HUNTINGTON’S DISEASE: GENETIC MODIFIERS OF AGE AT ONSET AND PATHOLOGICAL BIOMARKERS

Huntington’s disease (HD) is an autosomal dominant neurodegenerative disease, clinically characterized by movement disorders, cognitive deficits, and psychiatric problems. HD is caused by the expansion of a CAG repeat within exon 1 of IT15 gene. HD exhibits the typical phenomenon of genetic anticipation and the symptoms of the disease appear earlier and more severe in subsequent generations due to meiotic instability. The onset of HD is conventionally defined as motor onset although cognitive and psychiatric impairments may precede choreic movements or other movements disorders. The relationship between CAG repeats number and motor onset is well-known in HD; little is reported about the correlations between CAG repeats and non-motor onset. In the first part of this PhD thesis, we aimed to investigate the dependence of motor, cognitive and psychiatric onsets from expanded CAG repeat length and to study the correlation among these several modalities of clinical debut in a cohort of 188 patients with HD. We found that psychiatric and motor problems often represented the first symptoms of the disease, alone or in combination. The isolate cognitive onset was very rare. Lower but always consistent correlations were present between psychiatric onset and motor onset and between cognitive onset and psychiatric onset. Among the different psychiatric symptoms, Perseverative/Obsessive Behaviour and Apathy showed considerable positive correlation levels with motor and cognitive onsets. We evidenced that cognitive onset can depend from CAG repeats in IT15 pathological allele: in our cohort, the length accounts for the 54% of variability in age at cognitive onset. The CAG repeat accounts only for approximately 56%-70% of the variation in age at onset in HD. It is therefore possible to imagine that modifier genetic variations, that segregate independently from the primary mutation, could influence the age at onset. In the second part of this PhD thesis, we decided to study seven SCAs genes (ATXN1, ATXN2, ATXN3, CACNA1A, ATXN7, PPP2R2B, and TBP) as modifiers of age at onset in HD due to genetic, pathological, and clinical similarities between HD and SCAs. Our study did not find extensive correlations between CAG repeats in SCA genes and age at onset of HD. The only exceptions are represented by ATXN2 and CACNA1 for age at motor onset, and ATXN2 for age at psychiatric onset. When a multiple regression model was formulated and when the age at motor onset was considered, a small additional effect was identified only for CACNA1A. CAG repeats in expanded IT15 and larger CACNA1A alleles account for 64% of age at motor onset in HD patients. In the last part of this PhD thesis, we designed a clinical study to measure the expression levels of MAP1LC3, SQSTM1 and WDFY3 in 20 patients with HD, and to compare these levels with those found in healthy controls and patients suffering from SCA 2 (spino-cerebellar ataxia type 2), another polyglutamine repeat disorder. MAP1LC3, SQSTM1 and WDFY3 genes seem to have a critical role in aggrephagy and aggrephagy levels are reported pathologically increased in HD patients. We measured expression levels in peripheral blood mononuclear cells as they represent an easily accessible and repeatable matrix for clinical use such as clinical trials or observational studies. MAP1LC3B, SQSTM1, and WDFY3 were all increased in HD patients, suggesting a profound and intense induction in autophagy, aimed at counteracting the formation of protein aggregates. In contrast, SCA2 patients had a more modest modification with higher expression levels of WDFY3 alone

Complex phenotype in an Italian family with a novel mutation in SPG3A.

Mutations in the SPG3A gene represent a significant cause of autosomal dominant hereditary spastic paraplegia with early onset and pure phenotype. We describe an Italian family manifesting a complex phenotype, characterized by cerebellar involvement in the proband and amyotrophic lateral sclerosis-like syndrome in her father, in association with a new mutation in SPG3A. Our findings further widen the notion of clinical heterogeneity in SPG3A mutations

Cervical dystonia patients display subclinical gait changes

Gait disorders in cervical dystonia (CD) are reported in patients under DBS or in severe cases complicated with spinal deformities

Benign hereditary chorea: clinical and neuroimaging features in an Italian family.

Abstract: Benign hereditary chorea is an autosomal domi- nant disorder characterized by early onset nonprogressive chorea, caused by mutations of the thyroid transcription factor-1 (TITF-1) gene. Clinical heterogeneity has been reported and thyroid and respiratory abnormalities may be present. We describe 3 patients of an Italian family carrying the S145X mutation in the TITF-1 gene with mild motor delay, childhood onset dyskinesias, and subtle cognitive impairment. A child in the third generation pre- sented with congenital hypothyroidism and neonatal respi- ratory distress. Imaging studies in 2 patients showed mild ventricular enlargement and empty sella at magnetic reso- nance imaging and hypometabolism of basal ganglia and cortex at 18-Fluoro-2-deoxy-glucose positron emission tomography

The Effects of Temperature Management on Brain Microcirculation, Oxygenation and Metabolism

Purpose: Target temperature management (TTM) is often used in patients after cardiac arrest, but the effects of cooling on cerebral microcirculation, oxygenation and metabolism are poorly understood. We studied the time course of these variables in a healthy swine model.Methods: Fifteen invasively monitored, mechanically ventilated pigs were allocated to sham procedure (normothermia, NT; n = 5), cooling (hypothermia, HT, n = 5) or cooling with controlled oxygenation (HT-Oxy, n = 5). Cooling was induced by cold intravenous saline infusion, ice packs and nasal cooling to achieve a body temperature of 33-35 degrees C. After 6 h, animals were rewarmed to baseline temperature (within 5 h). The cerebral microvascular network was evaluated (at baseline and 2, 7 and 12 h thereafter) using sidestream dark-field (SDF) video-microscopy. Cerebral blood flow (laser Doppler MNP100XP, Oxyflow, Oxford Optronix, Oxford, UK), oxygenation (PbtO(2), Licox catheter, Integra Lifesciences, USA) and lactate/pyruvate ratio (LPR) using brain microdialysis (CMA, Stockholm, Sweden) were measured hourly. Results: In HT animals, cerebral functional capillary density (FCD) and proportion of small-perfused vessels (PSPV) significantly decreased over time during the cooling phase; concomitantly, PbtO(2) increased and LPR decreased. After rewarming, all microcirculatory variables returned to normal values, except LPR, which increased during the rewarming phase in the two groups subjected to HT when compared to the group maintained at normothermia. Conclusions: In healthy animals, TTM can be associated with alterations in cerebral microcirculation during cooling and altered metabolism at rewarming

Outcome Prediction in Patients with Severe COVID-19 Requiring Extracorporeal Membrane Oxygenation—A Retrospective International Multicenter Study

The role of veno-venous extracorporeal membrane oxygenation therapy (V-V ECMO) in severe COVID-19 acute respiratory distress syndrome (ARDS) is still under debate and conclusive data from large cohorts are scarce. Furthermore, criteria for the selection of patients that benefit most from this highly invasive and resource-demanding therapy are yet to be defined. In this study, we assess survival in an international multicenter cohort of COVID-19 patients treated with V-V ECMO and evaluate the performance of several clinical scores to predict 30-day survival. Methods: This is an investigator-initiated retrospective non-interventional international multicenter registry study (NCT04405973, first registered 28 May 2020). In 127 patients treated with V-V ECMO at 15 centers in Germany, Switzerland, Italy, Belgium, and the United States, we calculated the Sequential Organ Failure Assessment (SOFA) Score, Simplified Acute Physiology Score II (SAPS II), Acute Physiology And Chronic Health Evaluation II (APACHE II) Score, Respiratory Extracorporeal Membrane Oxygenation Survival Prediction (RESP) Score, Predicting Death for Severe ARDS on V-V ECMO (PRESERVE) Score, and 30-day survival. Results: In our study cohort which enrolled 127 patients, overall 30-day survival was 54%. Median SOFA, SAPS II, APACHE II, RESP, and PRESERVE were 9, 36, 17, 1, and 4, respectively. The prognostic accuracy for all these scores (area under the receiver operating characteristic—AUROC) ranged between 0.548 and 0.605. Conclusions: The use of scores for the prediction of mortality cannot be recommended for treatment decisions in severe COVID-19 ARDS undergoing V-V ECMO; nevertheless, scoring results below or above a specific cut-off value may be considered as an additional tool in the evaluation of prognosis. Survival rates in this cohort of COVID-19 patients treated with V-V ECMO were slightly lower than those reported in non-COVID-19 ARDS patients treated with V-V ECMO

Plasma Transfusion and Procoagulant Product Administration in Extracorporeal Membrane Oxygenation:A Secondary Analysis of an International Observational Study on Current Practices

OBJECTIVES: To achieve optimal hemostatic balance in patients on extracorporeal membrane oxygenation (ECMO), a liberal transfusion practice is currently applied despite clear evidence. We aimed to give an overview of the current use of plasma, fibrinogen concentrate, tranexamic acid (TXA), and prothrombin complex concentrate (PCC) in patients on ECMO.DESIGN: A prespecified subanalysis of a multicenter retrospective study. Venovenous (VV)-ECMO and venoarterial (VA)-ECMO are analyzed as separate populations, comparing patients with and without bleeding and with and without thrombotic complications. SETTING: Sixteen international ICUs.PATIENTS: Adult patients on VA-ECMO or VV-ECMO.INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Of 420 VA-ECMO patients, 59% (n = 247) received plasma, 20% (n = 82) received fibrinogen concentrate, 17% (n = 70) received TXA, and 7% of patients (n = 28) received PCC. Fifty percent of patients (n = 208) suffered bleeding complications and 27% (n = 112) suffered thrombotic complications. More patients with bleeding complications than patients without bleeding complications received plasma (77% vs. 41%, p &lt; 0.001), fibrinogen concentrate (28% vs 11%, p &lt; 0.001), and TXA (23% vs 10%, p &lt; 0.001). More patients with than without thrombotic complications received TXA (24% vs 14%, p = 0.02, odds ratio 1.75) in VA-ECMO, where no difference was seen in VV-ECMO. Of 205 VV-ECMO patients, 40% (n = 81) received plasma, 6% (n = 12) fibrinogen concentrate, 7% (n = 14) TXA, and 5% (n = 10) PCC. Thirty-nine percent (n = 80) of VV-ECMO patients suffered bleeding complications and 23% (n = 48) of patients suffered thrombotic complications. More patients with than without bleeding complications received plasma (58% vs 28%, p &lt; 0.001), fibrinogen concentrate (13% vs 2%, p &lt; 0.01), and TXA (11% vs 2%, p &lt; 0.01). CONCLUSIONS: The majority of patients on ECMO receive transfusions of plasma, procoagulant products, or antifibrinolytics. In a significant part of the plasma transfused patients, this was in the absence of bleeding or prolonged international normalized ratio. This poses the question if these plasma transfusions were administered for another indication or could have been avoided.</p

Transfusion of red blood cells in venoarterial extracorporeal membrane oxygenation: A multicenter retrospective observational cohort study

Background: Evidence-based recommendations for transfusion in patients with venoarterial extracorporeal membrane oxygenation (VA ECMO) are scarce. The current literature is limited to single-center studies with small sample sizes, therefore complicating generalizability. This study aims to create an overview of red blood cell (RBC) transfusion in VA ECMO patients. Methods: This international mixed-method study combined a survey with a retrospective observational study in 16 centers. The survey inventoried local transfusion guidelines. Additionally, retrospective data of all adult patients with a VA ECMO run >24 h (January 2018 until July 2019) was collected of patient, ECMO, outcome, and daily transfusion parameters. All patients that received VA ECMO for primary cardiac support were included, including surgical (i.e., post-cardiotomy) and non-surgical (i.e., myocardial infarction) indications. The primary outcome was the number of RBC transfusions per day and in total. Univariable logistic regressions and a generalized linear mixed model (GLMM) were performed to assess factors associated with RBC transfusion. Results: Out of 419 patients, 374 (89%) received one or more RBC transfusions. During a median ECMO run of 5 days (1st–3rd quartile 3–8), patients received a median total of eight RBC units (1st–3rd quartile 3–17). A lower hemoglobin (Hb) prior to ECMO, longer ECMO-run duration, and hemorrhage were associated with RBC transfusion. After correcting for duration and hemorrhage using a GLMM, a different transfusion trend was found among the regimens. No unadjusted differences were found in overall survival between either transfusion status or the different regimens, which remained after adjustment for potential confounders. Conclusion: RBC transfusion in patients on VA ECMO is very common. The sum of RBC transfusions increases rapidly after ECMO initiation, and is dependent on the Hb threshold applied. This study supports the rationale for prospective studies focusing on indications and thresholds for RBC transfusion