Longitudinal and Transverse Relaxivity Analysis of Native Ferritin and Magnetoferritin at 7 T MRI.

Magnetite mineralization in human tissue is associated with various pathological processes, especially neurodegenerative disorders. Ferritin's mineral core is believed to be a precursor of magnetite mineralization. Magnetoferritin (MF) was prepared with different iron loading factors (LFs) as a model system for pathological ferritin to analyze its MRI relaxivity properties compared to those of native ferritin (NF). The results revealed that MF differs statistically significantly from NF, with the same LF, for all studied relaxation parameters at 7 T: r1, r2, r2*, r2/r1, r2*/r1. Distinguishability of MF from NF may be useful in non-invasive MRI diagnosis of pathological processes associated with iron accumulation and magnetite mineralization (e.g., neurodegenerative disorders, cancer, and diseases of the heart, lung and liver). In addition, it was found that MF samples possess very strong correlation and MF's relaxivity is linearly dependent on the LF, and the transverse and longitudinal ratios r2/r1 and r2*/r1 possess complementary information. This is useful in eliminating false-positive hypointensive artefacts and diagnosis of the different stages of pathology. These findings could contribute to the exploitation of MRI techniques in the non-invasive diagnosis of iron-related pathological processes in human tissue.

Significant Impact of Coffee Consumption on MR-Based Measures of Cardiac Function in a Population-Based Cohort Study without Manifest Cardiovascular Disease.

Subclinical effects of coffee consumption (CC) with regard to metabolic, cardiac, and neurological complications were evaluated using a whole-body magnetic resonance imaging (MRI) protocol. A blended approach was used to estimate habitual CC in a population-based study cohort without a history of cardiovascular disease. Associations of CC with MRI markers of gray matter volume, white matter hyperintensities, cerebral microhemorrhages, total and visceral adipose tissue (VAT), hepatic proton density fat fraction, early/late diastolic filling rate, end-diastolic/-systolic and stroke volume, ejection fraction, peak ejection rate, and myocardial mass were evaluated by linear regression. In our analysis with 132 women and 168 men, CC was positively associated with MR-based cardiac function parameters including late diastolic filling rate, stroke volume (p < 0.01 each), and ejection fraction (p < 0.05) when adjusting for age, sex, smoking, hypertension, diabetes, Low-density lipoprotein (LDL), triglycerides, cholesterol, and alcohol consumption. CC was inversely associated with VAT independent of demographic variables and cardiovascular risk factors (p < 0.05), but this association did not remain significant after additional adjustment for alcohol consumption. CC was not significantly associated with potential neurodegeneration. We found a significant positive and independent association between CC and MRI-based systolic and diastolic cardiac function. CC was also inversely associated with VAT but not independent of alcohol consumption.

Biomarker-Driven Analysis Using High-Throughput Approaches in Neuroinflammation and Neurodegenerative Diseases.

Aging is responsible for homeostatic dysregulation and the primary risk for neurodegenerative diseases. The main signaling pathways may regulate inflammatory-related disorders and neurodegeneration include genomic instability, cell senescence, and mitochondria dysfunction. The use of high-throughput technologies has emerged as a powerful approach to the rapid discovery of many candidate biomarkers for age-related diseases. Various types of molecules, such as nucleic acids, proteins, or metabolites, can serve as soluble factors in clinical practice with deviations in their normal biological levels being an indication of an underlying disease state. The development of multifactorial biomarkers based on models involving molecular alterations in complex disorders may also provide specific challenges for translating biological findings and targeted diagnostic tools. As diseases are often regulated by a multiset of markers that coordinate and interact each other in a complex signaling network to maintain holistic processes within a cell, potent network-based approaches to data-driven biomarker identification are required. System-based biomarker discovery pipelines can offer an extraordinary adjustment opportunity for data heterogeneity and limitation, whereas integrated analysis of distinct networks clusters  can provide important information for the early detection of intracellular pathogenic processes as well as for monitoring the response to treatment.

Copper Dyshomeostasis in Neurodegenerative Diseases-Therapeutic Implications.

Copper is one of the most abundant basic transition metals in the human body. It takes part in oxygen metabolism, collagen synthesis, and skin pigmentation, maintaining the integrity of blood vessels, as well as in iron homeostasis, antioxidant defense, and neurotransmitter synthesis. It may also be involved in cell signaling and may participate in modulation of membrane receptor-ligand interactions, control of kinase and related phosphatase functions, as well as many cellular pathways. Its role is also important in controlling gene expression in the nucleus. In the nervous system in particular, copper is involved in myelination, and by modulating synaptic activity as well as excitotoxic cell death and signaling cascades induced by neurotrophic factors, copper is important for various neuronal functions. Current data suggest that both excess copper levels and copper deficiency can be harmful, and careful homeostatic control is important. This knowledge opens up an important new area for potential therapeutic interventions based on copper supplementation or removal in neurodegenerative diseases including Wilson's disease (WD), Menkes disease (MD), Alzheimer's disease (AD), Parkinson's disease (PD), and others. However, much remains to be discovered, in particular, how to regulate copper homeostasis to prevent neurodegeneration, when to chelate copper, and when to supplement it.

Dietary Gluten and Neurodegeneration: A Case for Preclinical Studies.

Although celiac disease (CD) is an autoimmune disease that primarily involves the intestinal tract, mounting evidence suggests that a sizeable number of patients exhibit neurological deficits. About 40% of the celiac patients with neurological manifestations have circulating antibodies against neural tissue transglutaminase-6 (tTG6). While early diagnosis and strict adherence to a gluten-free diet (GFD) have been recommended to prevent neurological dysfunction, better therapeutic strategies are needed to improve the overall quality of life. Dysregulation of the microbiota-gut-brain axis, presence of anti-tTG6 antibodies, and epigenetic mechanisms have been implicated in the pathogenesis. It is also possible that circulating or gut-derived extracellular structures and including biomolecular condensates and extracellular vesicles contribute to disease pathogenesis. There are several avenues for shaping the dysregulated gut homeostasis in individuals with CD, non-celiac gluten sensitivity (NCGS) and/or neurodegeneration. In addition to GFD and probiotics, nutraceuticals, such as phyto and synthetic cannabinoids, represent a new approach that could shape the host microbiome towards better prognostic outcomes. Finally, we provide a data-driven rationale for potential future pre-clinical research involving non-human primates (NHPs) to investigate the effect of nutraceuticals, such as phyto and synthetic cannabinoids, either alone or in combination with GFD to prevent/mitigate dietary gluten-induced neurodegeneration.

[Aceruloplasminemia, a rare condition not to be overlooked]. / L'acéruléoplasminémie héréditaire, une pathologie à ne pas méconnaître.

Aceruloplasminemia is a rare iron-overload disease that should be better known by physicians. It is an autosomal recessive disorder due to mutations in ceruloplasmin gene causing systemic iron overload, including cerebral and liver parenchyma. The impairment of ferroxidase ceruloplasmin activity leads to intracellular iron retention leading aceruloplasminemia symptoms. Neurologic manifestations include cognitive impairment, ataxia, extrapyramidal syndrome, abnormal movements, and psychiatric-like syndromes. Physicians should search for aceruloplasminemia in several situations with high ferritin levels: microcytic anaemia, diabetes mellitus, neurological and psychiatric disorders. Diagnosis approach is based on the study of transferrin saturation and hepatic iron content evaluated by magnetic resonance imaging of the liver. Ceruloplasmin dosage is required in case of low transferrin saturation and high hepatic iron content and genetic testing is mandatory in case of serum ceruloplasmin defect. Neurological manifestations occur in the sixties decade and leads to disability. Iron chelators are widely used. Despite their efficacy on systemic and cerebral iron overload, iron chelators tolerance is poor. Early initiation of iron chelation therapy might prevent or slowdown neurodegeneration, highlighting the need for an early diagnosis but their clinical efficacy remains uncertain.

Molecular Targets from Traditional Medicines for Neuroprotection in Human Neurodegenerative Diseases.

Neurodegeneration is one of the greatest threats to global public health. Neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease are among the major causes of chronic neurological conditions in the elderly populations. Hence, neuroprotection is at the epicenter of the current 21st-century research agenda in biomedicine. Yet, novel molecular targets are limited and solely needed for neuroprotection. Marked person-to-person variations in outcomes require a deeper understanding of drug targets in neurology and clinical neurosciences. In this context, traditional medicines offer untapped potentials for discovery and translation of novel molecular targets to human neurodegenerative disease research and clinical neurology. This expert review offers a synthesis of the prospects and challenges of harnessing new molecular targets from traditional medicines, with a view to applications for neuroprotection in human neurodegenerative diseases.

Multiple reversible encephalitic attacks: a rare manifestation of neuronal intranuclear inclusion disease.

BACKGROUND: Neuronal intranuclear inclusion disease (NIID) is a rare neurodegenerative condition characterized by the loss of neurons and the presence of eosinophilic nuclear inclusions in the central and peripheral nervous system, skin and visceral organs. In this paper, we present a case of NIID with recurrent encephalitic attacks that remained stable and nonprogressive for seven years; no such case has previously been reported. CASE PRESENTATION: A 63-year-old female was hospitalized due to light-headedness, vomiting, unstable gait and cognitive impairment. Seven years prior, she had experienced an episode of light-headedness, central facial paralysis, unstable gait, aphasia, nausea, vomiting and loss of consciousness. She regained consciousness within 12 h, and her other symptoms were completely resolved within one week. During the present hospitalization, a brain magnetic resonance imaging (MRI) examination detected high signal intensity on diffusion-weighted imaging (DWI) of the bilateral frontal grey matter-white matter junction. We reviewed the patient's previous MRI results and found that she had also had high signal intensity on DWI of the bilateral frontal grey matter-white matter junction seven years prior. In the intervening seven years, the high signal intensity in the frontal lobes had spread along the grey matter-white matter junction, but the deep white matter remained unaffected. Skin biopsy was performed, and intranuclear inclusions were found in adipocytes, fibroblasts and sweat gland cells. GGC repeat expansions in the NOTCH2NLC (Notch 2 N-terminal like C) gene confirmed the diagnosis of NIID. She received supportive treatment such as nutrition support therapy and vitamin B and C supplementation, as well as symptomatic treatment during hospitalization. The patient's symptoms were completely relieved within one week. CONCLUSION: This is a detailed report of a case of NIID with multiple reversible encephalitic attacks, diagnosed by clinical symptoms, intranuclear inclusions, characteristic DWI signals, and genetic tests.

Treatment of Neurodegeneration: Integrating Photobiomodulation and Neurofeedback in Alzheimer's Dementia and Parkinson's: A Review.

Objective: A review of photobiomodulation (PBM) in Alzheimer's dementia is submitted. The addition of PBM in neurodegenerative diseases is a dual modality that is at present gaining traction as it is safe, antiviral, and anti-inflammatory for treating neurodegeneration with photons that stimulate mitochondria increasing adenosine triphosphate and proteasomes increasing misfolded protein removal. Neurofeedback provides neural plasticity with an increase in brain-derived nerve factor mRNA and an increase in dendrite production and density in the hippocampus coupled with overall growth in dendrites, density, and neuronal survival. Background: Alzheimer's disease pathophysiology is the accumulation of hyperphosphorylated tau protein neurofibrillary tangles and subsequently amyloid-beta (Aß) plaques. PBM and neurobiofeedback (NBF)address the multiple gene expression and upregulation of multiple pathogenic pathway inflammation, reactive oxidative stress, mitochondrial disorders, insulin resistance, methylation defects, regulation of neuroprotective factors, and regional hypoperfusion of the brain. There is no human evidence to suggest a clinical therapeutic benefit from using consistent light sources while significantly increasing safety concerns. Methods: A PBM test with early- to mid-Alzheimer's was reported in 2017, consisting of a double-blind, placebo-controlled trial in a small pilot group of early- to mid-dementia subjects under Institutional Review Board (IRB)-approved Food and Drug Administration (FDA) Clinical Trial. Results: PBM-treated subjects showed that active treatment subjects tended to show greater improvement in the functioning of the executive: clock drawing, immediate recall, practical memory, and visual attention and task switching (Trails A&B). A larger study using the CerebroLite helmet in Temple Texas again of subjects in a double-blind, placebo-controlled IRB-approved FDA Clinical Trial demonstrated gain in memory and cognition by increased clock drawing. Conclusions: Next-generation trials with the Cognitolite for Parkinson's disease subjects will incorporate the insights regarding significant bilateral occipital hypocoherence deficits gained from the quantitative EEG analyses. Future applications will integrate noninvasive stimulation delivery, including full-body and transcranial and infrared light with pulsed electromagnetic frequencies.

[Acute Generalized Chorea, Dystonia and Brain Calcifications: A Case Report]. / Coreia Aguda Generalizada, Distonia e Calcificações Cerebrais: A Propósito de um Caso Clínico.

Pathological basal ganglia calcification, or Fahr's Syndrome, can be secondary to a variety of diseases, namely parathyroid disturbances. Movement disorders are common clinical features, in which chorea is seen in less than 20% of cases and dystonia just in 8%. We report the clinical case of a 49-year-old male with a history of thyroidectomy, who was admitted in Emergency Service with acute generalized chorea and focal painful feet dystonia. Laboratory analysis showed hypocalcemia and rhabdomyolysis, and computed tomography scan revealed parenchymal calcification with basal ganglia involvement. After complementary studies we established a Fahr's Syndrome diagnosis secondary to an iatrogenic hypoparathyroidism. Clinical management has been successful with stabilized calcium levels, with no more neurologic symptoms. Hypocalcemia should be readily investigated and treated after a thyroidectomy, given the irreversibility of intracerebral calcifications and potential neurological or systemic consequences.

A calcificação dos núcleos da base, ou síndrome de Fahr, pode ser secundária a variadas doenças, nomeadamente as que cursam com envolvimento da paratiróide. Distúrbios do movimento são achados clínicos comuns, mas a coreia é observada em menos de 20% dos casos e a distonia apenas em 8%. Apresentamos o caso de um homem de 49 anos com antecedentes de tiroidectomia, admitido no serviço de urgência com coreia aguda generalizada e distonia focal dolorosa dos pés, cujo estudo laboratorial revelava hipocalcémia e rabdomiólise e a tomografia computorizada crânio-encefálica mostrava calcificações parenquimatosas extensas com envolvimento dos núcleos da base. A alargada investigação complementar permitiu fazer o diagnóstico de síndrome de Fahr secundária a hipoparatiroidismo iatrogénico. Após estabilização da calcémia, a evolução clínica foi favorável com resolução dos sintomasneurológicos. A hipocalcémia deve ser investigada e corrigida depois de tiroidectomias, dada a irreversibilidade das calcificações intracerebrais e as potenciais consequências neurológicas e sistémicas.

Niemann-Pick type C: contemporary diagnosis and treatment of a classical disorder.

Niemann-Pick type C is an uncommon neurodegenerative lysosomal storage disorder that can cause a progressive neuropsychiatric syndrome associated with supranuclear vertical gaze palsy and a movement disorder. There have been recent developments in testing that make diagnosis easier and new therapies that aim to stabilise the disease process. A new biochemical test to measure serum cholesterol metabolites supersedes the skin biopsy and is practical and robust. It is treatable with miglustat, a drug that inhibits glycosphingolipid synthesis. We describe a patient, aged 22 years, with juvenile-onset Niemann-Pick type C who presented with seizures and a label of 'cerebral palsy'. We describe the approach to this syndrome in general, and highlight the classical features and red flags that should alert a neurologist to this treatable condition.

Increased Aluminum Content in Certain Brain Structures is Correlated with Higher Silicon Concentration in Alcoholic Use Disorder.

INTRODUCTION: Alcohol overuse may be related to increased aluminum (Al) exposure, the brain accumulation of which contributes to dementia. However, some reports indicate that silicon (Si) may have a protective role over Al-induced toxicity. Still, no study has ever explored the brain content of Al and Si in alcoholic use disorder (AUD). MATERIALS AND METHODS: To fill this gap, the present study employed inductively coupled plasma optical emission spectrometry to investigate levels of Al and Si in 10 brain regions and in the liver of AUD patients (n = 31) and control (n = 32) post-mortem. RESULTS: Al content was detected only in AUD patients at mean ± SD total brain content of 1.59 ± 1.19 mg/kg, with the highest levels in the thalamus (4.05 ± 12.7 mg/kg, FTH), inferior longitudinal fasciculus (3.48 ± 9.67 mg/kg, ILF), insula (2.41 ± 4.10 mg/kg) and superior longitudinal fasciculus (1.08 ± 2.30 mg/kg). Si content displayed no difference between AUD and control, except for FTH. Positive inter-region correlations between the content of both elements were identified in the cingulate cortex, hippocampus, and ILF. CONCLUSIONS: The findings of this study suggest that AUD patients may potentially be prone to Al-induced neurodegeneration in their brain-although this hypothesis requires further exploration.

Telemedicine in Neurological Disorders: Opportunities and Challenges.

Introduction: Telemedicine represents an emerging model for the assessment and management of various neurological disorders. Methods: We sought to discuss opportunities and challenges for the integration of telemedicine in the management of common and uncommon neurological disorders by reviewing and appraising studies that evaluate telemedicine as a means to facilitate the access to care, deliver highly specialized visits, diagnostic consultations, rehabilitation, and remote monitoring of neurological disorders. Results: Opportunities for telemedicine in neurological disorders include the replacement of or complement to in-office evaluations, decreased time between follow-up visits, reduction in disparities in access to healthcare, and promotion of education and training through interactions between primary care physicians and tertiary referral centers. Critical challenges include the integration of the systems for data monitoring with an easy-to-use, secure, and cost-effective platform that is both widely adopted by patients and healthcare systems and embraced by international scientific societies. Conclusions: Multiple applications may spawn from a model based on digitalized healthcare services. Integrated efforts from multiple stakeholders will be required to develop an interoperable software platform capable of providing not only a holistic approach to care but also one that reduces disparities in the access to care.

Curcumin derivatives and Aß-fibrillar aggregates: An interactions' study for diagnostic/therapeutic purposes in neurodegenerative diseases.

Several neurodegenerative diseases, like Alzheimer's (AD), are characterized by amyloid fibrillar deposition of misfolded proteins, and this feature can be exploited for both diagnosis and therapy design. In this paper, structural modifications of curcumin scaffold were examined in order to improve its bioavailability and stability in physiological conditions, as well as its ability to interfere with ß-amyloid fibrils and aggregates. The acid-base behaviour of curcumin derivatives, their pharmacokinetic stability in physiological conditions, and in vitro ability to interfere with Aß fibrils at different incubation time were investigated. The mechanisms governing these phenomena have been studied at atomic level by means of molecular docking and dynamic simulations. Finally, biological activity of selected curcuminoids has been investigated in vitro to evaluate their safety and efficiency in oxidative stress protection on hippocampal HT-22 mouse cells. Two aromatic rings, π-conjugated structure and H-donor/acceptor substituents on the aromatic rings showed to be the sine qua non structural features to provide interaction and disaggregation activity even at very low incubation time (2h). Computational simulations proved that upon binding the ligands modify the conformational dynamics and/or interact with the amyloidogenic region of the protofibril facilitating disaggregation. Significantly, in vitro results on hippocampal cells pointed out protection against glutamate toxicity and safety when administered at low concentrations (1 µM). On the overall, in view of its higher stability in physiological conditions with respect to curcumin, of his rapid binding to fibrillar aggregates and strong depolymerizing activity, phtalimmide derivative K2F21 appeared a good candidate for both AD diagnostic and therapeutic purposes.

Neuro-nutraceuticals: Further insights into their promise for brain health.

In this Special Issue on "Nutraceuticals: Molecular and Functional Insights into how Natural Products Nourish the Brain", the editors bring together contributions from experts in nutraceutical research to provide a contemporary overview of how select chemically identified molecules from natural products can beneficially affect brain function at the molecular level. Other contributions address key emergent issues such as bioavailability, neuronal health, inflammation and the holistic benefit of multi-targeted actions that impact upon how nutraceuticals ultimately leverage the brain to function better. In terms of the benefit of nutraceuticals it is clear that some naturally occurring molecules can be advantageous to both the young and aged brain, and that they have actions that ultimately can be directed to aid either in the improvement of cognition or in the management of debilitating neurodegenerative and neuropsychiatric conditions.

The relationship between hyperhomocysteinemia and neurodegeneration.

Homocysteine (Hcy) is a key junction in methionine metabolism. In inherited forms of hyperhomocysteinemia patients develop early vascular damage and cognitive decline. Hyperhomocysteinemia is a common consequence of dietary, behavioral and pathological conditions and is epidemiologically related to different diseases, among them neurodegenerative ones are receiving progressively more attention in the last years. Several detrimental mechanisms that see in Hcy a possible promoter seem to be implicated in neurodegeneration (protein structural and functional modifications, oxidative stress, cellular metabolic derangements, epigenetic modifications, pathological aggregates deposition, endothelial damage and atherothrombosis). Interventional studies exploring B group vitamins administration in terms of prevention of Hcy-related cognitive decline and cerebrovascular involvement have shown scant results. In this review, current and possible alternative/complementary approaches are discussed.

[Psychosis Associated With Fahr's Syndrome: A Case Report]. / Psicosis asociada con síndrome de Fahr: informe de un caso.

INTRODUCTION: Fahr syndrome (SF) is a rare neurological disorder, characterized by abnormal deposition of calcium in brain areas that control movement. OBJECTIVE: The case is presented of a 41-year-old female with a convulsive syndrome, psychotic disorder, neurocognitive disorde,r and intellectual disability associated with bilateral brain calcifications and altered calcium/phosphorus metabolism in the context of hypoparathyroidism. METHOD: Case report. RESULTS: The calcifications found in the patient could be the cause of psychotic symptoms and cognitive impairment. Diagnostic imaging, laboratory tests, psychiatric and neuropsychological assessments are presented. The clinical presentation of this case is compared with similar ones reported in the literature. Therapeutic approaches and clinical outcomes are described. CONCLUSIONS: Fahr's syndrome should be suspected in patients with neuropsychiatric disorders and seizures. Neuroimaging studies, and the determining of phosphorus and calcium metabolism and parathyroid hormone levels are important in this type of patient.