Cognizione Sociale e Malattia di Huntington: ruolo dell'ossitocina

La Malattia di Huntington (MH) è una patologia genetica autosomica dominante classicamente caratterizzata da sintomi motori cognitivi e psichiatrici. Nel corso degli anni l’evidenza clinica di compromissione dei comportamenti sociali, supportata dai dati di letteratura di alterata percezione delle emozioni, ha suscitato un crescente interesse per la cognitività sociale di questi pazienti. La cognizione sociale rappresenta un dominio cognitivo che abbraccia diversi temi tra cui la percezione dell’espressione dei volti, la prosodia, la “Teoria della Mente” (ToM), ovvero la capacità di attribuire uno stato mentale ad un soggetto e, sulla base di questo, poter predire o descrivere le sue azioni. Sin dal 1985 la base del processo neuropatologico nella MH è stato identificato a livello striatale, ma parallelamente alle ricerche in ambito cognitivo-comportamentale e tentativo di spiegare aspetti non motori della malattia quali l’eccessiva sudorazione, l’iperfagia, il dimagrimento, i disturbi sessuali e i disturbi autonomici, l’attenzione si è spostata anche su altre aree del SNC ed in particolare a livello ipotalamico. A tal proposito un recente studio anatomopatologico ha evidenziato significativa perdita neuronale a carico del nucleo tuberale laterale e del nucleo paraventricolare e, mediante indagini immunoistochimiche, una riduzione della popolazione neuronale secernente orexina, Ossitocina (OT) e Vasopressina con aumento della positività per il trascritto di regolazione cocaina-amfetamina e amine. Nel corso degli ultimi anni è stato sempre più discusso il ruolo dell’ossitocina nel controllo della socialità; questo sia per i dati emersi in letteratura da topi Knockout che mostrano una compromissione del riconoscimento sociale, associato a integrità dell’apprendimento e della memoria, deficit compensato dalla comministrazione di OT in particolare a livello dell’amigdala, sia perché nell’uomo è stato dimostrato come la somministrazione di OT migliori il riconoscimento dell’espressione dei volti, in particolare, nel caso in cui esprimano rabbia. Sulla base dei suddetti dati questa tesi si pone l’obiettivo di indagare, mediante un’estesa e mirata batteria di test neuropsicologici, l’effettiva compromissione della cognizione sociale in pazienti affetti da MH e parallelamente il coinvolgimento dell’OT nella MH e la relazione tra i livelli basali di questo ormone e la cognitivtà sociale. Lo studio ha coinvolto 8 pazienti di MH sintomatici con stadio II di Shoulson & Fahn e 9 controlli, senza differenze significative per età e scolarità. L’analisi statistica ha mostrato che soggetti più giovani e con scolarità maggiore riconoscono più facilmente le emozioni dalle espressioni dei volti. Allo stesso modo quanto minore è la compromissione cognitiva, indagata mediante Montreal Cognitive Assessment (MoCa), tanto migliori sono le performance a test cognitivi sociali quali Faux pas, Strange Stories e Bush test (p<0.01). Oltre a questi dati nella popolazione di MH è emerso che a durata di malattia maggiore corrispondono performance più basse al Faux pas test, allo stesso modo più alta è l’età di esordio migliore è la capacità di riconoscere espressioni di paura (p<0.05). L’analisi di regressione lineare ha supportato queste correlazioni dimostrando che il modello costituito da Scolarità, Età allo studio e MoCa corretto spiega il 66% circa della variabilità della scala di percezione delle emozioni valutata mediante la scala Karolinska Directed Emotional Faces (KDEF) nella popolazione generale (p<0.01). L’analisi dei livelli ematici di OT non ha mostrato differenze significative nelle due popolazioni, seppur evidenziando valori più bassi nei gruppo dei pazienti (Media 1.9±0.6 controlli, 1.8±0.4 MH), ma a livelli ematici maggiori corrispondono migliori prestazioni al Faux Pas test (p<0.05). Poiché i dati presenti in letteratura mostrano un’importante associazione tra OT e percezioni delle emozioni è stata condotta un’analisi di regressione lineare mirata ad indagare la relazione tra MoCa corretto e OT e KDEF, queste due variabili sono in grado di spiegare il 55% circa della variabilità di KDEF nella popolazione generale (p<0.01), dato che persiste anche nelle due popolazioni indagate separatamente. In conclusione il presente studio, seppur fortemente limitato dalla scarsa numerosità del campione, evidenzia un’estesa compromissione della cognizione sociale nella popolazione MH che correla anche con parametri di malattia quali durata e ed età di esordio. La compromissione coinvolge prevalentemente la percezione delle emozioni indagata mediante la scala KDEF, che risulta dipendente sia dalla compromissione cognitiva che dai livelli basali di ossitocina. Questo dato riscontrato nella popolazione generale, permane significativo anche nella sola popolazione dei pazienti in accordo con quanto presente in letteratura. Si potrebbe pertanto speculare, in base sia ai dati del presente studio sia ai dati anatomopatologici, che il deficit della cognizione sociale in corso di MH possa in parte essere legato all’ossitocina in particolare per quanto concerne la percezione delle emozioni

Brain-Derived Neurotrophic Factor (BDNF) and Serotonin Transporter (SERT) in Platelets of Patients with Mild Huntington’s Disease: Relationships with Social Cognition Symptoms

Peripheral biological correlates of early-stage Huntington’s disease (HD) are currently attracting much interest given their possible use as prognostic predictors of later neurodegeneration. Since deficits in social-cognition processing are present among the initial disease symptoms, aim of this work was to appraise, in blood platelets, Brain-Derived Neurotrophic Factor (BDNF) and serotonin (5-HT) transporter (SERT), two proteins involved in human adaptive behavior as potential biochemical correlates of such disabilities in mild-HD. Thirteen gene positive and symptomatic patients (9M/4W, HD-stage II, age> 40y) together 11 gender/age matched controls without a concurrent diagnosis of psychiatric disorders, underwent a blood test to determine BDNF storage and membrane-bound SERT in platelets by ELISA immune-enzyme and [3H]-paroxetine ([3H]-PAR) binding assays, respectively. Concomitantly, all subjects were examined through a battery of socio-cognitive and emotion recognition questionnaires. Results showed moderately increased intra-platelet BDNF amounts (+20-22%) in patients versus controls, whereas [3H]-PAR binding parameters, maximum density (Bmax) and dissociation constant (KD), did not appreciably vary between the two groups. While patients displaying significantly reduced cognitive/emotion abilities, biochemical parameters and clinical features or psychosocial scores did not correlate each other, except for platelet BDNF and the illness duration, positively correlated, or for SERT KDs and angry voice recognition ability, negatively correlated in both controls and patients. Therefore, in this pilot investigation, platelet BDNF and SERT did not specifically underlie psychosocial deficits in stage II-HD. Higher platelet BDNF storage in patients showing lasting-mild symptoms would derive from compensatory mechanisms. Thus, supplementary investigations are warranted by also comparing patients in other illness’s phases

Apomorphine hydrochloride for the treatment of Parkinson's disease.

Apomorphine (APO) is a potent D1 and D2 dopamine agonist. Plasma maximal concentration is reached in 8–16 min with a plasma half-life of 34–70 min. Bioavailability is close to 100%. It has a rapid antiparkinsonian action after subcutaneous (sc.) administration with a size effect comparable with that of levodopa. Trials of sc., oral, sublingual, intravenous, rectal, intranasal and iontophoretic transdermal administration of APO have been attempted in Parkinson’s disease (PD), each of these routes have shown some potential for clinical effectiveness but the majority of studies indicate that APO intermittent sc. administration, on which this review is mainly focused, is an effective therapy for the management of motor symptoms in PD, particularly in advanced phases mainly characterized by motor fluctuations, such as wearing OFF and unpredictable “off”. Data on the effect of APO on non-motor symptoms in PD patients are limited but there is strong suggestion of a beneficial effect that warrants further investigation

Antipsychotic drugs in Huntington's disease

The aim of this review is to overview the pharmacological features of neuroleptics experienced in the treatment of Huntington's disease (HD) symptoms. Despite a large number of case reports, randomized controlled trials (RCT) and drug comparison studies are lacking

Two cases of Huntington's disease unmasked by the COVID-19 pandemic

Movement disorders of new-onset are increasingly being described in patients with SARS-CoV-2 infection [1]. Imaging and cerebrospinal fluid (CSF) studies in such patients suggest a possible underlying post-viral immune mechanism, ruling out structural brain lesions and encephalitic processes [1]. Interestingly, SARS-CoV-2 infection appears to be able to affect several crucial cellular pathways, which are also relevant in cellular aging and in neurodegenerative diseases [2]. These include immune activation and inflammation. Of note, both these responses are induced following immunization with effective vaccines, which are enhanced in patients who previously recovered from COVID-19 [3]. As the pandemic continues, increasing evidence has drawn attention to the indirect and systemic effects of the virus, which could be an environmental modifier in patients genetically predisposed to develop Huntington’s disease (HD)

Serotonin and neurodegeneration: a preliminary study of platelet serotonin transporter (SERT) in patients with Huntington's disease

INTRODUCTION Huntington’s disease (HD) is a rare genetic disease caused by the abnormal expansion of the N-terminal polyglutamine site present in the huntingtin (Htt) protein. Mutant Htts enhance a neurodegenerative process characterized by the loss of striatal medium-sized spiny GABA neurons accompanied by severe psychiatric, cognitive and motor control disturbances. The prodromic phase of HD is defined by affective symptoms and, particularly, by depressive mood, albeit the neurobiology of this co-morbidity is unclear. Since serotonin (5-HT) levels are considered a depression biomarker and platelets a suitable peripheral model to apprise 5-HT re-uptake system, we aimed here at measuring the platelet 5-HT transporter (SERT) in HD. METHODS Platelet SERT was determined by means of [3H]paroxetine binding in 13 HD patients (9M, 4F) and 11 controls (8M, 3F) to obtain its maximal binding capacity, Bmax (fmol/mg) and dissociation constant, Kd (nM). All recruited subjects came from the Neurology Unit of the “St. Chiara” Hospital, Pisa University, after signing the informed consent approved by the institutional Ethics Committee. Subjects underwent a whole venous blood withdraw and subsequent neurological/psycho-emotional tests. Blood was then processed for separation of platelet membranes and binding studies. RESULTS The [3H]paroxetine Bmax was 1067 ± 119 fmol/mg in platelets of controls while resulting slightly but not significantly reduced in patients: 916 ± 70 fmol/mg. A weak, still not significant, increase in Kd was also obtained in HD, 0.18 ± 0.02 nM, vs. controls, 0.16 ± 0.03 nM, whilst reporting significant negative correlations between Kd, verbal emotions or perception of face expressions both in all subjects and patients. CONCLUSIONS This study shows, though not decisively, that platelet SERT affinity relays with emotional cognitive functions. This pushes us to enlarge subjects’recruitment and investigations also on platelet SERT number in HD vs. controls

Positive DAT-SCAN in SPG7: a case report mimicking possible MSA-C

Background: Spastic Paraplegia type 7 (SPG7) is one of the most common autosomal recessive Hereditary Spastic Paraplegias (HSP); Spastic Paraplegias (SPGs) can present as hereditary ataxias. However, ataxia is frequently the symptom of presentation of many other hereditary/sporadic disorders, such as Multiple system atrophy type C (MSA-C), an α-synuclein sporadic neurodegenerative disorder, in which cerebellar ataxia is one of the main clinical features. Dopamine Transporter imaging (DAT-SCAN), associated with clinical features, can be a helpful tool in order to distinguish MSA-C from other causes of ataxia. Case-presentation: We present the case of a 70-year-old man with gait difficulties over a period of 3 years and frequent backward/lateral falls. He also reported urinary urge incontinence, but no symptoms that are compatible with orthostatic hypotension. On neurological examination he showed ataxic gait, spasticity in the left lower limb and trunk and limb ataxia, especially on the left side. Mild hypokinesia was found in all 4 limbs, especially in the left foot. MRI revealed atrophy of the cerebellar hemispheres and vermis. DAT-SCAN imaging revealed bilateral nigro-striatal degeneration, which was compatible with a diagnosis of possible MSA-C. Considering the atypical disease course (the patient walked without any support after 3 years), we carried out a genetic investigation for Ataxia, and a mutation in SPG7 was found. Conclusions: DAT-SCAN imaging, evaluated together with the clinical findings, can be useful for differentiating MSA from other possible causes of adult-onset Ataxia. Indeed, patients with MSA-C generally show a decreased uptake of dopamine transporters in DAT-SCAN imaging. Ours is the first case reported in the literature of a patient with SPG7 mutation with nigrostriatal degeneration and a clinical presentation of a possible MSA-C. Performing genetic investigations in patients with an atypical disease course is important to avoid MSA-mimicries. Identifying the correct diagnosis is important not only for prognostic reasons, but also for possible future genetic therapies

Perampanel as a novel treatment for subcortical myoclonus in myoclonus-dystonia syndrome

BackgroundMyoclonus-dystonia (MD) is a syndrome characterized by subcortical myoclonus and milder dystonia. The main causative gene is the epsilon sarcoglycan gene (SGCE), but other genes may be involved. Response to medications is variable, with poor tolerability limiting their use.Case presentationWe present the case of a patient with severe myoclonic jerks and mild dystonia since childhood. At first neurological visit at the age of 46 years old, she presented brief myoclonic jerks predominating in the upper limbs and neck, mild at rest and elicited by action, posture and tactile stimulus. Myoclonus was accompanied by mild neck and right arm dystonia. Neurophysiological tests suggested subcortical origin of myoclonus, brain MRI was unremarkable. Myoclonus-dystonia was diagnosed, and genetic testing identified a novel mutation in SGCE gene (c.907delC) in heterozygosis. Over time she assumed a large variety of anti-epileptics without beneficial effect on myoclonus and low tolerability. Add-on treatment with Perampanel was started, with a beneficial effect. No adverse events were reported. Perampanel is the first selective non-competitive AMPA receptor antagonist approved in add-on for focal and generalized tonic-clonic seizures. To our knowledge, this is the first trial of Perampanel in MD.ConclusionsWe presented the case of a patient with MD due to SGCE mutation who was treated with Perampanel with beneficial effects. We propose Perampanel as a novel treatment for myoclonus in MD

Mesolimbic dopaminergic dysfunction in Parkinson's disease depression: evidence from a 123I-FP-CIT SPECT investigation.

Abstract We investigated the striatal and extrastriatal DAT availability (SPM8) by [123I]FP-CIT-SPECT in 15 PD patients with depression and 35 PD patients without depression. A cluster with significant (p\0.05) lower tracer binding in PD with depression was found in left cingulate cortex, persistent after correction for age, disease severity and duration, and inversely correlated with depression scores (r -0.336, p\0.05). Our data indicate a significant association between PD depression and cingulate dopaminergic denervation supporting the dopaminergic hypothesis of PD depression

Efficacy of a combined therapeutic approach in the management of Pisa Syndrome

Pisa syndrome (PS) represents an important source of disability in Parkinson's disease (PD). Currently no consensus has been reached on its definition or diagnostic criteria, and therapeutic approaches are unspecific and often futile. Recently the role of abdominal muscles, and in particular of the external oblique (EO), in the pathogenesis of PS was hypothesized