Is headache a risk factor for dementia? A systematic review and meta-analysis.

OBJECTIVE: In this systematic review and meta-analysis, we critically evaluate available evidence regarding the association between primary headaches and subsequent decline of cognitive function and dementia. BACKGROUND: Recent studies suggested that headache disorders may increase the risk for dementia. However, available studies are conflicting. METHODS: To identify qualifying studies, we searched scientific databases, including Pubmed, Scopus, Web of Science, Science Direct and BMC, screening for relevant papers. In order to reduce the heterogeneity between different studies, the analyses were further subdivided according to the clinical diagnoses and the study methodologies. RESULTS: We identified 23 studies investigating the association between primary headaches and the risk of dementia. Of these, 18 met our inclusion criteria for meta-analysis (covering 924.140 individuals). Overall effect-size shows that primary headaches were associated with a small increase in dementia risk (OR = 1,15; CI 95%: 1,03-1,28; p = 0,02). Analyzing subgroups, we found that migraine was associated with both a moderate increased risk of all-cause dementia (OR = 1,26; p = 0,00; 95% CI: 1,13-1,40) as well as a moderate increased risk of Alzheimer's disease (OR = 2,00; p = 0,00; 95% CI: 1,46-2,75). This association was significant in both case-control and retrospective cohort studies but not in prospective studies. CONCLUSIONS: Our study supports the presence of a link between primary headaches and dementia. However, in the subgroup analysis, only patients with migraine showed a moderate increase risk for all-cause dementia and for Alzheimer's disease. Additional rigorous studies are needed to elucidate the possible role of primary headaches on the risk of developing cognitive impairment and dementia.

Cognitive dysfunction, social behavior disorder, cerebellar ataxia, and atypical brain FDG-PET presentation in spinocerebellar ataxia 17: a case report.

BACKGROUND: Spinocerebellar ataxia 17 (SCA17) is a rare autosomal dominant form of inherited ataxia, caused by heterozygous trinucleotide repeat expansions encoding glutamine in the TATA box-binding protein (TBP) gene. CASE DESCRIPTION: We describe the clinical history, neuropsychological, and neuroimaging findings of a 42-year-old patient who presented for medical attention showing prevalent behavioral and cognitive problems along with progressively worsening gait disturbances. The patient's family history indicated the presence of SCA17 in the maternal lineage. Genetic analysis confirmed a heterozygous 52-CAG pathological expansion repeat in TBP (normal interval, 25-40 CAG. Brain 18-fluorodeoxyglucose positron emission tomography (FDG-PET) showed bilateral hypometabolism in the sensorimotor cortex, with a slight predominance on the right, as well as in the striatal nuclei and thalamic hypermetabolism, a finding similar to what is observed in Huntington's disease. The patient also underwent neuropsychological evaluation, which revealed mild cognitive impairment and difficulties in social interaction and understanding other's emotions (Faux Pas Test and Reading the Mind in the Eyes Test). CONCLUSION: Our report emphasizes the importance of considering SCA17 as a possible diagnosis in patients with a prevalent progressive cognitive and behavioral disorders, even with a pattern of FDG-PET hypometabolism not primarily indicative of this disease.

Increased orexin A concentrations in cerebrospinal fluid of patients with behavioural variant frontotemporal dementia.

Orexins are hypothalamic neuropeptides that regulate several physiological functions, such as appetite, arousal, cognition, stress, sleep and metabolism. Emerging pieces of evidence suggest an orexinergic dysfunction in several neuropsychiatric disorders, including depression, anxiety and addiction. A syndromic overlap between behavioural variant frontotemporal dementia (bvFTD) and several psychiatric disorders was recently demonstrated. Therefore, we analysed cerebrospinal fluid (CSF) orexin A concentrations of 40 bvFTD and 32 non-demented patients, correlating neuropeptide concentrations with several clinical characteristics. A significant increase of orexin A concentrations was found in bvFTD patients when compared to controls (p<0.001). CSF orexin A concentration showed a correlation with Mini-Mental State Examination scores, drug assumption, history of compulsive behaviour and extrapyramidal signs. Moreover, we found a relationship between CSF markers of neurodegeneration, total tau and Aß1-42 and CSF orexin A concentrations. Our study provides evidence of an orexinergic dysfunction in bvFTD, correlating with several clinical symptoms. Further larger studies are needed to confirm our data.

Hand grip strength in patients with LVADs: A scoping review.

BACKGROUND AND PURPOSE: Hand grip strength (HGS) is a simple test to evaluate the upper limb strength function in patients with different diseases. The purpose of this review was to investigate HGS in patients who have been implanted with left ventricular assist devices (LVADs) or waiting for implantation. The objectives were: (1) defining if HGS can predict rehabilitative outcomes such as the walked distance at the 6-minute walking test, and (2) identifying specific HGS cut-off values. METHODS: We searched eight primary databases for English-language studies published from their inception until April 2021. We excluded editorials, letters to the editor, and studies that did not describe HGS assessment procedures. RESULTS: A total of 30 articles were identified. We ultimately included 5 publications, and 217 patients constituted the cohort of the present study. In three studies, HGS was evaluated before implantation. Two studies were conducted during the postoperative course, and HGS measurements were taken before and after rehabilitation. In two studies, HGS has correlated with a significant increase of the 6-MWT passing from 300.1 to 404.8 m and 56.6 to 83.8 m, respectively. HGS in patients with LVADs ranges between (1) ca.18 and ca.33 Kg at the preoperative stage, (2) ca.24 and >40 Kg postoperatively, and (3) ca.33 and >36 Kg after having attended a postoperative rehabilitation program. CONCLUSION: HGS appears to be a simple and reliable measure to correlate rehabilitative outcomes, such as the 6-MWT, in patients receiving or awaiting LVADs.

Multiple organ retrieval in a brain dead left ventricular assist device donor.

Left ventricular assist device (LVAD) support in donors may contribute in preserving proper haemodynamics and systemic perfusion during organ retrieval thus decreasing the risk of multiple organ injury. This is an option to expand the current organ supply. We report on intra-abdominal organs procurement strategy in a selected LVAD recipient who suffered a fatal cerebrovascular accident at the time of COVID-19 pandemic outbreak. The liver and kidneys grafts have been successfully transplanted.

Polymorphisms of the Proinflammatory Cytokine Genes Modulate the Response to NSAIDs but Not to Triptans in Migraine Attacks.

Migraine is a common neurovascular disorder characterized by recurrent episodes of headache and associated neurological symptoms. At present, a significant portion of patients do not obtain a satisfactory response to acute pain-relieving therapies, including NSAIDs and triptans. In this context, pharmacogenetics plays a key role in the understanding of such a diverse response. In order to investigate whether functional polymorphisms in proinflammatory cytokine genes (IL-1α, IL-1ß, IL-1RN; IL-6 and TNF-α) may influence the response to acute treatment, 313 consecutive patients with episodic migraine without aura were enrolled. Pain relief by administration of NSAIDs or triptans for three consecutive migraine attacks was evaluated. We found a significant association between A allele of the TNF-α promoter (−308 A/G) and a lack of efficacy after NSAID administration (p < 0.01, OR 2.51, 95% CI: 1.33 < OR < 4.75 compared to the G allele). Remaining polymorphisms had no significant effect on pain relief. Our study showed that a functional polymorphism in the TNF-α gene significantly modulates the clinical response to NSAID administration in acute attacks. Patients with higher production of the active cytokine during stress showed a significantly lower anti-migraine effect. Our results further support a role for TNF-α in the pathophysiological mechanisms of migraine attack.

Impact of COVID-19 on chronic migraine treated with erenumab: a case report.

BACKGROUND: Headache is a frequent symptom of the novel coronavirus 19 disease (COVID-19). To date, there are limited information on how COVID-19 affects migraine and its treatment. CASE DESCRIPTION: A 47-year-old patient, suffering from chronic migraine and medication-overuse headache, in September 2020 started erenumab at 70 mg once monthly. Two months later, monthly migraine days decreased from 20 to 5. On the third month, the patient developed mild COVID-19 symptoms, experiencing extreme fatigue, hyposmia, and attention deficit, resulting positive for SARS-Cov-2 RNA. A significant increase in migraine attacks frequency was reported. Brain MRI and EEG were normal. Erenumab was increased to 140 mg/month, and attacks decreased to 3 monthly migraine days and remained stable. All the headaches experienced by our patient during the infection fulfilled the criteria of the migraine attacks, without tensive-like features. CONCLUSION: We report the first case showing the effects of SARS-CoV-2 infection in a patient with chronic migraine and medication-overuse headache treated with erenumab. Our case description suggests that inflammatory processes induced by SARS-CoV-2 infection may increase the frequency of migraine attacks, probably through an activation of the trigeminovascular system. Whether treatment with CGRP receptor antagonist may influence COVID is still debated. Additional studies regarding anti-CGRP monoclonal antibodies in COVID-19 patients are warranted.

Alteration of Iron Concentration in Alzheimer's Disease as a Possible Diagnostic Biomarker Unveiling Ferroptosis.

Proper functioning of all organs, including the brain, requires iron. It is present in different forms in biological fluids, and alterations in its distribution can induce oxidative stress and neurodegeneration. However, the clinical parameters normally used for monitoring iron concentration in biological fluids (i.e., serum and cerebrospinal fluid) can hardly detect the quantity of circulating iron, while indirect measurements, e.g., magnetic resonance imaging, require further validation. This review summarizes the mechanisms involved in brain iron metabolism, homeostasis, and iron imbalance caused by alterations detectable by standard and non-standard indicators of iron status. These indicators for iron transport, storage, and metabolism can help to understand which biomarkers can better detect iron imbalances responsible for neurodegenerative diseases.

Postoperative outcomes following rehabilitation in patients with left ventricular assist devices.

Postoperative rehabilitation is a cornerstone of the recovery pathway following left ventricular assist device implantation (LVAD), and patients are expected to conduct an autonomous life thanks to improved technology and increased knowledge of mechanical circulatory support. The primary purpose of the present study was to quantify clinical changes related to rehabilitation, in patients with LVAD: functional capacity, disability, and quality of life were identified as reliable outcomes to detect such changes. The current study was a scoping review conducted searching three primary databases, namely PubMed, Scopus, and Cochrane Library, from their inception until January 2020. After the selection process was completed, 12 citations were included in the present study. Three hundred eight three patients were included in the current analysis. Functional capacity, disability, and quality of life were investigated in 157, 215, 18 patients, respectively. Significant differences were found before and after rehabilitation. The mean walked distance at 6-Minute Walk Test improved from 319±96 to 412.8±86.2 metres (p<0.001), the mean score of the Functional Independence Measure from 68.4±11.8 to 92.5±10.8 points (p<0.001), the mean score of the Short Form-36 physical component from 32.7±29.9 to 55.5±24.7 points (p=0.009) and the mental component from 55.8±19.8 to 75.4±21.4 points (p=0.002). Postoperative rehabilitation is effective at improving functional capacity, disability, and quality of life in patients with left ventricular assist device; all these three domains are particularly expressive of the entity of patients' functional recovery.

Investigating the role of adipokines in chronic migraine.

Background and aims Adiponectin, leptin, and resistin are adipocyte-derived secretory factors involved in endothelial function, weight, inflammation, and insulin resistance. Recent studies suggested a role for adipokines in episodic migraine as mediators of inflammatory processes. The aim of this study was to investigate plasma concentrations of adiponectin, leptin, and resistin in patients with chronic migraine. Materials and methods Twenty-seven chronic migraineurs (20 females, 7 males; mean age 49.0 ± 9.0 yrs) and 37 healthy controls (23 females, 14 males; mean age 49.8 ± 15.0 yrs) were selected for the study. Fasting plasmatic levels of total adiponectin, leptin, and resistin were measured using ELISA kits during a pain-free period. Fasting glucose, insulin, total and HDL-cholesterol, triglycerides, and ESR were also determined. Results Serum levels of adiponectin and resistin were significantly increased in chronic migraineurs in comparison with controls ( p = 0.001 and p = 0.032, respectively). After correction for BMI, sex and age, leptin levels were significantly increased in chronic migraineurs ( p = 0.007). A positive correlation between leptin concentrations and both indices of insulin resistance and markers of inflammation was found. Discussion Our data suggest that adiponectin and resistin are altered in non-obese chronic migraineurs. Further studies are needed to elucidate the neurobiological mechanisms underlying adipokine dysfunction in migraine.

Magnetic Nanoparticles in the Central Nervous System: Targeting Principles, Applications and Safety Issues.

One of the most challenging goals in pharmacological research is overcoming the Blood Brain Barrier (BBB) to deliver drugs to the Central Nervous System (CNS). The use of physical means, such as steady and alternating magnetic fields to drive nanocarriers with proper magnetic characteristics may prove to be a useful strategy. The present review aims at providing an up-to-date picture of the applications of magnetic-driven nanotheranostics agents to the CNS. Although well consolidated on physical ground, some of the techniques described herein are still under investigation on in vitro or in silico models, while others have already entered in-or are close to-clinical validation. The review provides a concise overview of the physical principles underlying the behavior of magnetic nanoparticles (MNPs) interacting with an external magnetic field. Thereafter we describe the physiological pathways by which a substance can reach the brain from the bloodstream and then we focus on those MNP applications that aim at a nondestructive crossing of the BBB such as static magnetic fields to facilitate the passage of drugs and alternating magnetic fields to increment BBB permeability by magnetic heating. In conclusion, we briefly cite the most notable biomedical applications of MNPs and some relevant remarks about their safety and potential toxicity.

Is HCRTR2 a genetic risk factor for Alzheimer's disease?

BACKGROUNDS/AIMS: Alzheimer's disease (AD) is one of the main types of dementia affecting about 50-55% of all demented patients. Sleep disturbances in AD patients are associated with the severity of dementia and are often the primary reason for institutionalization. These sleep problems partly resemble the core symptoms of narcolepsy, a sleep disorder caused by a general loss of the neurotransmitter hypocretin. The aim of our study was to investigate whether genetic variants in the hypocretin (HCRT) and in the hypocretin receptors 1 and 2 (HCRTR1, HCRTR2) genes could modify the occurrence and the clinical features of AD and to examine if these possible variants influence the role of the protein in sleep regulation. METHODS: Using a case-control strategy, we genotyped 388 AD patients and 272 controls for 10 SNPs in the HCRT, HCRTR1 and HCRTR2 genes. In order to evaluate which residues belong to the HCRTR2 binding site, we built a molecular model. RESULTS: The genotypic and allelic frequencies of the rs2653349 polymorphism were different (χ(2) = 5.77, p = 0.016; χ(2) = 6.728, p = 0.035) between AD patients and controls. The carriage of the G allele was associated with an increased AD risk (OR 2.53; 95% CI 1.10-5.80). No significant differences were found in the distribution of either genotypic or allelic frequencies between cases and controls in the HCRTR1 polymorphisms rs2271933, rs10914456 and rs4949449 and in the HCRTR2 polymorphism rs3122156. CONCLUSION: Our data support the hypothesis that the HCRTR2 gene is likely to be a risk factor for AD. The increased risk inferred is quite small, but in the context of a multi-factorial disease, the presence of this polymorphism may significantly contribute to influencing the susceptibility for AD by interacting with other unknown genetic or environmental factors in sleep regulation.

KCNK18 (TRESK) genetic variants in Italian patients with migraine.

OBJECTIVES: To evaluate the prevalence of KCNK18 gene mutations in a dataset of Italian migraineurs, with and without aura, and in healthy controls, and to investigate in silico the functional effects of the mutations. BACKGROUND: A role for the KCNK18 gene encoding for TRESK, a member of the family of potassium channel, has been recently suggested in migraine with aura. METHODS: We sequenced the KCNK18 gene in 425 migraineurs (255 with aura and 170 without aura) and 247 healthy controls. RESULTS: Five genetic variants (R10G, C110R, Y163Y, S231P, and F372L) were found in 13 (5.1%) out of 255 migraine with aura patients, and 6 variants (R10G, D46D, C110R, Y163Y, S178T, and S231P) were identified in 12 (7.1%) out of 170 migraine without aura patients. In 2.8% of controls, the R10G and L20V substitutions were found. In silico analysis suggested that C110R, S178T, S231P, and F372L mutations may have potential damaging effect on channel function, whereas the remaining mutations may have low damaging effect. CONCLUSIONS: Our study shows the presence of several KCNK18 gene mutations in both migraine with aura and migraine without aura. However, the precise role of this gene in migraine predisposition deserves further studies.

Proposal of a magnetic resonance technique for the evaluation of the calcaneofibular ligament minimizing false positive results.

BACKGROUND: Magnetic resonance (MR) techniques used to detect lesions of the ligament complex for articulation of the ankle lack the desired accuracy for the study of the calcaneofibular ligament (CFL). The lack of sensitivity of the conventional techniques is due to variations in the dimensions of the CFL. The best results are obtained when the image plane is oriented parallel to the ligament. This study aims to develop a model that addresses the width, length and angle parameters of the CFL and the orientation of the MR image plane, and thus determine a technique in the oblique transversal plane with the foot in anatomical flexion, that is adequate for the majority of patients. METHOD: To determine this orientation and adapt it to the majority of people, images of the articulation of the ankle in the 3D isotropic, volumetric, sagittal plane of 100 volunteers were taken using the MR technique. None of the volunteers had a clinical history of ligament lesions, serious pathologies, or surgeries. A measurement of the length, width, and angle of the CFL relative to the sole of the foot was performed using the MR tools. A virtual model was developed that simulated the visualization of the CFL in the oblique transversal image plane from 35° to 45° using the CFL dimensions of 100 volunteers. The comparison of the simulations with the reconstructed images validated the model and permitted the calculation of the agreement and sensitivity of each technique in the detection of the complete CFL. RESULTS: Using the simulator, it was possible to obtain the limit angle for complete CFL visualization as a function of its dimensions for any angle of the oblique transversal image plane of the MR. CONCLUSION: The results suggest that a single image acquisition technique in the oblique transversal plane at 38° with the foot in anatomical flexion would serve the majority of patients.

Moniz Game: Usability and User Experience Evaluation of a Musical Game for Motor Coordination.

Purpose: The objective of this research was to develop a musical digital game for rehabilitation of upper limb and to verify its usability and user experience with professionals in the field (physical therapists). Materials and Methods: Thirty working professionals were recruited to evaluate the system. The usability was evaluated with the System Usability Scale (SUS) and the user experience was verified with the Game Flow scale. Results: The overall score of the SUS scale was 88.67 (±9.129); this score is interpreted as "Best Imaginable" (86-100). The user experience rating had most of its domains equal or higher than 4, which indicates that all the requirements for a good user experience were present in the game. Conclusions: The Moniz Game proved to be a game with good usability and can be a tool for application in clinical practice regarding motor coordination. However, further studies are needed to evaluate the effect of the Moniz Game on motor coordination in patients with neurological dysfunctions.

Genetic variants in the NOTCH4 gene influence the clinical features of migraine.

BACKGROUND: Recent studies suggested an important role for vascular factors in migraine etiopathogenesis. Notch4 belongs to a family of transmembrane receptors that play an important role in vascular development and maintenance. The aim of this study was to test the hypothesis that polymorphisms of the NOTCH4 gene would modify the occurrence and the clinical features of migraine. FINDINGS: Using a case-control strategy, we genotyped 239 migraine patients and 264 controls for three different non-synonymous polymorphisms (T320A, G835V, R1346P) of the NOTCH4 gene and for the (CTG) n-encoding polyleucine polymorphism in exon 1. Although the analyzed polymorphisms resulted not associated with migraine, the clinical characteristics of our patients were significantly influenced by the different NOTCH4 genotypes. Longer duration of disease and severity of neurovegetative symptoms during headache attacks were associated with the R1346P and G835V polymorphisms, respectively. In female patients, worsening of migraine symptoms at menarche was significantly correlated with T320A polymorphism. CONCLUSIONS: Our study shows that genetic variations within the NOTCH4 gene significantly modify the clinical characteristics of migraine and may have a role in disease pathogenesis.

A Novel PSEN1 Variant Leading to Posterior Cortical Atrophy: A Case Report.

We describe a 52-year-old patient with a progressive visuospatial disorder and apraxia. Neuropsychological assessment, neuroradiological findings, and Alzheimer's disease (AD) core biomarker assay on cerebrospinal fluid led to a diagnosis of posterior cortical atrophy due to AD. We performed a next generation sequencing dementia-gene panel and found the c.1301 C>T p.(Ala434Val) variant in the Presenilin1 (PSEN1) gene. The missense change affects the PAL (Pro433-Ala434-Leu435) motif critical for catalytic activity of the macromolecular γ-secretase complex. Evolutionary and integrated bioinformatic tools predicted a deleterious effect of the variant supporting its role in the AD pathogenesis.

Decreased resistin plasmatic concentrations in patients with Alzheimer's disease: A case-control study.

Previous studies suggested a role for adipokines in ageing and in several age-related diseases. The purpose of our study was to further elucidate adipokines involvement in neurodegeneration, investigating adiponectin, leptin and resistin in Alzheimer's disease (AD) and Frontotemporal Dementia (FTD). We enrolled for the study 70 subjects: 26 AD, 21 FTD, and 23 with other neurological (but not neurodegenerative) conditions (CTR, control group). According to a standardized protocol, we measured adipokines plasmatic levels, blood parameters of glucidic and lipidic metabolism, ESR, cerebrospinal fluid (CSF) markers of neurodegeneration (beta-amyloid, total-Tau, phosphorylated-Tau) and anthropometric parameters. In comparison with control group, we found lower resistin concentrations in patients with dementia, and in particular in AD (p < 0.001). In multivariate analysis, AD relative risk was reduced by resistin, when controlling for sex, age and anthropometric/metabolic parameters (RR = 0.71, P < 0.0001). Considering CSF biomarkers, we found a direct correlation between resistin and Aß1-42 CSF concentration in patients (p < 0.001, r = 0.50). Lower resistin characterized AD patients in our study and AD, but not FTD, diagnosis risk was found to be inversely associated with resistin when controlling for confounders. We hypothesize that resistin-linked metabolic profile has to be reconsidered and further investigated in AD.

Aß42 as a Biomarker of Alzheimer's Disease: Is Saliva a Viable Alternative to Cerebrospinal Fluid?

The identification of reliable biomarkers in biological fluids is paramount to optimizing the diagnosis of Alzheimer's disease (AD). Measurement of Aß42, t-tau, and p-tau in cerebrospinal fluid (CSF) is the most accepted method to support the diagnosis of AD. However, lumbar puncture represents an invasive investigation, whereas saliva is one of the most accessible body fluids. The aim of our study was to investigate salivary concentrations in AD and evaluate the correlation between salivary and CSF Aß42 concentrations in AD patients, patients with non-AD dementias, and controls. We recruited 100 subjects: 18 AD patients, 64 patients with non-AD dementias, and 18 controls. The mean saliva Aß42 concentrations in AD patients were higher than in controls (p < 0.001), and to patients with non-AD dementias (p = 0.001). A significant negative correlation between salivary and CSF Aß42 concentrations was found in the overall group (r = −0.562, p < 0.001) and in non-AD patients (r = −0.443, p < 0.001). Salivary Aß42 concentrations positively correlated with CSF t-tau (r = 0.321, p = 0.001) and p-tau (r = 0.297, p = 0.001). Our study showed that in AD patients' saliva, Aß42 concentrations are specifically increased, and we found an interesting negative correlation between CSF and salivary Aß42 concentrations that warrants further investigation.