BBS3015 Neurosciences and Control Lecture Notes PDF

BBS3015 - Neurosciences and control Neurodegenerative diseases Lecture 1 Neurodegeneration is the progressive deterioration and loss of nerve...

BBS3015 - Neurosciences and control Neurodegenerative diseases Lecture 1 Neurodegeneration is the progressive deterioration and loss of nerve cells in the brain and nervous system. Pathophysiological mechanisms in This process is initiated by metabolic disruption events in neurons, such as protein overexpression or misfolding. These events activate neurodegenerative disorders the microglial cells and the blood brain barrier (BBB), sending signals (cytokines) that induce inflammation in the brain to try to clean it up. However, the inflammation leads to neuronal damage and eventually to neurodegeneration. The nervous system The nervous system is the body’s communication network, responsible for sending, receiving, and processing signals. It is divided into two main parts: 1. Central nervous system (CNS) Brain & spinal cord Alzheimer’s disease (AD) This acts as the control center, processing info and directing Alzheimer’s disease is an irreversible, progressive brain disorder. It has responses three hallmarks: 2. Peripheral nervous system (PNS) 1. Extracellular aggregates of amyloid beta plaques Nerves extending from CNS to the rest of the body 2. Intracellular neurofibrillary tangles made of This connects the CNS to limbs and organs and is divided hyperphosphorylated tau-protein into two systems: 3. Brain atrophy Somatic nervous system (SNS) - voluntary movements Autonomic nervous system (ANS) - involuntary movements. Which is further divided into: - Sympathetic nervous system (fight or flight) - Parasympathetic nervous system (rest and digest) 1) Extracellular Aβ plaques Amyloid beta is a protein fragment produced naturally in the brain. It is derived from a larger transmembrane protein called amyloid precursor protein (APP), which is found in the cell membrane of neurons. In a healthy brain, APP can be processed through two main pathways: 1. Non-Amyloidogenic Pathway (most prevalent) - α and γ - Soluble APP-alpha (sAPP-α), which has neuroprotective and growth promoting properties - P3 peptide, that does not aggregate 2. Amyloidogenic Pathway - β and γ The cells of the nervous system that are specialized for - Aβ40 is produced, but it remains soluble and is typically transmitting information are called neurons. They consist of: cleared away to prevent accumulation. - Cell body (soma): contains the nucleus and is the neuron’s metabolic center - Dentrites: receive signals from other neurons - Axon: transmits signals away from the soma to other neurons. They are often insulated by a myelin sheath, to speed up signal transmission. - Synapse: the junction between two neurons where neurotransmitters are released to carry signals across the gap. Ganglion cells, such as astrocytes, oligodendrocytes, and microglial cells, are cells of the nervous system that support the neurons. In Alzheimer’s disease, the amyloidogenic pathway becomes 3) Brain atrophy more active, leading to an increase in the production of amyloid Brain atrophy is the reduction in brain volume and mass due to the beta, particularly Aβ42, which is two amino acids longer, more progressive loss of neurons and the connections between them. This hydrophobic, and more prone to aggregate than the normal Aβ40. loss affects various brain regions and leads to the deterioration of Amyloid beta isomers: 38 (10%) - 40 (80%) - 42 (10%). cognitive functions, including memory, language, and reasoning abilities. Aβ42 is produced when γ secretase cuts the APP at the wrong There are three main regions affected: point and it can also be produced in healthy brains but it can be 1. Cerebral cortex - shrinkage cleared away in small amounts. 2. Hippocampus - shrinkage 3. Ventricles - enlarged Parkinson's disease (PD) Parkinson’s disease is primarily known for its motor symptoms, such 2) Intracellular tau tangles as tremors, rigidity, and bradykinesia (slowness of movement). Tau proteins are found in neurons and bind to microtubules, In the substantia nigra, two events are happening: which are structural components within cells that help maintain 1. Dopaminergic neurons release dopamine, which is a hormone cell shape and facilitate intracellular transport. and neurotransmitter. Dopamine is important for initiating By binding at the microtubule-binding repeat domains, which are movements. located in the C-terminal half of the tau protein, it stabilizes the In Parkinson’s, these dopaminergic neurons degenerate and die, microtubules. which leads to movement (initiation) disorders. One of the Tau is normally phosphorylated at certain sites (proline-rich) causes of this, is due to Lewy Bodies: (T181 and T231 are most common phosphorylation sites), which helps regulate its binding to microtubules. However, in Alzheimer’s disease, tau proteins undergo abnormal changes that contribute to the disease’s progression: Hyperphosphorylation Tau cannot bind to microtubules anymore, leading to microtubule destabilization. This disrupts the normal transport system within neurons, impairing their function. Formation of Neurofibrillary Tangles (NFTs) The tau proteins aggregate into insoluble twisted fibers known as neurofibrillary tangles, which then accumulate inside neurons. They interfere with normal cellular function and contribute to the neuron’s breakdown and death. 2. In Parkinson’s there is a problem with a protein called alpha synuclein, leading to it sticking together and accumulate. The aggregates of alpha synuclein are known as Lewy Bodies. The accumulation of alpha-synuclein in Lewy Bodies is toxic to neurons and leads to neuronal dysfunction and eventually neuronal death. In Parkinson’s, the Lewy Bodies can be found at different locations depending on the Braak stages. Braak stages 3. Optic disc pallor - the optic disc may appear pale or pallor due to ○ Stage 1 & 2- lewy bodies first appear in the olfactory bulb the loss of nerve fibers. (early symptoms of Parkinson’s include loss of smell), the substantia nigra, and the nucleus of the vagus nerve in the brainstem (GI symptoms). ○ Stage 3 & 4 - The lewy bodies spread to the cortex, which contributes to sleep and motor disturbances. ○ Stage 5 & 6 - The lewy bodies are spread throughout the brain, leading to severe emotional and cognitive decline. Glaucoma Glaucoma is a group of irreversible eye conditions that damage ISNT rule the optic nerve, which is crucial for transmitting visual information The ISNT rule is a guideline used to assess the health of the optic from the eye to the brain. nerve and detect glaucomatous changes based on the appearance The most significant risk factor for glaucoma is elevated of the neuroretinal rim. intraocular pressure (IOP). When the trabecular meshwork is In a healthy optic nerve, the thickness of the neuroretinal rim is blocked, there will be a fluid build up in the eye. The pressure in the typically greatest in the inferior region, followed by the superior, nasal, eye will lead to changes in the optic nerve. and temporal regions. Inferior > Superior > Nasal > Temporal Glaucomatous Optic Neuropathy Damage to the optic nerve fibers typically affects the retinal ganglion cells, which are responsible for transmitting visual information from the retina to the brain. The optic nerve head, also known as the optic disc, is the point where the optic nerve fibers exit the retina and enter the brain. In glaucomatous optic neuropathy, characteristic changes occur at this place due to damage to the nerve fibers. These are the hallmarks of glaucoma: Visual field test results 1. Increased Cupping - due to the loss of nerve fibers, the ‘’cup’’ The patient will have a tunnel vision. The brain will fill the peripheral deepens. This is the central depression within the optic disc missing information. (like the hole in the donut). 2. Thinning of the Neuroretinal Rim - The nerve fibers in the retina bend at the rim of the optic disc before exiting the eye. So the rim is like the donut itself. Due to the loss of ganglion cell axons, the rim will become thinner. BBS3015 - Neurosciences and Control PET Lecture 2 PET scans can visualize amyloid plaques in the brain and detect tau tangles. However, some PET scans can also measure the glucose metabolism in the brain. A reduced metabolism in regions like the Biomarkers and biomarker-based temporoparietal cortex and posterior cingulate cortex is a common finding in AD. therapies - PiB PET scans can visualize amyloid plaques - Flortaucipir PET scans can detect amyloid plaques and tau tangles - FDG-PET scans measure glucose metabolism in the brain Biomarkers Biomarkers are the measures (such as blood pressure, cholesterol level, weight, etc.) used to perform a clinical assessment and are PiB PET scan: shows amyloid plaques used to monitor and predict health states in individuals so that In AD, there are higher levels (yellow & appropriate therapeutic intervention can be planned. red) of amyloid plaques. This can be seen in the frontal, parietal, and temporal An ideal biomarker should have the following features for lobes. checking a particular disease condition: - Safe and easy to measure - Cost efficient to follow up FDG-PET scan: shows - Modifiable with treatment glucose metabolism - Consistent across gender and ethnic groups In AD, there is a decline in brain metabolic activity. Types of biomarkers Classification based on their biophysical properties Imaging biomarkers (CT scan, PET, MRI) Fluid markers in AD Fluid biomarkers (found bodily fluids such as blood and saliva. Examples are DNA, RNA, proteins, lipids, etc.) Cerebrospinal fluid (CSF) Clinical biomarkers (signs & symptoms) CSF is typically obtained through a procedure called a lumbar puncture, also known as a spinal tap. The patient is usually positioned lyong on their side with their knees drawn up to their chest. A thin, Biomarkers in AD hollow needle is carefully inserted between the vertebrae of the lower Alzheimer’s disease is characterized by several biomarkers that spine (L3-L4 or L4-L5). The needle is advanced until it reaches the can be detected through imaging techniques and fluid analysis. subarachnoid space, which contains the CSF. These biomarkers help in the early diagnosis, monitoring of disease progression, and assessment of treatment efficacy. Imaging biomarkers in AD MRI MRI is used to detect three key characteristics of AD: 1. Brain atrophy (shrinkage) - hippocampal (memory) atrophy is one of the earliest and most reliable structural markers of AD. 2. Cortical thinning - especially in the temporal and parietal 1. Decreased Aβ42/Aβ40 ratio lobes the cerebral cortex tends to thin in AD. As more amyloid beta becomes sequestered in plaques in 3. Enlarged ventricles (ventriculomegaly) - this reflects the between neurons, less Aβ remains free and soluble, leading to overall brain volume loss decreased levels in the CSF. Aβ40 is less prone to forming plaques compared to Aβ42. Therefore, the Aβ42/Aβ40 ratio also decreases in AD because Aβ42 levels drop significantly relative to Aβ40 levels. 2. Increased tau levels Tau forms tangles inside neurons. When neurons are damaged or dying, they release more tau into the CSF, leading to increased tau levels in the fluid. 3. Neurofilament Light Chain (NfL) is a marker of axonal damage (it is a general marker of neurodegeneration) so it will also have elevated levels in the CSF of a AD patient Blood Fluid markers in PD - CSF Blood-based markers (BBMs) have recently shown promise to Fluid biomarkers are increasingly being studied in Parkinson’s disease revolutionise the diagnostic and prognostic work-up of AD. This to aid in diagnosis and monitor disease progression. These markers offers a less invasive alternative to CSF analysis. can be found in CSF, and, more recently, in blood. 1. Plasma Aβ42/Aβ40 ratio - low ratio in AD In the CNS, decreased levels of alpha-synuclein are measured in 2. Plasma phosphorylated tau - increased levels patients with AD. The total alpha-synuclein levels in CSF will be 3. Plasma Neurofilament Licht Chain - increased levels reduced in PD patients because the protein is sequestered in Lewy 4. Glial Fibrillary Acidic Protein (GFAP) - marker for astrocyte bodies in the brain. activation and neuroinflammation, which occurs in response to inflammation or injury in the brain. Therefore, in AD it is elevated in the blood. Biomarkers in glaucoma ! These blood-based markers are stillbeing developed and Clinical biomarkers in glaucoma validated, but hold great promise for early diagnosis, disease These are physiological of measurable signs related to the monitoring, and even screening at a larger scale ! development or progression of glaucoma: Intraocular Pressure (IOP) - High IOP is often found in patients with Biomarkers in PD open-angle glaucoma, but glaucoma can also occur with normal IOP (normal-tension glaucoma) Clinical biomarkers in PD Clinical diagnosis of PD typically revolves around motor symptoms such as tremors, bradykinesia, rigidity, and postural instability. However, there are also some non-motor symptoms such as sleep disturbances, mood changes, cognitive impairment, and autonomic dysfunction (such as constipation). These are used for tracking disease progression. Biomarkers like REM sleep behavior disorder (RBD) and hyposmia a. A probe (likely a tonometer) is placed on the cornea, (olfactory dysfunction) often appear years before motor applying force to indent it slightly. The pressure needed to symptoms and are considered early clinical indicators. flatten the cornea correlates with the IOP to estimate the pressure. b. An applanator tip (likely a Goldmann applanation Imaging biomarkers in PD - PET tonometer) is used to flatten a small area of the cornea. Two primary imaging techniques used for diagnosis and The force required to flatten the specific area is measured. monitoring PD are: This force is directly related to the IOP. This is the gold 1. DaT-SPECT scan - measures the dopamine transporters standard in clinical IOP measurement. (DaT) in the brain c. Non-contact tonometry (Air-Puff Tonometry): a puff of air is directed at the cornea, a detector measures the corneal 2. F-DOPA PET scan - measures the synthesis and storage of deformation caused by the air, and a laser diode is used to dopamine in the brain, providing more detailed and detect the change in corneal curvature. quantitative insights pinto dopamine system dysfunction. Cup-to-Disc Ratio (C/D ratio) - increases as the optic nerve fibers Fluorodopa (F-DOPA) is a radiolabeled form of the precursor are lost, resulting in a larger cup and thinning of the neuroretinal to dopamine (L-DOPA). By tracking how F-DOPA is taken up rim. A ratio above 0.6 is typically a concern and may suggest and converted into dopamine in the brain, researchers can optic nerve damage. assess the function of dopaminergic neurons. Visual Field Loss - peripheral vision loss. Visual field testing (perimetry) is used to detect and track this loss Imaging biomarkers - retinal imaging Retinal imaging techniques are crucial for detecting structural changes in the optic nerve and retinal layers in glaucoma. Optical Coherence Tomography (OCT) is a non-invasive imaging technique that provides cross-sectional images of the retina and optic nerve head. It measures the thickness of the retinal nerve fiber layer (RNFL) and ganglion cell complex (GCC). In patients with AD: RNFL thinning due to loss of retinal ganglion cells and their axons GCC thinning (the layer of retinal ganglion cell bodies) RNFL thickness map (left circle) is a circular color map that represents the thickness of the RNFL around the optic nerve. The green and yellow areas are where the RNFL thickness is within normal limits. All other colors (especially red) indicate thin RNFL due to nerve fiber loss. RNFL thickness graph (top right) represents the RNFL thickness across different sectors (superior, temporal, inferior, and nasal quadrants). Inthis patient, the graph shows areas of significant thinning (where the black line dips into the yellow or red regions) in the superior temporal and inferior nasal quadrants. Sectoral analysis (bottom circles) represent the RNFL thickness in specific sectors around the optic nerve, such as the superior, inferior, temporal, and nasal. Biomarker-based therapies In diseases like Alzheimer’s and autoimmune disorders, antibodies are injected or infused in patients to target specific biomarkers (such as amyloid beta). The antibodies bind to their target biomarker and neutralize it to prevent it from performing its harmful function. Additionally, by binding to it, the antibody tag the harmful protein or cell for destruction by the immune system. Amyloid-targeting antibodies = Aducanumab When injected, aducanumab binds to amyloid-beta aggregates in the brain. The immune system is then triggered to clear these plaques, potentially slowing the progression of the disease. However, it does nothing for the already developed symptoms. Drugs like ocrelizumab and natalizumab are used for multiple sclerosis (MS) (later case). This therapy for other neurodegenerative disorders, such as PD, glaucoma, Huntington’s disease and ALS are still being studied. BBS3015 - Neurosciences and Control It is a simple questionnaire where higher scores indicate better Case 1 cognitive function: 25-30 normal cognitive function 20-24 mild cognitive impairment Alzheimer’s disease and Glaucoma 10-19 moderate cognitive impairment a mutation of this allele can cause variant 4 ε4 - increased risk of LOAD The ApoE ε4 allele is the most significant genetic risk factor for developing LOAD. However, it’s important to note that while this allele increases risk, it does not guarantee that a person will develop AD. The ε4 allele contributes to Alzheimer’s pathophysiology by: - It is less efficient at clearing amyloid-beta peptides, which can accumulate to form plaques in the brain - It leads to increased brain inflammation, which contributes to neuronal damage APP, PSEN1, and PSEN2 mutation (EOAD) EOAD is typically caused by genetic mutations in the APP, PSEN1 or PSEN2 genes. These mutations directly impact the production and processing of amyloid-beta. APP mutations Disease progression (timeline, stages) Amyloid precursor protein (APP) is crucial for generating amyloid-beta peptides. Mutations in the APP gene lead to abnormal cleavage of the protein, resulting in the overproduction of Aβ, especially the Aβ42 form, which is more prone to aggregation and plaque formation. These mutations are autosomal dominant, meaning that inheriting one mutated copy of the gene from a parent can cause EOAD. Individuals with Down syndrome have a significantly increased risk of developing EOAD due to the extra copy of chromosome 21, which carries the APP gene. The overexpression of APP will result in an overproduction of Aβ. Every person’s journey with AD is different. In the end, AD becomes severe enough to disrupt day-to-day life. In later stages, people will By age 40, nearly all individuals with Down syndrome have Aβ need almost constant care. plaques in the brain. Early stage (mild/preclinical) PSEN1 mutations During this stage, two brain parts in the medial temporal lobe are Presenilin 1 is part of the γ -secretase complex, the enzyme that is affected: responsible for the cleavage of APP to produce Aβ (both Hippocampus - critical for forming new memories and spatial pathways). navigation Mutations in PSEN1 disrupt the normal functioning of the γ Entorhinal cortex (near hippocampus) - involved in memory and -secretase complex, leading to an overproduction of the toxic navigation Aβ42. The early stage is preclinical and is very subtle. The person may PSEN1 mutations are the most common cause of EOAD and function independently and not notice anything yet. These are the symptoms in these cases appear earlier and may progress more symptoms: rapidly than other forms of Alzheimer’s. ○ Subtle memory loss ○ Confusion PSEN2 mutations ○ Struggle with remembering recent events, appointments, or Presenilin 2 is also part of the γ -secretase complex and its conversations mutations have a similar affect on amyloid-beta productions as ○ Difficulty with planning and organizing tasks those of PSEN2. Middle stage (moderate) However, PSEN2 mutations are much rarer and the age of onset in During this stage, the disease spreads to: these cases is often more variable with a slower disease Temporal lobes - involved in processing auditory info and progression than with PSEN1 mutations. complex visual processing. -> difficulties with language and understanding Non-genetic risk factors Parietal lobes - important for integrating sensory information The other 93% is non-genetic due to other reasons such as: and spatial awareness. -> difficulties recognizing objects, Modifiable risk factors: people, and places ○ Diet (vitamins, antioxidants, etc) Frontal lobes - responsible for higher-order cognitive functions, ○ Physical activity such as behavior, planning, and decision-making. ○ Cardiovascular health (hypertension, cholesterol, Patients with AD usually stay longer in this stage, where the disease diabetes) progresses. These are some of the symptoms: ○ Smoking ○ Worsening memory loss and confusion ○ Alcohol (brain atrophy) ○ Trouble recognizing familiar people and places ○ Education (cognitive engagement, mental stimulation) ○ Changes in behavior and personality + moodswings ○ Sleep quality ○ Air pollution ○ Head injuries Non modifiable risk factors: ○ Age ○ Sex (women more prone to develop AD)  Late stage (severe) 2. Antiipsychotics such as Quetiapine (Seroquel) and risperidone As the disease progresses, the focus often shifts to providing (Risperdal) to address severe behavioral symptoms such as comfort and maintaining quality of life. aggression. However, these are used with caution due to an increased risk of stroke. During this stage, the previously mentioned brain parts have severe atrophy and the extensive damage across the various 3. Anxiolytics such as lorazepam (Ativan) are used short-term to cortical regions can lead to loss of communication and manage severe anxiety, though they are generally used with movement. Also, the patient completely depends on others for caution due to the risk of dependence and sedation. care. Also, the medulla oblongata in the brain stem is damaged during Disease-modifying immunotherapy medication this late stage, which can affect basic functions such as In immunotherapy, antibodies are injected or infused in patients to breathing, heart rate, and swallowing. target specific biomarkers (such as amyloid beta). Usually the cause of death in patients with AD is not the disease The antibodies bind to their target biomarker and neutralize it to itself, but the complications that arise as a result of the disease. prevent it from performing its harmful function. Additionally, by Common complications leading to death include: binding to it, the antibody tag the harmful protein or cell for Pneumonia - often due to aspiration (inhalin food or liquids destruction by the immune system. into the lungs) because of difficulties with swallowing and Amyloid-targeting antibodies = Aducanumab impaired cough reflexes When injected, aducanumab binds to amyloid-beta aggregates in Infections - These can be more severe due to weakened the brain. The immune system is then triggered to clear these immune responses plaques, potentially slowing the progression of the disease. However, Cardiovascular issues - such as heart disease or stroke, it does nothing for the already developed symptoms. which can be exacerbated by the overall decline in health and mobility Treatment options The average life expectancy for a person with Alzheimer’s disease is 5.8 years after diagnosis. However, early diagnosis can give people and their loved ones the chance to put in place lifestyle changes that can delay or prevent the onset of Alzheimer’s dementia. Medicines may improve or slow the progression of symptoms. However, there is no treatment that cures this disease. Medications for cognitive symptoms Non-pharmacological approaches There are two types of medications that are aimed at the In addition to medications, non-drug therapies, such as cognitive cognitive symptoms: stimulation, behavioral therapy, and environmental modifications, can also play a significant role in managing symptoms and 1. Cholinesterase inhibitors: improving quality of life. Increase the levels of acetylcholine, a neurotransmitter involved in memory and cognitive function. A healthy lifestyle with enough exercise and a healthy diet can have a - Donepezil (Aricept): mild to mod AD protective effect against cognitive decline and might slow down the - Rivastigmine (Exelon): mild to mod AD + PD disease progression. - Galantamine (Razadyne): mild to mod AD - Vitamin D is important for overall brain health. - Omega-3 fatty acids, particularly EPA and DHA, are known for 2. NMDA Receptor Antagonists: their anti-inflammatory properties and role in maintaining brain Regulate the activity of glutamate, a neurotransmitter health. involved in learning and memory - Memantine (Namenda): mod to severe AD Medications for behavioral and psychological symptoms There are three types: 1. Antidepressants known as Selective Serotonin Reuptake Inhibitors, such as sertraline (Zoloft) and citalopram (Celexa) to manage depression and anxiety Glaucoma Eye fluids Glaucoma is a heterogenous group of diseases characterized by There are three types of eye fluids: damage to the optic nerve, often resulting in irreversible vision 1. Aqueous humor loss. It is the leading cause of blindness worldwide, affecting ○ Produced by ciliary body approximately 70 million people globally. ○ Fills the anterior chamber ○ Drains through the trabecular meshwork and Schlemm’s Anatomy of the eye canal ○ Maintains IOP, provides To understand the pathophysiology of glaucoma, basic nutrients, and removes understanding of the eye anatomy is needed. metabolic waste 2. Vitreous humor ○ Fills the vitreous cavity ○ Is not being produced and drained like the aqueous humor ○ Helps maintain the eye’s shape and provides a clear optical path 3. Tear fluid ○ Produced by the lacrimal glands Conjunctiva - a thin, transparent membrane that keeps the eye ○ Contains water, electrolytes, and proteins moist and protects it from foreign particles ○ Drains through the tear ducts Ciliary body - a ring of tissue located behind the iris that produces ○ It lubricates, protects, nourishes and clears the eyes. aqueous humor and contains the ciliary muscle, which adjusts the lens’s shape for focusing. Intraocular pressure (IOP) Iris - the colored part of the eye that controls the size of the pupil It The fluid pressure inside the eye, regulated by the balance between regulates the amount of light entering the eye aqueous humor production and drainage. Pupil - The opening in the center of the iris that allows light to Normal IOP ranges between 10 and 21 mmHg. enter the eye Optic disc Cornea - The transparent, dome shape front surface of the eye The optic disc, also known as the optic Anterior chamber - the fluid-filled space between the cornea and nerve head is located at the point where the iris. It is filled with aqueous humor and pays a role in the optic nerve exits the back of the eye. maintaining intraocular pressure (IOP) and supplying nutrients to the cornea and lens. Sclera - The white protective outer layer of the eye that maintains its shape and provides an attachment for the eye muscles Choroid - layer between the sclera and retina that contains blood vessels supplying nutrients Retina - innermost layer at the back of the eye containing light-sensitive cells (photoreceptors) and converts light into electrical signals Macula - area of the retina that is essential for detailed and color vision. Optic nerve - the nerve that transmits visual information from the retina to the brain. It exits the eye at the optic disc Optic disc - the point where the optic nerve exits the eye and where blood vessels enter and exit the retina. It creates a blind spot as it lacks photoreceptors. Pathophysiology In patients with glaucoma, the trabecular meshwork (a network of tissue located at the angle where the cornea and iris meet) becomes blocked or less efficient at draining the aqueous humor. This blockage reduces the outflow of aqueous humor from the eye (through the Schlemm’s canal). When aqueous humor cannot drain properly, it accumulates in the anterior chamber, increasing the intraocular pressure. The increased IOP exerts pressure on the optic nerve, which can cause damage to the nerve fibers as they pass through the lamina cribrosa in the optic disc. Damage to the optic nerve fibers often results in observable changes to the optic disc, such as increased cupping (a deeper Signs & symptoms indentation of the disc). The symptoms of glaucoma can vary depending on the type and stage of the disease. The most common symptoms are: Types of glaucoma Eye pain & red eyes There are 3 types of glaucoma: Headache Nausea 1. Open-angle glaucoma (most common, 90%) Tunnel vision Drainage angle (formed by cornea and iris) remains open, Seeing halo’s around light but the trabecular meshwork is blocked or less efficient-> slows drainage of aqueous humor out of the eye -> Risk factors increased eye pressure (IOP) -> damage of optic nerve Modifiable risk factors: 2. Angle-closure glaucoma - bulging iris (partially) blocks ○ Hypertension & diabetes drainage angle -> slows drainage of aqueous humor out of ○ Use of corticosteroid medications (secondary glaucoma) the eye -> increased eye pressure -> damage of optic nerve ○ Eye injuries ○ Smoking 3. Normal tension glaucoma - normal pressure, but optic nerve ○ Diet and nutrition (indirect) is abnormally sensitive to pressure. ○ Uncorrected vision correction Non-modifiable risk factors: ○ Age ○ Genetics ○ Ethnicity (especially African descent, but also hispanic and asian) ○ Eye anatomy Assessment ISNT rule Hallmarks The ISNT rule is a guideline used to assess the health of the optic 3 hallmarks can be noticed: nerve and detect glaucomatous changes based on the appearance 1. Loss of retinal ganglion cells of the neuroretinal rim. 2. Increased Cupping - due to the loss of nerve fibers, the ‘’cup’’ In a healthy optic nerve, the thickness of the neuroretinal rim is deepens. This is the central depression within the optic disc typically greatest in the inferior region, followed by the superior, nasal, (like the hole in the donut), composed of neural, vascular and temporal regions. and connective tissue. Inferior > Superior > Nasal > Temporal 3. Thinning of the Neuroretinal Rim - The nerve fibers in the retina bend at the rim of the optic disc before exiting the eye. So the rim is like the donut itself. Due to the loss of ganglion cell axons, the rim will become thinner. Visual field test Glaucoma implant surgery: implanting a tiny tube or shunt onto the white of the eye, helping excess fluid to drain out. Minimally invasive glaucoma surgery (MIGS): creates tiny incisions to encourage eye draining. This surgery is used for mild glaucoma and tends to carry a lower risk of complications than other surgery types. Relation AD and glaucoma There is a potential relationship between these two diseases. While the exact mechanisms connecting the two diseases are still being studied, several factors suggest a link: Both AD and glaucoma involve the progressive loss of neurons (neurodegeneration): RGCs in glaucoma and cortical neurons in AD Current Treatment options Both age and lifestyle factors are important risk factors for both While there is no cure for glaucoma, there are several treatments diseases available that aim to manage the disease, slow its progression, Pathophysiology starts years before symptoms for both and preserve vision. diseases No cure, only symptomatic treatment to slow down for both The goal of treatment is to lower the IOP, which helps prevent further damage to the optic nerve. These are the main treatment Some other studies suggest: options: - In AD, abnormal deposits of amyloid beta and tau lead to Eye drops (most common treatment type for glaucoma) neurodegeneration. Similar changes have been found in the Eye drops that lower pressure in the eye by helping fluid retina of glaucoma patients. Some studies suggest that to drain from the eye: abnormaltau accumulation might also contribute to retinal - Prostaglandins ganglion cell death in glaucoma - Rho kinase inhibitors - Patients with AD have been shown to have retinal changes - Nitric oxides similar to those seen in glaucoma. Such as thinning of retinal - Miotic or cholinergic agents nerve fiber layer (RNFL) Eye drops that reduce eye pressure by limiting the - Just as ab plaques are found in the brains of AD patients, ab volume of fluid the eye makes: deposits have been found in the retina and optic nerve in - Alpha-adrenergic agonists glaucoma patients. - Beta-blockers - Carbonic anhydrase inhibitors Oral medications Resources This is rarely prescribed to treat glaucoma. However, if the - Alzheimer's disease - Symptoms and causes - Mayo Clinic pressure in the eye is too high, it could require emergency - Apolipoprotein E in Alzheimer’s disease trajectories and the treatment, in which case eye drops will not work fast enough. next-generation clinical care pathway | Nature Neuroscience - Alzheimer's Stages and Life Expectancy (healthline.com) Acetazolamide (Diamox) is used to help protect the person’s - How to treat glaucoma: An overview of the treatment options eyesight by reducing the volume of fluid that the eye (medicalnewstoday.com) produces, rapidly lowering the pressure. - The Amyloid-β Pathway in Alzheimer’s Disease - PMC (nih.gov) Laser treatment - https://www.medicalnewstoday.com/articles/how-to-treat-gla This helps to drain fluid and lowers the pressure inside the ucoma#surgery eye. Trabeculoplasty is a simple and noninvasive laser - Glaucoma Surgery | National Eye Institute (nih.gov) procedure for treating open-angle glaucoma. Surgery When the abovementioned methods have been unsuccessful, surgery might be recommended. This type of treatment also does not repair lost vision! Trabeculectomy: creates a tiny opening in the top of the eye (under eyelid) to allow excess fluid to drain away. This surgery is usually used to treat open-angle glaucoma. BBS3015 - Neurosciences and Control Practical 1 Use the given formula to calculate the concentrations of amyloid-beta 42, tau, and phospho-tau of the patients (using the table of the absorbances of the patients samples that is given). Fluid biomarkers identification Theoretical part A sample is anaylized using Sandwich ELISA. Using table 1 (old references for 50yr), check which concentrations are within the reference values (collored in pink). Using the table, make the AT(N) biomarker profile for each patient. The datafile is given during the practical to process and interpret fictive laboratory patient data in the diagnostic workup of Alzheimer’s disease. Practical part The goal of this practical is to transform raw laboratory data into clinical data using a standard curve and to classify patients Summary/Conclusion: according to the AT(N) biomarker profiles. All patients of this list with a AB42 concentration that is not within the 1. Calculate CSF concentrations for amyloid-beta 42, tau, and reference values have Alzheimer’s disease, whereas patients with a phospho-tau. concentration of either T or P tau that is not within the reference values do not necessarily have Alzheimer’s disease. Make 3 graphs using these 3 given tables: BBS3015 - Neurosciences and Control 2. Plan trajectory Guest lecture 1 Using imaging data and advanced software, neurosurgeons plan the trajectory of the electrodes (the exact path and target location for the electrode placement). Deep Brain Stimulation 3. Place leads Through a small incision in the scalp, a neurosurgeon drills a small hole in the skull and inserts the electrodes (leads) into the planned trajectory. First a recording electrode is inserted; every nucleus has a Deep brain stimulation (DBS) is a medical procedure used to different ‘’noise’’ to know when you are in the right place. Secondly, the actual treat certain neurological and psychiatric conditions by electrode is placed targeting specific areas of the brain with electrical impulses. It works by surgically implanting electrodes in specific brain regions associated with the disorder being treated. ○ Subthalamic nucleus Effective for tremor, slowness, rigidity, dystonia, and dyskinesia. -> used to treat Parkinson’s disease ○ Globus pallidus Effective for tremor, slowness, rigidity, dystonia, and dyskinesia. -> used to treat Parkinson’s disease and dystonia (condition characterized by abnormal muscle contractions, causing twisting 4. Programming movements and abnormal postures) A thin, insulated wire is tunneled under the skin, from head to chest. ○ Thalamus (VIM) Effective for tremor. -> used to treat essential tremor This wire connects the electrodes in the (movement disorder causing infoluntary shaking, often of the hands) brain to the pacemaker-like device, called pulse generator, that is implanted under the skin in the chest. Basal ganglia network The basal ganglia are a group of interconnected structures in the brain that are crucial for motor control. It involves excitatory and inhibitory connections between different brain structures. Striatum - formed by the caudate nucleus and putamen. This is the main input center of the basal ganglia. Receive signals from the cerebral cortex and send inhibitory signals (GABA) to the other parts of the basal ganglia. It’s still under investigation if cognitive disorders such as AD can be treated using DBS. Globus Pallidus Important output structure, sending info from the basal ganglia to the thalamus and other brain regions. Mechanism of action (MoA) - Globus Pallidus externus (GPe): involved in the indirect The process follows several key steps to ensure accuracy and pathway, which inhibits movement effectiveness: - Globus Pallidus internus (GPi): part of the direct pathway, controlling motor output by sending inhibitory signals to 1. Stereotactic frame the thalamus. By securing the patient’s head in the stereotactic frame, which is attached to imaging equipment (MRI, CT-scan), a Subthalamic Nucleus (STN) three-dimensional reference Is involved in the indirect pathway and has excitatory system is created. (glutamatergic) outputs that influence the GPi. This is a key target in DBS for Parkinson’s disease! This system guides the Substantia Nigra precise the placement of - Substantia Nigra pars compacta (SNc): contains electrodes in the brain. dopamine-producing neurons that project to the striatum. This modulates activity in both the direct and indirect pathways, facilitating normal movement. - Substantia Nigra pars reticulata (SNr): Similar to the GPi. It sends inhibitory signals to the thalamus. Pathways There are two pathways within the basal ganglia: Direct pathway Cortex -(excitatory glutamatergic neurons) -> striatum Striatum -(inhibitory GABAergic) -> GPi and SNr GPi and SNr -(inhibitory GABA)-> thalamus Thalamus -> cortex Important key points to remember ○ Glutamatergic STN neurons (from subthalamic nucleus) have primary outputs to the GPi and SNr ○ High-frequency DBS has been shown to alter neuronal activity in all parts of the basal ganglia (including thalamus) ○ In the GPi, STN-DBS causes significant excitation and inhibition in different neurons within the GPi. The firing frequency of these neurons in strongly entrained (synchronized) by the DBS frequency, restoring a more normal pattern of GPi activity. Indirect pathway Cortex -(excitatory glutamatergic neurons) -> striatum Striatum -(inhibitory GABAergic) -> GPe GPe -(inhibitory) -> STN STN -(excitatory) -> GPi and SNr GPi and SNr -(inhibitory GABA)-> thalamus Thalamus -> cortex DBS enhances GABA (inhibitory) signaling in afferent pathways (input signals) and inhibits GPi, helping to reduce overactivity or abnormal firing patterns. DBS also has an effect on neurotransmitters in the efferent pathways (output signals) This helps to modulate mood, movement, and cognitive functions. - Enhances dopamine - Enhanced noradrenaline release from the locus coeruleus (LC) -> STN Axonal response to DBS stimulation 6. Glial modulation DBS may also affect glial cells (non-neuronal cells that provide When a DBS electrode stimulates an axon, both orthodromic and support to neurons), altering their activity. antidromic activation can occur: 7. Blood vessel/BBB effect 1. Orthodromic fiber activation DBS can influence blood flow to certain brain regions. This could This refers to the normal, forward direction of action potential improve oxygen and nutrient delivery to neurons in the conduction along neurons. stimulated area In DBS, electrical stimulation causes action potentials to DBS may also impact the BBB, which regulates what substances travel in the usual direction (cell body -> axon -> synapse), can enter the brain from the bloodstream. which then leads to the release of neurotransmitters and communication between neurons. DBS for PD 2. Antidromic activation This is the opposite of orthdoromic activation. In this case, In a healthy brain, there is a balance between excitatory (red) and action potentials are sent backwards (axon -> cell body). inhibitory (blue) signals in the basal ganglia, which controls movement. By traveling back to the neuron’s cell body, the action potential can influence the neuron’s overall excitability and In PD, the dopaminergic neurons in the SNc degenerate, leading to the timing of future action potentials. reduced dopamine levels. Additionally, in some cases, the antidromic signal may meet Without enough dopamine, the inhibitory signals from the GPi (and an orthodromic action potential traveling from the cell body, SNr) become overactive, leading to excessive inhibition of the causing a collision and potentially cancelling both signals. thalamus and, subsequently, reduced motor output. This can temporarily block the transmission of signals This results in the characteristic motor symptoms of PD: bradykinesia coming from the neuron. (slowness), rigidity, and tremors. The other things that happen when a DBS electrode stimulates an axon are: 3. Entrainment of firing Effect of STN-DBS DBS can entrain (synchronize) the firing rate of neurons, The bold red line in C represents the placement of the electrode in the making them fire at the frequency of the electrical pulses. STN. The electrical impulses from DBS inhibit the hyperactive STN, This can reset abnormal patterns in diseases like Parkinson’s. reducing its excessive excitatory output to the GPi. 4. Depolarization of passing fibers This decreases the inhibitory signals from the GPi to the thalamus, Passing fibers refer to axons that pass near the site of allowing the thalamus to send more balanced signals to the motor stimulation but aren’t directly involved in the local circuits. cortex. DBS can cause depolarization of these fibers, leading to Optimization with directionality action potentials even if the axon isn’t the primary target of Different brain regions respond differently to DBS depending on the the stimulation. location of the stimulating contacts. 5. Neurotransmitter release Primary motor cortex responds more to stimulation near the STN DBS can increase or decrease neurotransmitter release Premotor cortex respons more to stimulation near SNr (GABA, dopamine, NA) , restoring chemical balance and improving symptoms related to neurotransmitter imbalances. Pro’s and cons DBS stimulation for PD has some positive benefits: - Tremor and stiffness reduced - Improved slowness - Dyskinesia/dystonia less severe However, it also has some side effects (which are manageable by optimization): - Muscle pulling (usually face) - Slurred speech - Tingling - Increased dyskinesia Spinal cord stimulation Spinal cord stimulation is a technique used to manage chronic pain by implanting a device that delivers electrical impulses to the spinal cord. The pulse generator sends electrical impulses through the electrodes near the spinal cord (usually in the epidural space). These impulses interfere with the normal processing of pain signals traveling up the spinal cord to the brain. READING TIP: Jakobs et al. 2018. Cellular, molecular, and clinical mechanisms of action of deep brain stimulation Touch and proprioceptive information are usually transmitted by Basal ganglia: Direct and Indirect pathways | Kenhub Aβ fibers (large, myelinated nerve fibers). Due to spinal cord stimulation, these fibers are activated antidromically (brain to spinal cord). This activation can enhance the release of neurotransmitters that activate inhibitory interneurons. The inhibitory interneurons can then inhibit the activity of pain-specific neurons, reducing the transmission of pain signals. Additionally, cerebrospinal fluid (CSF) buffers the stimulation, helping to modulate and distribute the electrical impulses more evenly, which further contributes to the effectiveness of the spinal cord stimulation. BBS3015 - Neurosciences and Control Question 1: Are all values within the normal limits? If not, Practical 2 specify which values. RNFL RNFL thickness The retina is composed of several retinal layers. Normal Measured TS 128 132 All values are within the normal limits :) NS 192 88 N 72 74 NI 103 82 TI 134 125 T 69 68 G 94 90 The retinal nerve fiber layer (RNFL) thickness is typically measured using optical coherence tomography (OCT), a non-invasive Cup-to-Disc Ratio imaging technique. The cup-to-disc ratio is measured by examining the optic nerve Increased thickness: conditions like retinal vein occlusion or head, which is the part of the retina where the optic nerve enters the inflammation eye. This is typically done using fundus photography or OCT. Decreased thinkess: loss of ganglion cells and their axons The ratio is calculated by dividing the diameter of the cup by the (e.g. in glaucoma) diameter of the disc. Normal ratio: around 0.3 to 0.4, though this can vary slightly based on individual anatomy and age Increased ratio: enlarged cup (thinner nerve fiber layer and dead ganglion cells). This is often seen in glaucoma (>0.5) Decreased ratio: less common and may be associated with conditions that lead to optic nerve swelling or increased pressure. Question 2: Are any values suspicious of glaucoma? Explain. No, there are no values that are suspicious of glaucoma. The ratio is less than 0.5. Question 3: Does the ISNT rule apply to your values? Explain Inferior > Superior > Nasal > Temporal No, this rule does not apply in boh eyes. This could be the result of mistakes in doing the measurements, since it was difficult to distinguish the optic cup and disc. IOP Non-Contact Tonometry (Air-Puff Tonometry) is used to flatten the cornea and measure the IOP. Normal IOP: between 10 and 21 mmHg Elevated IOP: significant risk factor for glaucoma. It can also occur due to other conditions, such as steroid use or certain types of eye inflammation Low IOP: can occur in conditions such as ocular hypotony or following certain types of eye surgery Question 4: Are all values within the normal limits? The measured IOP is 17 mmHg. This is within the normal range (10-21mmHg). Yes, the measured IOP is within the normal limits. BBS3015 - Neurosciences and Control Pathophysiology Case 2 In patients with PD, two events are happening in the substantia nigra pars compacta (SNc): 1. Degeneration of dopaminergic neurons in the SNc Parkinson’s disease These neurons release dopamine, which is a hormone and neurotransmitter. It is important for initiating movements. In Parkinson’s, these dopaminergic neurons degenerate and die, Parkinson’s disease is the second most common which leads to movement (initiation) disorders. (this is why when a PD neurodegenerative disease after AD. It is a progressive disorder patient is already moving, he doesn’t have much problems, but when he starts a movement he does) that affects the nervous system and the parts of the body controlled by nerves. Parkinson’s disease results in high rates of disability and the need for care. Many people with AD also develop dementia. Signs & symptoms Parkinson’s disease symptoms can be different for everyone. Early symptoms may be mild and go unnoticed. Symptoms often begin on one side of the body (unilateral) and usually remain worse on that side. Tremor - rhythmic shaking usually begins in a limb, often hand or finger -> pill-rolling tremor (rubbing thumb and forefinger back and forth). Bradykinesia - slow movement, making simple tasks difficult 2. Lewy Bodies (alpha-synuclein) and time-consuming. In PD, abdnormal cytoplasmic deposits known as Lewy bodies Rigidity - stiff muscles can be painful and limit the range of (LBs) are present in specific areas in the brain, particularly in motion. regions involved in movement control (such as SN). Postural instability & balance impairment The primary component of LBs is a protein known as alpha-synuclein, a protein ubiquitously expressed in the brain, Dyskinesia - involuntary movements with high concentrations at synapses. Dystonia - painful muscle contractions In Parkinson’s disease, alpha-synuclein misfolds, adopting a Hypomimia - ldecrease in facial expression beta-sheet conformation (instead of maintaining its normal Loss of automatic unconscious movements, such as blinking, alpha-helical structure). smiling, chewing (hypophagia), or swinging the arms when The beta-sheet structures are more prone to aggregation, and walking (gait) these misfolded alpha-synuclein proteins start to accumulate in Hypophonia (speech changes) - speaking softly, quickly, slur, clumps. These aggregates then form Lew bodies. or hesitate before talking. It may also become more of a The process of alpha-synuclein monotone. aggregation disrupts normal cellular Cognitive impairment functions, contributing to the progressive loss of dopaminergic neurons. Depression The cellular effects: Sleep disorders - Mitochondrial disfunction - ER stress - Proteolysis - Neuro inflammation - Increased oxidative stress - Lysosome dysfunction - Synapse dysfunction These build up and then leads to the cellular dysfunction Braak stages (spread of Lewy Bodies) Indirect pathway ○ Stage 1 & 2 - Premotor stages (non-motor symptoms) 1. Input Lewy bodies first appear in the olfactory bulb (loss of smell), Cortex -(excitatory glutamatergic neurons) -> striatum medulla oblongata (especially the vagus nerve), and parts Striatum -(inhibitory GABAergic) -> GPe of the autonomic nervous system. GPe -(inhibitory) -> STN ○ Stage 3 & 4- Early motor stages (classical motor symptoms) STN -(excitatory) -> GPi and SNr Disease progresses to the midbrain, particularly the 2. Output substantia nigra. There is also spread to the amygdala, pons, GPi and SNr -(inhibitory GABA)-> thalamus and other areas of the brainstem. Thalamus -> cortex ○ Stage 5 & 6 - Advanced motor and cognitive stages Additionally, the dopaminergic The lewy bodies are spread throughout the brain to cortical neurons in the SNc will bind to D2 regions, leading to severe emotional and cognitive decline. (inhibitory) receptor on the striatum Basal ganglia pathways Interpretation: the role of disinhibition The basal ganglia are a group of nuclein that fine-tune the In a normal, healthy situation, the dopaminergic neurons in the SNc voluntary motor activity. will release dopamine, which binds to the striatum by either: Cerebral cortex (motor) -> basal ganglia -> thalamus -> motor D1 (excitatory, direct pathway) receptor cortex -(spinal cord) -> muscles In this case, the GABAergic neurons in the striatum are In PD, there is a problem in the output from the basal ganglia to stimulated, leading to more inhibition of the GABAergic neurons the thalamus. in the GPi and SNr. There are two pathways within the basal ganglia. Since the GPi and SNr normally inhibit the thalamus, their inhibition (by the striatum) results in disinhibition of the Direct pathway thalamus, meaning it becomes more active. 1. Input Cortex -(excitatory glutamatergic neurons) -> striatum -> greater facilitation of movement Striatum -(inhibitory GABAergic) -> GPi and SNr D2 (inhibitory, indirect pathway) receptor 2. Output In this second case, the GABAergic neurons in the striatum are GPi and SNr -(inhibitory GABA)-> thalamus inhibited, which reduces inhibition of the GPe (disinhibition), Thalamus -> cortex allowing it to inhibit the STN more strongly. Additionally, the dopaminergic neurons in the SNc will bind to D1 Less STN activity means less excitation of the GPi/SNr, leading to (excitatory) receptor on the striatum less inhibition of the thalamus, meaning it becomes more active. Basal ganglia in PD In PD, the balance between the direct and indirect pathway is disrupted due to the loss of dopaminergic neurons in the SNc. This leads to decreased dopamine levels in the striatum. The indirect pathway’s influence becomes more pronounced, resulting in excessive inhibition of the thalamus and overall reduced facilitation of movement. Direct pathway (D1 receptor) Reduced dopamine -> less stimulation of D1 receptors -> Less excitation of striatal GABAergic neurons -> less inhibition of GABAergic neurons in GPi and SNr -> GPi and SNr continue to inhibit the thalamus -> reduced facilitation of movement Histology Indirect pathway (D2 receptor) In a healthy brain, the substantia nigra, particularly the pars Reduced dopamine -> less inhibition of D2 receptors compacta, appears darkly pigmented due to the presence of -> more inhibition of striatal GABAergic neurons (overactive) neuromelanin, which is a byproduct of dopamine metabolism. -> less inhibition of GPe -> more inhibition on STN The Locus Coeruleus, a small nucleus in the brainstem, also shows a -> less ecitation of the GPi/SNr dark pigment due to the presence of neuromelanin. -> Excessive inhibitory input to thalamus In PD, There is a loss of pigmentation in both the SNc and Locus -> Reduced facilitation of movement Coeruleus due to the loss of dopaminergic neurons. So on histological slides, both brainstructures will appear less pigmented or paler Biomarkers in PD compared to a healthy brain. Clinical biomarkers in PD Fluid markers in PD - CSF Parkinson’s disease is mostly diagnosed by clinical biomarkers. Fluid biomarkers are increasingly being studied in Parkinson’s disease Clinical diagnosis of PD typically revolves around motor to aid in diagnosis and monitor disease progression. These markers symptoms such as tremors, bradykinesia, rigidity, and postural can be found in CSF, and, more recently, in blood. instability. In the CNS, decreased levels of alpha-synuclein are measured in However, there are also some non-motor symptoms such as patients with AD. The total alpha-synuclein levels in CSF will be sleep disturbances, mood changes, cognitive impairment, and reduced in PD patients because the protein is sequestered in Lewy autonomic dysfunction (such as constipation). These are used for bodies in the brain. tracking disease progression. This alpha-synuclein levels are measured by seeding ampliciation Biomarkers like REM sleep behavior disorder (RBD) and hyposmia assay. (olfactory dysfunction) often appear years before motor symptoms and are considered early clinical indicators. Seeding amplification assay The seeding amplification assay (SAA) is a sensitive diagnostic Imaging biomarkers in PD - PET method used to detect misfolded proteins, such as alpha-synuclein. Pet-scans are not that common for PD diagnosis, as usually clinical biomarkers are used. The concept behind this assay is that misfolded proteins, which aggregate into pathological forms, can act as ‘’seeds’’ to trigger the Two primary imaging techniques used for diagnosis and misfolding and aggregation of normal proteins in a controlled monitoring PD are: laboratory setting. DaT-SPECT scan - measures the dopamine transporters How it works: (DaT) in the brain The sample (SCF), containing the misfolded proteins, is obtained F-DOPA PET scan - measures the synthesis and storage of from the patient dopamine in the brain, providing more detailed and The sample is then mixed with nomal, soluble forms of the same quantitative insights pinto dopamine system dysfunction. protein (alpha-synuclein). Fluorodopa (F-DOPA) is a radiolabeled form of the precursor This mixture is subjected to cycles of shaking and incubation, to dopamine (L-DOPA). By tracking how F-DOPA is taken up which promotes the interaction between the misfolded seed and converted into dopamine in the brain, researchers can proteins and the normal proteins, causing the normal proteins to assess the function of dopaminergic neurons. misfold and aggregate. Over time, the aggregates grow, amplifying the signal of the misfolded protein  The T50 value is a key metric in this aggregation study. T50 is the time Using fluorescence based techniques (thioflavin T it takes for 50% of the protein or biomarker to aggregate. It essentially fluorescence) which binds to the misfolded protein measures the time required for half of the protein in the sample to aggregates and emit a detectable signal. form aggregates. If aggregation occurs, the sample is considered positive for In PD, the aggregation of alpha-synuclein is faster, thus the T50 will be the presence of misfolded alpha-synuclein lower compared to a healthy person. The phases of seed amplification assay: 1. Lag phase or nucleation phase Risk factors During this phase, there is no observable aggregation. Genetic risk factors (10% of cases) Instead, small misfolded protein pieces (nuclei) are forming. Having a first-degree relative (parent, sibling) with PD, increases the risk of developing it. Genetic mutations: 2. Elongation phase or growth phase SNCA: autosomal dominant mutation in alpha-synuclein gene Once enough nuclei have been formed, there is a rapid PRKN: autosomal recessive mutation in the Parkin gene increase in the amount of observable aggregates, resulting in the formation of fibrils. Non genetic risk factors: 3. Stationary phase - Age The consumption of substrate slows down the aggregation - Gender: men are affected more often than women. (nuclei are used up), and the solution enters an equilibrium - Exposure to toxins such as air pollution and pesticides in which there is no further change in aggregation. - Head trauma If a (pre-formed) seed is added to the aggregation process, the - Lifestyle factors such as poor diet, high levels of stress, and low lag phase is decreased significantly, because the reaction level of physical activity bypasses the formation of nuclei. So, the more seeds there already are, the faster the process will Treatment be. In patients with PD, there are more seeds already in the Although Parkinson’s disease cannot be cured, medicines might sample, thus the process will be faster. significantly improve the symptoms. Levodopa is a precursor to dopamine. It is used because dopamine itself cannot cross the blood-brain barrier (BBB), but levodopa can. Once in the brain, levodopa is converted into dopamine, helping to alleviate symptoms of Parkinson’s disease. Common side effects of levodopa are: ○ Nausea and vomiting: due to dopamine’s effects on the GI ○ Dyskinesia: due to high levels of levodopa in the brain ○ IOP Most side effects occur when the levodopa or dopamine leaves the brain and enters the peripheral tissues. Carbidopa is often combined with levodopa to prevent premature conversion of levodopa into dopamine outside the brain (such as in the intestines). This ensures more levodopa reaches the brain and reduces peripheral side effects. Over time, the effectiveness of levodopa can diminish, leading to fluctuations in symptom control. Side effects may increase. The reaction happens in cycles of fragmentation and elongation. Fragmentation: Increases the number of seeds. By breaking down large alpha-synuclein aggregates into smaller fragments. These smaller fragments act as new seeds that can start the aggregation process again. Elongation: Growth of new aggregates from the fragments This cyclic process amplifies the aggregates, making them easier to detect (by thioflavin T fluorescence). In PD, due to more seeds, the recombinant is used up faster, so the cycling ends faster. Additional medications Resources The best effect is to combine levodopa with these additional - Parkinson's disease - Symptoms and causes - Mayo Clinic medications: - Parkinson disease (who.int) MAO-B inhibitors - Parkinson Disease Epidemiology, Pathology, Genetics and These block the enzyme that bre