Neurocognitive Psychiatric and Neuropsychological Alterations in Parkinson's Disease: A Basic and Clinical Approach.

The main histopathological hallmarks of Parkinson's disease (PD) are the degeneration of the dopaminergic neurons of the substantia nigra pars compacta and the loss of neuromelanin as a consequence of decreased dopamine synthesis. The destruction of the striatal dopaminergic pathway and blocking of striatal dopamine receptors cause motor deficits in humans and experimental animal models induced by some environmental agents. In addition, neuropsychiatric symptoms such as mood and anxiety disorders, hallucinations, psychosis, cognitive impairment, and dementia are common in PD. These alterations may precede the appearance of motor symptoms and are correlated with neurochemical and structural changes in the brain. This paper reviews the most crucial pathophysiology of neuropsychiatric alterations in PD. It is worth noting that PD patients have global task learning deficits, and cognitive functions are compromised in a way is associated with hypoactivation within the striatum, anterior cingulate cortex, and inferior frontal sulcus regions. An appropriate and extensive neuropsychological screening battery in PD must accurately assess at least five cognitive domains with some tests for each cognitive domain. This neuropsychological screening should consider the pathophysiological and clinical heterogeneity of cognitive dysfunction in PD.

Neuromyelitis optica spectrum disorder: pathophysiological approach.

Aim: To review the main pathological findings of Neuromyelitis Optica Spectrum Disorder (NMOSD) associated with the presence of autoantibodies to aquaporin-4 (AQP4) as well as the mechanisms of astrocyte dysfunction and demyelination. Methods: An comprehensive search of the literature in the field was carried out using the database of The National Center for Biotechnology Information from . Systematic searches were performed until July 2022. Results: NMOSD is an inflammatory and demyelinating disease of the central nervous system mainly in the areas of the optic nerves and spinal cord, thus explaining mostly the clinical findings. Other areas affected in NMOSD are the brainstem, hypothalamus, and periventricular regions. Relapses in NMOSD are generally severe and patients only partially recover. NMOSD includes clinical conditions where autoantibodies to aquaporin-4 (AQP4-IgG) of astrocytes are detected as well as similar clinical conditions where such antibodies are not detected. AQP4 are channel-forming integral membrane proteins of which AQ4 isoforms are able to aggregate in supramolecular assemblies termed orthogonal arrays of particles (OAP) and are essential in the regulation of water homeostasis and the adequate modulation of neuronal activity and circuitry. AQP4 assembly in orthogonal arrays of particles is essential for AQP4-IgG pathogenicity since AQP4 autoantibodies bind to OAPs with higher affinity than for AQP4 tetramers. NMOSD has a complex background with prominent roles for genes encoding cytokines and cytokine receptors. AQP4 autoantibodies activate the complement-mediated inflammatory demyelination and the ensuing damage to AQP4 water channels, leading to water influx, necrosis and axonal loss. Conclusions: NMOSD as an astrocytopathy is a nosological entity different from multiple sclerosis with its own serological marker: immunoglobulin G-type autoantibodies against the AQP4 protein which elicits a complement-dependent cytotoxicity and neuroinflammation. Some patients with typical manifestations of NMSOD are AQP4 seronegative and myelin oligodendrocyte glycoprotein positive. Thus, the detection of autoantibodies against AQP4 or other autoantibodies is crucial for the correct treatment of the disease and immunosuppressant therapy is the first choice.

Cognitive disorder and dementia in type 2 diabetes mellitus.

Insulin, a key pleiotropic hormone, regulates metabolism through several signaling pathways in target tissues including skeletal muscle, liver, and brain. In the brain, insulin modulates learning and memory, and impaired insulin signaling is associated with metabolic dysregulation and neurodegenerative diseases. At the receptor level, in aging and Alzheimer's disease (AD) models, the amount of insulin receptors and their functions are decreased. Clinical and animal model studies suggest that memory improvements are due to changes in insulin levels. Furthermore, diabetes mellitus (DM) and insulin resistance are associated with age-related cognitive decline, increased levels of ß-amyloid peptide, phosphorylation of tau protein; oxidative stress, pro-inflammatory cytokine production, and dyslipidemia. Recent evidence shows that deleting brain insulin receptors leads to mild obesity and insulin resistance without influencing brain size and apoptosis development. Conversely, deleting insulin-like growth factor 1 receptor (IGF-1R) affects brain size and development, and contributes to behavior changes. Insulin is synthesized locally in the brain and is released from the neurons. Here, we reviewed proposed pathophysiological hypotheses to explain increased risk of dementia in the presence of DM. Regardless of the exact sequence of events leading to neurodegeneration, there is strong evidence that mitochondrial dysfunction plays a key role in AD and DM. A triple transgenic mouse model of AD showed mitochondrial dysfunction, oxidative stress, and loss of synaptic integrity. These alterations are comparable to those induced in wild-type mice treated with sucrose, which is consistent with the proposal that mitochondrial alterations are associated with DM and contribute to AD development. Alterations in insulin/IGF-1 signaling in DM could lead to mitochondrial dysfunction and low antioxidant capacity of the cell. Thus, insulin/IGF-1 signaling is important for increased neural processing and systemic metabolism, and could be a specific target for therapeutic strategies to decrease alterations associated with age-related cognitive decline.

Adherence to treatment in Parkinson's disease: A multicenter exploratory study with patients from six Latin American countries.

BACKGROUND: Adherence to treatment in Parkinson's disease (PD) is compromised due to the need for multiple therapies, comorbidities related to aging, and the complexity of therapeutic schemes. In the present study, we aimed to explore adherence to treatment in groups of PD patients from six Latin-American (LA) countries and identify its associated demographic and clinical parameters. METHODS: A multicenter, cross-sectional, exploratory study was conducted from September 2016 to March 2017. Treatment adherence was assessed using the simplified medication adherence questionnaire (SMAQ), applied to patients and caregivers. Sociodemographic and clinical variables (MDS-UPDRS Part III-IV, MMSE, Beck Depression Inventory-II (BDI-II)) were recorded. RESULTS: Eight hundred patients from six LA countries were evaluated. Nonadherence was reported in 58.25% of the population, according to patients. The most frequent issues were forgetfulness and correct timing of doses. A high level of agreement in adherence prevalence and most SMAQ items were observed between patients and their caregivers. The nonadherent population had a significantly higher proportion of unemployment, free access to medication, troublesome dyskinesias and off-periods, lesser years of education, and worse motor, cognitive, and mood scores. In multiple logistic and linear regression analyses, MDS-UPDRS Part III, BDI-II, gender, free access to medication, treatment with dopamine agonists alone, years of education, excessive concerns about adverse effects, and beliefs about being well-treated remained significant contributors to adherence measures. CONCLUSION: Educational strategies, greater involvement of PD patients in decision-making, and consideration of their beliefs and values might be of great need to improve medication adherence in this PD population.

Effect of Melatonin Administration on Mitochondrial Activity and Oxidative Stress Markers in Patients with Parkinson's Disease.

Mitochondrial dysfunction and oxidative stress are extensively linked to Parkinson's disease (PD) pathogenesis. Melatonin is a pleiotropic molecule with antioxidant and neuroprotective effects. The aim of this study was to evaluate the effect of melatonin on oxidative stress markers, mitochondrial complex 1 activity, and mitochondrial respiratory control ratio in patients with PD. A double-blind, cross-over, placebo-controlled randomized clinical trial study was conducted in 26 patients who received either 25 mg of melatonin or placebo at noon and 30 min before bedtime for three months. At the end of the trial, in patients who received melatonin, we detected a significant diminution of lipoperoxides, nitric oxide metabolites, and carbonyl groups in plasma samples from PD patients compared with the placebo group. Conversely, catalase activity was increased significantly in comparison with the placebo group. Compared with the placebo group, the melatonin group showed significant increases of mitochondrial complex 1 activity and respiratory control ratio. The fluidity of the membranes was similar in the melatonin group and the placebo group at baseline and after three months of treatment. In conclusion, melatonin administration was effective in reducing the levels of oxidative stress markers and restoring the rate of complex I activity and respiratory control ratio without modifying membrane fluidity. This suggests that melatonin could play a role in the treatment of PD.

Generalized Dystonia and Paroxysmal Dystonic Attacks due to a Novel ATP1A3 Variant.

Background: Paroxysmal movement disorders are a heterogeneous group of neurological diseases, better understood in recent years thanks to widely available genetic testing. Case report: A pair of monozygotic twins with dystonia and paroxysmal attacks, resembling paroxysmal non-kinesigenic dyskinesias, due to a novel ATP1A3 variant are reported. The complete resolution of their paroxysms was achieved using levodopa and deep brain stimulation of the internal globus pallidus. Improvement of interictal dystonia was also achieved with this therapy. Discussion: Paroxysmal worsening of movement disorders should be suspected as part of the ATP1A3 spectrum. Treatment outcome might be predicted based on the phenotype.

Beyond dystonia and ataxia: Expanding the phenotype of SQSTM1 mutations.

BACKGROUND: Homozygous sequestomosome-1 gene mutations have been recently linked to neurodegeneration with dystonia, ataxia and gaze palsy. Seven affected families were identified thus far. OBJECTIVE: To describe four new cases with additional phenotypical features. RESULTS: Four affected patients from two unrelated families were identified. Two compound heterozygous variants of the gene (c.257_259delins35 and c.301+1G > T) were found in one family (cases 1 and 2), and homozygous c.823_824delAG variant was identified in cases 3 and 4. In addition to the previously described syndrome characterized by cerebellar ataxia, dystonia, choreoathetosis, cognitive impairment and gaze palsy, two subjects presented with iridoplegia. Furthermore, we report dysautonomic features such as orthostatic hypotension and sudomotor dysfunction, along with other non-motor symptoms. CONCLUSIONS: We expand the phenotype of dystonia caused by Sequestomosome-1 gene by identifying dysautonomic features along with other non-motor symptoms.

Oxidative Stress: Love and Hate History in Central Nervous System.

Molecular oxygen is essential for aerobic organisms in order to synthesize large amounts of energy during the process of oxidative phosphorylation and it is harnessed in the form of adenosine triphosphate, the chemical energy of the cell. Oxygen is toxic for anaerobic organisms but it is also less obvious that oxygen is poisonous to aerobic organisms at higher concentrations of oxygen. For instance, oxygen toxicity is a condition resulting from the harmful effects of breathing molecular oxygen at increased partial pressures. Reactive oxygen species (ROS) are chemically reactive molecules containing oxygen that are formed as a natural byproduct of the normal metabolism of oxygen and have important roles in cell signaling and homeostasis. However, in pathological conditions ROS levels can increase dramatically. This may result in significant damage to cell structures. Living organisms have been adapted to the ROS in two ways: they can mitigate the unwanted effects through removal by the antioxidant systems and can advantageously use them as messengers in cell signaling and regulation of body functions. Some other physiological functions of ROS include the regulation of vascular tone, detection, and adaptation to hypoxia. In this review, we describe the mechanisms of oxidative damage and its relationship with the most highly studied neurodegenerative diseases.

Neuronopatía isquémica cervical y cardioembolismo: otra causa de síndrome del hombre en el barril / Cervical ischaemic neuronopathy and cardioembolism: another cause of man-in-the-barrel syndrome

Introducción. Los infartos de la médula espinal ocurren aproximadamente en el 1% de todos los infartos del sistema nervioso. El cardioembolismo es una causa rara. Las áreas comúnmente afectadas en infartos medulares son zonas de circulación limítrofe en la región dorsal o lumbar; sin embargo, se han descrito previamente infartos medulares en la zona cervical asociados a la disección de arterias vertebrales. Caso clínico. Se presenta un nuevo caso de síndrome del hombre en el barril asociado con fibrilación auricular durante un infarto agudo de miocardio, que causó una neuronopatía cervical isquémica (infarto de astas anteriores). Conclusiones. Los hallazgos clásicos de isquemia medular cervical son tetraplejía aguda, disfunción vesical, intestinal y cardiovascular, así como pérdida de la sensibilidad disociada. La colateralización incompleta y las características anatómicas de la arteria espinal anterior en la médula cervical hacen de la porción C3-C5 la región más vulnerable de daño isquémico, ya que la irrigación de las arterias radiculares se inicia debajo de C5 y la fisiopatología de la lisis rápida de un coágulo fresco produce únicamente daño bilateral de las células de las astas neuronales (AU)

Introduction. Spinal infarction accounts for 1% of all strokes. Cardioembolism is a rare cause. Common areas of ischemic spinal damage are watershed in the dorsal or lumbar regions; however cervical spinal cord infarction has been reported previously. Case report. We present a new case of a man-in-the-barrel syndrome produced by cardiac embolization associated with atrial fibrillation during an acute myocardial infarction, which caused cervical ischemic neuronopathy (infarction of the anterior horn). Conclusions. Classic features of cervical spinal cord ischemia are acute tetraplegia, bladder, bowel and cardiovascular dysfunction and dissociate sensory loss. Incomplete collateralization and anatomical characteristics of the circulation of the anterior spinal artery in the cervical spinal cord, makes of the portion C3 to C5, the most vulnerable portion to ischemic damage, since the radicular arteries supply begins bellow C5 and the pathophysiology of a fast fresh clot lysis produced unique bilateral neuronal horn cells damage (AU)