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Background: Recurrent complex visual hallucinations (VHs) are common in dementia with Lewy bodies (DLB). Previous investigations suggest that VHs are associated with connectivity changes within and...

Peripherin (PRPH), a type III intermediate filament, assembles with neurofilaments in neurons of the peripheral nervous system, including lower motor neurons (LMN). To evaluate the role of PRPH in LMN degeneration, we assessed PRPH and neurofilament light chain (NfL) in cerebrospinal fluid (CSF) and serum of 91 patients with motor neuron diseases (MND) and 69 controls. Overall, we found PRPH to be more concentrated in serum than in CSF. Serum PRPH resulted significantly increased in MND patients but it was unrelated to CSF‐NfL or survival in the amyotrophic lateral sclerosis (ALS) subset. PRPH might represent a marker of LMN involvement.

Background Functional neurological disorders (FND) are disabling medical conditions commonly seen in neurological practice. Neurologists play an essential role in managing FND, from establishing a diagnosis to coordination of multidisciplinary team-based treatment for patients. With this study, we investigated the knowledge and the clinical experience of Italian neurologists in managing patients with FND. Methods Members of the Italian Society of Neurology were invited via e-mail to participate in this ad hoc online survey; 492 questionnaires were returned completed. Results The term “Functional neurological disorders” in reference to FND was used more frequently than other psychological (e.g., psychogenic or conversion), or descriptive terms (e.g., non-organic or stress-related). When speaking with patients, the respondents stated that they preferred explaining symptoms based on abnormal functioning of the nervous system than discussing mental illness and that they would refer their patient to a psychologist rather than to a psychiatrist. Few considered that physiotherapy and psychiatric interventions are useful approaches to treating FND. Some believed that patients simulate their symptoms. Conclusions Overall, the responses suggest that knowledge about scientific advances in FND is somewhat sparse. A psychiatric-centered view of FND opens the way to an approach in which neurobiological and psychological aspects constitute essential factors of the condition. In this context, professional education could improve understanding of FND and optimize patient management.

Around half of the patients with Guillain-Barré syndrome (GBS) present autonomic dysfunction requiring admission to intensive care unit in up to a quarter of patients. Treatment of GBS consists of plasma exchange (PE) and intravenous immunoglobulins (IVIG). Posterior reversible encephalopathy syndrome (PRES) consists in a reversible subcortical vasogenic brain edema caused by endothelial damage triggered by abrupt blood pressure changes. We report on a woman who presented with PRES in the course of GBS treated first with IVIG, and then with PE. The present report underlines the challenge that the clinicians face when these two rare syndromes concur. The literature is not helpful considering that both blood pressure fluctuations and IVIG are reported to be involved in the pathogenesis of PRES. In the present letter, both pathogenic mechanisms and clinical management considerations are discussed.

Objectives: Visual hallucinations (VH) are common in Lewy body disease (LBD), and have been associated with cognitive and structural brain alterations. Evidence so far concerns mainly Parkinson’s disease (PD), but little is known about symptom-specific pathophysiological mechanisms across the LBD spectrum, especially related to the presence of dementia. The aim of the present pilot study was to investigate the neuroanatomical, and neuropsychological characteristics related to VH in two forms of LBD, namely dementia with Lewy bodies (DLB) and PD without dementia. Methods: Whole brain voxel-based morphometry (VBM) analyses on 3D MRI acquired structural brain scans, and neuropsychological testing were performed on 28 clinically diagnosed DLB (11 with VH, 17 NVH), and 24 PD (9 with VH, and 15 NVH) patients. In order to assess differences in gray matter (GM) regional volumes, and cognitive performance, hallucinating patients for each group were compared with corresponding non-hallucinating ones. Results: DLB patients with VH presented significantly worse visual attention deficits compared to those without, which persisted even when controlling for visual perception. Whole brain VBM analysis revealed decreased GM volume in DLB with VH in the right superior and medial frontal gyri, putamen, caudate nucleus and insula. Subcortical regional volumes were also significantly associated with visual attention performance. Hallucinating PD patients, instead, presented more severe executive dysfunction, but VBM showed no volumetric differences between the two PD subgroups. Post hoc region of interest analyses revealed striatal GM loss in PD with VH. Conclusion: Frontal and striatal GM atrophy may contribute to the emergence of VH in DLB, which may be fostered by the more severe attention deficits. Striatal GM loss and executive dysfunction, instead, appeared to underlie VH in PD without dementia.

We investigated in a longitudinal multicenter cohort study functional cortical connectivity changes along the course of frontotemporal dementia (FTD) and Alzheimer’s disease (AD) from the prodromal stage of the diseases. Electroencephalography (EEG) was recorded in 18 FTD and 18 AD patients at the prodromal stage of dementia, at dementia onset, and 3 years after dementia onset. Twenty healthy controls (HC) underwent EEG recordings at the same time interval as the patients. Mutual information (MI) analysis measured the strength of functional network connectivity. FTD and AD patients showed greater MI at the prodromal stage of dementia (FTD vs. HC P = 2 × 10−8; AD vs. HC P = 4 × 10–3). Local connectivity was higher in left and right frontal areas of FTD (P = 7 × 10−5 and 0.03) and in left and right posterior areas in AD (P = 3 × 10−5 and 5 × 10−5) versus HC. We showed cortical hyperconnectivity at the prodromal stage of dementia in areas involved in the specific pathological process of FTD (frontal regions) and AD (posterior regions). Hyperconnectivity disappeared during follow-up, thus suggesting that it is an early electrophysiological feature of dementia, potentially useful to identify prodromal FTD and AD.

Dementia in Lewy Body Diseases (Parkinson’s disease and dementia with Lewy Bodies) affects progression of disabilities, quality of life and well-being. Understanding its pathogenetic mechanisms is critical to properly implement disease-modifying strategies. It has been hypothesized that synuclein- and amyloid-pathology act synergistically aggravating cognitive decline in elderly patients but their precise contribution to dementia is debated. In this study, we aimed at exploring if presence of amyloid deposits influences clinical, cognitive and neuroanatomical correlates of mental decline in a cohort of 40 Parkinson’s disease patients with normal cognition (n = 5), mild cognitive impairment (n = 22), and dementia (n = 13) as well as in Dementia with Lewy Bodies (n = 10). Patients underwent simultaneous 3 T PET/MRI with [18F]-flutemetamol and were assessed with an extensive baseline motor and neuropsychological examination, which allowed level II diagnosis of mild cognitive impairment and dementia. The role of amyloid positivity on each cognitive domain, and on the rate of conversion to dementia at 1-year follow-up was explored. A Kaplan Meier and the Log Rank (Mantel–Cox) test were used to assess the pairwise differences in time-to-develop dementia in Parkinson’s disease patients with and without significant amyloidosis. Furthermore, the presence of an Alzheimer’s dementia-like morphological pattern was evaluated using visual and automated assessment of T1-weighted and T2-weighted MRI images. We observed similar percentage of amyloid deposits in Parkinson’s disease dementia and dementia with Lewy Bodies cohorts (50% in each group) with an overall prevalence of 34% of significant amyloid depositions in Lewy Body Diseases. PET amyloid positivity was associated with worse global cognition (Montreal Cognitive Assessment and Mini Mental State Examination), executive and language difficulties. At 12-month follow-up, amyloid positive Parkinson’s disease patients were more likely to have become demented than those without amyloidosis. Moreover, there was no difference in the presence of an Alzheimer’s disease-like atrophy pattern and in vascular load (at Fazekas scale) between Lewy Body Diseases with and without significant amyloid deposits. Our findings suggest that in Lewy Body Diseases, amyloid deposition enhances cognitive deficits, particularly attention-executive and language dysfunctions. However, the large number of patients without significant amyloid deposits among our cognitively impaired patients indicates that synuclein pathology itself plays a critical role in the development of dementia in Lewy Body Diseases., Biundo et al. used PET/3TMRI to study amyloidosis influence on cognition and conversion to dementia in Lewy Body disorders. A similar percentage of patients were amyloid-β negative, but general cognition was more severe and conversion to dementia was faster in amyloid-β positive. Amyloid-β contributes to cognitive decline in Lewy Body disorders., Graphical Abstract Graphical Abstract

IntroductionPrevious studies showed that quarantine for pandemic diseases is associated with several psychological and medical effects. The consequences of quarantine for COVID-19 pandemic in patients with dementia are unknown. We investigated the clinical changes in patients with Alzheimer’s disease and other dementias, and evaluated caregivers’ distress during COVID-19 quarantine.MethodsThe study involved 87 Italian Dementia Centers. Patients with Alzheimer’s Disease (AD), Dementia with Lewy Bodies (DLB), Frontotemporal Dementia (FTD), and Vascular Dementia (VD) were eligible for the study. Family caregivers of patients with dementia were interviewed by phone in April 2020, 45 days after quarantine declaration. Main outcomes were patients’ changes in cognitive, behavioral, and motor symptoms. Secondary outcomes were effects on caregivers’ psychological features.Results4913 patients (2934 females, 1979 males) fulfilled the inclusion criteria. Caregivers reported a worsening in cognitive functions in 55.1% of patients, mainly in subjects with DLB and AD. Aggravation of behavioral symptoms was observed in 51.9% of patients. In logistic regression analysis, previous physical independence was associated with both cognitive and behavioral worsening (odds ratio 1.85 [95% CI 1.42–2.39], 1.84 [95% CI 1.43–2.38], respectively). On the contrary, pandemic awareness was a protective factor for the worsening of cognitive and behavioral symptoms (odds ratio 0.74 [95% CI 0.65–0.85]; and 0.72 [95% CI 0.63–0.82], respectively). Approximately 25.9% of patients showed the onset of new behavioral symptoms. A worsening in motor function was reported by 36.7% of patients. Finally, caregivers reported a high increase in anxiety, depression, and distress.ConclusionOur study shows that quarantine for COVID-19 is associated with an acute worsening of clinical symptoms in patients with dementia as well as increase of caregivers’ burden. Our findings emphasize the importance to implement new strategies to mitigate the effects of quarantine in patients with dementia.

Trazodone is indicated for the treatment of Major Depressive Disorder (MDD), often associated with anxiety, insomnia, agitation, nervousness, or irritability.The aim of this review was to summarise the pharmacological proper- ties of trazodone in improving depressive symptoms in elderly patients and in patients with neurological comorbidities, for whom secondary depression is often present.Five different pharmaceutical formulations of trazodone are available: intravenous or intramuscular liquid solution, immediate-release tablets (I.R.), oral drops, prolonged-release tablets (P.R.), and extended-release Contramid® tablets (COAD). The initial dose of trazodone should range from 75 to 100 mg/day. For COAD formulation, the starting recom- mended dose is 150 mg once daily. In elderly patients, trazodone may be administered at very low dosages (25-50 mg/day for I.R. formula- tion, and 50-100 mg for the P.R. or E.R. formulations). The maximum daily dose should not exceed 300 mg/day, split over two administra- tions across the day.In elderly patients, trazodone has reported excellent results, keeping high-quality standards for safety and tolerability. It can help to improve insomnia and anxiety without resorting to benzodiazepines. In patients with neurological conditions, trazodone helps to treat anxiety-depres- sive symptoms. In patients with Alzheimer’s disease or frontotemporal dementia, trazodone can help to handle behavioural symptoms, also acting as a putative neuroprotective agent.Trazodone is well tolerated. Somnolence/sedation, dizziness, consti- pation, and blurred vision are common side effects with an incidence slightly greater than 5%. Orthostatic hypotension and headache are relatively common side effects.The great availability of formulations allows to personalise trazodone administration according to patient profile characteristics.

Background: In March 2020, the World Health Organization declared a global pandemic due to the novel coronavirus SARS-CoV-2 and several governments planned a national quarantine in order to control the virus spread. Acute psychological effects of quarantine in frail elderly subjects with special needs, such as patients with dementia, have been poorly investigated. The aim of this study was to assess modifications of neuropsychiatric symptoms during quarantine in patients with dementia and their caregivers. Methods: This is a sub-study of a multicenter nation-wide survey. A structured telephone interview was delivered to family caregivers of patients with diagnosis of Alzheimer disease (AD), dementia with Lewy bodies (DLB), frontotemporal dementia (FTD), and vascular dementia (VD), followed regularly at 87 Italian memory clinics. Variations in behavioral and psychological symptoms (BPSD) were collected after 1 month since quarantine declaration and associations with disease type, severity, gender, and caregiver’s stress burden were analyzed. Results: A total of 4,913 caregivers participated in the survey. Increased BPSD was reported in 59.6% of patients as worsening of preexisting symptoms (51.9%) or as new onset (26%), and requested drug modifications in 27.6% of these cases. Irritability, apathy, agitation, and anxiety were the most frequently reported worsening symptoms and sleep disorder and irritability the most frequent new symptoms. Profile of BPSD varied according to dementia type, disease severity, and patients’ gender. Anxiety and depression were associated with a diagnosis of AD (OR 1.35, CI: 1.12–1.62), mild to moderate disease severity and female gender. DLB was significantly associated with a higher risk of worsening hallucinations (OR 5.29, CI 3.66–7.64) and sleep disorder (OR 1.69, CI 1.25–2.29), FTD with wandering (OR 1.62, CI 1.12–2.35), and change of appetite (OR 1.52, CI 1.03–2.25). Stress-related symptoms were experienced by two-thirds of caregivers and were associated with increased patients’ neuropsychiatric burden (p

Cortical network modularity underpins cognitive functions, so we hypothesized its progressive derangement along the course of frontotemporal (FTD) and Alzheimer's (AD) dementing diseases. EEG was recorded in 18 FTD, 18 AD, and 20 healthy control s (HC). In the FTD and AD patients, the EEG recordings were performed at the prodromal stage of dementia, at the onset of dementia, and three years after the onset of dementia. HC underwent three EEG recordings at 2-3-year time interval. Information flows underlying EEG activity recorded at electrode pairs were estimated by means of Mutual Information (MI) analysis. The functional organization of the cortical network was modelled by means of the Graph theory analysis on MI adjacency matrices. Graph theory analysis showed that the main hub of HC (Parietal area) was lost in FTD patients at onset of dementia, substituted by provincial hubs in frontal leads. No changes in global network organization were found in AD. Despite a progressive cognitive impairment during the FTD and AD progression, only the FTD patients showed a derangement in the cortical network modularity, possibly due to dysfunctions in frontal functional connectivity.

Transcranial sonography (TCS) of the brain parenchyma detects alterations in the substantia nigra (SN), raphe nuclei and basal ganglia; this technique has been established as a tool for the early diagnosis of Parkinson's disease and differential diagnosis from atypical parkinsonian syndromes. Here, we aimed to review the main applications of TCS in neurodegenerative diseases presenting with dementia syndrome, focusing on Alzheimer's disease (AD), dementia with Lewy bodies (DLB), frontotemporal lobar degeneration, idiopathic normal pressure hydrocephalus, and atypical and secondary parkinsonisms. The finding of bilaterally marked hyperechogenicity of the SN appears as a characteristic feature of DLB, while it is found only in a minority of AD patients. SN hyperechogenicity is also detected in most patients with corticobasal degeneration and in about one third of patients with progressive supranuclear palsy, in which is constantly associated with hyperechogenic alterations of the basal ganglia. In conclusion, TCS is a valid supportive tool in the diagnostic workup of patients with dementia due to different neurodegenerative conditions. A promising new application is the differentiation of DLB from AD even at the early stages of these diseases.

Introduction: A few 18F-FDG (FDG) PET-CT studies revealed the presence of brain hypermetabolism in the brainstem and cervical spinal cord of patients within the Amyotrophic Lateral Sclerosis - Frontotemporal Dementia (ALS/FTD) spectrum. We aim to investigate this finding through a hybrid PET-MR system, allowing a more precise spatial pattern of metabolic changes in the brainstem and cervical spinal cord. Methods: Twenty-eight patients with a diagnosis of ALS or behavioural variant FTD plus motoneuron disease and 13 healthy subjects underwent 18F-FDG PET-MR study. Mean normalized FDG uptake values in the midbrain/pons, medulla oblongata, and cervical spinal cord defined on individual's MR scans were compared between groups. Furthermore, the associations between regional FDG uptake values and clinical and demographic characteristics, including gene mutation, type of onset (bulbar, spinal, dementia), and clinical characteristics were investigated. Results: A significant (P < 0.005) increment in glucose metabolism in the midbrain/pons and medulla oblongata was found in ALS/FTD patients in comparison to controls, independent from the type of disease onset. No relevant associations between clinical and metabolic features were reported, although medulla oblongata hypermetabolism was associated with shortened survival (P < 0.001). Conclusion: Increased glucose metabolism in the brainstem might be due to the local activation of astrocytes. FDG PET/MR could be a valuable tool to assess glial changes in the ALS/FTD spectrum and could serve as a prognostic biomarker. Large prospective initiatives would likely shed more light on the promising application of PET/MR in this setting.

BACKGROUND Standard measures of commonly used memory tests may not be appropriate to distinguish different neurodegenerative diseases affecting memory. OBJECTIVE To study whether specific measures of verbal memory obtained with the Rey Auditory Verbal Learning test (RAVLT) could help distinguish dementia with Lewy bodies (DLB) from Alzheimer's disease (AD). METHODS Twenty-nine DLB and 32 AD patients participated in the study and were followed longitudinally for 3 years until the diagnosis was confirmed according to standard clinical criteria. Twenty-eight healthy elderly subjects served as controls. The following verbal memory measures were evaluated: verbal learning (VL), verbal forgetting (VF), percentage of verbal forgetting (VF%), and serial position effects of the immediate recall performance. RESULTS DLB and AD groups have comparable performances at the RAVLT immediate and delayed recall tasks. However, VL was higher in DLB than AD while VF% was greater in AD. With a VF% cut-off ≥75%, AD and DLB patients were differently distributed, with 58% of AD versus 21% of DLB above this cut-off. The recency effect was significant higher in AD than DLB. DISCUSSION DLB patients had a better performance in VL than AD, but worse VF and recency effect. These specific measures of verbal memory could be used as cognitive markers in the differential diagnosis between these two conditions.

In May 2017 some representatives of the Italian nuclear medicine and neurological communities spontaneously met to discuss the issues emerged during the first two years of routine application of amyloid PET with fluorinated radiopharmaceuticals in the real world. The limitations of a binary classification of scans, the possibility to obtain early images as a surrogate marker of regional cerebral bloos flow, the need for (semi-)quantification and, thus, the opportunity of ranking brain amyloidosis, the correlation with Aβ42 levels in the cerebrospinal fluid, the occurrence and biological meaning of uncertain/boderline scans, the issue of incidental amyloidosis, the technical pittfalls leading to false negative/positive results, the position of the tool in the diagnostic flow-chart in the national reality, are the main topics that have been discussed. Also, a card to justify the examination to be filled by the dementia specialist and a card for the nuclear medicine physician to report the exam in detail have been approved and are available in the web, which should facilitate the creation of a national register, as previewed by the 2015 intersocietal recommendation on the use of amyloid PET in Italy. The content of this discussion could stimulate both public institutions and companies to support further research on these topics.

We applied RT-QuIC assay to detect α-synuclein aggregates in cerebrospinal fluid (CSF) of patients with suspected Creutzfeldt–Jakob disease who had a neuropathological diagnosis of dementia with Lewy bodies (DLB) (n=7), other neurodegenerative diseases with α-synuclein mixed pathology (n=20), or without Lewy-related pathology (n=49). The test had a sensitivity of 92.9% and specificity of 95.9% in distinguishing α-synucleinopathies from non-α-synucleinopathies. When performed in the CSF of patients with DLB (n=36), RT-QuIC was positive in 17/20 with probable DLB, 0/6 with possible DLB, and 0/10 with Alzheimer disease. These results indicate that RT-QuIC for α-synuclein is an accurate test for DLB diagnosis.

An asymptomatic 74-year-old woman, on follow-up for a carotid body tumor, showed magnetic resonance imaging (MRI) focal restricted diffusion confined to the left temporal and occipital cortices. Thirteen months later, diffusion-weighted images revealed a bilateral cortical ribbon sign involving all lobes. After 1 month, the patient developed gait instability and cognitive decline rapidly evolving to severe dementia and death within 3 months. Prion protein gene sequence, molecular, and neuropathological studies confirmed the diagnosis of sporadic Creutzfeldt-Jakob disease (sCJD) MM1 subtype. Here we show the kinetics of MRI changes and prion spreading in preclinical sCJD MM1. Ann Neurol 2016;80:629-632.

Neural Plasticity is an interdisciplinary journal dedicated to the publication of articles related to all aspects of neural plasticity, with special emphasis on its functional significance as reflected in behavior and in psychopathology.

Background and purpose Acute onset of amnestic syndrome may represent a challenging diagnostic issue. In addition to non-vascular etiology, thalamic strokes or infarction involving several temporal lobe structures have been reported. Methods We describe three patients in whom an isolated bilateral anterior fornix infarction presented with an acute amnestic syndrome. Clinical presentation, differential diagnosis and magnetic resonance images are discussed for each patient and vascular anatomy of the involved brain regions is also considered. Results Bilateral anterior columns of the fornix showed cytotoxic edema and bilateral narrowing of anterior cerebral artery was demonstrated. Conclusions We suggest that bilateral fornix infarction should always be considered in the diagnostic work-up of an amnestic syndrome with acute onset.

BACKGROUND Idiopathic normal-pressure hydrocephalus (iNPH) can resemble or occur in combination with other brain disorders frequently present in the elderly such as Alzheimer's disease (AD) and dementia with Lewy bodies (DLB). OBJECTIVE To study the accuracy of a simplified callosal angle measure in differentiating iNPH from DLB and AD using conventional brain MRI. METHODS 76 patients (24 iNPH, 30 DLB, 22 AD) and 40 healthy controls served as discovering cohort. The callosal angle measure was obtained on standard coronal brain MRI images crossing the corpus callosum midpoint. 41 patients (21 iNPH and 20 DLB/AD) were used as independent validation cohort. A set of other conventional MRI markers of iNPH was also evaluated. RESULTS iNPH showed a significantly decreased mean callosal angle value compared to both disease groups and controls (iNPH = 109±9; DLB = 136.9±8.2; AD = 135.4±11.3; Controls = 138.5±5.2; p < 0.00001). Using a cut off angle of 123, derived by the mean -3SD of the control group, an accuracy of 96% (sensitivity 100% , specificity 95.4% ) was obtained. By ROC analysis, the area under the curve was 0.99 (95% CI: 0.97-1). The measure was consistent (intra-rater: r = 0.94) and reproducible (inter-rater: r = 0.89). In the validation cohort, this cut off angle value discriminated iNPH from DLB/AD with 97.5% accuracy. None of the conventional MRI signs reached the same accuracy. CONCLUSIONS This simplified callosal angle measure represents an accurate, reproducible, and easy marker of iNPH.

Preservation of calculation processing in brain surgery is crucial for patients' quality of life. Over the last decade, surgical electrostimulation was used to identify and preserve the cortical areas involved in such processing. Conversely, subcortical connectivity among different areas implicated in this function remains unclear, and the role of surgery in this domain has not been explored so far. The authors present the first 2 cases in which the subcortical functional sites involved in calculation were identified during right parietal lobe surgery. Two patients affected by a glioma located in the right parietal lobe underwent surgery with the aid of MRI neuronavigation. No calculation deficits were detected during preoperative assessment. Cortical and subcortical mapping were performed using a bipolar stimulator. The current intensity was determined by progressively increasing the amplitude by 0.5-mA increments (from a baseline of 1 mA) until a sensorimotor response was elicited. Then, addition and multiplication calculation tasks were administered. Corticectomy was performed according to both the MRI neuronavigation data and the functional findings obtained through cortical mapping. Direct subcortical electrostimulation was repeatedly performed during tumor resection. Subcortical functional sites for multiplication and addition were detected in both patients. Electrostimulation interfered with calculation processing during cortical mapping as well. Functional sites were spared during tumor removal. The postoperative course was uneventful, and calculation processing was preserved. Postoperative MRI showed complete resection of the tumor. The present preliminary study shows for the first time how functional mapping can be a promising method to intraoperatively identify the subcortical functional sites involved in calculation processing. This report therefore supports direct electrical stimulation as a promising tool to improve the current knowledge on calculation processing connectivity.

A novel neuronal tauopathy, mainly confined to hypothalamus and brainstem tegmentum, has recently been reported in patients with autoantibodies to the neuronal cell-adhesion molecule IgLON5. We describe a patient with anti-IgLON5 syndrome, who presented with dysautonomia and sleep disorder, followed by subacute dementia. Postmortem brain examination disclosed neuronal tau pathology prevailing in the hippocampus, amygdala, and locus coeruleus, in addition to microglial/neuronal TDP-43 pathology, with overexpression of aberrantly phosphorylated forms and neurotoxic truncated fragments, in basal ganglia, nucleus basalis, thalamus, and midbrain. These findings suggest that neurodegeneration in anti-IgLON5 syndrome might also occur via a microglia-triggered non-cell autonomous pathway.

Compromised liver function, as a consequence of acute liver insufficiency or severe chronic liver disease may be associated with various neurological syndromes, which involve both central and peripheral nervous system. Acute and severe hyperammoniemia inducing cellular metabolic alterations, prolonged state of "neuroinflammation", activation of brain microglia, accumulation of manganese and ammonia, and systemic inflammation are the main causative factors of brain damage in liver failure. The most widely recognized neurological complications of serious hepatocellular failure include hepatic encephalopathy, diffuse cerebral edema, Wilson disease, hepatic myelopathy, acquired hepatocerebral degeneration, cirrhosis-related Parkinsonism and osmotic demyelination syndrome. Neurological disorders affecting liver transplant candidates while in the waiting list may not only significantly influence preoperative morbidity and even mortality, but also represent important predictive factors for post-transplant neurological manifestations. Careful pre-transplant neurological evaluation is essential to define severity and distribution of the neurological impairment, to identify the abnormalities still responsive to current treatment, and to potentially predict the inherent post-operative prognosis. The preferred specific indices of neurological pre-transplant assessment may vary among centers, however, even with the aid of the current biochemical, neurophysiological, neuropsychological and neuroimaging diagnostic tools, the correct diagnosis and differential diagnosis of various syndromes may be difficult. In this article the relevant pathophysiological and clinical aspects of the most frequent brain and peripheral nervous system diseases affecting liver transplant candidates with acute or advanced chronic liver failure are briefly reported. The practical diagnostic findings useful for the preoperative assessment and treatment, as well as the expected neurological evolution after liver transplantation are also evaluated.

In the initial evaluation of patients with suspected dementia and Alzheimer’s disease, there is no consensus on how to perform semiquantification of amyloid in such a way that it: (1) facilitates visual qualitative interpretation, (2) takes the kinetic behaviour of the tracer into consideration particularly with regard to at least partially correcting for blood flow dependence, (3) analyses the amyloid load based on accurate parcellation of cortical and subcortical areas, (4) includes partial volume effect correction (PVEC), (5) includes MRI-derived topographical indexes, (6) enables application to PET/MRI images and PET/CT images with separately acquired MR images, and (7) allows automation. A method with all of these characteristics was retrospectively tested in 86 subjects who underwent amyloid (18F-florbetaben) PET/MRI in a clinical setting (using images acquired 90–110 min after injection, 53 were classified visually as amyloid-negative and 33 as amyloid-positive). Early images after tracer administration were acquired between 0 and 10 min after injection, and later images were acquired between 90 and 110 min after injection. PVEC of the PET data was carried out using the geometric transfer matrix method. Parametric images and some regional output parameters, including two innovative “dual time-point” indexes, were obtained. Subjects classified visually as amyloid-positive showed a sparse tracer uptake in the primary sensory, motor and visual areas in accordance with the isocortical stage of the topographic distribution of the amyloid plaque (Braak stages V/VI). In patients classified visually as amyloid-negative, the method revealed detectable levels of tracer uptake in the basal portions of the frontal and temporal lobes, areas that are known to be sites of early deposition of amyloid plaques that probably represented early accumulation (Braak stage A) that is typical of normal ageing. There was a strong correlation between age and the indexes of the new dual time-point amyloid imaging method in amyloid-negative patients. The method can be considered a valuable tool in both routine clinical practice and in the research setting as it will standardize data regarding amyloid deposition. It could potentially also be used to identify early amyloid plaque deposition in younger subjects in whom treatment could theoretically be more effective.

A clearer definition of the role of neurofilament light chain (NFL) as a biomarker in amyotrophic lateral sclerosis (ALS) is needed.To assess the ability of NFL to serve as a diagnostic biomarker in ALS and the prognostic value of cerebrospinal fluid NFL in patients with ALS.In this single-center, retrospective, longitudinal study, disease progression was assessed by the ALS Functional Rating Score-Revised and the ALS Milano-Torino Staging system at baseline and 6, 12, 24, and 36 months. Cerebrospinal fluid samples were obtained from 176 patients admitted to the Department of Neurosciences of the University of Padua, Padova, Italy, from January 1, 2010, through February 29, 2016. Patients with ALS underwent ambulatory follow-up at the same department.Levels of NFL.The study included 94 patients with ALS (64 men [36.4%] and 30 women [17.0%]; median age, 62.5 years), 20 patients with frontotemporal dementia (FTD) (8 men [4.5%] and 12 women [6.8%]; median age, 65 years), 18 patients with motor neuropathies (14 men [8.0%] and 4 women [2.3%]; median age, 63 years), and 44 controls (24 men [13.6%] and 20 women [11.4%]; median age, 54 years). Log-transformed NFL (log[NFL]) concentrations were higher in the ALS and FTD groups compared with the motor neuropathies and control groups (hazard ratio [HR], 2.45; 95% CI, 1.66-3.61; P .001). Patients with typical ALS (HR, 1.0 [reference]), progressive bulbar palsy (HR, 1.48; 95% CI, 0.58-3.75; P = .41), and upper motor neuron dominant ALS (HR, 0.12; 95% CI, 0.02-0.61; P = .01) had higher levels of NFL than did those with flail arm or leg syndrome (HR, 0.28; 95% CI, 0.08-0.10; P = .049) and progressive muscular atrophy (HR, 0.17; 95% CI, 0.22-1.36; P = .10). There was an inverse correlation between log[NFL] concentration and overall survival (HR, 2.45; 95% CI, 1.66-3.61; P .001). There was no evidence of different log[NFL] concentrations and survival in genetic ALS.This study confirms the role of NFL as a biomarker in ALS. Elevation in NFL levels in patients with upper motor neuron involvement and FTD might reflect the corticospinal tract degeneration. Low NFL levels in patients with lower motor neuron signs might be a prognostic indicator of milder phenotypes of disease.

Nela Jelcic,1 Michela Agostini,1 Francesca Meneghello,1 Cinzia Bussè,2 Sara Parise,2 Antonietta Galano,2 Paolo Tonin,1 Mauro Dam,1 Annachiara Cagnin1,2 1Foundation IRCCS San Camillo Hospital, Laboratory of Kinematics and Robotics and Laboratory of Psychology, Neurorehabilitation Department, Venice, Italy; 2Department of Neurosciences: Sciences NPSRR, University of Padova, Padova, Italy Background: This pilot study compared the effects of lexical-semantic stimulation through telecommunication technology (LSS-tele) with in-person LSS (LSS-direct) and unstructured cognitive treatment (UCS) in patients with early Alzheimer’s disease.Methods: Twenty-seven patients with Alzheimer’s disease in the very early stage (Mini-Mental State Examination [MMSE] >26/30) were divided into three groups: seven patients received LSS-tele treatment, ten received standard LSS-direct intervention, and ten participants underwent UCS as control condition. Intervention treatments consisted of two weekly sessions of LSS (through teleconference or face to face depending on group assignment) or UCS exercises administered to small groups throughout a 3-month period. The main outcome measures were changes of global cognitive performance, language abilities, and memory function. Secondary outcome measures were changes in attention, working memory, executive functions, and visual-spatial abilities tests.Results: The mean MMSE score improved significantly in LSS-tele and LSS-direct treatments; LSS-tele improved language abilities, both phonemic and semantic, and stabilized delayed verbal episodic memory with respect to an improved performance after the LSS-direct intervention and to a memory decline observed in the control group. Improvement was not achieved in any neuropsychological test score after UCS.Conclusion: Clinical application of telecommunication technology to cognitive rehabilitation of elderly patients with neurodegenerative cognitive impairment is feasible and may improve global cognitive performance. Technical aspects to ameliorate efficacy of delivery may further improve its impact on domain-specific cognitive abilities. Keywords: cognitive rehabilitation, telecommunication, telemedicine

Importance Early and accurate in vivo diagnosis of Creutzfeldt-Jakob disease (CJD) is necessary for quickly distinguishing treatable from untreatable rapidly progressive dementias and for future therapeutic trials. This early diagnosis is becoming possible using the real-time quaking-induced conversion (RT-QuIC) seeding assay, which detects minute amounts of the disease-specific pathologic prion protein in cerebrospinal fluid (CSF) or olfactory mucosa (OM) samples. Objective To develop an algorithm for accurate and early diagnosis of CJD by using the RT-QuIC assay on CSF samples, OM samples, or both. Design, Setting, and Participants In this case-control study, samples of CSF and OM were collected from 86 patients with a clinical diagnosis of probable (n = 51), possible (n = 24), or suspected (n = 11) CJD and 104 negative control samples (54 CSF and 50 OM). The CSF and OM samples were analyzed using conventional RT-QuIC. The CSF samples underwent further testing using improved RT-QuIC conditions. In addition, the diagnostic performance of a novel, easy-to-use, gentle flocked swab for sampling of OM was evaluated. Data were collected from January 1 to June 30, 2015. Main Outcome and Measures Correlations between RT-QuIC results and the final diagnosis of recruited patients. Results Among the 86 patients (37 men [43%] and 49 women [57%]; mean [SD] age, 65.7 [11.5] years) included for analysis, all 61 patients with sporadic CJD had positive RT-QuIC findings using OM or CSF samples or both for an overall RT-QuIC diagnostic sensitivity of 100% (95% CI, 93%-100%). All patients with a final diagnosis of non–prion disease (71 CSF and 67 OM samples) had negative RT-QuIC findings for 100% specificity (95% CI, 94%-100%). Of 8 symptomatic patients with various mutations causing CJD or Gerstmann-Straussler-Scheinker syndrome, 6 had positive and 2 had negative RT-QuIC findings for a sensitivity of 75% (95% CI, 36%-96%). Conclusions and Relevance A proposed diagnostic algorithm for sporadic CJD combines CSF and OM RT-QuIC testing to provide virtually 100% diagnostic sensitivity and specificity in the clinical phase of the disease.

BACKGROUND Alterations of the sleep-wake cycle are common features of neurodegenerative dementia. OBJECTIVES To study differences in sleep-wake profiles in dementia with Lewy bodies (DLB), Alzheimer's disease (AD), and healthy controls. METHODS 30 DLB and 32 AD patients, and 33 healthy elderly participants were studied. Patients were evaluated for global cognitive impairment, extrapyramidal signs, fluctuations of attention, and behavioral disorders. A comprehensive sleep-wake profile was obtained including a set of questionnaires [Pittsburgh Sleep Quality Index (PSQI), REM Sleep Behavior Disorder Single-Question screen (RBD1Q), Epworth Sleepiness Scale (ESS)] and 12-day sleep diaries. RESULTS Patients were matched for age, gender, and disease severity. DLB patients showed more severe daytime somnolence/dysfunction due to somnolence, and a higher proportion of RBD-like symptoms (70%) compared to AD and controls (p

Objective: To explore the efficacy of spinal MRI study with subtraction analysis as a rapid, reliable, and noninvasive procedure to detect epidural CSF collection in spontaneous intracranial hypotension (SIH) syndrome. Methods: Seventeen patients (mean age 42 years, age range 17–65 years; 11 female) with SIH diagnosed using the International Classification of Headache Disorders criteria and 13 age-matched control subjects underwent standard sagittal spinal MRI. Postprocessing image analysis with subtraction of T1-weighted from T2-weighted MRI scans was performed and tested for the detection of the CSF leak. Results: The CSF epidural collection was visible in all patients with SIH and was detected at the dorsal (16 of 17), cervical (13 of 17), lumbar (13 of 17), and sacral (12 of 17) levels. None of the control subjects showed a CSF leak. Diverticula were present in 23% of patients, whereas the actual site of the CSF leak was recognized in only one patient. Eight patients were treated conservatively, whereas 9 patients required an epidural blood patch, performed at a fixed L2–L3 or L3–L4 spinal level, with complete recovery. Conclusions: Spinal MRI with dedicated subtraction analysis could represent the first-line diagnostic tool in the management of patients with SIH, thus leaving invasive investigation for selected patients, such those requiring dural surgery.