Neurological and Degenerative Disorders
Neurological Disorders
This section introduces various neurological disorders, including movement, perceptual, language, and memory disorders. It focuses on the neuropathological conditions affecting the brain and their behavioral effects and treatments.
Basal Ganglia and Substantia Nigra
These brain structures are particularly important in the examination of neurological conditions, as shown in the provided figure.
Tumors and Seizures
Prevalence
Over 680,000 individuals in the United States are living with brain tumors.
3–5% of the global population will experience a seizure during their lifetime.
Approximately 2.5 million people in the United States have a seizure disorder.
Relationship
Tumors and seizures can occur separately, or a tumor may cause a seizure.
Tumors
Definition
A tumor is a mass of cells with uncontrolled growth that serves no useful function.
Types
Malignant: Cancerous.
Benign: Non-cancerous ("harmless").
Encapsulation
The major distinction between malignancy and benignancy is whether the tumor is encapsulated:
Benign Tumors: Encapsulated with a distinct border between the tumor and surrounding tissue. Can be surgically removed without regrowth.
Malignant Tumors: Grow by infiltrating surrounding tissue, with no clear-cut border. Removal may miss cells, leading to new tumor growth. Often give rise to metastases.
Metastases
A metastasizing tumor sheds cells that travel through the bloodstream, lodge in capillaries, and serve as seeds for new tumors in different locations in the body.
Damage Mechanisms
Tumors damage brain tissue through:
Compression: Pushing against the brain, directly destroying tissue or indirectly blocking cerebrospinal fluid flow, causing hydrocephalus.
Infiltration: Malignant tumors invade the surrounding region, destroying cells in their path.
Causes
Tumors do not arise from nerve cells (which cannot divide) but from other brain cells or metastases.
Serious types include metastases and gliomas (derived from glial cells), which are usually malignant and fast-growing.
Meningiomas are encapsulated, benign tumors originating from the dura mater or arachnoid membrane.
Tumor location examples:
Gliomas in the basal ganglia.
Gliomas in the pons.
Ependymoma (a type of glioma) in the lateral ventricles.
Meningioma near the primary motor cortex
Malignancy Cause
Caused by rare subpopulations of cells. Malignant gliomas contain tumor-initiating cells originating from transformations of neural stem cells.
Treatments
Radiation: Destroying tumors with focused radiation beams.
Often follows surgical removal of as much of the tumor as possible.
Surgery: Complete removal of encapsulated tumors (e.g., meningiomas).
Chemotherapy: Using drugs to kill rapidly dividing cells (cancer cells) by interfering with DNA replication.
Administered orally, intravenously, or by implantation.
Systemic administration targets all dividing cells, causing side effects like hair loss.
Bevacizumab
Inhibits angiogenesis (growth of new blood vessels) by binding with and deactivating vascular endothelial growth factor, slowing glioma growth. Increases survival by only a few months; more effective drugs are needed.
Seizures
Definition
A period of sudden, excessive activity of cerebral neurons.
Convulsions
Seizures can cause convulsions, which are uncontrollable muscle activity.
Cultural Perspectives
Considered variously as punishment from a deity, the work of demons, or evidence of a spiritual connection.
Medical History
Hippocrates suggested seizures had a physical cause, linking them to head injuries.
Occurrence
Can occur as a single event (e.g., due to injury or tumor) or as repeated episodes.
Terminology
Some physicians prefer "seizure disorder" to "epilepsy" due to negative connotations.
Classification of Seizure Disorders
Generalized Seizures
Widespread, involving most of the brain.
Tonic-clonic (grand mal)
Absence (petit mal)
Atonic (loss of muscle tone; temporary paralysis)
Partial Seizures
Have a definite focus, or source of irritation (e.g., scarred region or developmental abnormality).
Simple Partial Seizures
Often cause changes in consciousness but not loss of consciousness.
Complex Partial Seizures
Lead to loss of consciousness due to location and severity.
Grand Mal Seizures
Generalized and accompanied by convulsions.
Warning Symptoms
Changes in mood or sudden muscular jerks.
Aura
A few seconds before the seizure, caused by excitation of neurons surrounding the seizure focus.
The nature of the aura varies with the location of the focus.
Structures in the temporal lobe are involved in the control of emotional behaviors, so seizures there often begin with feelings of fear and dread or euphoria.
Tonic Phase
All muscles contract forcefully. The arms are rigidly outstretched, and the person may make an involuntary cry as the tense muscles force air out of the lungs. The person is unconscious and holds a rigid posture for about fifteen seconds.
Clonic Phase
The muscles begin trembling, then start jerking convulsively, quickly at first, then more and more slowly. the eyes roll, the person’s facial muscles contract, and the tongue may be bitten. Intense activity of the autonomic nervous system manifests itself in sweating and salivation.
Post-Seizure
Muscles relax, and regular breathing begins. The person may fall into an unresponsive sleep, which can last for several minutes, and then awaken briefly but usually falls back into an exhausted sleep that may last for several hours.
Partial Seizures
Involve relatively small portions of the brain. Symptoms can include sensory changes, motor activity, or both. A simple partial seizure that begins in or near the motor cortex can involve jerking movements that begin in one place and spread throughout the body as the excitation spreads along the precentral gyrus.
Occipital Lobe Seizures
May produce visual symptoms (spots of color, flashes of light, or temporary blindness).
Parietal Lobe Seizures
Can evoke somatosensations (pain, heat, or cold).
Temporal Lobe Seizures
May cause hallucinations that include old memories.
Absence Seizures (Petit Mal)
Very brief seizures common in children, involving staring off into the distance for a few seconds, often with repeated blinking. Can disrupt a child’s performance in school.
Consequences
Seizures can cause brain damage, with approximately 50% of patients with seizure disorders showing evidence of hippocampal damage. The amount of damage is correlated with the number and severity of seizures.
Status Epilepticus
A rare condition involving a series of seizures without regaining consciousness. The damage is caused by excessive glutamate release, leading to glutamate excitotoxicity.
Causes
Scarring (from injury, stroke, developmental abnormality, or tumor).
Genetic factors (genes controlling ion channels).
Nongenetic factors.
Drugs and infections causing high fever (especially in children).
Withdrawal from chronic alcohol, barbiturate, or benzodiazepine use.
Treatments
Anticonvulsant Drugs: Increase the effectiveness of inhibitory synapses (often via GABAergic synapses).
Brain Surgery: Removal of the seizure focus (usually in the medial temporal lobe).
Tumor Removal: Eliminates the source of irritation and ends seizures.
Seizure Focus Removal Effects
Improvement in neuropsychological functioning.
The seizure focus irritates the surrounding brain tissue.
Traumatic Brain Injury
Prevalence
Approximately 1.4 million people are treated in an emergency department.
270,000 people are hospitalized.
52,000 people die due to TBI in the United States annually.
Causes
Projectile or fall against a sharp object that fractures the skull.
Closed-head injuries (no brain penetration).
Injury by explosive devices (among military personnel).
Penetrating injuries directly damage the brain and blood vessels, causing further damage by disrupting blood supply and exerting pressure.
Closed-head injuries can cause bruising (coup and contrecoup), tearing and twisting of axons, ruptured blood vessels, and distortion of ventricles.
Chronic Traumatic Encephalopathy (CTE)
A form of TBI resulting in neurodegeneration due to repeated head trauma. Diagnosed postmortem by examination of brain tissue. Symptoms of mood and cognitive impairment appear years after the injury. Abnormal tau protein accumulates, and there is reduced brain volume and enlarged ventricles.
Treatments
Immediate treatments include reducing swelling and intracranial pressure and ensuring adequate blood flow.
Long-term treatments address symptoms that develop after the initial injury. Increased levels of adenosine and glutamate are treated with drugs that inhibit glutamate release.
Behavioral and cognitive effects are treated with strategies similar to those for cerebrovascular accidents (e.g., constraint-induced movement therapy).
Disorders of Development
Inherited Metabolic Disorders
Genetic abnormalities in which the recipe for a particular enzyme is in error, so the enzyme cannot be synthesized. If the enzyme is a critical one, the results can be very serious.
Phenylketonuria (PKU)
Caused by an inherited lack of an enzyme that converts phenylalanine into tyrosine.
Excessive phenylalanine in the blood interferes with myelinization of neurons in the central nervous system.
The result is severe intellectual disability (average IQ of approximately 20 by six years of age).
Treated by putting the infant on a low-phenylalanine diet. Once myelinization is complete, the dietary restraints can be relaxed somewhat, because a high level of phenylalanine no longer threatens brain development.
Newborns are mandated to have a PKU test
During prenatal development a fetus is protected by its mother’s metabolism, so the mother must follow a strict diet during pregnancy or the baby’s brain will not develop correctly.
If the mother eats a typical diet, rich in phenylalanine, the high blood level of this compound will not damage her brain, but it will damage that of her fetus.
Pyridoxine dependency
Untreated leads to damage to cerebral white matter, to the thalamus, and to the cerebellum. It is treated by large doses of vitamin B_6 .
Galactosemia
An inability to metabolize galactose, a sugar found in milk.
If it is not treated, it too causes damage to cerebral white matter and to the cerebellum.
The treatment is use of a milk substitute that does not contain galactose.
Tay-Sachs disease
Occurs mainly in children of Eastern European Jewish descent, causes the brain to swell and damage itself against the inside of the skull and against the folds of the dura mater that encase it. The neurological symptoms begin by four months of age and include an exaggerated startle response to sounds, listlessness, irritability, spasticity, seizures, dementia, and finally death.
storage disorders
Metabolic storage disorders are genetic errors of metabolism in which one or more vital enzymes are missing. Particular kinds of waste products cannot be destroyed, so they accumulate in the lysosomes. The lysosomes get larger and larger, the cells get larger and larger, and eventually the brain begins to swell and become damaged.
Researchers investigating hereditary errors of metabolism hope to prevent or treat these disorders in several ways. Some will be treated like PKU or galactosemia, by avoiding a constituent of the diet that cannot be tolerated. Others, such as pyridoxine dependency, will be treated by administering a substance that the body requires. Still others may be cured someday by the techniques of genetic engineering. Researchers hope to develop genetically modified viruses that will insert into infants’ cells the genetic information needed to produce the enzymes that the cells lack, leaving the rest of the cells’ functions intact.
Down Syndrome
A congenital disorder caused by the presence of an extra twenty-first chromosome, resulting in abnormal brain development and intellectual disability.
The syndrome is associated with the mother’s age which increases the likelihood of meiosis errors
Brain Differences in individuals with Down Syndrome:
Brain of a person with Down syndrome is approximately 10 percent lighter than that of a typically developing peer
Convolutions (gyri and sulci) are smaller and less folded
Frontal lobes are smaller,
The superin temporal gyrus (location of wernicke’s area) is thinner
After age 30, the brain develops abnormal microscopic structures and begins to degenerate, resembling Alzheimer’s disease.
Treatment focuses on GABA antagonists or selective serotonin reuptake inhibitors to improve learning and memory by reducing GABA concentrations in the brain.
Degenerative Disorders
Cause degeneration of brain cells, with targeted effects on particular cell types. Includes prion infection (transmissible spongiform encephalopathies) and affects motor behavior (Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis, multiple sclerosis) and cognition (Alzheimer’s disease, Korsakoff’s syndrome).
Transmissible Spongiform Encephalopathies (TSEs)
Fatal contagious brain diseases caused by prions (protein infectious agents). Examples include bovine spongiform encephalopathy (BSE), Creutzfeldt-Jakob disease, fatal familial insomnia, and kuru. TSEs are caused by simple proteins, called prions, or “protein infectious agents”. Prion proteins are found primarily in the membrane of neurons, where they are believed to play a role in synaptic function and in preservation of the myelin sheath.
The sequence of amino acids of normal prion protein (PrP^c) and infectious prion (PrP^{Sc}) are identical. The only difference between PrP^c and PrP^{Sc} is the way the protein is folded.
Normal PrPc does not seem to be essential for cell life. The cells of mice with a targeted mutation of the prion protein gene produced absolutely no prion protein and did not develop mouse scrapie when they were inoculated with the misfolded prions that cause this disease. Normal mice inoculated with these prions died within six months.
TSEs Transmission
Genetic: a familial form can be transmitted as a dominant trait
sporadic: occur in people without a family history of prion protein disease
transplantation of tissues: dura mater or corneas
cannibalism: kuru was transmitted through cannibalism
Mallucci et al suggest that inactivation of caspase-12, the enzyme that appears to be responsible for the death of neurons infected with PrP^{Sc}, may provide a treatment that could arrest the progress of transmissible spongiform encephalopathies.
Parkinson’s Disease
Caused by degeneration of the nigrostriatal system (dopamine-secreting neurons of the substantia nigra that send axons to the basal ganglia). Affects approximately 1% of people over 65 years of age.
Symptoms
Muscular rigidity, slowness of movement, a resting tremor, and postural instability. Motor deficits can be described as a deficiency of automatic, habitual responses caused by damage to the basal ganglia. A resting tremor is vibratory movements of the arms and hands that diminish somewhat when the individual makes purposeful movements. The tremor is accompanied by rigidity; the joints appear stiff.
Causes
Mutation of a gene on chromosome 4 that produces α-synuclein. Abnormal α-synuclein becomes misfolded and forms aggregations, especially in dopaminergic neurons. Another hereditary form is caused by mutation of a gene on chromosome 6 that produces parkin. Normal parkin assists in the tagging of abnormal or misfolded proteins with numerous molecules of ubiquitin Ubiquitination targets the abnormal proteins for destruction by the proteasomes, which break them down into their constituent amino acids
Most cases are sporadic due to toxins in the environment, faulty metabolism, or unrecognized infectious disorders. Rodent models of Parkinson’s disease suggest that the presence of α-synuclein, elevated intracellular calcium ions, and elevated levels of intracellular dopamine combine to kill these cells. Interference with any of these three factors prevents damage to these cells
DA neurons of the mesolimbic/mesocortical system do not contain elevated levels of calcium ions, so they are spared.
Treatments
L-DOPA, the precursor of dopamine to creates increased level of L-DOPA in the brain causes a patient’s remaining dopaminergic neurons to produce and secrete more dopamine and, for a time, alleviates the symptoms of the disease. Deprenyl is a drug that inhibits the activity of the enzyme MAO-B to prevent unknown toxins from producing further damage to dopaminergic neurons
Surgical Procedures:
Transplantation of fetal tissues
attempts to reestablish the secretion of dopamine in the neostriatum. Unfortunately, transplant patients later developed severe, persistent dyskinesias troublesome and often painful involuntary movements. Further examination of the fate of fetal transplants has shown that, although the transplanted cells can survive and form connections with neurons in the recipient’s tissue, these cells eventually develop deposits of α-synuclein Misfolded α-synuclein is transferred from the recipient’s own neurons to the grafted neurons
Pallidotomies
surgical destruction of the internal division of the globus pallidus pallidotomies in patients with severe Parkinson’s disease. The surgery often reduced the rigidity and enhanced the patient’s ability to move.
Surgical lesions/Deep brain stimulation
Deep brain stimulation has an inhibitory effect on STN neurons, but an optogenetic study Indicates that the effects of DBS are more complex than that
A trial of gene therapy designed to reduce excitation in the subthalamic nucleus produced promising results.
Huntington’s Disease
Caused by degeneration of the caudate nucleus and putamen. Huntington’s disease affects approximately 1% of people over 65 years of age.
Symptoms:
Causes uncontrollable movements, especially jerky limb movements, includes cognitive and emotional changes, and eventually causes death, usually within 10–15 years after the symptoms begin. The Movements look like fragments of purposeful movements but occur involuntarilyLoss of this control leads to involuntary movements. As the disease progresses, neural degeneration is seen in many other regions of the brain, including the cerebral cortex.
Causes:
Hereditary disorder, caused by a dominant gene on chromosome 4 In Huntington’s disease, a sequence of bases (CAG) for the amino acid glutamine is repeated many times, The excess CAG repeats lead to an elongated stretch of glutamine. The elongated sequence causes the gene product—a protein called huntingtin Abnormal Htt may trigger apoptosis by impairing the function of the ubiquitinproease system, which activates caspase, one of the enzymes involved in apoptosis.
Mice treated with caspase inhibitor have lived longer. Normal Htt is found in cells throughout the body, but it occurs in especially high levels in neurons and in cells of the testes. Researchers have debated the role played by the accumulations of misfolded Htt in the nucleus In development of the disease These inclusions could cause neural degeneration, they could have a protective role, or they could play no role at all . The inclusions promote protection
Normal Htt is necessary for development, as targeted mutation is fatal
Normal Protein: vesicular transport, release of neurotransmitters and vesicular membrane recycling
Treatments: At present there is no treatment for Huntington’s disease.
Happ1 intrabody suppress the production of of mutant Htt
siRNA blocked the tescritption Htt genes in the striatum.
block transcription decreased the size of the cells and prolonged life of striatal neurons
### Amyotrophic Lateral Sclerosis (ALS)
Degenerative disorder that attacks spinal cord and cranial nerve motor neurons Affects approximately 5 in 100,000Symptoms included spasticity, exaggerated stretch reflexes, progressive weakness and muscular atrophy, and paralysis. The muscles that control eye movements are spared. Some cognitive abilities, such as executive function, working-memory, language and social cognition may also be affected. Death usually occurs 5–10 years after the onset of the disease as a result of failure of respiratory muscles.
Ten percent of the cases of ALS are hereditary; the other 90 percent are sporadic. Of the hereditary cases, 10–20 percent are caused by a mutation in the gene that produces the enzyme superoxide dismutase 1 enzyme known as SOD1 found on chromosome 21 Faulty editing of mRNA that codes for a particular glutamate receptor subunit GluR2 in motor neurons results in the production of glutamate AMPA receptors that admit increased amounts of calcium ions into these neurons.
Treatments:
The only current pharmacological treatment for ALS is Riluzole, a drug that reduces glutamate-induced excitotoxicity, probably by decreasing the release of glutamate. Clinical trials found that patients treated with riluzole lived an average of approximately two months longer than those who received a placebo.
Multiple Sclerosis (MS)
Autoimmune demyelinating disease in which the person’s immune system attacks myelin sheaths, leaving behind hard patches of debris called sclerotic plaques Symptoms increase over a prolonged period of time The symptoms of multiple sclerosis often appear, increase in intensity and then decrease, to be followed by another increase in symptoms after varying periods of time.
Only a few treatments for multiple sclerosis have shown promise. The first is interferon β, a protein that modulates the responsiveness of the immune system. The patients must contract measles early in life Only reduces symptoms for remitting-relapsing MS
Glatiramer Acetate
Glaitramer acetate This compound stimulates stimulation cells of the immune system to secrete- inflammatory chemicals, such as interleukin 4
Clinical trials
Patients treated are reported a significant improvements in neurological patients. Recent clinical trials have suggested that a new drug, BG-12, may be effective in reducing the number of brain lesions, the rate of relapse, and the rate of disability progression in relapsing MS
To end exploitation of MS patients by people selling useless treatments is to develop genuinely effective therapies.
Dementia
Deterioration of intellectual abilities resulting from an organic brain disorder the most common form is caller Alzheimers Disease which occurs in approximately and 10 percent of the population above the age of 65 and almost 50 percent of people older than 85. The memory deficit most critically involves recent events and thus it resembles the anterograde amnesia of Korsakoff’s syndrome Alzheimers disease produces severe degeneration of the hippocampus, entorhinal cortex, neocortex-nucleus basalis, locus coeruleus, and raphe nuclei.
The brains of people with Down syndrome develop abnormal structures that are also seen in patients with Alzheimer’s disease amyloid plaques and neurofibrillary tangles.
Mice that contain a train of gene have caused a delayed accumulation of amyloid- B and slower decline of the animals performances. To prevent or delayed accumulation of amyloid-B, It is important to get a combination active life and to continuously practice memory tactics by engaging the brain.
Recent and early forms are thought to be Hereditary The patients are known to have defective genes because amyloid protein is high. People that contain Apolopoprotein E E4 is known to increase Amyloid in Amyloid the Amyloid Plaques
Causes of Alzheimer's Disease
Genetic: Defective genes for the amyloid precursor protein (APP) genetic mutations of the two proteins, PS1 or PS2 result in the production of long- form B
Environmental: Traumatic brain injury such as those incurred by boxing increase the release of amyloid into the Amyloid Plaques
Treatment of Alzheimer's Disease
Acetylcholinesterase Inhbitors are what drugs that help with the destruction Amyloid or B temporary
Vaccination is to target the IS antibodies will assist in memory. The results shows reduction of cognitive decline .