Does hyperphenylalaninemia induce brain glucose hypometabolism? Cerebral spinal fluid findings in treated adult phenylketonuric patients.

Despite numerous studies in human patients and animal models for phenylketonuria (PKU; OMIM#261600), the pathophysiology of PKU and the underlying causes of brain dysfunction and cognitive problems in PKU patients are not well understood. In this study, lumbar cerebral spinal fluid (CSF) was obtained immediately after blood sampling from early-treated adult PKU patients who had fasted overnight. Metabolite and amino acid concentrations in the CSF of PKU patients were compared with those of non-PKU controls. The CSF concentrations and CSF/plasma ratios for glucose and lactate were found to be below normal, similar to what has been reported for glucose transporter1 (GLUT1) deficiency patients who exhibit many of the same clinical symptoms as untreated PKU patients. CSF glucose and lactate levels were negatively correlated with CSF phenylalanine (Phe), while CSF glutamine and glutamate levels were positively correlated with CSF Phe levels. Plasma glucose levels were negatively correlated with plasma Phe concentrations in PKU subjects, which partly explains the reduced CSF glucose concentrations. Although brain glucose concentrations are unlikely to be low enough to impair brain glucose utilization, it is possible that the metabolism of Phe in the brain to produce phenyllactate, which can be transported across the blood-brain barrier to the blood, may consume glucose and/or lactate to generate the carbon backbone for glutamate. This glutamate is then converted to glutamine and carries the Phe-derived ammonia from the brain to the blood. While this mechanism remains to be tested, it may explain the correlations of CSF glutamine, glucose, and lactate concentrations with CSF Phe.

Metabolic network alterations as a supportive biomarker in dementia with Lewy bodies with preserved dopamine transmission.

PURPOSE: Metabolic network analysis of FDG-PET utilizes an index of inter-regional correlation of resting state glucose metabolism and has been proven to provide complementary information regarding the disease process in parkinsonian syndromes. The goals of this study were (i) to evaluate pattern similarities of glucose metabolism and network connectivity in dementia with Lewy bodies (DLB) subjects with subthreshold dopaminergic loss compared to advanced disease stages and to (ii) investigate metabolic network alterations of FDG-PET for discrimination of patients with early DLB from other neurodegenerative disorders (Alzheimer's disease, Parkinson's disease, multiple system atrophy) at individual patient level via principal component analysis (PCA). METHODS: FDG-PETs of subjects with probable or possible DLB (n = 22) without significant dopamine deficiency (z-score < 2 in putamen binding loss on DaT-SPECT compared to healthy controls (HC)) were scaled by global-mean, prior to volume-of-interest-based analyses of relative glucose metabolism. Single region metabolic changes and network connectivity changes were compared against HC (n = 23) and against DLB subjects with significant dopamine deficiency (n = 86). PCA was applied to test discrimination of patients with DLB from disease controls (n = 101) at individual patient level. RESULTS: Similar patterns of hypo- (parietal- and occipital cortex) and hypermetabolism (basal ganglia, limbic system, motor cortices) were observed in DLB patients with and without significant dopamine deficiency when compared to HC. Metabolic connectivity alterations correlated between DLB patients with and without significant dopamine deficiency (R2 = 0.597, p < 0.01). A PCA trained by DLB patients with dopamine deficiency and HC discriminated DLB patients without significant dopaminergic loss from other neurodegenerative parkinsonian disorders at individual patient level (area-under-the-curve (AUC): 0.912). CONCLUSION: Disease-specific patterns of altered glucose metabolism and altered metabolic networks are present in DLB subjects without significant dopaminergic loss. Metabolic network alterations in FDG-PET can act as a supporting biomarker in the subgroup of DLB patients without significant dopaminergic loss at symptoms onset.

Increased risk of functional neurological disorders following SARS-CoV-2 vaccination.

BACKGROUND AND PURPOSE: The purpose of this study was to evaluate the possible correlation between SARS-CoV-2 vaccines and the onset of neurological syndromes. The aim was to challenge the association between SARS-CoV-2 vaccinations and the onset of acute functional neurological disorders (FNDs) compared to other neurological syndromes in hospitalized patients. METHODS: In this prospective cohort study, all adult inpatients consecutively admitted to a tertiary neurological centre were included. The prevalence and characteristics of neurological syndromes were compared between unvaccinated and vaccinated cases stratified according to the onset from vaccination. The study involved 843 subjects, namely 411 unvaccinated (UVC) and 432 vaccinated cases; these groups were comparable for demographics and clinical diagnosis distribution. RESULTS: Compared to UVC, subjects hospitalized within the first 30 days from vaccine exhibited higher prevalence of FNDs (12.3% vs. 3.6%; odds ratio 4.2, 95% confidence interval 1.6-11.1) and headache (10.8% vs. 5%; odds ratio 4.1, 95% confidence interval 1.9-8.8) but no other neurological syndromes. The FND cases following vaccinations showed similar premorbid conditions and severity but a higher percentage of sensory symptoms and pain compared to UVC FND cases. CONCLUSIONS: SARS-CoV-2 vaccination is associated with a significant short-term increased risk of FND and headache requiring hospitalization in an acute neurological setting.

Unveiling New Genetic Variants Associated with Age at Onset in Alzheimer's Disease and Frontotemporal Lobar Degeneration Due to C9orf72 Repeat Expansions.

Alzheimer's disease (AD) and Frontotemporal lobar degeneration (FTLD) represent the most common forms of neurodegenerative dementias with a highly phenotypic variability. Herein, we investigated the role of genetic variants related to the immune system and inflammation as genetic modulators in AD and related dementias. In patients with sporadic AD/FTLD (n = 300) and GRN/C9orf72 mutation carriers (n = 80), we performed a targeted sequencing of 50 genes belonging to the immune system and inflammation, selected based on their high expression in brain regions and low tolerance to genetic variation. The linear regression analyses revealed two genetic variants: (i) the rs1049296 in the transferrin (TF) gene, shown to be significantly associated with age at onset in the sporadic AD group, anticipating the disease onset of 4 years for each SNP allele with respect to the wild-type allele, and (ii) the rs7550295 in the calsyntenin-1 (CLSTN1) gene, which was significantly associated with age at onset in the C9orf72 group, delaying the disease onset of 17 years in patients carrying the SNP allele. In conclusion, our data support the role of genetic variants in iron metabolism (TF) and in the modulation of the calcium signalling/axonal anterograde transport of vesicles (CLSTN1) as genetic modulators in AD and FTLD due to C9orf72 expansions.

NF-κB/c-Rel DNA-binding is reduced in substantia nigra and peripheral blood mononuclear cells of Parkinson's disease patients.

Although Parkinson's disease (PD) key neuropathological hallmarks are well known, the underlying pathogenic mechanisms of the disease still need to be elucidated to identify innovative disease-modifying drugs and specific biomarkers. NF-κB transcription factors are involved in regulating several processes associated with neurodegeneration, such as neuroinflammation and cell death, that could be related to PD pathology. NF-κB/c-Rel deficient (c-rel-/-) mice develop a progressive PD-like phenotype. The c-rel-/- mice present both prodromal and motor symptoms as well as key neuropathological features, including nigrostriatal dopaminergic neurons degeneration, accumulation of pro-apoptotic NF-κB/RelA acetylated at the lysine 310 residue (Ac-RelA(lys310)) and progressive caudo-rostral brain deposition of alpha-synuclein. c-Rel inhibition can exacerbate MPTP-induced neurotoxicity in mice. These findings support the claim that misregulation of c-Rel protein may be implicated in PD pathophysiology. In this study, we aimed at evaluating c-Rel levels and DNA-binding activity in human brains and peripheral blood mononuclear cells (PBMCs) of sporadic PD patients. We analyzed c-Rel protein content and activity in frozen substantia nigra (SN) samples from post-mortem brains of 10 PD patients and 9 age-matched controls as well as in PBMCs from 72 PD patients and 40 age-matched controls. c-Rel DNA-binding was significantly lower and inversely correlated with Ac-RelA(lys310) content in post-mortem SN of sporadic PD cases, when compared to healthy controls. c-Rel DNA-binding activity was also reduced in PBMCs of followed-up PD subjects. The decrease of c-Rel activity in PBMCs from PD patients appeared to be independent from dopaminergic medication or disease progression, as it was evident even in early stage, drug-naïve patients. Remarkably, the levels of c-Rel protein were comparable in PD and control subjects, pointing out a putative role for post-translational modifications of the protein in c-Rel dysfunctions. These findings support that PD is characterized by the loss of NF-κB/c-Rel activity that potentially has a role in PD pathophysiology. Future studies will be aimed at addressing whether the reduction of c-Rel DNA-binding could constitute a novel biomarker for PD.

CSF alpha-synuclein aggregates by seed amplification and clinical presentation of AD.

INTRODUCTION: Accumulating evidence suggests that α-synuclein (αSyn) can modulate Alzheimer's disease (AD) pathology. The aim of this study was to evaluate the prevalence and clinical features associated with cerebrospinal fluid (CSF) αSyn detected by seed amplification assay (SAA) in AD. METHODS: Eighty AD patients with CSF AT(N) biomarker positivity (mean age 70.3 ± 7.3 years) and 28 non-AD age-matched controls were included. All subjects underwent standardized clinical assessment; CSF αSyn aggregates were detected by SAA. RESULTS: CSF was αSyn-SAA positive (αSyn+) in 36/80 AD patients (45%) and in 2/28 controls (7.1%). AD αSyn+ and αSyn- patients were comparable for age, disease severity, comorbidity profile, and CSF core biomarkers. AD αSyn+ presented a higher prevalence of atypical phenotypes and symptoms. CONCLUSIONS: Our findings demonstrate that concomitant CSF αSyn pathology is present in a significant proportion of AD patients starting in the early stages and can affect clinical presentation. Longitudinal studies are warranted to evaluate the significance for the disease course.

Research diagnostic criteria for mild cognitive impairment with Lewy bodies: A systematic review and meta-analysis.

INTRODUCTION: Operationalized research criteria for mild cognitive impairment with Lewy bodies (MCI-LB) were published in 2020. The aim of this systematic review and meta-analysis was to review the evidence for the diagnostic clinical features and biomarkers in MCI-LB set out in the criteria. METHODS: MEDLINE, PubMed, and Embase were searched on 9/28/22 for relevant articles. Articles were included if they presented original data reporting the rates of diagnostic features in MCI-LB. RESULTS: Fifty-seven articles were included. The meta-analysis supported the inclusion of the current clinical features in the diagnostic criteria. Evidence for striatal dopaminergic imaging and meta-iodobenzylguanidine cardiac scintigraphy, though limited, supports their inclusion. Quantitative electroencephalogram (EEG) and fluorodeoxyglucose positron emission tomography (PET) show promise as diagnostic biomarkers. DISCUSSION: The available evidence largely supports the current diagnostic criteria for MCI-LB. Further evidence will help refine the diagnostic criteria and understand how best to apply them in clinical practice and research. HIGHLIGHTS: A meta-analysis of the diagnostic features of MCI-LB was carried out. The four core clinical features were more common in MCI-LB than MCI-AD/stable MCI. Neuropsychiatric and autonomic features were also more common in MCI-LB. More evidence is needed for the proposed biomarkers. FDG-PET and quantitative EEG show promise as diagnostic biomarkers in MCI-LB.

Dementia with Lewy bodies: Impact of co-pathologies and implications for clinical trial design.

Dementia with Lewy bodies (DLB) is clinically defined by the presence of visual hallucinations, fluctuations, rapid eye movement (REM) sleep behavioral disorder, and parkinsonism. Neuropathologically, it is characterized by the presence of Lewy pathology. However, neuropathological studies have demonstrated the high prevalence of coexistent Alzheimer's disease, TAR DNA-binding protein 43 (TDP-43), and cerebrovascular pathologic cases. Due to their high prevalence and clinical impact on DLB individuals, clinical trials should account for these co-pathologies in their design and selection and the interpretation of biomarkers values and outcomes. Here we discuss the frequency of the different co-pathologies in DLB and their cross-sectional and longitudinal clinical impact. We then evaluate the utility and possible applications of disease-specific and disease-nonspecific biomarkers and how co-pathologies can impact these biomarkers. We propose a framework for integrating multi-modal biomarker fingerprints and step-wise selection and assessment of DLB individuals for clinical trials, monitoring target engagement, and interpreting outcomes in the setting of co-pathologies.

Near-infrared spectroscopy estimation of combined skeletal muscle oxidative capacity and O2 diffusion capacity in humans.

The final steps of the O2 cascade during exercise depend on the product of the microvascular-to-intramyocyte P O 2 ${P}_{{{\rm{O}}}_{\rm{2}}}$ difference and muscle O2 diffusing capacity ( D m O 2 $D{{\rm{m}}}_{{{\rm{O}}}_2}$ ). Non-invasive methods to determine D m O 2 $D{{\rm{m}}}_{{{\rm{O}}}_2}$ in humans are currently unavailable. Muscle oxygen uptake (m V ̇ O 2 ${\dot{V}}_{{{\rm{O}}}_{\rm{2}}}$ ) recovery rate constant (k), measured by near-infrared spectroscopy (NIRS) using intermittent arterial occlusions, is associated with muscle oxidative capacity in vivo. We reasoned that k would be limited by D m O 2 $D{{\rm{m}}}_{{{\rm{O}}}_2}$ when muscle oxygenation is low (kLOW ), and hypothesized that: (i) k in well oxygenated muscle (kHIGH ) is associated with maximal O2 flux in fibre bundles; and (ii) ∆k (kHIGH  - kLOW ) is associated with capillary density (CD). Vastus lateralis k was measured in 12 participants using NIRS after moderate exercise. The timing and duration of arterial occlusions were manipulated to maintain tissue saturation index within a 10% range either below (LOW) or above (HIGH) half-maximal desaturation, assessed during sustained arterial occlusion. Maximal O2 flux in phosphorylating state was 37.7 ± 10.6 pmol s-1  mg-1 (∼5.8 ml min-1  100 g-1 ). CD ranged 348 to 586 mm-2 . kHIGH was greater than kLOW (3.15 ± 0.45 vs. 1.56 ± 0.79 min-1 , P < 0.001). Maximal O2 flux was correlated with kHIGH (r = 0.80, P = 0.002) but not kLOW (r = -0.10, P = 0.755). Δk ranged -0.26 to -2.55 min-1 , and correlated with CD (r = -0.68, P = 0.015). m V ̇ O 2 ${\dot{V}}_{{{\rm{O}}}_{\rm{2}}}$ k reflects muscle oxidative capacity only in well oxygenated muscle. ∆k, the difference in k between well and poorly oxygenated muscle, was associated with CD, a mediator of D m O 2 $D{{\rm{m}}}_{{{\rm{O}}}_2}$ . Assessment of muscle k and ∆k using NIRS provides a non-invasive window on muscle oxidative and O2 diffusing capacity. KEY POINTS: We determined post-exercise recovery kinetics of quadriceps muscle oxygen uptake (m V ̇ O 2 ${\dot{V}}_{{{\rm{O}}}_{\rm{2}}}$ ) measured by near-infrared spectroscopy (NIRS) in humans under conditions of both non-limiting (HIGH) and limiting (LOW) O2 availability, for comparison with biopsy variables. The m V ̇ O 2 ${\dot{V}}_{{{\rm{O}}}_{\rm{2}}}$ recovery rate constant in HIGH O2 availability was hypothesized to reflect muscle oxidative capacity (kHIGH ) and the difference in k between HIGH and LOW O2 availability (∆k) was hypothesized to reflect muscle O2 diffusing capacity. kHIGH was correlated with phosphorylating oxidative capacity of permeabilized muscle fibre bundles (r = 0.80). ∆k was negatively correlated with capillary density (r = -0.68) of biopsy samples. NIRS provides non-invasive means of assessing both muscle oxidative and oxygen diffusing capacity in vivo.

Gender differences in dopaminergic system dysfunction in de novo Parkinson's disease clinical subtypes.

Parkinson's disease (PD) is characterized by heterogeneity in clinical syndromes, prognosis, and pathophysiology mechanisms. Gender differences in neural anatomy and function are emerging as fundamental determinants of phenotypic variability. Different clinical subtypes, defined as mild motor predominant, intermediate, and diffuse-malignant, have been recently proposed in PD. This study investigated gender influence on clinical features, dopaminergic dysfunction, and connectivity in patients with de novo idiopathic PD stratified according to the clinical criteria for subtypes (i.e., mild motor, intermediate, and diffuse-malignant). We included 286 drug-naïve patients (Males/Females: 189/97, age [mean ± standard deviation]: 61.99 ± 9.67; disease duration: 2.08 ± 2.21) with available [123I]FP-CIT-SPECT and high-resolution T1-weighted MRI from the Parkinson's Progression Markers Initiative. We assessed gender differences for clinical and cognitive features, and dopaminergic presynaptic dysfunction in striatal or extra-striatal regions using molecular analysis of [123I]FP-CIT-bindings. We applied an advanced multivariate analytical approach - partial correlations molecular connectivity analyses - to assess potential gender differences in the vulnerability of the nigrostriatal and mesolimbic dopaminergic pathways. In the mild motor and intermediate subtypes, male patients with idiopathic PD showed poorer cognitive performances than females, who - in contrast - presented more severe anxiety symptoms. The male vulnerability emerged also in the motor system in the same subtypes with motor impairment associated with a lower dopamine binding in the putamen and more severe widespread connectivity alterations in the nigrostriatal dopaminergic pathway in males than in females. In the diffuse-malignant subtype, males showed more severe motor impairments, consistent with a lower dopamine uptake in the putamen than females. On the other hand, a severe dopaminergic depletion in several dopaminergic targets of the mesolimbic pathway, together with extensive altered connectivity in the same system, characterized females with idiopathic PD in all the subtypes. The anxiety level was associated with a lower dopaminergic binding in the amygdala only in females. This study provides evidence on gender differences in idiopathic PD across clinical subtypes, and, remarkably, since the early phase. The clinical correlations with the nigrostriatal or mesolimbic systems in males and females support different vulnerabilities and related disease expressions. Gender differences must be considered in a precision medicine approach to preventing, diagnosing, and treating idiopathic PD.

Rivastigmine in Parkinson's Disease Dementia with Orthostatic Hypotension.

OBJECTIVE: The purpose of this study was to evaluate if the cognitive benefit of rivastigmine is affected by the presence of orthostatic hypotension (OH) in patients with Parkinson's disease dementia (PDD). METHODS: We conducted a post hoc analysis on 1,047 patients with PDD from 2 randomized controlled trials comparing rivastigmine versus placebo at week 24 (n = 501) and rivastigmine patch versus capsule at week 76 (n = 546). A drop ≥ 20 mm Hg in systolic blood pressure (SBP) or ≥ 10 in diastolic blood pressure (DBP) upon standing classified subjects as OH positive (OH+); otherwise, OH negative (OH-). The primary end point was the Alzheimer's Disease Assessment Scale - Cognitive subscale (ADAS-Cog) at week 24 and the Mattis Dementia Rating Scale (MDRS) at week 76, using intention-to-treat with retrieved dropout at week 24 and observed cases at week 76, consistent with the original analyses. RESULTS: Overall safety was comparable between OH+ (n = 288, 27.5%) and OH- (n = 730, 69.7%), except for higher frequency of syncope (9.2%) in the OH+ placebo arm. The placebo-adjusted effect of rivastigmine on ADAS-Cog at week 24 was 5.6 ± 1.2 for OH+ and 1.9 ± 0.9 in OH- (p = 0.0165). Among subjects with OH, the MDRS change from baseline at week 76 was higher for rivastigmine capsules versus patch (10.6 ± 2.9 vs -1.5 ± 3.0, p = 0.031). The overall prevalence of OH was lower for rivastigmine than placebo at week 24 (28.3% vs 44.6%, p = 0.0476). INTERPRETATION: The cognitive benefit from rivastigmine is larger in patients with PDD with OH, possibly mediated by a direct antihypotensive effect. ANN NEUROL 2021;89:91-98.

A 3D deep learning model to predict the diagnosis of dementia with Lewy bodies, Alzheimer's disease, and mild cognitive impairment using brain 18F-FDG PET.

PURPOSE: The purpose of this study is to develop and validate a 3D deep learning model that predicts the final clinical diagnosis of Alzheimer's disease (AD), dementia with Lewy bodies (DLB), mild cognitive impairment due to Alzheimer's disease (MCI-AD), and cognitively normal (CN) using fluorine 18 fluorodeoxyglucose PET (18F-FDG PET) and compare model's performance to that of multiple expert nuclear medicine physicians' readers. MATERIALS AND METHODS: Retrospective 18F-FDG PET scans for AD, MCI-AD, and CN were collected from Alzheimer's disease neuroimaging initiative (556 patients from 2005 to 2020), and CN and DLB cases were from European DLB Consortium (201 patients from 2005 to 2018). The introduced 3D convolutional neural network was trained using 90% of the data and externally tested using 10% as well as comparison to human readers on the same independent test set. The model's performance was analyzed with sensitivity, specificity, precision, F1 score, receiver operating characteristic (ROC). The regional metabolic changes driving classification were visualized using uniform manifold approximation and projection (UMAP) and network attention. RESULTS: The proposed model achieved area under the ROC curve of 96.2% (95% confidence interval: 90.6-100) on predicting the final diagnosis of DLB in the independent test set, 96.4% (92.7-100) in AD, 71.4% (51.6-91.2) in MCI-AD, and 94.7% (90-99.5) in CN, which in ROC space outperformed human readers performance. The network attention depicted the posterior cingulate cortex is important for each neurodegenerative disease, and the UMAP visualization of the extracted features by the proposed model demonstrates the reality of development of the given disorders. CONCLUSION: Using only 18F-FDG PET of the brain, a 3D deep learning model could predict the final diagnosis of the most common neurodegenerative disorders which achieved a competitive performance compared to the human readers as well as their consensus.

Do demographic and clinical features and comorbidities affect the risk of spread to an additional body site in functional motor disorders?

The aim of this study is to assess changes in the body distribution and the semeiology of functional motor disorder (FMD) in patients who reported only one or more than one body site affected at FMD onset. Data were obtained from the Italian Registry of Functional Motor Disorders, which included patients with a diagnosis of clinically definite FMDs. The relationship between FMD features and spread to other body sites was estimated by multivariate Cox regression analysis. We identified 201 (49%) patients who reported only one body site affected at FMD onset and 209 (51%) who reported multiple body sites affected at onset. FMD spread from the initial site to another site in 43/201 (21.4%) patients over 5.7 ± 7.1 years in those with only one site affected at FMD onset; FMD spread to an another body site in 29/209 (13.8%) over 5.5 ± 6.5 years. The spread of FMD was associated with non-motor functional symptoms and psychiatric comorbidities only in the patients with one body site affected at FMD onset. Our findings provide novel insight into the natural history of FMD. The number of body sites affected at onset does not seem to have a consistent influence on the risk of spread. Furthermore, our findings suggest that psychiatric comorbidities and non-motor functional symptoms may predict the spread of FMD symptoms, at least in patients with one body site affected at onset.

Rabphilin-3A as a novel target to reverse α-synuclein-induced synaptic loss in Parkinson's disease.

Toxic aggregates of α-synuclein (αsyn) are considered key drivers of Parkinson's disease (PD) pathology. In early PD, αsyn induces synaptic dysfunction also modulating the glutamatergic neurotransmission. However, a more detailed understanding of the molecular mechanisms underlying αsyn-triggered synaptic failure is required to design novel therapeutic interventions. Here, we described the role of Rabphilin-3A (Rph3A) as novel target to counteract αsyn-induced synaptic loss in PD. Rph3A is a synaptic protein interacting with αsyn and involved in stabilizing dendritic spines and in promoting the synaptic retention of NMDA-type glutamate receptors. We found that in vivo intrastriatal injection of αsyn-preformed fibrils in mice induces the early loss of striatal synapses associated with decreased synaptic levels of Rph3A and impaired Rph3A/NMDA receptors interaction. Modulating Rph3A striatal expression or interfering with the Rph3A/αsyn complex with a small molecule prevented dendritic spine loss and rescued associated early motor defects in αsyn-injected mice. Notably, the same experimental approaches prevented αsyn-induced synaptic loss in vitro in primary hippocampal neurons. Overall, these findings indicate that approaches aimed at restoring Rph3A synaptic functions can slow down the early synaptic detrimental effects of αsyn aggregates in PD.

Imaging features and ultraearly hematoma growth in intracerebral hemorrhage associated with COVID-19.

PURPOSE: Intracerebral hemorrhage (ICH) is an uncommon but deadly event in patients with COVID-19 and its imaging features remain poorly characterized. We aimed to describe the clinical and imaging features of COVID-19-associated ICH. METHODS: Multicenter, retrospective, case-control analysis comparing ICH in COVID-19 patients (COV19 +) versus controls without COVID-19 (COV19 -). Clinical presentation, laboratory markers, and severity of COVID-19 disease were recorded. Non-contrast computed tomography (NCCT) markers (intrahematoma hypodensity, heterogeneous density, blend sign, irregular shape fluid level), ICH location, and hematoma volume (ABC/2 method) were analyzed. The outcome of interest was ultraearly hematoma growth (uHG) (defined as NCCT baseline ICH volume/onset-to-imaging time), whose predictors were explored with multivariable linear regression. RESULTS: A total of 33 COV19 + patients and 321 COV19 - controls with ICH were included. Demographic characteristics and vascular risk factors were similar in the two groups. Multifocal ICH and NCCT markers were significantly more common in the COV19 + population. uHG was significantly higher among COV19 + patients (median 6.2 mL/h vs 3.1 mL/h, p = 0.027), and this finding remained significant after adjustment for confounding factors (systolic blood pressure, antiplatelet and anticoagulant therapy), in linear regression (B(SE) = 0.31 (0.11), p = 0.005). This association remained consistent also after the exclusion of patients under anticoagulant treatment (B(SE) = 0.29 (0.13), p = 0.026). CONCLUSIONS: ICH in COV19 + patients has distinct NCCT imaging features and a higher speed of bleeding. This association is not mediated by antithrombotic therapy and deserves further research to characterize the underlying biological mechanisms.

Predictors of "brain fog" 1 year after COVID-19 disease.

INTRODUCTION: Brain fog has been described up to 1 year after SARS-CoV-2 infection, notwithstanding the underlying mechanisms are still poorly investigated. In this study, we aimed to evaluate the prevalence of cognitive complaints at 1-year follow-up and to identify the factors related to persistent brain fog in COVID-19 patients. METHODS: Out of 246 COVID patients, hospitalized from March 1st to May 31st, a sample of 137 patients accepted to be evaluated at 1 year from discharge, through a full clinical, neurological, and psychological examination, including the Montreal Cognitive Assessment (MoCA), impact of event scale-revised (IES-R), Zung self-rating depression scale (SDS), Zung self-rating anxiety scale (SAS), and fatigue severity scale (FSS). Subjects with prior cognitive impairment and/or psychiatric disorders were excluded. RESULTS: Patients with cognitive disorders exhibited lower MoCA score (22.9 ± 4.3 vs. 26.3 ± 3.1, p = 0.002) and higher IES-R score (33.7 ± 18.5 vs. 26.4 ± 16.3, p = 0.050), SDS score (40.9 ± 6.5 vs. 35.5 ± 8.6, p = 0.004), and fatigue severity scale score (33.6 ± 16.1 vs. 23.7 ± 12.5, p = 0.001), compared to patients without cognitive complaints. Logistic regression showed a significant correlation between brain fog and the self-rating depression scale values (p = 0.020), adjusted for age (p = 0.445), sex (p = 0.178), premorbid Cumulative Illness Rating Scale (CIRS) (p = 0.288), COVID-19 severity (BCRSS) (p = 0.964), education level (p = 0.784) and MoCA score (p = 0.909). CONCLUSIONS: Our study showed depression as the strongest predictor of persistent brain fog, adjusting for demographic and clinical variables. Wider longitudinal studies are warranted to better explain cognitive difficulties after COVID-19.

Neurological involvement associated with COVID-19 disease: a study on psychosocial factors.

BACKGROUND: Several people affected by COVID-19 experienced neurological manifestations, altered sleep quality, mood disorders, and disability following hospitalization for a long time. OBJECTIVE: To explore the impact of different neurological symptoms on sleep quality, mood, and disability in a consecutive series of patients previously hospitalized for COVID-19 disease. METHODS: We evaluated 83 patients with COVID-19 around 3 months after hospital discharge. They were divided into 3 groups according to their neurological involvement (i.e., mild, unspecific, or no neurological involvement). Socio-demographic, clinical data, disability level, emotional distress, and sleep quality were collected and compared between the three groups. RESULTS: We found that higher disability, depressive symptoms, and lower sleep quality in patients with mild neurological involvement compared to patients with unspecific and no neurological involvement. Differences between groups were also found for clinical variables related to COVID-19 severity. CONCLUSION: After 3 months from hospital discharge, patients with more severe COVID-19 and mild neurological involvement experienced more psychosocial alterations than patients with unspecific or no neurological involvement. Both COVID-19 and neurological manifestations' severity should be considered in the clinical settings to plain tailored interventions for patients recovering from COVID-19.

Clinical outcome of neurological patients with COVID-19: the impact of healthcare organization improvement between waves.

OBJECTIVE: The aim of this study is to evaluate the differences in clinical presentations and the impact of healthcare organization on outcomes of neurological COVID-19 patients admitted during the first and second pandemic waves. METHODS: In this single-center cohort study, we included all patients with SARS-CoV-2 infection admitted to a Neuro-COVID Unit. Demographic, clinical, and laboratory data were compared between patients admitted during the first and second waves of the COVID-19 pandemic. RESULTS: Two hundred twenty-three patients were included, of whom 112 and 111 were hospitalized during the first and second pandemic waves, respectively. Patients admitted during the second wave were younger and exhibited pulmonary COVID-19 severity, resulting in less oxygen support (n = 41, 36.9% vs n = 79, 70.5%, p < 0.001) and lower mortality rates (14.4% vs 31.3%, p = 0.004). The different healthcare strategies and early steroid treatment emerged as significant predictors of mortality independently from age, pre-morbid conditions and COVID-19 severity in Cox regression analyses. CONCLUSIONS: Differences in healthcare strategies during the second phase of the COVID-19 pandemic probably explain the differences in clinical outcomes independently of disease severity, underlying the importance of standardized early management of neurological patients with SARS-CoV-2 infection.

The Italian tremor Network (TITAN): rationale, design and preliminary findings.

INTRODUCTION: The recently released classification has revised the nosology of tremor, defining essential tremor (ET) as a syndrome and fueling an enlightened debate about some newly conceptualized entities such as ET-plus. As a result, precise information of demographics, clinical features, and about the natural history of these conditions are lacking. METHODS: The ITAlian tremor Network (TITAN) is a multicenter data collection platform, the aim of which is to prospectively assess, according to a standardized protocol, the phenomenology and natural history of tremor syndromes. RESULTS: In the first year of activity, 679 patients have been recruited. The frequency of tremor syndromes varied from 32% of ET and 41% of ET-plus to less than 3% of rare forms, including focal tremors (2.30%), task-specific tremors (1.38%), isolated rest tremor (0.61%), and orthostatic tremor (0.61%). Patients with ET-plus were older and had a higher age at onset than ET, but a shorter disease duration, which might suggest that ET-plus is not a disease stage of ET. Familial aggregation of tremor and movement disorders was present in up to 60% of ET cases and in about 40% of patients with tremor combined with dystonia. The body site of tremor onset was different between tremor syndromes, with head tremor being most commonly, but not uniquely, associated with dystonia. CONCLUSIONS: The TITAN study is anticipated to provide clinically relevant prospective information about the clinical correlates of different tremor syndromes and their specific outcomes and might serve as a basis for future etiological, pathophysiological, and therapeutic research.

Accuracy of the clinical diagnosis of dementia with Lewy bodies (DLB) among the Italian Dementia Centers: a study by the Italian DLB study group (DLB-SINdem).

INTRODUCTION: Dementia with Lewy bodies (DLB) may represent a diagnostic challenge, since its clinical picture overlaps with other dementia. Two toolkits have been developed to aid the clinician to diagnose DLB: the Lewy Body Composite Risk Score (LBCRS) and the Assessment Toolkit for DLB (AT-DLB). We aim to evaluate the reliability of these two questionnaires, and their ability to enhance the interpretation of the international consensus diagnostic criteria. METHODS: LBCRS and AT-DLB were distributed to 135 Italian Neurological Centers for Cognitive Decline and Dementia (CDCDs), with the indication to administer them to all patients with dementia referred within the subsequent 3 months. We asked to subsequently apply consensus criteria for DLB diagnosis, to validate the diagnostic accuracy of the two toolkits. RESULTS: A total of 23 Centers joined the study; 1854 patients were enrolled. We found a prevalence of possible or probable DLB of 13% each (26% total), according to the consensus criteria. LBCRS toolkit showed good reliability, with a Cronbach alpha of 0.77, stable even after removing variables from the construct. AT-DLB toolkit Cronbach alpha was 0.52 and, after the subtraction of the "cognitive fluctuation" criterion, was only 0.31. Accuracy, sensitivity, and specificity were higher for LBCRS vs. AT-DLB. However, when simultaneously considered in the logistic models, AT-DLB showed a better performance (p < 0.001). Overall, the concordance between LBCRS positive and AT-DLB possible/probable was of 78.02% CONCLUSIONS: In a clinical setting, the LBCRS and AT-DLB questionnaires have good accuracy for DLB diagnosis.