BMS2046_Disorders of CNS_Part 3_v1.0_04 MAR 2024.pdf

BMS2046 Disorders of the Central Nervous System (CNS): Part 3 Dr Vikki Revell [email protected] Office: 03MA00 - Clinical Research Building, Manor Park Campus Part 3: Learning Outcomes Describe the cause, symptom and treatment of neurodegenerative diseases including Alzheimer’s disease Parkinson...

BMS2046 Disorders of the Central Nervous System (CNS): Part 3 Dr Vikki Revell [email protected] Office: 03MA00 - Clinical Research Building, Manor Park Campus Part 3: Learning Outcomes Describe the cause, symptom and treatment of neurodegenerative diseases including Alzheimer’s disease Parkinson’s disease Huntington’s disease Describe the cause, symptom and treatment of CNS infections including Meningitis Creutzfeldt-Jakob Disease (CJD) Dementia & Neurodegenerative diseases Dementia Dementia is a syndrome (a group of related symptoms) not a specific disease Associated with a progressive decline of brain functioning that affects quality of life Many different causes & many different types Most prevalent: Alzheimer’s Disease & Vascular dementia Lewy body dementia, Frontotemporal dementia (Pick’s disease) Parkinson’s disease Huntington’s disease Creutzfeldt-Jakob disease Mostly affects older adults but not part of normal ageing Dementia Symptoms Memory loss Reduction in cognitive ability and processing Problems with understanding Problems with language (using correct word) or speech Difficulty carrying out daily activities Personality changes Behavioural changes – agitation Sleep disturbance Alzheimer’s disease Most common form of dementia Progressive cognitive decline Symptoms Early Memory lapses Mid-stage Worsening memory problems Increasing confusion and disorientation Obsessive and repetitive behaviours Changes in mood Symptoms Mid-stage Sleep disturbance Hallucinations Aphasia (communication) Later Dysphagia Weight loss Incontinence Severe short and long term memory problems Difficulty moving Gradual loss of speech Neuropathology of Alzheimer’s disease Senile plaques Extracellular deposition of β-amyloid peptide Neurofibrillary tangles Intracellular Phosphorylated tau protein Tau – microtubule associated protein Neuroinflammation Massive loss of neurons and synapses in the hippocampus & cortex Alzheimer’s disease Risk factors Age (risk doubles every 5 years after 65 years old) Downs syndrome Cardiovascular disease Head injuries Apolipoprotein (APOE) on xsome 19 – APOE ε4 Early Onset Dementia 3 gene mutations that affect breakdown of APP Amyloid precursor protein (APP) on xsome 21 Presenilin 1 (PSEN1) on xsome 14 Presenilin 2 (PSEN2) on xsome 1 Brain atrophy in Alzheimer’s disease Treatment: No cure Acetylcholinesterase inhibitors – increase Ach levels Gene-environment interactions in AD Nithianantharajah and Hannan Nature Reviews Neuroscience 7, 697–709 (September 2006) | doi:10.1038/nrn1970 Frontotemporal dementia (FTD) (Pick’s disease) Rare form of dementia Shrinking of the frontal and temporal lobes of the brain Tends to occur at a younger age than AD (40 - 65 years) but also later in life Causes: Intracellular depositions of abnormal form of tau protein inside neurons Degeneration of neurons, microvacuoles formation, and astrocytosis Frontotemporal dementia (FTD) (Pick’s disease) Symptoms: Dramatic changes in personality Inappropriate social behaviour Loss of empathy Loss of inhibition Lack of interest Overeating Language disturbance Difficulty using and understanding language Hesitant speech Spatial skills and memory remain intact Treatment: No cure or specific treatment Medications used to manage symptoms Antidepressants Anti-psychotics Therapies Vascular Dementia Cause Reduced blood flow to the brain Sub-cortical vascular dementia: narrowing of blood vessels in the brain Single-infarct dementia: stroke cuts of blood supply to part of the brain (blood clot) Multi-infarct dementia: multiple strokes Symptoms Confusion Short-term memory problems Wandering & getting lost in familiar places Losing bladder or bowel control Difficulty following instructions Vascular Dementia Treatment No treatment to reverse brain damage Prevention of future strokes Address risk factors Hypertension Diabetes High cholesterol Cardiovascular disease Overweight or obese Lack of exercise High alcohol consumption Smoking Parkinson’s disease Motor system disorder Cause Loss of dopamine-producing neurons in the substantia nigra Symptoms Tremor Rigidity – muscle stiffness Slowed movement (bradykinesia) Postural instability Impaired balance and coordination Speech changes Parkinson’s disease Treatment No cure Levodopa Enters brain and converted to dopamine Combined with carbidopa to prevent premature conversion Deep brain stimulation Control dyskinesia (involuntary movements) Huntington’s disease Motor system disorder Cause Familial hereditary disease (autosomal dominant ) Huntingtin gene mutation Abnormally long version of huntingtin protein Expansion of CAG repeats (normally 10-35; mutation 36 – 120 repeats) Smaller, toxic fragments - bind together and accumulate in neurons Loss of huntingtin protein's DNA repair function Accumulation of DNA damage in neurons? Striatum and cerebral cortex particularly affected Co-ordinate movement and control thinking and emotions Huntington’s disease Symptoms Early Memory lapses Stumbling and clumsiness Mood swings Advanced Uncontrolled jerking ("Huntington's Chorea") Slurred speech Slow or rigid movements Personality changes Breathing and swallowing problems Treatment No cure Medications to manage symptoms Gene-environment interactions in Huntington's disease Nithianantharajah and Hannan Nature Reviews Neuroscience 2006 Cerebral Aneurysm Cerebral Aneurysm Characteristics Ballooning/bulge in the wall of a blood vessel in the brain Caused by a weakness in the blood vessel wall, usually where it branches Symptoms Unruptured Depends on size and rate of growth - loss of feeling in the face or visual problems After rupture Sudden agonising headache Stiff neck, vomiting & loss of consciousness Cerebral Aneurysm Treatment Unruptured Only treated if high risk Surgery Endovascular coiling - fill the aneurysm with tiny platinum coils Neurosurgical clipping - tiny metal clip clamped on aneurysm Ruptured Nimodipine - reduce risk of disruption to brain blood supply (cerebral ischaemia) Clipping or coiling CNS infections Leptomeningitis & Encephalitis Inflammatory conditions of the brain (encephalitis) and meninges of brain & spinal cord (meningitis) Causes: Meningitis: bacterial or viral infections Encephalitis: viral infections e.g., HSV, enteroviruses Symptoms of meningitis High fever Severe & persistent headache Stiff neck, nausea and vomiting Confusion, sleepiness, and difficulty waking up Increased sensitivity to light Infants: irritability or fatigue, lack of appetite, fever Leptomeningitis & Encephalitis Symptoms of encephalitis Sudden fever, headache, vomiting Increased sensitivity to light Stiff neck, confusion and impaired judgment Drowsiness Weak muscles, unsteady gait Irritability Severe: loss of consciousness, seizures, muscle weakness, or sudden severe dementia Leptomeningitis & Encephalitis Treatment Bacterial infections: antibiotics Viral infections: antiviral medications Anticonvulsants to prevent or treat seizures Corticosteroids to reduce brain swelling & inflammation Sedatives may be needed for irritability or restlessness Medications for fever and headache Usually hospitalized for treatment Vaccinations for meningitis Creutzfeldt-Jakob Disease (CJD) Characteristics Rare, degenerative, invariably fatal brain disorder Spongiform encephalopathy Cause Abnormal, infectious protein = prion (no nucleic acid) Prions accumulate at high levels in the brain & cause irreversible damage to neurons No diagnostic test - confirmed by brain biopsy or autopsy Treatment None available Death usually as a result of respiratory infections Creutzfeldt-Jakob Disease (CJD) Types Sporadic Normal brain protein changes abnormally ("misfolds") and turns into a prion Variant Likely caused by consuming meat from a cow with bovine spongiform encephalopathy (BSE, or "mad cow" disease) Familial Very rare genetic condition Mutation causes prions to form in the brain during adulthood Creutzfeldt-Jakob Disease (CJD) – Initial symptoms Neurological symptoms Problems with walking, balance & coordination Slurred speech Numbness Dizziness Visual problems Hallucinations Psychological symptoms Severe depression Anxiety Irritability Insomnia Withdrawing Creutzfeldt-Jakob Disease (CJD) – Advanced symptoms Neurological symptoms Loss of physical co-ordination Muscle twitches and spasms Loss of bladder & bowel control Blindness Dysphagia Loss of speech Psychological symptoms Severe memory loss Confusion Agitation Aggression Paranoia Appetite loss Kuru Kuria = “to shake” Rare and fatal brain disorder Epidemic levels during the 1950s-60s Fore people in the highlands of New Guinea Cause Transmissible spongiform encephalopathy (prion protein) Ritualistic cannibalism Symptoms Cerebellum affected Unsteady gait, tremors, and slurred speech Behavioural & mood changes often present Part 3: Learning Outcomes Describe the cause, symptom and treatment of neurodegenerative diseases including Alzheimer’s disease Parkinson’s disease Huntington’s disease Describe the cause, symptom and treatment of CNS infections including Meningitis Creutzfeldt-Jakob Disease (CJD)