Intraoperative neurophysiological monitoring (IONM) consists of the continuous analysis of the patients’ neurological status using a set of tools and methods that allows us to assess the functional state of the neurological systems and pathways of interest. Different techniques, such as somatosensory evoked potentials (SSEPs), motor evoked potentials (MEPs), and others are employed according to the type of surgery and neurological tissue to be monitored.
This study focuses on the diagnosis and management of pain in Parkinson’s disease. Separating Parkinson’s disease related pain from pain of other origin is very difficult. They all come under one umbrella among the different forms of Parkinson’s disease related pain, musculoskeletal pain is the most common form accounting for 40% in PD. Pain occurs in about 60% of Parkinson’s disease patients, two to three times more frequent in this population than in age matched healthy individuals. It is an early and potentially disabling symptom that can precede motor symptoms by several years. The lower back and lower extremities are the most commonly affected areas. The most used classification for pain in PD defines musculoskeletal, dystonic, central, or neuropathic/radicular forms. Its different clinical characteristics, variable relationship with motor symptoms and inconsistent response to dopaminergic drugs suggest that the mechanism underlying pain in Parkinson’s disease is complex and multifaceted, involving the peripheral nervous system, generation and amplification of pain by motor symptoms and neuro-degeneration of areas related to pain. The basal ganglion processes somatosensory information differently. Increased subjective pain sensitivity with lower electrical and heat pain threshold has been reported in Parkinson’s disease patients. The mechanism is assumed to be diminished activity of the descending inhibitory system of the basal ganglia. Promising perspectives for this have come from studies using different pain scales in Parkinson’s disease. Selection criteria- “King’s Parkinson’s disease pain scale,” which was proposed by a multicenter group that included King’s College Hospital in London, is officially advocated by the “International Parkinson’s and Movement Disorder Society Non-Motor PD Study Group” for evaluating pain in Parkinson’s disease treatment prevalence.
Background: Multiple sclerosis, characterized by demyelination or loss of myelin sheaths affects the discharge of nerve impulses and the ability of the central nervous system CNS, to transmit commands, resulting in disorders of functions that are directed by the CNS such as: sight, speech, walking, writing and memory. Depending on the location of the demyelination, patients have a wide range of symptoms that differ from person to person and may change as the condition progresses. The most common symptoms are: fatigue, balance and coordination disorders, vision and sensitivity disorders, pain and depression. Objective: In this study we aimed to demonstrate that the treatment of sclerosis by combining a drug treatment with a rehabilitation treatment, represented by physical therapy and occupational therapy, has superior therapeutic effects compared to simple drug treatment. Methods: In order to highlight the superior therapeutic efficacy of the mentioned combination, we studied, during one year, two groups of patients: the group that respects the home rehabilitation program and the group that does not respect the home rehabilitation program. In our study, we evaluated the following parameters: number of patients with falls, timed 25-Foot Walk and Multiple Sclerosis Quality of Life-54. Results: The results of our study highlight the superior therapeutic benefits of drug treatment associated with rehabilitation treatment. Conclusion: Patients who follow the rehabilitation program associated with drug treatment we found the following benefits: improving body stability; increase in muscle strength in the lower limbs; improving coordination and balance while walking; improving the QoL.
Guillain–Barre Syndrome (GBS) is a serious post-infectious immune mediated neuropathy presented with diminished reflexes and resultant weakness. Global report on GBS depicted with an incidence of 1 to 4 cases per 100,000 annually and carries a high maternal risk. It is very rare among post-partum women. The study is case of 24 year women within 2 month of post-partum period who presented with flaccid quadriplegia diagnosed as GBS. The case is discussed in all the aspects of diagnosis, treatment and outcome.
Cryptic Arteriovenous Malformations (AVM) have increased risks of re-bleeding but sometimes undetectable on conventional neuroimaging modalities, thus delaying definitive treatment. Bleeding into the confined space of the posterior cranial fossa poses increased risks of mortality due to increasing intracranial pressure and early detection and surgical resolution is of utmost urgency. We present a case of cerebellar cryptic AVM diagnosed using high-resolution cone beam Computerized Tomography angiography (CBCT-A) and three-Dimensional Rotational Angiography (3-DRA), with a definitive diagnosis confirmed on histology. Surgery was performed without complications and the patient resumed normal functioning.
Background: Drugs primarily affect the way individuals think, feel and behave. Illicit substances such as crystal methamphetamine show a strong association to abnormalities in the process of neurotransmission. Objective: The main aim of this review is to analyse substance abuse and abnormalities in neurotransmission focusing on crystal methamphetamine and its physiological, psychological and social implications. Methods: Extensive systematic electronic databases (EBSCOhost, JSTOR, ProQuest Science, Science Direct, Research Gate, Google Scholar and PubMed) were used. Research articles and books were searched using the keywords ‘effects of crystal methamphetamine’, ‘neurotransmission in substance abuse’, ‘substance abuse by homosexual males’. Discussion and Conclusion: This thematic review draws close attention to the physiological changes, psychological disorders and abuse of crystal methamphetamine among homosexual men tested positive for Human Immunodeficiency Virus (HIV) as well as a need for better social care services and treatment in order to overcome homophobic stigmatization.
A 38 year old male client presenting at outdoor patient department as symptoms of difficulty in breathing, uneven running heart beats, heaviness in head, trembling of body, fear that something will happen to him and he will die suddenly. With the scenario of COVID-19 pandemic, this case reports evaluates the psychiatric differential diagnosis of these symptoms. Illness Anxiety Disorder (IAD) being 4 to 6% in general population is a psychiatric illness in which a person is preoccupied of being seriously ill. IAD needs to be ruled out if clinical examination and investigations are normal. This will not only reduce the cost of treatment but also will be an in time psychiatric management of symptoms.
Background: Augmenter of liver regeneration (ALR) is an antioxidant, antiapoptotic and mitochondrial-protective factor. Evidence exists that (i) ALR is variously expressed by many neurons in the central nervous system; (ii) ALR is differently expressed in female and male cells; (iii) neurodegenerative diseases triggered by dysregulation of cell normoxic conditions differently affect the 2 sexes. Aim: Aim of the present study was to analyze the ALR presence in the prosencephalon of female and male mice and evaluate whether differences in expression exist between the two genders. Methods: Harvested prosencephala were investigated by Western blotting and immunohistochemistry to assess ALR expression. Results: Western blotting revealed 2 ALR isoforms, ALR-21 and ALR-23, both more expressed in male prosencephalon. Immunohistochemistry revealed ALRimmunoreactive neurons diffusely distributed in the prosencephalon, but with a significantly higher number in male prosencephalon. Conclusion: The different ALR expression level in female and male mouse prosencephalon may represent a marker of sexual dimorphism. The higher ALR expression seen in male prosencephalic neurons suggests that ALR, an antioxidant factor, could parallel the antioxidant effect of female sex steroid hormones that are known to be more effective compared to the male sexual steroids in protecting against the oxidative stress. These data open new options to study the neurodegenerative diseases, particularly those showing gender differences in terms of epidemiology.
Cerebral venous thrombosis (CVT) is a rare cause of acute ischemic stroke (AIS). There is no existing literature on the use of recombinant tissue plasminogen activator (rtPA) for venous strokes if they present within the window for thrombolysis. In addition, establishing venous thrombosis as a cause of acute stroke when deciding to administer rtPA can be challenging. We present a case of acute venous stroke who received rtPA when she presented within 4.5- hour window. The report discusses early imaging findings and role of thrombolysis in acute phase of CVT
Angioedema can be a life-threatening complication after thrombolytic therapy (tPA). The incidence is 1-5%, the risk of developing bradykinin-mediated angioedema is multiplied by 6 in patient on angiotensin converting enzyme inhibitor. Most therapeutic options are ineffective or expensive and not available. FFP is known as effective treatment for bradykinin-mediate angioedema since 1969 but never reported in case of angioedema tPA induced. We report a case of 60year old patient with history of hypertension treated with angiotensin converting enzyme inhibitor, who developing severe bradykinin-mediates angioedema 10 min after the end of thrombolytic therapy. The patient was treated successfully with FFP. We are reporting this case to increase the awareness of physicians and to widen their therapeutic options when encountering this clinically significant condition.
Background In Patients and Methods they included 60 patients presenting with acute ischemic stroke; 20 patients were eligible for TPA therapy (group 1 patients) and 40 patients not received r-TPA due to contraindications or came after time window (group 2, control). All patients underwent clinical assessment using NIHSS and quantitative measurement of IGF-1 in serum by ELISA at the onset of stroke (before receiving r-TPA) and at day 7 follow up. Results NIHSS was significantly lower and Serum IGF-1 level was significantly higher in day 7compared to that of day 1 in the group (1) patients receiving r-TPA (P-valueE? 0.001). No significant difference was found in the control group (2). There was a significant negative correlation between age & door to needle time and IGF-1 serum level. There was a significant positive correlation between fo NIHSS and IGF-1 serum level Conclusion The r-TPA decrease clinical disability and improve neuroplasticity through increasing serum level of IGF-1.
he Blood-Brain Barrier (BBB) acts as a hindrance to the transport of potential therapeutic agents in the brain; hence it serves as a major limiting factor to treat pharmacological dysfunction of the central nervous system (CNS). In a healthy brain, the BBB act as an essential barrier for protecting normal brain functions by preventing the transportation of foreign substances from the systemic circulation into the brain.
Complex Regional Pain Syndrome (CRPS) is a chronic, debilitating pain condition thought to be caused by heightened sympathetic nervous system activation in response to an injury. CRPS can present with features including pain that is out of proportion to the initial injury or trauma, skin and nail changes, redness, discoloration, and edema of the affected extremity. CRPS is a difficult disease to treat due to a lack of understanding of its cause and predisposing factors
Tumefactive Demyelinating Lesions (TDL) is characterized by large demyelinating lesions that frequently mimic intracranial neoplasm or abscess. Proton Magnetic Resonance Spectroscopy (MRS) imaging is a potentially exciting tool to help in the diagnosis. Literature reports, studying the potential utility of MRS in differentiating TDLs from neoplasms, have focused on the quantification of biochemical metabolites such as N-acetyl aspartate (NAA), Choline (Cho), Creatine (Cr), Lactate (Lac), mobile Lipids (Lip) and Glutamate (Glx). We hereby report MRS findings of three patients with tumefactive lesions, i.e. elevated Choline and Lactate (except patient 3) peaks with reduced NAA peaks, consistent with demyelination. Based on the improvements in clinical and imaging outcomes during subsequent follow ups confirming Multiple Sclerosis (MS), we propose that elevation of Lactate and Choline peaks together with reduction of NAA peak on MRS study together with clinical picture may serve as an important non-invasive tool to differentiate TDL from other radiological correlates.
Intravenous tissue plasminogen activator (IV-tPA) is first line treatment for acute ischaemic stroke (AIS). After AIS, many patients are anticoagulated, which is a contraindication to IV-tPA. Endovascular thrombectomy (EVT) provides an alternative treatment for AIS patients who have contraindications for IV-tPA. Limited data exists regarding the safety of EVT in anticoagulated patients. We aim to determine the safety of EVT in anticoagulated patients through comparing the rates of symptomatic intracranial haemorrhage (sICH) in anticoagulated and nonanticoagulated patients. Furthermore, we aim to compare differences in functional outcome and mortality after EVT in both patient groups. A meta-analysis of 10 studies was performed to assess the risk of developing sICH in anticoagulated patients who underwent EVT to treat AIS. Odds ratios and 95% confidence intervals were extracted from the studies. Meta-analysis showed no difference in the rate of sICH between anticoagulated patients and those with normal haemostasis (OR =1.21; 95% C.I.: 0.88, 1.67). Ninety-day mortality was similar among both groups. Most authors report similar rates of good functional outcome at 90-days between patient groups. EVT appears to be a safe treatment option in patients who are therapeutically anticoagulated.
A brain infarct is a tissue death due to inadequate blood supply to the affected area. While large or massive infarcts present with a very vague motor symptom, small thalamic infarcts can present with a variety of sensory deficits that can be difficult to diagnose clinically because of their seemingly disconnected manifestations. Cheiro-oral Syndrome is a pure sensory deficit which is confined to the perioral region and ipsilateral distal fingers. This very subtle clinical presentation might be missed in acute settings. We are reporting a case of a 46-year-old who was admitted with the complaints of peri-oral numbness on right side associated with weakness in right upper limb and lower limb.
Background: The use of Nitrous Oxide (N2O) in a recreational setting has been documented since the late 18th century as a euphoric agent termed “laughing gas”. There has been resurgence in its use in the recreational setting particular among the youth in the community despite falling into disrepute in anaesthetics due to its associated haematological and neurological complications. The primary aims of this systematic review is to detail the common neurological manifestations associated with the recreational use of N2O, detail its many mobility and functional impairments and identify potential predictors of neurological recovery including a period of rehabilitation prior to discharge. Methods and findings: A detailed systematic review of the available literature was conducted using six different databases. Key Medical Subject Heading (MESH) terms were identified including “Nitrous Oxide”, “Laughing Gas”, “Vitamin B12”, “Spinal Cord” and “Substance Related Disorders”. Only case reports and case series were included. Patient demographics, presenting neurological impairments, neurological examination findings, laboratory, imaging and neurophysiological results were extracted. Mobility and functional deficits on presentation, treatment instituted including the provision of rehabilitation was also extracted. 66 unique articles met our inclusion criteria which included 88 individual cases. This included 43 males and 32 females with a mean age of 26 (± 7.51) years. The most common presenting neurological impairment was sensory disturbance (72%) and gait disturbance (47%). The most common neurological findings on clinical examination included vibration loss (68%) and proprioceptive loss (59%). 79 cases had some form of mobility and functional impairment on presentation but only 34 cases demonstrated residual neurological deficits on discharge. Of this, 59% had moderate to severe deficits while 41% had mild deficits. Despite most patients receiving supplemental vitamin B12, only 12 patients received a period of rehabilitation prior to discharge who had ongoing deficits. Conclusion: The recreational use of nitrous oxide is an underreported cause of significant neurological impairments causing significant mobility and functional deficits. However, many of the patients with ongoing deficits are not offered a period of intensive multidisciplinary rehabilitation which could address many of these impairments and improve outcomes.
Intravascular lymphoma and Acute Haemorrhagic Leucoencephalitis are rapidly progressive diseases with poor prognosis. Differentiated between CNS variant of IVL and AHLE can be challenging, as they both can be clinically identical. Our case is about 63-year-old female, who presented with rapid onset of cognitive impairment. During her hospitalization, another rapid deterioration has occurred, and she became tetraplegic, with aphasia, and obtunded. Brain MRI showed many confluent lesions in the white matter, with. Most lesions appeared hemorrhagic. After the MRI, a radiological and clinical differential diagnosis between intravascular lymphoma and Acute Haemorrhagic Leucoencephalitis was made. Rapid brain biopsy has revealed the diagnosis of IVL. She had a good responsive to therapy, and regained most of her cognitive and motor functions.
Alzheimer's & DementiaVolume 16, Issue 2 p. 365-383 THEORETICAL ARTICLEFree Access A unified model of dementias and age-related neurodegeneration Michael Fossel, Corresponding Author Michael.fossel@telocyte.com Telocyte LLC, Grand Rapids, Michigan Correspondence Michael Fossel, Telocyte LLC, 250 Monroe NW, Grand Rapids, Michigan 49503 USA. Email: Michael.fossel@telocyte.comSearch for more papers by this author Michael Fossel, Corresponding Author Michael.fossel@telocyte.com Telocyte LLC, Grand Rapids, Michigan Correspondence Michael Fossel, Telocyte LLC, 250 Monroe NW, Grand Rapids, Michigan 49503 USA. Email: Michael.fossel@telocyte.comSearch for more papers by this author First published: 14 January 2020 https://doi.org/10.1002/alz.12012Citations: 3 Funding information: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinked InRedditWechat …but ignorance more frequently begets confidence than does knowledge: it is those who know little, and not those who know much, who so positively assert that this or that problem will never be solved by science. Charles Darwin The Descent of Man, 1871 1 PART 1: THE NEED FOR A MODEL 1.1 Overview Those working with Alzheimer's and other dementias have been frustrated by the implacability of these diseases. Regardless of limited symptomatic treatment,1 there are no proven disease-modifying interventions. Despite huge and growing costs of care,2 a pipeline of candidate drugs,3 >400 registered trials,4 tens of thousands of patients,5 billions of dollars in both US federal6 and pharmaceutical company investment,7, 8 more than a century of clinical expertise, and thousands of professional careers, dozens of pharmaceutical and biotechnology firms have foundered and failed9 in attempts to prevent, slow, or alter the course of the dementias. This article presents a novel model to explain the relationships between age-related neurodegenerative disorders (eg, dementias) and the underlying molecular mechanisms of the aging process. The hypothesis is prompted by the fact that accepted conceptual models have failed to yield effective interventions for Alzheimer's or other dementias.10 This article is a specific response to the Alzheimer's & Dementia editorial of November 2015,11 which called for a systemic re-evaluation of our current models and their ability to answer fundamental questions regarding complex brain disorders and their relationship to clinical dementia, as well as the failure to yield effective clinical interventions. The article is divided into three parts. The first part explores current models of age-related neurogenerative diseases. The second part proposes a specific model and details both its working and its implications. The third part applies the model to answering the 10 key questions proposed by the Alzheimer's & Dementia editorial. The intent is to provide a conceptual model that accords with known data and proposes a novel point of clinical intervention. The model is intended to provoke discussion and provide a point of departure, rather than to offer a complete and final model for age-related neurodegenerative disease. The value of any such model rests on the outcome of clinical trials, but the model offers potentially innovative pathways to such trials. 1.2 Current dementia models Although there is no general explanation for the failure to identify an effective intervention, there is growing consensus that a major factor is the lack of a comprehensive model for the dementias.12 Over the past century,13 several models have attained varying degrees of acceptance. Such models generally assume (or imply) a predominant single cause of Alzheimer's disease (AD; Figure 1). Figure 1Open in figure viewer Single predominant cause models of age-related CNS dysfunction. A, B, C, D, and E, represent known pathologic findings or biomarkers, including Aβ changes, tau protein tangles, and mitochondrial dysfunction Such models suggest that, although several factors may contribute to the pathology, most Alzheimer's pathology results from a single predominant cause, such as amyloid plaque. In Figure 1, A (the predominant cause) is the leading causal factor, whereas B, C, D, and E represent contributing (but less significant or even incidental) factors. Until recently, the foremost among such explanations has been amyloid β (Aβ) theory,14-17 in various iterations. Other candidates have been tau tangles,18-20 mitochondrial dysfunction,21, 22 or other etiologies. Despite academic argument, and in line with Alois Alzheimer's original warning about confusing histological findings with causation,13 these models have targeted biomarkers (whether classic biomarkers such as amyloid and tau protein or less common biomarkers such as inflammation,23, 24 or mitochondrial dysfunction), but a comprehensive, systems model explaining causation often remains unclear. Some models assume or imply a single causal agent which, in turn, drives other common pathological findings (and biomarkers) of AD, although this view (which assumes a predominant interacting cause) is seldom explicit. One leading model used by many pharmaceutical firms, for example, has been that AD is caused by Aβ deposition and other markers of AD are secondary, implying that an intervention targeting the primary cause (Aβ) would prove effective in dealing with secondary factors (tau protein changes, and so on). Equally, pharmaceutical interventions targeting other putatively primary causes, such tau proteins, mitochondrial dysfunction, and microglial activation, imply that their primary target lies "upstream" and is causal not only for dementia, but for other, secondary pathological findings and biomarkers (Figure 2). Thus, for example, primary abnormalities in tau protein physiology might result in secondary Aβ plaque formation and other secondary biomarkers. Figure 2Open in figure viewer Interacting predominant cause models of age-related CNS dysfunction. A, B, C, D, and E, represent known pathologic findings or biomarkers, including Aβ changes, tau protein tangles, and mitochondrial dysfunction Such models have failed to result in effective interventional human trials and, despite the suspicion that the underlying pathology of AD might well share mechanisms with other dementias, none of these models accounts for potentially shared mechanisms in all dementias, such as Parkinson disease, frontotemporal dementia (FTD), vascular dementias, mixed dementias, Lewy body dementia, primary progressive aphasia (PPA), LATE (limbic-predominant age-related TDP-43 encephalopathy),26 LOAD (late-onset AD), and so on (hereafter referred to collectively as dementias). Current models also fail to account for age-related cognitive decline in animals. Lack of an overarching model for both age-related human dementias and cognitive decline in animals likely plays a role in our consistent clinical failures in human trials. Lacking a comprehensive model, we fail to develop effective interventions. In AD, there has been a growing, if informal, consensus27 that a more fundamental upstream mechanism underlies the pathognomonic findings. The mechanism is often attributed to glial cell dysfunction,28-33 although there is no agreement on the glial cell changes that result in downstream findings.34-38 This type of model (Figure 3) can be represented by a single fundamental upstream mechanism causing multiple downstream findings, including amyloid plaque, tau tangles, mitochondrial dysfunction,39 lipid processing,40 TDP-43 proteinopathy,41 immune function, and synaptic loss.42 Figure 3Open in figure viewer Fundamental upstream model of age-related CNS dysfunction. A, B, C, D, and E, represent downstream pathologic findings or biomarkers, (eg, Aβ changes, tau protein tangles, alpha-synuclein deposits, Lewy bodies, and mitochondrial dysfunction) This model pertains to age-related human dementias (eg, AD and PD) as well as to the behavioral decline in aging animals. Although the outcome is cognitive decline, the specific features of the decline (the neurochemistry, neuroanatomy, and clinical manifestations) vary depending upon genetic and epigenetic differences both within (human) and between (animal) species. A more general model would encompass all dementias, offering an underlying and shared upstream mechanism expressed variably in specific dementias. The putative upstream, fundamental mechanism is shared, with clinical expression depending on its coupling with individual genetic and epigenetic variables, which differ between patients (Figure 3). Optimally, it would encompass age-related human dementias and age-related cognitive decline in animals. The bane of human trials based on animal studies is that "everything works in mice, nothing works in humans." This caveat suggests that although age-related cognitive decline is common in both animals and humans, the expression of such decline—and hence the underlying mechanisms of such decline—might preclude effective animal models.43-47 Just as age-related human dementias may share a fundamental upstream mechanism, whose expression (depending on its coupling with patient-specific genetic and epigenetic differences) varies between patients, so too the age-related cognitive declines in animals, including non-human primates,48-50 may share a fundamental upstream mechanism, the expression of which (depending on its coupling with species-specific genetic and epigenetic differences) varies between species (Figure 3). HIGHLIGHTS Age-related dementia research lacks a comprehensive systems model. Translational and clinical trials fail due to the lack of such a model. The cell senescence model is a comprehensive systems model. The cell senescence model addresses 10 key questions in the field. A novel point of intervention is suggested and supported by the literature. Although the fundamental upstream mechanism may be shared—for example, between mice and humans—the genetic and epigenetic differences between species will not only result in different biomarker findings (eg, the degree of Aβ plaque or the preeminence of tau tangles) but will also result in therapeutic failures when we decline to acknowledge these markedly different intermediate pathways. For example, if glial cell dysfunction is a shared upstream mechanism causing cognitive decline in mice and dementia in humans, we cannot expect (a priori) that the two species would share identical findings in terms of the neuronal effects (eg, amyloid metabolism, and tau protein metabolism) or the neuroanatomical locations of the most common lesions (eg, medial temporal lobe, neocortex, and subthalamic nuclei). To the contrary, if we attend solely to the intermediate expression of an underlying mechanism, we should expect poor extrapolation from mouse models to human trials. A model that can clarify, define, and allow confirmation or disproof could explain both the lack of extrapolation from animal models to human trials51 and the failure of human trials generally. A fundamental upstream mechanism that is variably expressed in multiple biomarkers and in an array of neuropathological findings (in coupling with the varying genetic and epigenetic landscape) implying that any intervention targeting exclusively downstream biomarkers (eg, Aβ plaques, tau tangles, and mitochondrial dysfunction) will fail precisely because each such biomarker is merely one among several downstream findings with none of these downstream findings being causal per se. Treating a single biomarker (eg, amyloid) will not necessarily have a significant beneficial impact on another downstream finding (eg, tau tangles). We might target multiple downstream biomarkers simultaneously, but the optimal target lies upstream, at a more fundamental level of the cascade of pathology (Figure 4). Figure 4Open in figure viewer Targets: Symptomatic drugs, current targets, and most-effective target. Current drugs target downstream symptoms. Current interventional targets include Aβ changes, tau protein tangles, and mitochondrial dysfunction. The most effective target is the fundamental, upstream mechanism Symptomatic interventions, such as neurotransmitter drugs, should have no significant impact on disease progression, as neuronal dysfunction is attributable to intermediate processes (eg, amyloid and tau changes), which are themselves attributable to a fundamental upstream mechanism. Current clinical targets (eg, monoclonal antibody approaches) aim at intermediate targets and likewise should have no significant impact on disease expression, because neuronal dysfunction is the combined result of multiple intermediate processes (including plaque or soluble52 Aβ, tau tangles, soluble or hyperphosphorylated tau,53 and mitochondrial dysfunction) rather than a single intermediate process, and since these intermediate processes are driven by a more fundamental upstream mechanism. We fail to affect AD because we aim at the wrong targets. 1.3 Need for a systems model To cure, prevent, or even slow age-related CNS disease—in humans or animals—requires that we identify the optimal target. Too often, as one editor lamented,54 our focus has been on neuropathology rather than the function of the system. Geneticists see alleles; pathologists see pathology. Rather than a systems approach, we often adopt a component approach, employing a narrow view that ultimately results in clinical failure and lost investment. A systems approach10, 55 suggests an optimal upstream target, with the downstream findings (often used as interventional targets) being merely symptomatic results of the upstream process. There is a growing interest in glial cell dysfunction as playing a central role in such a systems approach. Glial cells demonstrate prominent changes in age-related cognitive failure, for example, memory loss, in both humans and animals,56 including glial cell activation,57, 58 inadequate amyloid turnover,59-62 tau proteins,63, 64 methylation,65 homeostatic changes,66 and so on. Although the cascade of causation remains undefined, the indictment of glia as key players has become common in the literature. Clinical failure suggests that we "reassess current ideas on biological underpinnings … [and] … reinforces the necessity for a reexamination of the neurobiological premises for therapy development."67 A comprehensive model must account for the gamut of age-related CNS dysfunction in both humans and animals, and encompass current clinical, pathology, and other data, including neuronal and glial changes, as well as the physiological and epigenetic findings. Current models not only fail to account for the gamut of age-related human CNS disease and parallel age-related animal changes but, more critically, fail to intervene effectively in human disease. 1.4 Requirements of a systems model The need for an effective model has prompted delineation of the required characteristics of such a model, accounting for known risk factors, particularly biological age and genetic predisposition but also head trauma, gum disease, sleep disturbances, behavioral factors, education, cognitive reserve, and so on. The influence of comorbid conditions such as tobacco use, hypertension, diabetes, and cardiovascular disease (CVD) should also be incorporated.68, 69 One example includes 10 questions that a comprehensive model should address (Figure 5). Figure 5Open in figure viewer Requirements for a comprehensive model. Adapted from Khachaturian et al. (2018) The first point raised by Khachaturian et al.70 is that the model must account for the role of the aging process itself. The single most reliable risk factor is not genetic or environmental, but biological age.71, 72 Age is the best predictive independent variable for (appropriately termed) "age-related" dementias.73 Although the central importance of the aging process is often glossed over or even ignored, it is central to not only the demography, but also the conceptual basis of any model of the dementias. As Leonard Hayflick aptly observed: "The cause of aging is ignored by the same people who argue that aging is the greatest risk factor for their favorite disease."74 A systems model must therefore: (1) account for the role of aging; (2) account for known human and animal data, including demographic, genetic, clinical, anatomic, and laboratory data; and (3) offer an effective point of intervention. 2 Part 2: SUMMARY OF THE MODEL 2.1 A systems model for dementia One example of a systems model posits a central role for cell senescence with downstream effects on cell function (Figure 6), resulting in secondary alterations in cell and tissue function, which then result in tertiary clinical findings. This model was outlined initially to account for age-related human pathology as well as the basic laboratory findings associated with cell senescence75 and aging phenomenon but has grown to encompass recent laboratory and clinical findings as well.76 Figure 6Open in figure viewer Cell senescence model of dementia. Cell division results in shorter telomeres, which alter gene expression and cell function, resulting in pathology Cell senescence was first described >50 years ago,77, 78 and its implications for age-related disease were outlined in both the lay79 and medical literature >20 years ago80, 81 and repeatedly implicated since.82 Cell senescence was first shown to correlate with,83-85 then to be the causal result of, telomere shortening and amenable to resetting in vitro.86 Subsequently, resetting of telomere length was shown to reset function in aging human tissue both ex vivo87 and in vitro,88, 89 further supporting cell senescence as a viable point of clinical intervention.90 A textbook describes the role of cell senescence in detail, tissue-by-tissue, including the role of cell senescence in age-related CNS disease, as well as potential techniques for intervention.91 A subsequent article reviewed,92 independent animal studies supported,93, 94 and a recent book95 outlined the potential for cell senescence as an effective point of intervention, and other authors made the same suggestion for etiology and intervention.96 Cell senescence correlates not with absolute but with relative changes in telomere length. Key changes in cell function occur because changes in telomere lengths result in changes in gene expression.97, 98 This phenomenon, TPE (telomere position effect) is insufficiently understood, but can result in both local (subtelomeric) and distant changes in gene expression,99 including SAGE (senescence-associated gene expression) and SASP (senescence-associated secretory phenotype). The effects of cell senescence on dividing cells (eg, glial cells) can accrue in non-dividing cells (eg, neurons), the normal function of which depends critically on dividing cells. Although these issues are addressed in detail in subsequent text, a few points should be made here. As glial cells transition to senescence, secondary dysfunction in local neuron populations occurs. Age-related CNS dysfunction is associated with glial cell activation, inflammation, and deceleration in glial turnover of local protein pools, such as Aβ, which affect neuronal function. Discussion will focus on glial cells (often microglia), but references to glia should be construed to include not only microglia, but also astroglia, oligodendrocytes, ependymal cells, and others. More direct effects of cell senescence, due to neuronal cell division, are probably minimal in comparison, although the issue remains controversial. 2.2 Genetic and epigenetic baseline effects Central to the cell senescence model is that it is not changes in telomere length per se, but rather the subsequent changes in gene expression (epigenetic changes) that play the functional role in cell senescence and in subsequent clinical disease. This is in line with the current emphasis on regulatory rather than coding variables, that is, EQTLs (expression quantitative trait loci), particularly in the context of age-related dementias.100, 101 A natural implication of the central role of epigenetic shifts is that both the cell's underlying genetics and its prior epigenetic state will strongly affect the functional outcome of these epigenetic shifts. Because of different genes, different species will express different cellular outcomes despite equivalent changes in telomere lengths. Consequently, even with equivalent levels of cell senescence, species will differ in the type and degree of cell and tissue dysfunction and will have different clinical presentations. Given the parallel process of cell senescence in the CNS, two different species may both show cognitive decline as they age, but (given those genetic differences) still vary markedly in species-specific biochemical, histological, and clinical behavioral findings. Cell senescence may be a shared mechanism, but the outcomes may vary. Pari passu, individuals within a species (with different alleles and with different epigenetic baselines) demonstrate differing cellular, pathological, and clinical outcomes. Although the underlying process—cell senescence—is shared among different species and among different individuals within the same species, the outcomes will vary between and within those species. Mice, for example, may share both the fundamental mechanisms of cell senescence and the behavioral outcome (age-related cognitive decline), yet the intermediate mechanisms—Aβ plaques, tau tangles, and so on—vary from those seen in humans. Although the variance in intermediate mechanisms accounts for the frustration in taking translational research from one species (eg, Mus musculus) to another (eg, Homo sapiens), the shared fundamental mechanism (eg, cell senescence and epigenetic shifts) suggests a viable point of intervention. Likewise, although human patients may share the same fundamental mechanisms, the individual outcome—AD, Parkinson disease, frontotemporal dementia, and so on—will depend on genetic and epigenetic differences between patients. Shifts in epigenetic expression102 resulting from the senescence process are gradual and subtle but still cause progressive cell dysfunction. The rate of turnover is surprisingly critical103 and can be defined and quantified numerically by formula.104 The process itself, however, is simple. Molecular pools (for example, Aβ) are not static, but in dynamic equilibrium as the molecules turn over, and turnover slows as cell senescence progresses. Even if the rate of molecular damage (oxidation, denaturation, and so on) remains constant, the slower rate of molecular turnover results in a gradual increase in the accrual of damage (as a percentage of the molecular pool). The percentage of damaged or dysfunctional molecules increases with cellular aging not as a result of chronological age per se, but as a result of cell senescence, which correlates with, but is distinct from, chronological age. Biological or cellular age (rather than chronologic age) drives the age-correlated increase in molecular damage, the loss of cell function, and the clinical progression of disease. Cell senescence results in age-related damage, not the other way around. This effect—slower rates of molecular turnover as cell senescence increases—renders the cell increasingly dysfunctional. The slowed turnover affects protein pools (such as Aβ), mitochondrial function (ATP and reactive oxygen species [ROS] production), lipids (eg, mitochondrial and nuclear membranes), DNA repair (increasing DNA damage especially with shorter telomeres105), and so on. In the case of Aβ, we see slower binding,59 uptake (eg, endocytosis106), ingestion, and degradation61 of Aβ in older glial cells and that these effects can be normalized by implantation of younger microglia.60 The slower molecular turnover in glial cell senescence not only results in amyloid molecules with longer "lifetimes" but increases the percentage of denatured molecules as senescence progresses. The outcome is an increasingly inefficient and dysfunctional cell. The dynamic (rather than static) nature of protein pools explains the failure of previous interventions that focused on removal of denatured molecules (eg, Aβ plaque) rather than on increasing the recycling rate of the molecular pool. Targeting amyloid plaques or tau tangles as static targets will prove ineffective, because we need to target the dynamic process that creates and dynamically maintains such plaques and tangles. 2.3 Upstream variables Cell senescence has a species-specific basal rate roughly correlating with chronological age (the lifetime cumulative number of cell divisions), but even in a single genetically homogeneous species, the senescence of equivalent cell populations may vary. A plethora of upstream, independent variables have a significant impact on the cell division rates. Although the basal rate of cell senescence correlates with chronological age within a species, these upstream variables can accelerate the basal rate of cell division and thus cell senescence. These effects have been documented in many organs and tissues, and in the CNS. For example, damage to and loss of glial cells, secondary to infection, trauma, or radiation, results in glial cell replacement via cell division, accelerating the basal rate of cell senescence. Many independent variables can affect (almost always increase) the rate of cell senescence including genes,40, 107-109 chemotherapy,110, 111 toxins,112-114 trauma,115-117 hypertension,118, 119 stroke,120 hyperglycemia,121, 122 microbiome,123, 124 stress,125, 126 hormones,127-129 infection,130, 131 senolytic therapy,132, 133 and so on (Figure 7). These variables may be subdivided into subcategories, with supportive data, such as the host of possible infectious etiologies due to bacterial,134 chlamydial,135 fungal,136 viral,137-140 or prion-related141, 142 causes. Despite the number of upstream, independent variables, the mechanism of telomere shortening and changes in epigenetic expression is shared and provides a common diagnostic, prognostic, and therapeutic focal point. In AD, for example, data show telomere shortening in older glial cells143 and correlations between glial (or other) telomere lengths and AD status144-150 (as well as Parkinson disease151, 152) and lifespan,153 as well as epigenetic changes in neurons.154, 155 Not surprisingly,156 studies looking at inappropriate cells (such as peripheral leukocytes)157, 158 often find inclusive or misleading results. One animal study had contradictory results, as shortened telomeres are associated with early onset behavioral problems in normal mice, but if transgenic mice have been altered to produce Alzheimer's precursor protein (APP), then shortened telomeres appear to blunt the effects of the APP gene normally seen in the transgenic mice, although the relevance of the transgenic background in this context can be argued.159 Figure 7Open in figure viewer Upstream, downstream, and central targets. In age-related CNS disease (eg, AD), cell senescence progresses with age, although multiple upstream variables can affect the rate of progression Regarding glia, the clustering of microglia around Aβ-containing senile plaques has long been noted,160 and the argument made that aged microglia are unable to clear amyloid,161 with deleterious consequences to both glia and neurons. Synaptic loss, a hallmark of declining memory function with aging, may be linked to impairment of neuronal and/or glial function. Neuronal integrity and function, in turn, are highly dependent on fully functional glia. In the normal CNS, microglia engage in continuous monitoring of neuronal well-being. To ensure proper neuronal functioning, complex molecular and cellular interactions occur between neurons and glia.162 Because glia are capable of producing both neuroprotective and neurotoxic molecules, depending on neuronal signals,163 any impairment in glial function due to cellular senescence may impair neuronal activity and cognitive function in the aging brain.164-166 Over time, glia senesce, becoming less able, or unable, to maintain neuronal health. When sufficient glia senesce, neurons they once supported may become dysfunctional and ultimately die due to diminished support and maintenance. Neuronal cell death and synaptic loss results in the memory loss and other clinical findings in the dementias. Although not a dementia, a similar process may be relevant in other neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS).167 Within the adult CNS, progressive senescence in both glia and vascular endothelial cells—which routinely divide in the adult organism—can be expected to result in dysfunction and secondary loss of neurons. Neurons themselves divide less frequently in adult humans, although (despite earlier reports168) neurogenesis occurs in the adult hippocampus169 and arguably other areas, with age-related changes in the rate of neuronal cell division. Furthermore, such neurogenesis drops sharply in patients with AD170, 171 or (in mice) with short telomeres172 or increased age.105 Moreover, telomerase expression may be protective, particularly against hyperphosphorylated tau production in both humans and mice.173 More importantly, telomerase interventions spur neural stem
Despite the prevalence of autoimmune diseases, and the variety of proposed factors involved in their aetiology, the exact cause of autoimmune disorders is still unknown [1]. As psychotherapist specializing in work with parents for the last sixteen years, and a physician who has worked with adolescents for seventeen years, in this presentation, we propose to consider the analogy between the dynamics of the overprotective family and those of the overactive immune system in autoimmune disorders, and that they are both manifestations of the structures and mechanisms of narcissistic anxiety. The overprotective parenting style is characterised by parents who present guarding behaviour that is excessive considering the child’s developmental stage and the actual risk level in their environment. Overprotective parents tend to obsess over their children’s physical and emotional safety, at a level that exceeds the actual level of risk [2]. The impact of overprotective family dynamics upon the emotional development of a child has been extensively discussed [3]. Analogous to this, autoimmune diseases are clinical manifestations of aberrant and "hyper-reactive" autoimmune responses to self-antigens of normal bodily constituents leading to inflammation, cell injury, or a functional disturbance [1]. Medical literature has suggested the correlation between emotional disorders and a variety of autoimmune diseases [4]. This presentation suggests to consider the possibility that high levels of anxiety underlie both overprotective manifestations. Instead of functioning as defence mechanisms aimed to protect the self, they are diverted into a direct attack on it.
