Is blood pTau a reliable indicator of the CSF status? A narrative review.

BACKGROUND: The identification of biomarkers for the early diagnosis of Alzheimer's disease (AD) is a crucial goal of the current research. Blood biomarkers are less invasive, easier to obtain and achievable by a cheaper means than those on cerebrospinal fluid (CSF) and significantly more economic than functional neuroimaging investigations; thus, a great interest is focused on blood isoforms of the phosphorylated Tau protein (pTau), indicators of ongoing tau pathology (i.e. neurofibrillary tangles, NFTs, an AD neuropathological hallmark) in the central nervous system (CNS). However, current data often highlight discordant results about the ability of blood pTau to predict CSF status. OBJECTIVE: We aim to synthesise the studies that compared pTau levels on CSF and blood to assess their correlation in AD continuum. METHODS: We performed a narrative literature review using, first, MEDLINE (via PubMed) by means of MeSH terms, and then, we expanded the reults by means of Scopus and Web of Sciences to be as inclusive as possible. Finally, we added work following an expert opinion. Only papers presenting original data on pTau values on both blood and CSF were included. RESULTS: The 33 included studies show an extreme heterogeneity in terms of pTau isoform (pTau181, 217 and 231), laboratory methods, diagnostic criteria and choice of comparison groups. Most studies evaluated plasma pTau181, while data on other isoforms and serum are scarcer. DISCUSSION: Most papers identify a correlation between CSF and blood measurements. Furthermore, even when not specified, it is often possible to show an increase in blood pTau values as AD-related damage progresses in the AD continuum and higher values in AD than in other neurodegenerative diseases. Notably, plasma pTau231 seems the first biomarker to look for in the earliest and pre-clinical stages, quickly followed by pTau217 and, finally, by pTau181. CONCLUSIONS: Our results encourage the use of blood pTau for the early identification of patients with AD continuum.

A new perspective on positive symptoms: expression of damage or self-defence mechanism of the brain?

Usually, positive neurological symptoms are considered as the consequence of a mere, afinalistic and abnormal increase in function of specific brain areas. However, according to the Theory of Active Inference, which argues that action and perception constitute a loop that updates expectations according to a Bayesian model, the brain is rather an explorer that formulates hypotheses and tests them to assess the correspondence between internal models and reality. Moreover, the cerebral cortex is characterised by a continuous "conflict" between different brain areas, which constantly attempt to expand in order to acquire more of the limited available computational resources, by means of their dopamine-induced neuroplasticity. Thus, it has recently been suggested that dreams, during rapid eye movement sleep (REMS), protect visual brain areas (deprived of their stimuli during rest) from being conquered by other normally stimulated ones. It is therefore conceivable that positive symptoms also have a functional importance for the brain. We evaluate supporting literature data of a 'defensive' role of positive symptoms and the relevance of dopamine-induced neuroplasticity in the context of neurodegenerative and psychiatric diseases. Furthermore, the possible functional significance of idiopathic REMS-related behavioural disorder as well as phantom limb syndrome is examined. We suggest that positive neurological symptoms are not merely a passive expression of a damage, but active efforts, related to dopamine-induced plasticity, to maintain a correct relationship between the external world and its brain representation, thus preventing healthy cortical areas from ousting injured ones.

Characterizing practice-dependent motor learning after a stroke.

BACKGROUND: After stroke, patients must learn to use residual motor function correctly. Consistently, motor learning is crucial in stroke motor recovery. We assessed motor performance, practice-dependent on-line motor learning, and factors potentially affecting them in stroke patients. METHODS: This is a cross-sectional observational study. Twenty-six patients with first brain stroke leading to upper limb motor deficit in the subacute or chronic timeframe were enrolled. They performed a Finger Tapping Task (FTT) with both the affected and unaffected limbs. We assessed how patients learn to perform motor tasks despite the motor deficit and the differences in performance between the unaffected and affected limbs. Furthermore, by randomizing the order, we evaluated the possible inter-limb transfer of motor learning (i.e. transfer of a motor skill learned in one limb to the opposite one). Moreover, sleep, attention, anxiety, and depression were assessed through specific tests and questionnaires. RESULTS: Improved FTT accuracy and completed sequences for the affected limb were observed, even if lower than for the unaffected one. Furthermore, when patients initially performed the FTT with the unaffected limb, they showed higher accuracy in subsequent task completion with the affected limb than subjects who started with the affected limb. Only anxiety and attentional abilities showed significant correlations with motor performance. CONCLUSIONS: This work provides relevant insights into motor learning in stroke. Practice-dependent on-line motor learning is preserved in stroke survivors, and an inter-limb transfer effect can be observed. Attentional abilities and anxiety can affect learning after stroke, even if the effect of other factors cannot be excluded.

Frontotemporal Dementia, Where Do We Stand? A Narrative Review.

Frontotemporal dementia (FTD) is a neurodegenerative disease of growing interest, since it accounts for up to 10% of middle-age-onset dementias and entails a social, economic, and emotional burden for the patients and caregivers. It is characterised by a (at least initially) selective degeneration of the frontal and/or temporal lobe, generally leading to behavioural alterations, speech disorders, and psychiatric symptoms. Despite the recent advances, given its extreme heterogeneity, an overview that can bring together all the data currently available is still lacking. Here, we aim to provide a state of the art on the pathogenesis of this disease, starting with established findings and integrating them with more recent ones. In particular, advances in the genetics field will be examined, assessing them in relation to both the clinical manifestations and histopathological findings, as well as considering the link with other diseases, such as amyotrophic lateral sclerosis (ALS). Furthermore, the current diagnostic criteria will be explored, including neuroimaging methods, nuclear medicine investigations, and biomarkers on biological fluids. Of note, the promising information provided by neurophysiological investigations, i.e., electroencephalography and non-invasive brain stimulation techniques, concerning the alterations in brain networks and neurotransmitter systems will be reviewed. Finally, current and experimental therapies will be considered.

Relation Between EEG Measures and Upper Limb Motor Recovery in Stroke Patients: A Scoping Review.

Current clinical practice does not leverage electroencephalography (EEG) measurements in stroke patients, despite its potential to contribute to post-stroke recovery predictions. We review the literature on the effectiveness of various quantitative and qualitative EEG-based measures after stroke as a tool to predict upper limb motor outcome, in relation to stroke timeframe and applied experimental tasks. Moreover, we aim to provide guidance on the use of EEG in the assessment of upper limb motor recovery after stroke, suggesting a high potential for some metrics in the appropriate context. We identified relevant papers (N = 16) from databases ScienceDirect, Web of Science and MEDLINE, and assessed their methodological quality with the Joanna Briggs Institute (JBI) Critical Appraisal. We applied the Preferred Reporting Systems for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews (PRISMA-ScR) Framework. Identified works used EEG to identify properties including event-related activation, spectral power in physiologically relevant bands, symmetry in brain dynamics, functional connectivity, cortico-muscular coherence and rhythmic coordination. EEG was acquired in resting state or in relation to behavioural conditions. Motor outcome was mainly evaluated with the Upper Limb Fugl-Meyer Assessment. Despite great variability in the literature, data suggests that the most promising EEG quantifiers for predicting post-stroke motor outcome are event-related measures. Measures of spectral power in physiologically relevant bands and measures of brain symmetry also show promise. We suggest that EEG measures may improve our understanding of stroke brain dynamics during recovery, and contribute to establishing a functional prognosis and choosing the rehabilitation approach.

The Effectiveness of Paired Associative Stimulation on Motor Recovery after Stroke: A Scoping Review.

Paired associative stimulation (PAS) is a non-invasive brain stimulation technique combining transcranial magnetic stimulation and peripheral nerve stimulation. PAS allows connections between cortical areas and peripheral nerves (C/P PAS) or between cortical regions (C/C PAS) to be strengthened or weakened by spike-timing-dependent neural plasticity mechanisms. Since PAS modulates both neurophysiological features and motor performance, there is growing interest in its application in neurorehabilitation. We aimed to synthesize evidence on the motor rehabilitation role of PAS in stroke patients. We performed a literature search following the PRISMA Extension for Scoping Reviews Framework. Eight studies were included: one investigated C/C PAS between the cerebellum and the affected primary motor area (M1), seven applied C/P PAS over the lesional, contralesional, or both M1. Seven studies evaluated the outcome on upper limb and one on lower limb motor recovery. Although several studies omit crucial methodological details, PAS highlighted effects mainly on corticospinal excitability, and, more rarely, an improvement in motor performance. However, most studies failed to prove a correlation between neurophysiological changes and motor improvement. Although current studies seem to suggest a role of PAS in post-stroke rehabilitation, their heterogeneity and limited number do not yet allow definitive conclusions to be drawn.

The cerebellum and the Mirror Neuron System: A matter of inhibition? From neurophysiological evidence to neuromodulatory implications. A narrative review.

Mirror neurons show activity during both the execution (AE) and observation of actions (AO). The Mirror Neuron System (MNS) could be involved during motor imagery (MI) as well. Extensive research suggests that the cerebellum is interconnected with the MNS and may be critically involved in its activities. We gathered evidence on the cerebellum's role in MNS functions, both theoretically and experimentally. Evidence shows that the cerebellum plays a major role during AO and MI and that its lesions impair MNS functions likely because, by modulating the activity of cortical inhibitory interneurons with mirror properties, the cerebellum may contribute to visuomotor matching, which is fundamental for shaping mirror properties. Indeed, the cerebellum may strengthen sensory-motor patterns that minimise the discrepancy between predicted and actual outcome, both during AE and AO. Furthermore, through its connections with the hippocampus, the cerebellum might be involved in internal simulations of motor programs during MI. Finally, as cerebellar neuromodulation might improve its impact on MNS activity, we explored its potential neurophysiological and neurorehabilitation implications.

Amyotrophic Lateral Sclerosis and Air Pollutants in the Province of Ferrara, Northern Italy: An Ecological Study.

The etiopathogenesis of amyotrophic lateral sclerosis (ALS) is still largely unknown, but likely depends on gene-environment interactions. Among the putative sources of environmental exposure are air pollutants and especially heavy metals. We aimed to investigate the relationship between ALS density and the concentration of air pollution heavy metals in Ferrara, northern Italy. An ecological study was designed to correlate the map of ALS distribution and that of air pollutants. All ALS cases diagnosed between 2000 and 2017 (Ferrara University Hospital administrative data) were plotted by residency in 100 sub-areas, and grouped in 4 sectors: urban, rural, northwestern and along the motorway. The concentrations of silver, aluminium, cadmium, chrome, copper, iron, manganese, lead, and selenium in moss and lichens were measured and monitored in 2006 and 2011. Based on 62 ALS patients, a strong and direct correlation of ALS density was observed only with copper concentrations in all sectors and in both sexes (Pearson coefficient (ρ) = 0.758; p = 0.000002). The correlation was higher in the urban sector (ρ = 0.767; p = 0.000128), in women for the overall population (ρ = 0.782, p = 0.000028) and in the urban (ρ = 0.872, p = 0.000047) population, and for the older cohort of diagnosed patients (2000-2009) the assessment correlated with the first assessment of air pollutants in 2006 (ρ = 0.724, p = 0.008). Our data is, in part, consistent with a hypothesis linking copper pollution to ALS.

Anti-Inflammatory and Cortical Responses after Transcranial Direct Current Stimulation in Disorders of Consciousness: An Exploratory Study.

Disorders of consciousness (DoC) due to severe traumatic brain injury (TBI) are associated with severe disability and an alteration of cortical activation, angiogenesis, and inflammation, which are crucial elements for behavioural recovery. This exploratory study aimed to evaluate anti-inflammatory and cortical responses after transcranial direct current stimulation (tDCS) in traumatic prolonged disorders of consciousness. Ten minimally conscious state (MCS) patients underwent ten sessions of anodal tDCS (five sessions/week, two weeks, 40 min/session) on the primary motor cortex bilaterally. Clinical evaluations were performed using the Coma Recovery Scale-Revised (CRS-R) pre- and post-treatment. In contrast, after single and multiple tDCS sessions, the haemodynamic cortical response was obtained with functional near-infrared spectroscopy (fNIRS). Moreover, angiogenesis (angiopoietin-2, BMP9, endoglin, HbEFG, HGF, IL8, Leptin, PLGF, VEGF-A, and VEGF-C) and inflammation (GM-CSF, IFNg, IP10, MCP1, and TNFα) circulating biomarkers were collected. A significant haemodynamic response was observed after a single tDCS session, with an increased activation from 4.4 (3.1-6.1) to 7.6 (2.9-15.7) a.u. (p = 0.035). After ten tDCS sessions, a significant reduction of angiopoietin-2, VEGF-C, and IP-10 was detected. Moreover, a correlation between behavioural (CRS-R), TNFα (r = 0.89; p = 0.007), and IP10 (r = 0.81; p = 0.014) variation was found. In conclusion, a single tDCS session can increase the cortical activation in MCS patients. Moreover, multiple tDCS sessions showed an anti-inflammatory effect related to behavioural improvement.

The Incidence of Myasthenia Gravis in the Province of Ferrara, Italy, in the Period of 2008-2022: An Update on a 40-Year Observation and the Influence of the COVID-19 Pandemic.

Myasthenia gravis (MG) is the most common neuromuscular junction disorder. We evaluated the MG incidence rate in the province of Ferrara, Northern Italy, over two time frames (2008-2018 and 2019-2022, i.e., the COVID-19 pandemic) and considered early-onset (EOMG), late-onset (LOMG), and thymoma- and non-thymoma-associated MG. Moreover, in the second period, we assessed its possible relationship with SARS-CoV-2 infection or COVID-19 vaccination. We used a complete enumeration approach to estimate the MG incidence and its temporal trend. For the period of 2008-18, 106 new cases were identified (mean incidence rate 2.7/100,000 people). The highest rates were observed for the over-70 age group and in rural areas, with 17% of thymoma-associated MG. During the COVID-19 period, 29 new cases were identified (average incidence rate 2.1/100,000 people), showing a marked (though not statistically significant) decrease in the mean annual incidence compared to the previous period. Again, the highest rate was observed for the over-70 age group. The first period was in line with our previous observations for the period between 1985 and 2007, highlighting a rising incidence of LOMG and a marked decrease in EOMG. During the COVID-19 period, incidence rates were lower in the first years whereas, when the pandemic ended, the previous trend was confirmed.

A Multimodal Analysis to Explore Upper Limb Motor Recovery at 4 Weeks After Stroke: Insights From EEG and Kinematics Measures.

Background. Stroke is a leading cause of death and disability worldwide and there is a very short period of increased synaptic plasticity, fundamental in motor recovery. Thus, it is crucial to acquire data to guide the rehabilitation treatment. Promising results have been achieved with kinematics and neurophysiological data, but currently, few studies integrate these different modalities. Objectives. We explored the correlations between standardized clinical scales, kinematic data, and EEG measures 4 weeks after stroke. Methods. 26 patients were considered. Among them, 20 patients also performed the EEG study, beyond the kinematic analysis, at 4 weeks. Results. We found correlations between the Fugl-Meyer Assessment-Upper Extremity, movement duration, smoothness measures, and velocity peaks. Moreover, EEG measures showed a tendency for the healthy hemisphere to vicariate the affected one in patients characterized by better clinical conditions. Conclusions. These results suggest the relevance of kinematic (in particular movement duration and smoothness) and EEG biomarkers to evaluate post-stroke recovery. We emphasize the importance of integrating clinical data with kinematic and EEG analyses from the early stroke stages, in order to guide rehabilitation strategies to best leverage the short period of increased synaptic plasticity.

Cerebral Venous Thrombosis during Thyrotoxicosis: Case Report and Literature Update.

Cerebral venous thrombosis (CVT) is a rare cause of stroke, particularly in young adults. Several known thrombophilic conditions may lead to an increased CVT risk. Interestingly, few cases in the literature have reported an association between CVT and thyrotoxicosis. Here, we describe the case of a young woman with CVT and concomitant thyrotoxicosis, without any other known prothrombotic conditions. We also performed a literature review of CVT cases and hyperthyroidism, searching for all articles published in peer-reviewed journals. We identified 39 case reports/case series concerning patients with CVT associated with thyrotoxicosis, highlighting, in most cases, the association with additional known prothrombotic factors. We then discussed the possible mechanisms by which hyperthyroidism could underlie a pro-coagulative state resulting in CVT. Thyroid disease might be a more common prothrombotic risk factor than expected in determining CVT. However, in most cases, a coexistence of multiple risk factors was observed, suggesting a multifactorial genesis of the disorder. We hope that this work may alert clinicians to consider thyrotoxicosis as a potential risk factor for CVT, even in patients who apparently have no other pro-coagulative conditions.

Development of Parkinsonism in a Patient with Central Pontine Myelinolysis.

Osmotic demyelination syndrome (ODS) is caused by damage to the pons myelin sheath and nerve cells. Although the pathophysiological mechanism responsible for the damage is not yet fully understood, it is currently believed that osmotic-type changes (especially if they are massive and too rapid) cause oedema that leads to compression and, subsequently, demyelination of white matter fibres. It generally manifests with acute paraparesis/tetraparesis, dysphagia, dysarthria, diplopia, and loss of consciousness, as well as hallucinations, spasms, and other neurological symptoms related to brainstem damage. In extreme cases, the locked-in syndrome may also appear. Of note, in some cases an association between osmotic demyelinating damage and the onset of movement disorders has been documented and, although the pathophysiology is still unknown, a correlation has been postulated between ODS and movement disorders. Here, we present a patient with ODS who developed parkinsonism, thus supporting the hypothesis of a correlation between these pathological events.

Case Report: A Case of Creutzfeldt-Jakob Heidenhain Variant Simulating PRES.

The Heidenhain Variant of Creutzfeldt-Jakob disease (CJD) is an uncommon early clinical syndrome of the otherwise regular sporadic CJD, which belongs to the group of prion diseases caused by a transmissible agent, the misfolded form of the prion protein. The most characteristic symptoms of CJD are rapidly progressive cognitive impairment, typical motor manifestations and mental and behavioural changes. Conversely, in the Heidenhain Variant, different kinds of visual disturbances are observed at onset due to microvacuolar spongiform degeneration or, less frequently, confluent spongiform changes in the parieto-occipital area, detectable through brain MRI with hyperintensity in T2-FLAIR or DWI in the same areas. Since this an extremely rare condition with a heterogeneous clinical presentation, it may easily be misdiagnosed with other diseases at the earlier stages. Here, we describe the case of a patient initially diagnosed with posterior reversible encephalopathy syndrome (PRES), presenting with visual disturbances and headache at onset in a context of poorly controlled arterial hypertension. Subsequently, a rapid worsening of cognitive decline, associated with myoclonus and startle reaction led to further investigations, shifting the diagnosis toward a rapidly evolving neurodegenerative form. This hypothesis was also supported by EEG traces, MRI and CSF analysis. Finally, the clinical-instrumental evolution confirmed the diagnosis of Heidenhain Variant of CJD.

Italian Case Report with a Double Mutation in PSEN1 (K311R and E318G).

Alzheimer's disease (AD) is the most common cause of dementia worldwide. The clinical spectrum of suspected AD has been extended from mild cognitive impairment (MCI) to preclinical AD which includes people who have typical cognitive function but harbor the underlying biological features of AD. We report the first case of an Italian patient affected by MCI (MMSE 24\30), characterized by a double mutation p.Lys311Arg (K311R) and p.Glu318Gly (E318G) in Presenilin-1 but with the absence of abnormal accumulation of amyloid beta.

Factors Associated with Delirium in COVID-19 Patients and Their Outcome: A Single-Center Cohort Study.

BACKGROUND: A significant proportion of patients with coronavirus disease 2019 (COVID-19) suffer from delirium during hospitalization. This single-center observational study investigates the occurrence of delirium, the associated risk factors and its impact on in-hospital mortality in an Italian cohort of COVID 19 inpatients. METHODS: Data were collected in the COVID units of a general medical hospital in the South of Italy. Socio-demographic, clinical and pharmacological features were collected. Diagnosis of delirium was based on a two-step approach according to 4AT criteria and DSM5 criteria. Outcomes were: dates of hospital discharge, Intensive Care Unit (ICU) admission, or death, whichever came first. Univariable and multivariable proportional hazards Cox regression models were estimated, and risks were reported as hazard ratios (HR) along with their 95% confidence intervals (95% CI). RESULTS: A total of 47/214 patients (22%) were diagnosed with delirium (21 hypoactive, 15 hyperactive, and 11 mixed). In the multivariable model, four independent variables were independently associated with the presence of delirium: dementia, followed by age at admission, C-reactive protein (CRP), and Glasgow Coma Scale. In turn, delirium was the strongest independent predictor of death/admission to ICU (composite outcome), followed by Charlson Index (not including dementia), CRP, and neutrophil-to-lymphocyte ratio. The probability of reaching the composite outcome was higher for patients with the hypoactive subtype than for those with the hyperactive subtype. CONCLUSIONS: Delirium was the strongest predictor of poor outcome in COVID-19 patients, especially in the hypoactive subtype. Several clinical features and inflammatory markers were associated with the increased risk of its occurrence. The early recognition of these factors may help clinicians to select patients who would benefit from both non-pharmacological and pharmacological interventions in order to prevent delirium, and in turn, reduce the risk of admission to ICU or death.

A Case of Hyperekplexia That Started From Childhood: Clinical Diagnosis With Negative Genetic Investigations.

Here, we report the case of a 63-year-old woman affected by abnormal, excessive, and involuntary reactions to harmless and unexpected sensory stimuli, compatible with the diagnosis of hyperekplexia. It is a pathology that involves the glycinergic system on a hereditary basis, and even if genetic proof compatible with the diagnosis is not present in this case, the fact that an aunt on her father's side suffered from the same disorders supports the clinical suspicion. From an early age, clinical history shows anomalous motor manifestations, initially framed as a form of focal epilepsy or ordinary disorders of the mood sphere, later excluded by the lack of effectiveness of a targeted therapy. Despite this, intellectual, psychological, and socio-emotional development was regular. The manifestations, present throughout childhood, adolescence, and early adulthood in moderate entity, worsened after the age of 50, perhaps due to hormonal changes. The presence of consequent anxiety and depression has compromised her quality of life, and in order to improve it, therapies were resorted, which, however, produced cognitive-attention deficits. No diagnostic exam has confirmed the diagnosis, although some scars in some brain areas involved in the control of reactions are elements favorable to this condition in genetically predisposed subjects. Therapies currently in use attenuate the motor symptomatology without resolving it and cause side effects in the psychological and cognitive sphere. In this case, we want to highlight the difficulty of diagnosing a very rare genetic condition, still not well-known, which presents symptoms easily mistaken for other more common diseases, because there are no specific clinical-diagnostic tools for the time being. In this particular case, we describe a female patient with an atypical onset age and negative genetic investigations compared with what is known in literature regarding this rare disorder. That is why it has been thought she was affected by epilepsy or anxiety-related disorders for several years.

Hirayama Disease: A Case of an Albanian Woman Clinically Stabilized Without Surgery.

Hirayama Disease (HD) is a rare clinical condition that usually affects young people with preference for Asian males. It appears with unilateral distal amyotrophy or asymmetric bilateral amyotrophy of an upper limb which is to refer to an involvement of the spinal metamers C7-C8-T1. A clinical case of a female patient of Albanian nationality is described, with onset of the disease in adulthood and clinical and electrophysiological features suggestive of HD, without any characteristic imaging findings. Clinical investigations, EMG and radiological data facilitated the diagnosis and allowed the exclusion of degenerative forms of the motor neuron and radiculopathies. In this paper, we want to point out that the diagnosis of this pathology should be hypothesized even in the absence of characteristic epidemiological and imaging data.