AD is a significant risk factor of epilepsy in the elderly. Imfeld et al. Similar results were presented by Amatniek et al. The risk of seizure onset is higher in AD patients with hyperlipidemia and severe dementia [ 82 ]. The epileptogenetic mechanism has not yet been elucidated in patients with neurodegeneration.
The modulation of synaptic transmission has an important effect on producing epileptiform activity [ 85 ]. Another degenerative disorder which may potentially induce seizures is MS, a chronic disease of the CNS. MS usually occurs in young adults aged 20 to 40 years. However, 1. The prevalence of seizures among MS patients was shown to be higher than the general population, which may indicate the relationship between seizures and MS [ 87 ].
One possible explanation is that MS lesions act as epileptogenic sites [ 88 ]. Generally, a small fraction 2. The study of epilepsy in the elderly among MS patients is inconclusive, but clinicians should be aware of the risk of epilepsy in people with MS [ 88 ]. Dementia—as a form of cognitive decline—is strongly associated with old age.
Neurobiology of Epilepsy and Aging, Volume 81 - 1st Edition
The most common causes of dementia include AD and vascular dementia VaD. Dementia is a progressive disorder, finally leading to severe disability and complete dependence of sufferers on caregivers [ 90 ]. VaD was initially understood to be an advanced effect of repetitive brain lesions [ 91 ]. The development of brain imaging techniques revealed that silent ischemic lesions appeared to be quite common and later became known as a significant cause of dementia [ 92 , 93 ].
The frequency of VaD in the general population varies from 1. The prevalence of VaD is strongly connected with age. A Canadian study described that frequency of vascular cognitive impairment increased from 2. A meta-analysis from , synthesizing the results of 23 studies from around the world, confirmed the trend of increasing incidence of VaD in senescence [ 98 ]. Increasing longevity in many populations has also increased the importance and burden of vascular-related memory deficits. A long-term survey demonstrated that the incidence of post-stroke dementia between and had doubled [ 99 ].
Several studies have analyzed the risk factors, other than age, of CNS vascular lesions.
What Happens During A Seizure?
They identified hypertension, heart disease, diabetes with insulin resistance, and dyslipidemia to be related to an increased risk to develop VaD. It is important to note that the results obtained by different authors occasionally contradict each other [ — ]. Additionally, patients with fully symptomatic metabolic syndrome obtained lesser scores in neuropsychological testing [ ].
Moreover, HHcy, previously associated with vascular diseases and stroke, was shown to be associated with VaD [ ]. MCI preceding stroke increases the probability of post-stroke dementia [ , ], and memory decline seemed to progress more rapidly with later stroke episodes [ ]. AD is the most common form of dementia in older adults [ ]. AD is a progressive incurable neurodegenerative disease where aging is the primary risk factor.
This genetic triad is responsible for nearly half of the FAD cases seen [ ]. However, mutations in these genes occur very rarely in the human population. The multifactorial character of the disease makes it extremely difficult to determine a causative factor for SAD [ ]. Martin et al. This explains why older patients with unfavorable genetic variants are more prone to excessive neuroinflammatory responses leading to neuronal loss and dementia.
Loss and degeneration of this type of cells is another hallmark of dementia and occurs gradually with age and the course of the disease [ ]. ACh has been proven to be the neurotransmitter that is most reduced in the majority of AD patients [ ]. It seems that genetic factors, such as the presence of the pathogenic APOE E4 allele, may also significantly influence the production and release of ACh. The main cholinergic structure of the brain is the basal forebrain BF , the underlying neurodegeneration of which may be observed in advanced aging as well as in the early phase of AD and other dementias [ ].
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BF degeneration occurs due to a decrease in cholinergic neurotransmission and a reduction in the amount of ACh in synaptic clefts, followed by a loss of cholinergic receptors, finally resulting in AChN death. It is worth noting that in AD, similarly to VaD and stroke, the concentration of Hcy may be increased and so may inflict damage to the vasculature, thereby leading to decreased blood flow and inefficient nutrient delivery to neurons. Subsequently, the starving cells become more prone to ROS and apoptosis. HHcy is also associated with a decrease of the glutathione pool, the deficiency of which results in the deterioration of protection mechanisms from free radicals, further contributing to neuronal loss and neurodegeneration [ ].
PD is an age-related neurodegenerative disease characterized by resting tremor, rigidity, and bradykinesia. The number of PD patients increases over the years due to population aging. The exact pathomechanism of PD remains unclear, but it is known that the degeneration process starts many years before the occurrence of clinical symptoms.
The hallmark of PD is dopaminergic DA neuron death in the substantia nigra SN , which is a result of Lewy body LB formation due to impairment of the ubiquitin-proteasome system and disturbances in the proteins alpha-synuclein ASN and Parkin [ , ]. Molecular characteristic of PD include increased ROS production due to mitochondrial dysfunction and accompanied by decreased mitophagy [ ], neuroinflammation and loss of neurotrophic factors [ , ], exposure to 1-methylphenyl-1, 2,3,6-tetrahydropyridine MPTP or paraquat [ ], exposure to trichloroethylene or polychlorinated biphenyls [ ], iron the level of which increase in the SN with age , copper, manganese [ , ], or mutations in PARK genes [ ].
Mitochondrial dysfunction is associated with aggregation of ASN, apoptosis, accumulation of damaged mitochondria, and changes in the activity of complex 1 [ ].
A decline in mitochondrial function as well as inflammation and changes in DA metabolism are linked with the aging process. Advancing age is the most important risk factor of developing PD. It has been since that the loss of DA neurons progresses with aging, but the rate of the physiological process is slower than that seen in PD [ ]. Moreover, LB may be present in elderly individuals without PD [ ].
The aging brain is also more prone to stressor stimuli and generation of ROS, which results in the injury and eventual death of SN neurons. On the other hand, a decreased level or even loss of ROS scavengers, e. Many epigenetic mechanisms, such as changes in DNA methylation profile and histone modification, play an important role in aging and contribute to PD. The epigenetic clock can be characterized just by measuring the DNA methylation pattern. Interestingly, PD patients represent an increased acceleration in aging when compared to controls of the same age [ ].
ASN can also influence histone acetylation a feature of transcriptionally active genes and enhance ASN fibrillation [ ]. During normal aging, the functional decline of the BBB can cause neuroinflammation and the development of neurodegenerative diseases [ ]. Disturbances in BBB permeability observed in the senescence process may be involved in the genesis of WM lesions, which may also affect the efficacy of treatment. HHcy observed in PD may be involved in the disease pathogenesis; however, the exact mechanism of interaction remains unrecognized.
Both HHcy and age are risk factors for developing dementia in PD patients [ ]. Other side effects of L-dopa at the molecular level include increased oxidative stress, as well as altered concentrations of catecholamines and apoptotic proteins [ ]. Another type of CNS disease, manifesting particularly in the elderly, are brain tumors, classified according to WHO criteria to four grades, with grade IV considered most malignant [ ].
In adults, the most prevalent type of primary brain tumor is malignant glioma MGs , with the highest incidence between 40 and 65 years of age. The majority of MGs are sporadic, with ionizing radiation as the only known risk factor. The most common type of glioma is glioblastoma multiforme GBM , qualified as a WHO grade IV astrocytic tumor, and constituting about half of all MGs with the highest incidence in the elderly, between 70 and 90 years of age [ — ]. Old age is a negative prognostic factor in GBM [ ].
One of the most significant characteristics of GBM is an increasing prevalence with age; thus, due to an increasing median length of life, the number of patients is expected to grow in the coming decades. Although both types are indistinguishable under the microscope, they appear to differ genetically. The authors distinguished four subtypes of GBM. Each subtype of GBM differs in its sensitivity to radiotherapy and chemotherapy, thus determining the genetic type of a surgically removed or biopsied lesion could protect patients against unnecessary ineffective therapy [ ].
Unfortunately, GBMs are mostly incurable in the elderly, with most of these patients surviving less than 6 months [ ].
Neuroscience at the University of Iowa
Diagnosis of primary brain tumors in old age can be further complicated and delayed due to nonspecific symptoms that can be masked by physical and cognitive changes observed in the normal aging process [ ]. Moreover, elderly patients are an underrepresented group in many clinical trials [ ]. Although pathological processes differ depending on the glioma subtype, there is a common core of molecular events.
Growth factor receptor tyrosine kinases cause downstream signaling by activation of extracellular signal-regulated kinases ERK or protein kinase B Akt pathways. Lack of p53 activation is followed by the loss of the ability to activate DNA repair processes and cell death by apoptosis. An additional adverse characteristic occurring in GBM is that the cells provoke the secretion of vascular endothelial growth factor VEGF , which is responsible for angiogenesis. Finally, due to vasculature growth, there is progression of tumor invasion [ ]. Thus, BV promotes tumor regression and helps to decrease the risk of cerebral edema [ ].
These findings were in line with the study published by Nghiemphu et al. The increased incidence of brain tumors in the elderly may also be due to decreased efficiency of repair mechanisms. This may lead to increased accumulation of DNA damage, in turn resulting in further activation of proto-oncogenes and silencing of tumor suppressor genes.
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Of mice and men: the influence of human genetic variation on cognitive function Time to rethink the future of psychiatry and medicine Dopamine or Glutamate: which is the psychotic fire-starter? Fonagy P. Our research and that of other scientists delineates a constellation of brain abnormalities associated with childhood abuse. There are four major components:. People with temporal lobe epilepsy TLE —.
TLE can cause hallucinations or illusions in any sense modality. Other common hallucinations are of a ringing or buzzing sound or repetitive voice, a metallic or foul taste, an unpleasant odor, or the sensation of something crawling on or under the skin. Emotional manifestations of temporal lobe seizures usually occur suddenly, without apparent cause, and cease as abruptly as they began; they include sadness, embarrassment, anger, explosive laughter usually without feeling happy , serenity, and, quite often, fear.
Without this objective EEG data, a diagnosis must be based on the frequency and severity of symptoms and the ruling out of other likely causes of those symptoms. To explore the relationship between early abuse and dysfunction of the temporolimbic system, we devised the Limbic System Checklist LSCL , which calibrates the frequency with which patients experience symptoms of temporolimbic seizures. Compared to patients who reported no abuse, average LSCL scores were 38 percent greater in the patients with physical but not sexual abuse, and were 49 percent greater in the patients with sexual but not other physical abuse.
Males and females were similarly affected by abuse. As we expected, abuse before age 18, when the brain is still rapidly developing, had a greater impact on limbic irritability than later abuse. We reviewed the records of consecutive admissions to a child and adolescent psychiatric hospital to search for a link between different categories of abuse and evidence of abnormalities in brain-wave studies. In the nonabused group, left-sided EEG abnormalities were rare, whereas in the abused group they were much more common, and more than twice as common as right-sided abnormalities.
In the psychologically abused group, all the EEG abnormalities were left-sided. To dig deeper into the possibility that abuse may affect development of the left hemisphere, we looked for evidence of right-left hemispheric asymmetries in the results of neuropsychological testing. This corroborated our hypothesis that abuse is associated with an increased prevalence of left-sided EEG abnormalities and of left-hemisphere defects in neuropsychological testing.
Patients and volunteers were between 6 and 15 years of age, right-handed, and with no history of neurological disorders or abnormal intelligence. Measuring EEG coherence indicated that the left cortex of the healthy controls was more developed than the right cortex, which is consistent with what is known about the anatomy of the dominant hemisphere. The abused patients, however, were notably more developed in the right than the left cortex, even though all were right-handed.
The right hemisphere of abused patients had developed as much as the right hemisphere of the controls, but their left hemispheres lagged substantially, as though arrested in their development. It extended throughout the entire left hemisphere, but the temporal regions were most affected. The hippocampus, located in the temporal lobe, is involved in memory and emotion. Developing very gradually, the hippocampus is one of the few parts of the brain that continues to produce new cells after birth.
Cells in the hippocampus have an unusually large number of receptors that respond to the stress hormone cortisol. Since animal studies show that exposure to high levels of stress hormones like cortisol has toxic effects on the developing hippocampus, this brain region may be adversely affected by severe stress in childhood. Douglas Bremner and his colleagues at Yale Medical School compared magnetic resonance imaging MRI scans of 17 adult survivors of childhood physical or sexual abuse, all of whom had PTSD, with 17 healthy subjects matched for age, sex, race, handedness, years of education, body size, and years of alcohol abuse.
Not surprisingly, given the role of the hippocampus in memory, these patients also had lower verbal memory scores than the nonabused group. Murray Stein and his colleagues also found left hippocampal abnormalities in women who had been sexually abused as children. Fifteen of the 21 sexually abused women had PTSD; 15 had a dissociative disorder.
They suffered a reduction in the size of the left hippocampus proportionate to the severity of their symptoms. The left hemisphere is specialized for perceiving and expressing language, the right hemisphere for processing spatial information and also for processing and expressing negative emotions. We wondered, then, whether abused children might store their disturbing childhood memories in the right hemisphere, and whether recollecting these memories would activate the right hemisphere more than it is activated in those without such a history.
To test this hypothesis, we measured hemispheric activity in adults during recall of a neutral memory, then during recall of an upsetting early memory. Those in the control group had a more integrated bilateral response. Furthermore, in boys, neglect exerted a far greater effect than any other type of maltreatment; physical and sexual abuse exerted relatively minimal effects. In girls, however, sexual abuse was a more powerful factor, associated with a major reduction in size of the middle portions of the corpus collosum.
Building on this work, other scientists discovered that these consequences were less severe if the surrogate mother swung from side to side, a type of movement that may be conveyed to the cerebellum, particularly the part called the cerebellar vermis, located at the back of the brain, just above the brain stem. Like the hippocampus, this part of the brain develops gradually and continues to create new neurons after birth.
It also has an extraordinarily high density of receptors for stress hormone, so exposure to such hormones can markedly affect its development. We have gone from thinking of the entire cerebellum as involved only in motor coordination to believing that it plays an important role in regulating attention and emotion.
The cerebellar vermis, in particular, seems to be involved in the control of epilepsy or limbic activation. Testing this hypothesis, we found that the vermis seems to become activated to control— and quell—electrical irritability in the limbic system. It appears less able to do this in people who have been abused.
If, indeed, the vermis is important not only for postural, attentional, and emotional balance, but in compensating for and regulating emotional instability, this latter capacity may be impaired by early trauma. By contrast, stimulation of the vermis through exercise, rocking, and movement may exert additional calming effects, helping to develop the vermis.
By contrast, long isolation produces stress that has a deleterious effect on brain and behavior development. If we assume that lots of attention, licking, and grooming are the natural state of affairs and that lower levels of attention are a form of neglect, we can use this model to explore some of the biological consequences of neglect or abuse in children.
Low rates of maternal attention decrease the production of thyroid hormone by the rat pups. This, in turn, decreases serotonin in the hippocampus and affects the development of receptors for the stress hormone glucocorticoid. Since corticosterone, one of our primary stress hormones, is kept in check by a complicated feedback mechanism that depends on these same stress hormone receptors, their inadequate development increases the risk of an excessive stress hormone response to adversity.
For this and certain other reasons, lack of maternal attention predisposes the animals to have a heightened level of fear and a heightened adrenaline response. These consequences seem consistent with inadequate development of the corpus collosum, which is a highly myelinated structure, and abnormal development of the hippocampus and cerebellum. High levels of cortisol can also hinder development of the cerebral cortex, the extent of vulnerability dependent on how rapidly the brain was growing at the time of the insult.
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During the years of rapid language acquisition approximately years of age , the left brain develops more rapidly than the right, making it more vulnerable to the effects of early maltreatment. Finally, diminished maternal attention also appears to be associated with a lifelong decrease in production of the hormone oxytocin in the brain, and enhanced production of the stress hormone vasopressin.
Both hormones may also help control sexual response, with vasopressin enhancing sexual arousal and oxytocin triggering climax and release. In summary, we now know that childhood abuse is linked with excess neuronal irritability, EEG abnormalities, and symptoms suggestive of temporal lobe epilepsy. It is also associated with diminished development of the left cortex and left hippocampus, reduced size of the corpus callosum, and attenuated activity in the cerebellar vermis. Many disorders are associated with childhood abuse. One is depression or heightened risk for developing it. Many scientists believe that depression may be a consequence of reduced activity of the left frontal lobes.
If so, the stunted development of the left hemisphere related to abuse could easily enhance the risk of developing depression. Similarly, excess electrical irritability in the limbic system, and alterations in development of receptors that modulate anxiety, set the stage for the emergence of panic disorder and increase the risk of post-traumatic stress disorder. Alterations in the neurochemistry of these areas of the brain also heighten the hormonal response to stress, producing a state of hyper vigilance and right-hemisphere activation that colors our view with negativity and suspicion.
Alterations in the size of the hippocampus, along with limbic abnormalities shown on an EEG, further enhance the risk for developing dissociative symptoms and memory impairments. Very early childhood abuse appears particularly likely to be associated with emergence of ADHD-like behavior problems. Some studies have also found an association between reduced size of the mid portions of the corpus callosum and emergence of ADHD-like symptoms of impulsivity. Hence, early abuse may produce brain changes that mimic key aspects of ADHD.