Manuela Pennisi

Transcranial magnetic stimulation in Alzheimer’s disease: a neurophysiological marker of cortical hyperexcitability

Recently, neuropathological studies have shown an important motor cortex involvement in Alzheimer’s disease (AD), even in its early stages, despite the lack of clinically evident motor deficit. Transcranial magnetic stimulation (TMS) studies have demonstrated that cortical excitability is enhanced in AD patients. This cortical hyperexcitability is believed to be a compensatory mechanism to execute voluntary movements, despite the progressive impairment of associative cortical areas. At present, it is not clear if these motor cortex excitability changes might be the expression of an involvement of intracortical excitatory glutamatergic circuits or an impairment of inhibitory cholinergic and, to a lesser extent, gabaergic activity. Although the main hypothesis for the pathogenesis of AD remains the degeneration of the basal forebrain cholinergic neurons, the development of specific TMS protocols, such as the paired-pulse TMS and the study of the short-latency afferent inhibition, points out the role of other neurotransmitters, such as gamma-amino-butyric acid, glutamate and dopamine. The potential therapeutic effect of repetitive TMS in restoring or compensating damaged cognitive functions, might become a possible rehabilitation tool in AD patients. Based on different patterns of cortical excitability, TMS may be useful in discriminating between physiological brain aging, mild cognitive impairment, AD and other dementing disorders. The present review provides a perspective of these TMS techniques by further understanding the role of different neurotransmission pathways and plastic remodelling of neuronal networks in the pathogenesis of AD.

Neurotoxicity of Acrylamide in Exposed Workers

Acrylamide (ACR) is a water-soluble chemical used in different industrial and laboratory processes. ACR monomer is neurotoxic in humans and laboratory animals. Subchronic exposure to this chemical causes neuropathies, hands and feet numbness, gait abnormalities, muscle weakness, ataxia, skin and in some cases, cerebellar alterations. ACR neurotoxicity involves mostly the peripheral but also the central nervous system, because of damage to the nerve terminal through membrane fusion mechanisms and tubulovescicular alterations. Nevertheless, the exact action mechanism is not completely elucidated. In this paper we have reviewed the current literature on its neurotoxicity connected to work-related ACR exposure. We have analyzed not only the different pathogenetic hypotheses focusing on possible neuropathological targets, but also the critical behavior of ACR poisoning. In addition we have evaluated the ACR-exposed workers case studies. Despite all the amount of work which have being carried out on this topic more studies are necessary to fully understand the pathogenetic mechanisms, in order to propose suitable therapies.

Clinical Presentation and Outcome of Geriatric Depression in Subcortical Ischemic Vascular Disease

Background: Vascular damage of frontal-subcortical circuits involved in mood regulation and cognition might be the main contributor to the pathogenesis of late-life depression, and it is linked to poor response to treatment. Objective: To investigate the relationship between executive dysfunction and outcome of depressive symptoms among elderly patients with subcortical ischemic vascular disease. Methods: Ninety-two elderly patients with white matter lesions (WMLs) or lacunar infarcts (LAs) on brain MRI and depressive symptomatology were consecutively recruited. Depression was rated with the Hamilton Depression Rating Scale (HDRS). Evaluation of executive functions by means of the Stroop color-word test was performed at entry of the study, and WMLs were categorized into mild, moderate or severe. Mood was reevaluated by means of HDRS after the 12th week of pharmacological treatment. Results: Psychomotor retardation, difficulties at work, apathy, and lack of insight were the predominant symptoms. Fifty-six patients (62.8%) had a neuroradiological picture of WMLs, while the remaining 33 (37.1%) had LAs. Executive dysfunctions significantly and independently predict poor outcome of depressive symptoms. Patients with the severest WMLs showed not only a greater executive dysfunction, but also a minor response to antidepressant treatment. Conclusion: This study supports the vascular depression hypothesis. WMLs are of crucial clinical relevance as they are linked with cognitive symptoms and poor antidepressant outcome.

Redox regulation of cellular stress response in multiple sclerosis

Multiple sclerosis (MS) is an autoimmune-mediated neurodegenerative disease with characteristic foci of inflammatory demyelination in the brain, spinal cord, and optic nerves. Recent studies have demonstrated not only that axonal damage and neuronal loss are significant pathologic components of MS, but that this neuronal damage is thought to cause the permanent neurologic disability often seen in MS patients. Emerging finding suggests that altered redox homeostasis and increased oxidative stress, primarily implicated in the pathogenesis of MS, are a trigger for activation of a brain stress response. Relevant to maintenance of redox homeostasis, integrated mechanisms controlled by vitagenes operate in brain in preserving neuronal survival during stressful conditions. Vitagenes encode for heat shock proteins (Hsp) Hsp32, Hsp70, the thioredoxin and the sirtuin protein systems. In the present study we assess stress response mechanisms in the CSF, plasma and lymphocytes of control patients compared to MS patients. We found that the levels of vitagenes Hsp72, Hsc70, HO-1, as well as oxidative stress markers carbonyls and hydroxynonenals were significantly higher in the blood and CSF of MS patients than in control patients. In addition, an increased expression of Trx and sirtuin 1, together with a decrease in the expression of TrxR were observed. Our data strongly support a pivotal role for redox homeostasis disruption in the pathogenesis of MS and, consistently with the notion that new therapies that prevent neurodegeneration through nonimmunomodulatory mechanisms can have a tremendous potential to work synergistically with current MS therapies, unravel important targets for new cytoprotective strategies.

A Review of Transcranial Magnetic Stimulation in Vascular Dementia

Vascular dementia (VaD) is a clinical syndrome that encompasses a wide spectrum of cognitive disorders caused by cerebrovascular disease. The subcortical ischemic form of VaD is clinically homogeneous and a major cause of cognitive impairment in the elderly. Vascular lesions contribute to cognitive decline in neurodegenerative dementias, and VaD and Alzheimer’s disease often coexist and share clinical features and multiple neurotransmission involvement. These similarities have led several investigators to use transcranial magnetic stimulation (TMS) to enucleate a neurophysiological profile of VaD. TMS studies have identified a pattern of cortical hyperexcitability probably related to the disruption of the integrity of white matter lesions due to cerebrovascular disease. The present review provides a perspective of these TMS techniques by further understanding the role of different neurotransmission pathways and plastic remodeling of neuronal networks in the pathogenesis of VaD.

Enhanced motor cortex facilitation in patients with vascular cognitive impairment-no dementia.

Data on Transcranial Magnetic Stimulation (TMS) derived measures of cortical excitability and intracortical circuits in age-related white matter changes are scarce. We aimed to assess early changes of motor cortex excitability in nondemented elderly patients with subcortical ischemic vascular disease (SVD). Ten SVD elderly and ten age-matched controls underwent paired-pulse TMS for the analysis of intracortical inhibition (ICI) and facilitation (ICF). All subjects performed neuropsychological assessment and brain magnetic resonance imaging. SVD patients showed abnormal executive control function. No statistically significant differences were found for resting motor threshold, cortical silent period between SVD patients and controls or between the two hemispheres, in patients. A significant enhancement of mean ICF was observed in SVD patients. This study provides the first evidence of functional changes in intracortical excitatory neuronal circuits in patients with SVD and clinical features of vascular cognitive impairment-no dementia. Further studies are required to evaluate whether the observed change of ICF might predict cognitive and/or motor impairment in a population at risk for subcortical vascular dementia.

Inflammasomes, hormesis, and antioxidants in neuroinflammation: Role of NRLP3 in Alzheimer disease

Alzheimer disease (AD) is a progressive neurodegenerative disorder leading to cognitive decline, neuropsychiatric symptoms, disability, caregiver burden, and premature death. It represents the most prevalent cause of dementia, and its incidence rates exponentially increase with increasing age. The number of Americans living with AD is rapidly increasing. An estimated 5.4 million Americans of all ages have AD in 2016. One in nine people aged 65 and older has AD, and by midcentury, someone in the United States will develop the disease every 33 sec. It is now accepted that neuroinflammation is a common feature of neurological disease. Inflammasomes, which are a multiprotein complex part of the innate immune system, induce inflammation in response to various stimuli, such as pathogens and stress. Inflammasomes activate proinflammatory caspases, such as caspase‐1, leading to the activation of the proinflammatory cytokines interleukin (IL)‐1b, IL‐18, and IL‐33, which promote neuroinflammation and brain pathologies. The nucleotide‐binding oligomerization domain‐like receptor family, pyrin domain‐containing‐3 (NLRP3) inflammasome is the best characterized in neurodegenerative diseases, in particular AD. Recent research suggests that NLRP3 could possibly be used in targeted therapies to alleviate neuroinflammation. Modulation of endogenous cellular defense mechanisms may be an innovative approach to therapeutic intervention in AD and other disorders associated with neuroinflammation and neurodegeneration. Herein, we introduce the hormetic dose–response concept and present possible mechanisms and applications to neuroprotection. We summarize the mechanisms involved in activation of the NLRP3 inflammasome and its role in neuroinflammation. We also address and propose the potential therapeutic utility of the nutritional antioxidants sulforaphane and hydroxytyrosol against particular signs and symptoms of AD.

Cellular stress response, sirtuins and UCP proteins in Alzheimer disease: role of vitagenes

Alzheimer’s Disease (AD) is a neurodegenerative disorder affecting up to one third of individuals reaching the age of 80. Different integrated responses exist in the brain to detect oxidative stress which is controlled by several genes termed Vitagenes. Vitagenes encode for cytoprotective heat shock proteins (Hsp), as well as thioredoxin, sirtuins and uncouple proteins (UCPs). In the present study we evaluate stress response mechanisms in plasma and lymphocytes of AD patients, as compared to controls, in order to provide evidence of an imbalance of oxidant/antioxidant mechanisms and oxidative damage in AD patients and the possible protective role of vitagenes.We found that the levels of Sirt-1 and Sirt-2 in AD lymphocytes were significantly higher than in control subjects. Interestingly, analysis of plasma showed in AD patients increased expression of Trx, a finding associated with reduced expression of UCP1, as compared to control group.This finding can open up new neuroprotective strategies, as molecules inducing this defense mechanisms can represent a therapeutic target to minimize the deleterious consequences associated to oxidative stress, such as in brain aging and neurodegenerative disorders.

Transcranial Magnetic Stimulation in the Assessment of Motor Cortex Excitability and Treatment of Drug-Resistant Major Depression

Major depression is one of the leading causes of disabling condition worldwide and its treatment is often challenging and unsatisfactory, since many patients become refractory to pharmacological therapies. Transcranial magnetic stimulation (TMS) is a noninvasive neurophysiological investigation mainly used to study the integrity of the primary motor cortex excitability and of the cortico-spinal tract. The development of paired-pulse and repetitive TMS (rTMS) paradigms has allowed investigators to explore the pathophysiology of depressive disorders and other neuropsychiatric diseases linked to brain excitability dysfunctions. Repetitive transcranial magnetic stimulation has also therapeutic and rehabilitative capabilities since it is able to induce changes in the excitability of inhibitory and excitatory neuronal networks that may persist in time. However, the therapeutic effects of rTMS on major depression have been demonstrated by analyzing only the improvement of neuropsychological performance. The aim of this study was to investigate cortical excitability changes on 12 chronically-medicated depressed patients (test group) after rTMS treatment and to correlate neurophysiological findings to neuropsychological outcomes. In detail, we assessed different parameters of cortical excitability before and after active rTMS in the test group, then compared to those of 10 age-matched depressed patients (control group) who underwent sham rTMS. In line with previous studies, at baseline both groups exhibited a significant interhemispheric difference of motor cortex excitability. This neurophysiological imbalance was then reduced in the patients treated with active rTMS, resulting also in a clinical benefit as demonstrated by the improvement in neuropsychological test scores. On the contrary, after sham rTMS, the interhemispheric difference was still evident in the control group. The reported clinical benefits in the test group might be related to the plastic remodeling of synaptic connection induced by rTMS treatment.

Ischaemic myelopathy associated with cocaine: clinical, neurophysiological, and neuroradiological features

Two patients with spinal infarction and one patient with the previously unreported complication of spinal transient ischaemic attack associated with cocaine misuse are reported. Spinal MRI documented an infarction in the territory of the anterior spinal artery in the first two patients and was completely normal in the patient with a transient ischaemic attack. Motor evoked potentials were abnormal in all three patients.