associated with duplications (classical ADLD) or noncoding deletions (atypical ADLD) in the LMNB1 locus. METHODS: High-throughput chromosome conformation capture, RNA sequencing, histopathological analyses of postmortem brain tissues, and clinical and neuroradiological investigations were performed. RESULTS: We collected data from >20 families worldwide carrying SVs in the LMNB1 locus and reported strong clinical variability, even among patients carrying duplications of the entire LMNB1 gene, ranging from classical and atypical ADLD to asymptomatic carriers. We showed that patients with classic ADLD always carried intra-TAD duplications, resulting in a simple gene dose gain. Atypical ADLD was caused by LMNB1 forebrain-specific misexpression due to inter-TAD deletions or duplications. The inter-TAD duplication, which extends centromerically and crosses the 2 TAD boundaries, did not cause ADLD. Our results provide evidence that astrocytes are key players in ADLD pathology. INTERPRETATION: Our study sheds light on the 3D genome and TAD structural changes associated with SVs in the LMNB1 locus, and shows that a duplication encompassing LMNB1 is not sufficient per se to diagnose ADLD, thereby strongly affecting genetic counseling. Our study supports breaking TADs as an emerging pathogenic mechanism that should be considered when studying brain diseases. ANN NEUROL 2024;96:855-870.

Temporal implementation of a regional referral pathway in transthyretin cardiac amyloidosis: Emilia-Romagna experience.

AIMS: Transthyretin cardiac amyloidosis (ATTR-CA) is a rare and progressive cardiomyopathy caused by amyloid fibril deposition in myocardial tissue. Diagnostic challenges have historically hampered timely detection. Recent advances in noninvasive diagnostic techniques have facilitated ATTR-CA diagnosis. We aimed to examine the development of a regional network for the diagnosis and management of ATTR-CA and describe a cohort of patients with ATTR-CA, investigate diagnostic pathways and assess clinical outcomes according to diagnosis periods. METHODS: We performed a survey study analyzing answers from 11 cardiology centers and we conducted a retrospective study including patients with ATTR-CA attending a referral center between 1 January 2012 and 31 December 2022, and categorized by the period of diagnosis (2012-2016 and 2017-2022). RESULTS: Over the years, a growing number of patients reached a diagnosis and were treated in the surveyed nonreferral centers of the region. The retrospective study showed a more significant diagnostic delay in the earlier period rather than the later one [13.4 (5-30.2) vs. 10.6 (5.0-17.9) months, P = 0.04]. Patients diagnosed after 2017 showed a greater survival rate than those diagnosed earlier ( P = 0.02). In the multivariate analysis, the year of diagnosis from 2017 remained independently associated with mortality [hazard ratio (HR) 0.46, 95% confidence interval (CI) 0.28-0.79; P = 0.005]. CONCLUSION: This study emphasized the shift toward noninvasive diagnostic criteria. It revealed a positive impact on patient survival and disease management with the use of disease-modifying therapies and diagnostic developments in more recent years. The findings underscore the importance of disease awareness and networking to reduce diagnostic delays and enhance patient journeys for ATTR-CA.

Patisiran for the treatment of patients with p.Ile88Leu hereditary transthyretin amyloidosis: an Italian real-life experience.

Objectives: Evidence on the activity of patisiran therapy in specific subgroups of patients with hereditary transthyretin amyloidosis variant (ATTRv) is still scarce. This prospective real-world study was designed to provide the first in-depth clinical data on the effectiveness of patisiran in patients with ATTRv reporting the p.Ile88Leu variant, the most widespread variant in the Emilia-Romagna regional area, which has been less represented in previous clinical trials. Patients and methods: This prospective study evaluated all the patients with genetically proven ATTRv (p.Ile88Leu) and polyneuropathy treated with patisiran in the Emilia-Romagna referral centers for ATTRv (Institute of Neurological Sciences in Bologna and Division of Neurology in Rimini) from March 2021 to April 2023. All subjects underwent clinical and neurological evaluations at baseline and after 9-12 months of treatment. Results: A total of 22 patients were included in the study; the median age was 73 years (IQR: 9), the age at diagnosis was 72 years (IQR: 10), and the disease duration was 1.6 years (IQR: 2.3). We observed stability of all considered neurological and cardiological parameters at 9-12 months after the beginning of patisiran treatment. Conclusion: Our findings support the clinical data regarding the effectiveness of patisiran in stabilizing the disease course and extend this activity to the subset of patients with the p.Ile88Leu variant.

Enhancing stroke risk prediction in patients with transient ischemic attack: insights from a prospective cohort study implementing fast-track care.

Background and aims: Fast-track care have been proved to reduce the short-term risk of stroke after transient ischemic attack (TIA). We aimed to investigate stroke risk and to characterize short- and long-term stroke predictors in a large cohort of TIA patients undergoing fast-track management. Methods: Prospective study, enrolling consecutive TIA patients admitted to a Northern Italy emergency department from August 2010 to December 2017. All patients underwent fast-track care within 24 h of admission. The primary outcome was defined as the first stroke recurrence at 90 days, 12 and 60 months after TIA. Stroke incidence with 95% confidence interval (CI) at each timepoint was calculated using Poisson regression. Predictors of stroke recurrence were evaluated with Cox regression analysis. The number needed to treat (NNT) of fast-track care in preventing 90-day stroke recurrence in respect to the estimates based on baseline ABCD2 score was also calculated. Results: We enrolled 1,035 patients (54.2% males). Stroke incidence was low throughout the follow-up with rates of 2.2% [95% CI 1.4-3.3%] at 90 days, 2.9% [95% CI 1.9-4.2%] at 12 months and 7.1% [95% CI 5.4-9.0%] at 60 months. Multiple TIA, speech disturbances and presence of ischemic lesion at neuroimaging predicted stroke recurrence at each timepoint. Male sex and increasing age predicted 90-day and 60-month stroke risk, respectively. Hypertension was associated with higher 12-month and 60-month stroke risk. No specific TIA etiology predicted higher stroke risk throughout the follow-up. The NNT for fast-track care in preventing 90-day stroke was 14.5 [95% CI 11.3-20.4] in the overall cohort and 6.8 [95% CI 4.6-13.5] in patients with baseline ABCD2 of 6 to 7. Conclusion: Our findings support the effectiveness of fast-track care in preventing both short- and long-term stroke recurrence after TIA. Particular effort should be made to identify and monitor patients with baseline predictors of higher stroke risk, which may vary according to follow-up duration.

CAR+ extracellular vesicles predict ICANS in patients with B cell lymphomas treated with CD19-directed CAR T cells.

BACKGROUNDPredicting immune effector cell-associated neurotoxicity syndrome (ICANS) in patients infused with CAR T cells is still a conundrum. This complication, thought to be consequent to CAR T cell activation, arises a few days after infusion, when circulating CAR T cells are scarce and specific CAR T cell-derived biomarkers are lacking.METHODSCAR+ extracellular vesicle (CAR+EV) release was assessed in human CD19.CAR T cells cocultured with CD19+ target cells. A prospective cohort of 100 patients with B cell lymphoma infused with approved CD19.CAR T cell products was assessed for plasma CAR+EVs as biomarkers of in vivo CD19.CAR T cell activation. Human induced pluripotent stem cell-derived (iPSC-derived) neural cells were used as a model for CAR+EV-induced neurotoxicity.RESULTSIn vitro release of CAR+EVs occurs within 1 hour after target engagement. Plasma CAR+EVs are detectable 1 hour after infusion. A concentration greater than 132.8 CAR+EVs/µL at hour +1 or greater than 224.5 CAR+EVs/µL at day +1 predicted ICANS in advance of 4 days, with a sensitivity and a specificity outperforming other ICANS predictors. ENO2+ nanoparticles were released by iPSC-derived neural cells upon CAR+EV exposure and were increased in plasma of patients with ICANS.CONCLUSIONPlasma CAR+EVs are an immediate signal of CD19.CAR T cell activation, are suitable predictors of neurotoxicity, and may be involved in ICANS pathogenesis.TRIAL REGISTRATIONNCT04892433, NCT05807789.FUNDINGLife Science Hub-Advanced Therapies (financed by Health Ministry as part of the National Plan for Complementary Investments to the National Recovery and Resilience Plan [NRRP]: E.3 Innovative health ecosystem for APC fees and immunomonitoring).

Neurological abnormalities in individuals with Marfan syndrome: results from a genetically confirmed Italian cohort.

BACKGROUND AND AIMS: Neurological abnormalities have been frequently reported in individuals with Marfan Syndrome (MFS). However, available data relies solely on retrospective studies predating current diagnostic criteria. METHODS: Cross-sectional study comprehensively investigating neurological abnormalities within a prospective cohort of adults (≥ 18 years) with genetically confirmed MFS referred to an Italian hub center for heritable connective tissue diseases (Jan. 1st - Nov. 15th, 2021). RESULTS: We included a total of 38 individuals (53% female). The commonest neurological symptom was migraine (58%), usually without aura (73%). Neuropsychological testing was generally unremarkable, whilst anxiety and depression were highly prevalent within our cohort (42% and 34%, respectively). The most frequent brain parenchymal abnormality was the presence of cortico-subcortical hypointense spots on brain MRI T2* Gradient-Echo sequences (39%), which were found only in patients with a prior history of aortic surgery. Migraineurs had a higher frequency of brain vessels tortuosity vs. individuals without migraine (73% vs. 31%; p = 0.027) and showed higher average and maximum tortuosity indexes in both anterior and posterior circulation brain vessels (all p < 0.05). At univariate regression analysis, the presence of brain vessels tortuosity was significantly associated with a higher risk of migraine (OR 5.87, CI 95% 1.42-24.11; p = 0.014). CONCLUSIONS: Our study confirms that neurological abnormalities are frequent in individuals with MFS. While migraine appears to be associated with brain vessels tortuosity, brain parenchymal abnormalities are typical of individuals with a prior history of aortic surgery. Larger prospective studies are needed to understand the relationship between parenchymal abnormalities and long-term cognitive outcomes.

Exploring Cardiovascular Autonomic Function before and after Chronic Deep Brain Stimulation in Parkinson's Disease.

BACKGROUND: Blood pressure control in Parkinson's disease (PD) under subthalamic deep brain stimulation (STN-DBS) is influenced by several intertwined aspects, including autonomic failure and levodopa treatment. OBJECTIVE: To evaluate the effect of chronic STN-DBS, levodopa, and their combination on cardiovascular autonomic functions in PD. METHODS: We performed cardiovascular reflex tests (CRTs) before and 6-months after STN-DBS surgery in 20 PD patients (pre-DBS vs. post-DBS). CRTs were executed without and with medication (med-OFF vs. med-ON). RESULTS: CRT results and occurrence of neurogenic orthostatic hypotension (OH) did not differ between pre- and post-DBS studies in med-OFF condition. After levodopa intake, the BP decrease during HUTT was significantly greater compared to med-OFF, both at pre-DBS and post-DBS evaluation. Levodopa-induced OH was documented in 25% and 5% of patients in pre-DBS/med-ON and post-DBS/med-ON study. CONCLUSION: Chronic stimulation did not influence cardiovascular responses, while levodopa exerts a relevant hypotensive effect. The proportion of patients presenting levodopa-induced OH decreases after STN-DBS surgery.

Soccer (football) and brain health.

Soccer is one of the most popular sports worldwide, played by over 270 million people and followed by many more. Several brain health benefits are promoted by practising soccer and physical exercise at large, which helps contrast the cognitive decline associated with ageing by enhancing neurogenesis processes. However, sport-related concussions have been increasingly recognised as a pressing public health concern, not only due to their acute impact but also, more importantly, due to mounting evidence indicating an elevated risk for the development of neurological sequelae following recurrent head traumas, especially chronic traumatic encephalopathy (CTE). While soccer players experience less frequent concussions compared with other contact or combat sports, such as American football or boxing, it stands alone in its purposeful use of the head to hit the ball (headings), setting its players apart as the only athletes exposed to intentional, sub-concussive head impacts. Additionally, an association between soccer and amyotrophic lateral sclerosis has been consistently observed, suggesting a potential "soccer-specific" risk factor. In this review, we discuss the neurological sequelae related to soccer playing, the emerging evidence of a detrimental effect related to recurrent headings, and the need for implementation of comprehensive strategies aimed at preventing and managing the burden of head impact in soccer.

Tacrolimus-associated neurotoxicity isolated to the brainstem: two illustrative cases and a systematic review of the literature.

INTRODUCTION: Tacrolimus-associated neurotoxicity (TAN) manifests with wide clinical spectrum, ranging from mild tremors to severe encephalopathy. The isolated involvement of the brainstem is a rarely documented presentation of TAN, and its clinical and diagnostic characteristics are unclear. METHODS: We report two cases of brainstem-isolated TAN (bi-TAN). Moreover, we performed a systematic review of the literature on bi-TAN and extracted data concerning demographics, clinical characteristics, radiological features, and management. The systematic literature search followed PRISMA guidelines and a pre-defined protocol. RESULTS: Eleven patients, including our two, were identified (mean age: 41.3 years, ± 18.8; five males, 45%). Speech disturbance was the most common clinical presentation (45%). The mean latency from Tacrolimus initiation to bi-TAN onset was 26 days (± 30.8). Tacrolimus serum level tested above the reference range in three patients (mean: 26.83 ± 5.48). Brain MRI showed T2-FLAIR hyperintensities; three showed restricted diffusion on ADC maps. Neurological symptoms resolved completely in seven patients (63%) after Tacrolimus withdrawal or dose reduction. CONCLUSIONS: Our findings suggest that bi-TAN could represent a brainstem variant of posterior reversible encephalopathy syndrome. Recognition of bi-TAN as a potential cause of isolated brainstem lesions is crucial to disentangle the diagnostic work-up and ensure prompt withdrawal or reduction of the offending agent.

Spontaneous Intracranial Hypotension and Subdural Hematomas Treatment Management Using MMA Embolization and Target Blood Patch: A Case Report.

We report a patient suffering from spontaneous intracranial hypotension (SIH) who, following a non-selective lumbar blood patch, returned to his healthcare provider with severe symptoms of neurological deficits. It was subsequently discovered that the aforementioned deficits were due to a bilateral subdural hematoma, and an emergency surgical drainage of the hematoma has been performed. However, the hematoma reformed and potential cerebrospinal fluid leakage was consequently investigated through myelography. Following the diagnostic finding of a venous diverticulum, a selective blood patch was executed in the affected area, and in order to stabilize the hematoma, an embolization of the middle meningeal arteries was performed. The combination of such operations allowed for the resorption of the hematoma and the improvement of neurological symptoms.

The Degree of Cardiovascular Autonomic Dysfunction is not Different in GBA-Related and Idiopathic Parkinson's Disease Patients: A Case-Control Instrumental Evaluation.

Background: Increased prevalence of cardiovascular autonomic failure might play a key role on Parkinson's disease (PD) progression of glucocerebrosidase gene (GBA)-mutated patients, determining a malignant phenotype of disease in these patients. Objective: To objectively characterize, for the first time, the cardiovascular autonomic profile of GBA-mutated patients compared to idiopathic PD patients by means of cardiovascular reflex tests (CRTs). Methods: This is a case-control (1 : 2) study on PD patients belonging to well-characterized prospective cohorts. For each PD patient carrying GBA variants, two idiopathic PD patients, matched for sex and disease duration at CRTs, were selected. Patients recruited in these cohorts underwent a complete clinical and instrumental evaluation including specific autonomic questionnaires, CRTs and extensive genetic analysis. Results: A total of 23 GBA-PD patients (19 males, disease duration 7.7 years) were included and matched with 46 non-mutated PD controls. GBA-mutated patients were younger than controls (59.9±8.1 vs. 64.3±7.2 years, p = 0.0257) and showed a more severe phenotype. Despite GBA-mutated patients reported more frequently symptoms suggestive of orthostatic hypotension (OH) than non-mutated patients (39.1% vs 6.5%, p = 0.001), the degree of cardiovascular autonomic dysfunction, when instrumentally assessed, did not differ between the two groups, showing the same prevalence of neurogenic OH, delayed OH and cardiovascular reflex impairment (pathological Valsalva maneuver). Conclusion: GBA-PD patients did not show different instrumental cardiovascular autonomic pattern than non-mutated PD. Our findings suggested that symptoms suggestive of OH should be promptly investigated by clinicians to confirm their nature and improve patient care and management.

Migraine chronification as an allostatic disorder: a proof-of-concept study.

OBJECTIVE: The underpinning biologics of migraine chronification are not well understood. We aim to investigate the role of the cumulative burden of stress, namely the allostatic load, in migraine chronification. METHODS: This was a cross-sectional study. The allostatic load was measured with a composite multi-system score (BALI: Bologna Allostatic Load Index), evaluating 20 biomarkers representing four physiological systems: immune, metabolic, cardiovascular, and neuroendocrinological systems. BALI score was subdivided into high score and low score based on the distribution in controls. Migraine patients were included and subclassified into low-frequency episodic migraine group (low-EM group), high-frequency episodic migraine group (high-EM group), and chronic migraine group (CM group). RESULTS: The distribution of BALI high-score increased in parallel with headache attacks monthly frequency: 16% in low-EM group (n = 10), 24% in high-EM group (n = 12), and 40% in CM group (n = 21) (p = 0.017). In a multivariable analysis, the odds ratio of having a high-score BALI in CM patients (vs. low-EM patients) was 2.78 (95% CI 1.07-7.22; p = 0.036). Individual BALI biomarkers values which were significantly different among migraine subgroups included systolic blood pressure (p = 0.018), diastolic blood pressure (p < 0.001), and heart rate (p = 0.019). CONCLUSION: Our study substantiates this emerging concept of migraine chronification as an allostatic disorder.

Characterization and natural history of different phenotypes in hereditary transthyretin amyloidosis: 40-year experience at a single Italian referral centre.

AIMS: Hereditary transthyretin amyloidosis (ATTRv) is one of the leading aetiologies of systemic amyloidosis with more than 135 mutations described and a broad spectrum of clinical manifestations. We aimed to provide a systematic description of a population of individuals carrying pathogenic mutations of transthyretin (TTR) gene and to investigate the major clinical events during follow-up. METHODS AND RESULTS: This was an observational, retrospective, cohort study including consecutive patients with mutations of TTR gene, admitted to a tertiary referral centre in Bologna, Italy, between 1984 and 2022. Three hundred twenty-five patients were included: 106 asymptomatic carriers, 49 cardiac phenotype, 49 neurological phenotype, and 121 mixed phenotype. Twenty-two different mutations were found, with Ile68Leu (41.8%), Val30Met (19%), and Glu89Gln (10%) being the most common. After a median follow-up of 51 months, 111 patients (38.3%) died and 9 (11.5%) of the 78 asymptomatic carriers developed ATTRv. Carriers had a prognosis comparable with healthy population, while no significant differences were seen among the three phenotypes adjusted by age. Age at diagnosis, New York Heart Association class III, left ventricular ejection fraction, modified polyneuropathy disability score IV, and disease-modifying therapy were independently associated with survival. CONCLUSION: This study offers a wide and comprehensive overview of ATTRv from the point of view of a tertiary referral centre in Italy. Three main phenotypes can be identified (cardiac, neurological, and mixed) with specific clinical and instrumental features. Family screening programmes are essential to identify paucisymptomatic affected patients or unaffected carriers of the mutation, to be followed through the years. Lastly, disease-modifying therapy represents an evolving cornerstone of the management of ATTRv, with a great impact on mortality.

A total of 325 consecutive patients harbouring a pathogenic mutation in the TTR gene, admitted to a tertiary referral centre in Bologna, Italy, between 1984 and 2022, were included in the study.These patients exhibited significant clinical diversity: 106 were asymptomatic carriers, 49 presented with a cardiac phenotype, 49 had a neurological phenotype, and 121 had a mixed phenotype.Asymptomatic carriers demonstrated a prognosis comparable with healthy population, but some of them may develop signs and symptoms of the disease during follow-up.Survival curves adjusted by age are similar among the three phenotypes.Age at diagnosis, New York Heart Association class, modified polyneuropathy disability score, left ventricular ejection fraction, and disease-modifying therapy were identified as independent factors associated with prognosis.