Amyloid-β, p-tau, and reactive microglia load are correlates of MRI cortical atrophy in Alzheimer's disease

INTRODUCTION: The aim of this study was to identify the histopathological correlates of MRI cortical atrophy in (a)typical Alzheimer’s disease (AD) donors. METHODS: 19 AD and 10 control donors underwent post-mortem in-situ 3T-3DT1-MRI, from which cortical thickness was calculated. Upon subsequent autopsy, 21 cortical brain regions were selected and immunostained for amyloid-beta, phosphorylated-tau, and reactive microglia. MRI-pathology associations were assessed using linear mixed models. Post-mortem MRI was compared to ante-mortem MRI when available. RESULTS: Higher amyloid-beta load weakly correlated with a higher cortical thickness globally. Phosphorylated-tau strongly correlated with cortical atrophy in temporo-frontal regions. Reactive microglia load strongly correlated with cortical atrophy in the parietal region. Post-mortem scans showed high concordance with ante-mortem scans acquired <1 year before death. DISCUSSION: Distinct histopathological markers differently correlate with cortical atrophy, highlighting their different roles in the neurodegenerative process. This study contributes in understanding the pathological underpinnings of MRI atrophy patterns

Exploring in vivo multiple sclerosis brain microstructural damage through T1w/T2w ratio: a multicentre study

Objectives: To evaluate white matter and grey matter T1-weighted (w)/T2w ratio (T1w/T2w ratio) in healthy controls and patients with multiple sclerosis, and its association with clinical disability. Methods: In this cross-sectional study, 270 healthy controls and 434 patients with multiple sclerosis were retrospectively selected from 7 European sites. T1w/T2w ratio was obtained from brain T2w and T1w scans after intensity calibration using eyes and temporal muscle. Results: In healthy controls, T1w/T2w ratio increased until 50-60 years both in white and grey matter. Compared with healthy controls, T1w/T2w ratio was significantly lower in white matter lesions of all multiple sclerosis phenotypes, and in normal-appearing white matter and cortex of patients with relapsing-remitting and secondary progressive multiple sclerosis (p≤0.026), but it was significantly higher in the striatum and pallidum of patients with relapsing-remitting, secondary progressive and primary progressive multiple sclerosis (p≤0.042). In relapse-onset multiple sclerosis, T1w/T2w ratio was significantly lower in white matter lesions and normal-appearing white matter already at Expanded Disability Status Scale (EDSS) <3.0 and in the cortex only for EDSS ≥3.0 (p≤0.023). Conversely, T1w/T2w ratio was significantly higher in the striatum and pallidum for EDSS ≥4.0 (p≤0.005). In primary progressive multiple sclerosis, striatum and pallidum showed significantly higher T1w/T2w ratio beyond EDSS=6.0 (p≤0.001). In multiple sclerosis, longer disease duration, higher EDSS, higher brain lesional volume and lower normalised brain volume were associated with lower lesional and cortical T1w/T2w ratio and a higher T1w/T2w ratio in the striatum and pallidum (β from -1.168 to 0.286, p≤0.040). Conclusions: T1w/T2w ratio may represent a clinically relevant marker sensitive to demyelination, neurodegeneration and iron accumulation occurring at the different multiple sclerosis phases

Relation of sensorimotor and cognitive cerebellum functional connectivity with brain structural damage in patients with multiple sclerosis and no disability

Background and purpose To investigate the relationship between the functional connectivity (FC) of the sensorimotor and cognitive cerebellum and measures of structural damage in patients with multiple sclerosis (MS) and no physical disability. Methods We selected 144 relapsing-remitting MS patients with an Expanded Disability Status Scale score of &lt;= 1.5 and 98 healthy controls from the Italian Neuroimaging Network Initiative database. From multimodal 3T magnetic resonance imaging (MRI), including functional MRI at rest, we calculated lesion load, cortical thickness, and white matter, cortical gray matter, and caudate, putamen, thalamic, and cerebellar volumes. Voxel-wise FC of the sensorimotor and cognitive cerebellum was assessed with seed-based analysis, and multiple regression analysis was used to evaluate the relationship between FC and structural damage. Results Whole brain, white matter, caudate, putamen, and thalamic volumes were reduced in patients compared to controls, whereas cortical gray matter was not significantly different in patients versus controls. Both the sensorimotor and cognitive cerebellum showed a widespread pattern of increased and decreased FC that were negatively associated with structural measures, indicating that the lower the FC, the greater the tissue loss. Lastly, among multiple structural measures, cortical gray matter and white matter volumes were the best predictors of cerebellar FC alterations. Conclusions Increased and decreased cerebellar FC with several brain areas coexist in MS patients with no disability. Our data suggest that white matter loss hampers FC, whereas, in the absence of atrophy, cortical volume represents the framework for FC to increase

Outcome after 10 years of Panic Disorder: A longitudinal naturalistic study. [Esito a 10 anni di Disturbo da Attacchi di Panico : uno studio longitudinale naturalistico]

La letteratura risulta carente di studi che esaminino l'esito clinico, a lungo termine, di pazienti con Disturbo da Attacchi di Panico (DAP) per un periodo superiore ai 2 anni. Scopo di questo studio è stato quello di valutare il follow- up a lungo termine di pazienti con diagnosi di DAP con agorafobia trattati secondo protocolli farmaco-psicoterapeutici in ambito naturalistico. Metodo. 20 pazienti consecutivi (7 maschi e 13 femmine, range di età 21-38 anni) che soddisfacevano i criteri diagnostici del DSMIII-R per un DAP con agorafobia sono stati seguiti per 10 anni. Sono stati utilizzati farmaci antipanico (triciclici, SSRI), psicoterapia o terapia integrata. La valutazione psicometrica è stata condotta utilizzando la Marks-Sheehan Phobia Scale (MSPS), le Scale Hamilton per l'ansia (HAM-A) e per la depressione (HAM-D), la Scala per la Valutazione Globale del Funzionamento (VGF) e la Clinical Global Impression (CGI). Gli strumenti di valutazione sono stati somministrati rispettivamente in tre tempi: all'inizio dello studio, e comunque prima dell'inizio di qualsiasi trattamento (TO); dopo 5 anni, con una variabilità di 2 anni (TI) e al termine dei 10 anni di studio (T2). Risultati e Discussione. Terminato il trattamento, alla valutazione a 5 (TI) e a 10 anni (T2) si è registrata una riduzione statisticamente significativa (p.01) dei punteggi delle scale psicometriche. Solo 4 pazienti (20%) non hanno avuto alcuna ricaduta nel corso dei 10 anni, mentre nei rimanenti 16 (80%) al TI si sono manifestate da 1 a 10 ricadute, presentandosi però di intensità inferiore rispetto al primo episodio di malattia. Tali ricadute hanno richiesto un ripristino delle cure in tutti i casi. Alla valutazione a 10 anni, il 95% dei pazienti è risultato libero da ricadute attive con valori di CGI da 1 a 3, con sintomi residui o marginali nel 40% dei casi. Tali risultati metterebbero in discussione la stessa definizione di DAP come un disturbo dall'andamento cronico-recidivante in un lungo periodo di tempo. Lo studio, di tipo naturalistico, ha alcuni limiti metodologici rappresentati dall'esiguità del campione, dai rigidi criteri di selezione utilizzati per arruolare i pazienti e dai soli 2 punti di osservazione nel corso dei 10 anni di studio

Una ricerca sugli esiti del trattamento dell'anoressia nervosa grave con Disturbi di Personalità

Vengono presentati i dati condotti su un gruppo di pazienti con Anoressia Nervosa grave e Disturbi di Personalità, trattate in regime di ricovero. Contrariamente ad una certa letteratura il BMI, che all'ingresso presntava valori molto bassi, alla dimissione delle pazienti era mediamente al di sopra di 17,5. Alcuni autori addirittura sostengono l’utilità del raggiungimento tra il ricovero e la dimissione, seppure con ricoveri di alcuni mesi, di valori di BMI significativamente superiori, includendo questo criterio tra i criteri tassativi per essere ricoverati. Non siamo assolutamente d’accordo con questi criteri sia perché in quanto struttura pubblica non possiamo rifiutare il ricovero soprattutto di anoressiche gravi, prospettando loro aumenti ponderali di 20-30 kg. Questa tipologia di pazienti, spesso, quasi sempre, riluttante al ricovero, con questa regola contrattuale rifiuterebbe decisamente il ricovero obbligandoci ad operare un TSO, struttura certamente non ideale al trattamento di questa patologia che richiede specifiche competenze specialistiche. Abbiamo stimato che con questa clausula non meno di 8 pazienti su 10 rifiutano tassativamente il ricovero. Si è constatato altresì, che in tempi relativamente brevi queste pazienti raggiungono risultati soddisfacenti e soprattutto se giovani e ricoverate il più precocemente possibile molto più difficilmente vanno incontro a ricaduta e soprattutto a “cronicizzazione”. Il nostro intento in sostanza è quello di raggiungere un aumento ponderale il più possibile parallelo ad un miglioramento delle dinamiche psicologiche sottostanti e quindi quanto meno ad una parziale accettazione di un fisico corrispondente a pesi ripetutamente contrattati. Il processo di guarigione proseguirà attraverso un processo psicoterapeutico ambulatoriale e, ora che ne disponiamo con un eventuale passaggio intermedio in day hospital. Anche se non è stato argomento di trattazione in questa sede, riteniamo doveroso citare il possibile rischio di viraggio in queste pazienti da anoressia in bulimia (nel nostro studio si è verificato nell’8% dei casi). Per quanto attiene ai disturbi di personalità è importante sottolineare che essi non sono stati oggetto di un trattamento specifico, avendo posto primaria attenzione al grave quadro di anoressia delle pazienti. Tuttavia a seguito del miglioramento del quadro clinico e con il recupero del peso da parte delle pazienti sono conseguiti miglioramenti nell’ambito del disturbo di personalità. Questo ci permette si ipotizzare che entrambi gli aspetti non possano essere scissi. In particolare i tratti della sfera ossessiva al T1 sono diminuiti del 22%, mentre i punteggi del Pt sono diminuiti del 25%. Solo i tratti della sfera istrionica sono persistiti in modo più marcato dopo il miglioramento clinico. La valutazione dei predetti aspetti si rivela utile per una terapia integrata precoce e successivi controlli ambulatoriali atti al monitoraggio del disturbo di personalità sottostante. A tal fine questo studio risulta pertanto meritorio di ulteriori approfondimenti e studi che indaghino le interconnessioni tra le due patologie nel tempo

Depressive symptoms, anxiety and cognitive impairment: emerging evidence in multiple sclerosis

Abstract Neuropsychiatric abnormalities may be broadly divided in two categories: disorders of mood, affect, and behavior and abnormalities affecting cognition. Among these conditions, clinical depression, anxiety and neurocognitive disorders are the most common in multiple sclerosis (MS), with a substantial impact on patients’ quality of life and adherence to treatments. Such manifestations may occur from the earliest phases of the disease but become more frequent in MS patients with a progressive disease course and more severe clinical disability. Although the pathogenesis of these neuropsychiatric manifestations has not been fully defined yet, brain structural and functional abnormalities, consistently observed with magnetic resonance imaging (MRI), together with genetic and immunologic factors, have been suggested to be key players. Even though the detrimental clinical impact of such manifestations in MS patients is a matter of crucial importance, at present, they are often overlooked in the clinical setting. Moreover, the efficacy of pharmacologic and non-pharmacologic approaches for their amelioration has been poorly investigated, with the majority of studies showing marginal or no beneficial effect of different therapeutic approaches, possibly due to the presence of multiple and heterogeneous underlying pathological mechanisms and intrinsic methodological limitations. A better evaluation of these manifestations in the clinical setting and improvements in the understanding of their pathophysiology may offer the potential to develop tools for differentiating these mechanisms in individual patients and ultimately provide a principled basis for treatment selection. This review provides an updated overview regarding the pathophysiology of the most common neuropsychiatric symptoms in MS, the clinical and MRI characteristics that have been associated with mood disorders (i.e., depression and anxiety) and cognitive impairment, and the treatment approaches currently available or under investigation

Pediatric multiple sclerosis: developments in timely diagnosis and prognostication

Introduction Pediatric-onset (PO) multiple sclerosis (MS) accounts for about 2-10% of the total MS cases. Recently, a greater attention has been given to POMS, with substantial improvements in the understanding of its pathophysiology, in the diagnostic work-up and in the identification of reliable prognosticators associated with long-term disability in these patients. Areas covered This review summarizes the most recent updates regarding the pathophysiology of POMS, the current diagnostic criteria and the clinical, neuroradiological and laboratoristic markers that have been associated with disease progression (i.e. occurrence of a second clinical attack at disease onset and accumulation of disability in definite MS). Expert opinion The study of POMS, where the clinical onset is closer to the biological onset of MS, may contribute to better understand how the different pathological processes impact brain maturation and contribute to disease progression, but also how brain plasticity may counterbalance structural damage accumulation. Although rare, POMS is a severe disease, characterized by a prominent clinical and radiological activity at disease onset and by the accumulation of physical and cognitive disability at a younger age compared to the adult counterpart, with significant detrimental consequences at long-term. Early and accurate diagnosis, together with early treatment, is highly warranted

Interactive patterns in the schizophrenic family during hospitalization.

Our research is based on the cases of 40 patients diagnosed as schizophrenics and the patterns of their family interaction at the moment of the hospitalization, in order to formulate an initial analysis of the reason of admission as the first phase in a therapeutic process. With this intent the authors have conducted a catamnestic research on the charts of patients who have been divided in three groups according to the presence or absence of the parents. The following variables have been therefore taken into consideration: the referrals, her/his behavior at the moment of hospitalization, expectations and difficulties in widening the field of observation within the family

Does Ocrelizumab Limit Multiple Sclerosis Progression? Current Evidence from Clinical, MRI, and Fluid Biomarkers

Multiple sclerosis (MS) is a chronic inflammatory, demyelinating, and neurodegenerative disease affecting the central nervous system, often characterized by the accumulation of irreversible clinical disability over time. In recent years, there has been a dramatic evolution in several key concepts of MS treatment. The demonstration of the effects of ocrelizumab, a selective monoclonal antibody against CD20(+) B cells, has significantly modified our knowledge of the immune-pathophysiology of MS and has provided a new therapeutic target for relapsing and progressive MS patients. Emerging findings suggest that, besides its strong anti-inflammatory activity, ocrelizumab may limit disability progression and may exert beneficial effects on cognitive function, fatigue, and quality of life of MS patients. The significant reductions of the rate of global and regional brain atrophy and of serum neurofilament light chain levels, which were found to be partially independent of overt inflammatory activity, suggest that this treatment may also limit neuro-axonal damage. By discussing the most recent evidence regarding the effects of ocrelizumab on clinical measures as well as on magnetic resonance imaging and fluid biomarkers, this review summarizes current knowledge on the possible mechanisms underlying the effects of ocrelizumab in limiting MS progression and neurodegeneration