Neuro-Pathology I: Neurodegenerative Diseases PDF

Neuro-Pathology I: Neurodegenerative Disorders Joshua Mastin, MD South College School of Pharmacy Neurodegenerative Disorders, General Neurogenerative disorders, in general, classically result in a qualitative and/or quantitative loss of functional neurons throughout the neuroaxis (central...

Neuro-Pathology I: Neurodegenerative Disorders Joshua Mastin, MD South College School of Pharmacy Neurodegenerative Disorders, General Neurogenerative disorders, in general, classically result in a qualitative and/or quantitative loss of functional neurons throughout the neuroaxis (central, peripheral nervous systems). This loss of neurons can be characterized by: Demyelination of neurons Impairment of neurotransmitter transmission across the synaptic cleft Impairment of inter-neuronal connections (e.g., axo-dendritic connections, axo-axonic connections, axo-somatic connections) Impairment of homeostatic feedback mechanisms within the central nervous system (i.e., an inability to induce negative/positive feedback) Chronic imbalance in electrolyte concentrations (especially sodium and potassium, which are intimately involved with the neuronal action potential)—MORE ON THIS LATER! Realistically most neurodegenerative disorders are MULTI-FACTORIAL, meaning that many of the factors listed above could be involved with the development of pathophysiologic disease manifestations! Demyelination of Myelinated Neuron Neurons RECALL: myelin sheath = glycolipid + protein-based structure which encapsulates the axon of the neuron Myelin is an insulative substance (remember, insulators downregulate the transmission of charge through them); due to the insulating nature of myelin, positive charge (produced by the nerve action potential) “skips” around myelin sheath and jumps form “node” to “node” (nodes = Nodes of Ranvier) saltatory conduction (significantly faster transmission of charge than unmyelinated neurons!) Demyelination of neurons decreased transmission of electrical information decreased activation of structures/centers which involve myelinated neurons Causes of Demyelination Vascular Ischemic damage, resulting in hyper-inflammation Infectious Mostly viral, but can be caused by parasites and bacteria HIV/AIDS can induce demyelination secondary to opportunistic infections (most commonly Cytomegalovirus, which also causes retinitis-associated blindness) JC Virus a polyoma-virus which leads to progressive multifocal leukoencephalopathy (PML) Herpesviruses classically reside within the CNS; can lead to demyelination of bilateral temporal lobes Epstein-Barr Virus STRONG association with multiple sclerosis Borrelia Burgdorferi (Lyme Disease) peripheral neuropathy in late stages Treponema Pallidum (Syphilis) Tabes Dorsalis (demyelination of dorsal columns proprioceptive difficulties) Measles causes a lethal demyelinating process known as sub-acute sclerosing panencephalitis which leads to frontal lobe destruction Inflammatory/Autoimmune Adaptive immune cells more highly involved Guillain-Barre Syndrome auto-antibodies which target gangliosides in myelin loss of reflexes (areflexia) + muscle weakness ADEM (Acute Disseminated Encephalomyelitis) classically follows very severe viral infections (RSV, Sars-CoV-19, Norovirus, etc.) Accumulation of abnormal proteins activation of the immune system, which targets these proteins Multiple Sclerosis Type IV Hypersensitivity Reaction-like syndrome (CD8 T cells, NK cells, macrophages), along with oligoclonal IgG formation Causes of Demyelination Metabolic/Vitamin Deficiency Vitamin B12 Deficiency peripheral neuropathy, pernicious anemia Diabetes Mellitus Diabetic neuropathy, which primarily affects peripheral NS; also, retinopathy Illicit Drugs/Alcohol Chronic Alcohol consumption both CNS and PNS demyelination Heroin, Opioid abuse potentially lethal demyelination of brainstem nuclei, resulting in autonomic instability Pharmacologic Agents Isoniazid Peripheral neuropathy secondary to pyridoxine deficiency (REMEMBER: low pyridoxine increased accumulation of glutamate, decreased conversion of glutamate to GABA glutamate-induced peripheral neuropathy) Chemotherapeutic agents Vinblastine, Vincristine Cisplatin (platinum-based drugs such as these can activate neuroglial cells, which secrete pro-inflammatory cytokines resulting in demyelination)  Impaired Neurotransmitter transmission RECALL: in response to an action potential, positive electric current is transmitted down the axon of the neuron to the synaptic cleft, which consists of 3 key structural components: Pre-synaptic neuron releases neurotransmitter (REMEMBER: neurotransmitter release is HIGHLY DEPENDENT ON CALCIUM!) Vesicular docking + release of neurotransmitter through voltage-gated calcium channels Synaptic Cleft “space” between the pre-synaptic neuron and post-synaptic neuron/structure; often contains enzymes which aid in regulation of neurotransmitter activity (e.g., acetylcholinesterase, monoamine oxidase) Post-synaptic Neuron/Structure contains receptors for the neurotransmitter Aberrations in one or more of these 3 structural components impaired neurotransmitter transmission pathophysiologic disease processes Destruction of the pre-synaptic neuron decreased NT release Increased presence of proteolytic enzymes within synaptic left increased breakdown of NT, decreased availability for physiologic effect Destruction of NT receptors in the post-synaptic neuron Impairment of Inter-Neuronal Connections Impaired connectivity among neuronal systems throughout the CNS and PNS can predispose to a loss of viable neurons and, therefore, neurodegenerative disease AS A REVIEW: remember that though axodendritic connections are the most common, axosomatic connections are by far the strongest! Due to the fact that the axon hillock (located in the soma, at the take-off point of the axon) is the most highly excitable portion of the neuron! Failure of Homeostatic Feedback Mechanisms RECALL: Many features of the CNS and PNS are dependent upon negative feedback mechanisms, which help in the downregulation of excessive stimulation The most prominent locations for this within the neuroaxis are the hypothalamus and pituitary gland (anterior), where hormones can affect their expression by inhibiting the hypothalamus (or anterior pituitary gland) Certain cortical/subcortical structures provide important negative feedback responses to modulate a plethora of functions: Basal Ganglia (Caudate, Putamen, Subthalamic nuclei, substantia nigra, globus pallidus) Limbic Cortex (projections throughout the frontal and parietal cortices) Predictably, failure of these negative feedback mechanisms can result in large-scale consequences within the CNS! Important Neurodegenerative Diseases to Focus On: Parkinson’s Disease Huntington’s Disease Amyotrophic Lateral Sclerosis Parkinson’s Disease, General Parkinson’s Disease neurodegenerative disease which involves both motor and non-motor phenotypes Epidemiology mean age of diagnosis is 70 years of age, with a slight, statistically insignificant predilection toward Hispanic males; approximately 90-100,000 cases per year Parkinson’s Disease is highly characterized as a disease with both genetic and epigenetic contributors “Contributors” is used here because in most patients, there isn’t just ONE CAUSE! Parkinson’s Disease, General Parkinson’s Disease is considered an “idiopathic” disease given that there is no known distinct cause. There are SEVERAL FACTORS which are highly correlated with the diagnosis (which may have a synergistic function when more than one factor is present): Genetic If a first-degree relative has PD, then their offspring are 2-3x more likely to develop it; several polymorphisms are involved Environmental Exposures to: Large amounts of air pollution Pesticides, agricultural work Consumption of well water (very common in southeastern US) Excessive consumption of dairy products Exposure to, or use of, strong hydrocarbon-based solvents for cleaning Co-existent Medical/Pathologic Disease States: Metabolic Syndrome (Obesity, Type II DM, other causes of hypercholesterolemia) History of repeated bouts of TBI (e.g., boxers, MMA fighters, football players) possible association with CTE? Cancer (melanoma, colon, prostate, and breast are most commonly correlated) Long-standing/Inadequately treated Depression/Anxiety Anatomy of the Basal Ganglia, Striatum The basal ganglia is an important network of subcortical (deep within the cortex) neurons which are highly involved with neuronal connections to a plethora of locations throughout the CNS: Frontal Cortex personality, emotional lability (due to limbic cortical inputs), concrete reasoning, motor production of speech (Broca’s Area), Primary Motor Cortex Parietal Cortex philosophical reasoning, abstract reasoning, speech interpretation and appropriate output (Wernicke’s Area), Primary Somatosensory Cortex Limbic Cortex Emotion, Fear/Aggression (via input from the amygdala), memory (hippocampus) The basal ganglia consists of the following important centers: Globus Pallidus Substantia Nigra Subthalamic Nuclei Striatum (Caudate, Putamen) Anatomy of the Basal Ganglia, Striatum The striatum (caudate, putamen) and basal ganglia interact with each other via cross-talk with neurotransmitters, particularly GABA and glutamate. ULTIMATELY the basal ganglia, along with the substantia nigra, modulates signals (either excitatory or inhibitory) to the thalamus and motor areas of the frontal cortex and, therefore, play important roles in motor coordination! REMEMBER: GABA is inhibitory Glutamate is excitatory Dopamine is critically important within these interactions, as it can either be excitatory or inhibitory depending on: 1) the dopaminergic receptor involved; 2) the location of dopamine release. Anatomy of the Basal Ganglia, Striatum The basal ganglia and substantia nigra modulate movement via two distinct pathways: an indirect pathway and a direct pathway. BOTH are highly dependent on dopamine! Indirect Pathway LEADS TO THE INHIBITION OF MOVEMENT! 1) Striatum receives excitatory input from the motor cortex in the frontal lobe (glutamate). NEGATIVE FEEDBACK OF THE STRIATUM: Dopamine binds to D2 receptors in striatum, which are inhibitory (meaning that it reduces GABA release from the striatum) leads to DECREASED INHIBITION OF THE GLOBUS PALLIDUS, EXTERNAL SEGMENT DECREASED SUBTHALAMIC NUCLEUS ACTIVITY DECREASED ACTIVATION OF GpiDECREASED THALAMIC INHIBITION INCREASED ACTIVATION OF MOTOR AREAS IN THE CEREBRAL CORTEXleads to increased movement! II) Stimulation of the striatum results in GABA transmission to the globus pallidus, external segment (GPe). III) The GPe binds GABA and becomes inhibited; this inhibition of the GPe ultimately leads to INCREASED activation of the subthalamic nucleus (which releases glutamate) and, therefore, globus pallidus, internal segment (GPi). IV) The GPi, when activated, will release GABA on to the thalamus (ONLY THE NUCLEI INVOLVED WITH MOVEMENT CONTROL); this, effectively, will result in DECREASED EXCITATION OF MOTOR AREAS IN THE BRAIN Anatomy of the Basal Ganglia, Striatum Direct Pathway LEADS TO THE INITIATION/POTENTIATION OF MOVEMENT! I) The striatum, upon receiving excitatory stimulation (glutamate) from the cortex OR the substantia nigra (pars compacta) releases GABA onto the Gpi and substantia nigra (pars reticulata). Unlike the Indirect Pathway dopamine from the substantia nigra, pars compacta, binds to D1 receptors, which largely promotes excitation/initiation of movement! II) The binding of GABA to the Gpi, as before, is inhibitory; under normal conditions, this prevents the Gpi from releasing GABA onto the thalamus. III)Due to the inhibition of Gpi (and, therefore, the release of GABA by Gpi), thalamic neurons which project to the motor cortex in the frontal lobe are LESS INHIBITED, meaning that they can fire more freely to the cortex and promote the initiation of movement! Parkinson’s Disease, Pathophysiology Parkinson’s Disease is highly characterized as destruction of the substantia nigra (specifically, the pars compacta). This affects both the direct and indirect pathways. Effects of substantia nigra degeneration (diminished dopamine production) within the direct pathway decreased D1 receptor activation, resulting in decreased inhibition of the striatum increased Gpi activity, resulting in increased GABA release onto thalamus decreased thalamic activation decreased supplemental motor cortex activity, decreased ability to initiate movements Effects of substantia nigra degeneration (diminished dopamine production) within the indirect pathway decreased D2 receptor activation, resulting in increased GABA release from the striatum (remember, the D2 receptor is inhibitory, so less dopamine = less inhibition) increased activity of the Gpe, resulting in DECREASED GABA release onto the subthalamic nucleus increased subthalamic nucleus activity, resulting in increased Gpi activation + thalamus activation decreased supplemental motor cortex activity, decreased ability to initiate movements As disease progresses neurodegeneration leads to the development of abnormally folded proteins known as Lewy Bodies (misfolding of alpha-synuclein). These Lewy Bodies can be neurotoxic and can translocate to the cerebrum and limbic cortex, resulting in dementia Lewy Body Dementia, often a late stage finding in Parkinson’s Disease Parkinson’s Disease, Pathophysiology PET scan (positron emission tomography) demonstrating increased microglial activity within the basal ganglia and substantia nigra, suggestive of Parkinson’s Disease Parkinson’s Disease, Clinical Phenotypes Motor Findings usually manifest first Bradykinesia slowness of movements Decreased ability to initiate movements due to rigidity Resting tremors Gait abnormalities (Shuffling gait) Hypophonia (talking low) Non-Motor Findings usually manifest in advanced disease Masked facial expression (looking bored or unimpressed) hypomimia Akathisia (feeling as if one HAS TO BE MOVING) Dementia hallucinations (usually visual), anxiety [can occur either due to the disease process OR as a side effect of the pharmacologic therapy!] Memory Loss Anterograde, Retrograde Parkinson’s Disease, Management Pharmacologic Therapy Levodopa + Carbidopa --> Levodopa precursor of dopamine which is capable of crossing the blood-brain barrier and being converted to dopamine in the brain via dopa decarboxylase. Carbidopa Peripheral dopa-decarboxylase inhibitor; PREVENTS the breakdown of levodopa in the peripheral tissues, reducing the adverse reactions associated with excessive dopamine AND increasing bioavailability of levodopa in the brain Dopaminergic Agonists can sometimes aid in the restoration of balance within the indirect and direct pathways Pramipexole, Ropinirole non-ergot based Bromocriptine ergot-based; significantly more concerning side effect profile! Rarely used except as last resort! MAOI (Monoamine oxidase inhibitors), specifically MAO-B inhibitors_ downregulation of MAO-B mediated dopamine breakdown, promoting increased dopamine levels Selegiline, Rasagiline Amantadine Unique because it enhances dopamine release + INHIBITS glutamatergic effects Parkinson’s Disease, General Protective Factors (reduce development and/or severity of disease progression) SMOKING (nicotine cigarettes; vapes still up for debate) Nicotine appears to have a neuroprotective functionality; HOWEVER, randomized clinical trials utilizing nicotine alone have not shown statistically significant trends in PD risk reduction, suggesting that perhaps there may be something else in the tobacco plant that induces this effect Caffeine Adenosine A2A receptor antagonist, which aids by: increasing/potentiating dopaminergic activity in the basal ganglia Decreasing the activation of microglial cells within the basal ganglia, resulting in decreased inflammation and preservation of substantia nigra dopaminergic neurons Exercise reduction of inflammation GLP-1 agonists (Semaglutide) possibly helpful, though clinical trials have not demonstrated a statistically significant trend sufficient to support their use for PD management Huntington’s Disease, General Huntington’s Disease can be characterized as progressive neurodegenerative disease which is highly based on heredity. Inherited in an autosomal dominant pattern (meaning that either parent can transmit the disease if he/she is carrying one copy of the mutated gene). Mutation associated with Huntington’s Disease CAG Trinucleotide repeats (cytosine – adenine – guanine) in the HTT gene on chromosome 4. which corresponds to the formation of an abnormal protein known as Huntingtin. More copies of CAG = earlier onset + increased severity of the disease! Normally, most individuals have < 26 CAG copies in their genome. With each successive generation, however, the number of CAG trinucleotide repeats increases, until at some point, the mutation randomly “drops” (meaning that it doesn’t show up). Slightly more common in males, though worse phenotypes seen in females Huntington’s Disease, Pathophysiology CAG trinucleotide repeats (on chromosome 4) accumulation of Huntingtin protein CAG encodes the amino acid glutamine (denoted by the letter Q) Multiple CAG trinucleotide repeats formation of large Huntingtin (PolyQ, or polyglutamine) proteins. Why is this harmful? Huntingtin accumulation disrupts multiple critical cellular functions! Disrupts transcription of important neuronal proteins, most notably BDNF (brain- derived neurotrophic factor), which promotes neural plasticity and regeneration of neurons Impairs mitochondrial function increases the damage of oxidative stress secondary to microglial cell activation Disrupts axonal transport of both electrolytes and vesicles containing neurotransmitters Disrupts lysosomal degradation of damaged/aged/dysfunctional organelles and proteins/enzymes Huntingtin also increases NMDA (glutamate) receptor expression promotes glutamate- mediated toxicity of neurons Huntington’s Disease, Pathophysiology Which portions of the brain are most highly affected by Huntington’s Disease? The striatum (caudate, putamen nuclei) undergo atrophy due to the loss of neurons secondary to Huntingtin protein accumulation + death secondary to oxidative stress in the early stages of the disease. Over time, the limbic and cerebral cortices are also affected! On imaging enlargement of the lateral ventricles is seen! How does the degradation of the striatum (caudate and putamen nuclei) affect neuronal/cerebral function? Indirect Pathway Usually in the early phases destruction of the striatum decreased release of GABA onto Gpe INCREASED inhibition of subthalamic nuclei decreased glutamate release from subthalamic nuclei onto Gpi decreased inhibition of thalamus, which leads to hyperkinetic phenotypes (chorea, athetosis) Chorea Dance-like flailing motions Athetosis Writhing, worm-like movements with the limb or trunk Direct Pathway Prominent in late phases; results in BRADYKINESIA, RIGIDITY! Huntington’s Disease, Pathophysiology Non-Motor manifestations of Huntington’s Disease Disruption of striatal neurons projecting to the frontal cortex lack of behavioral/social inhibitions Disruption of striatal neurons projecting to the occipital cortex visuospatial deficits (knowing where objects/people are in space, inability to discriminate the size/depth of a room/area) Disruption of striatal neurons projecting to limbic cortex, hippocampus neuropsychiatric deficits, dementia Anterograde, retrograde memory loss Increased irritability, aggression Depression, Anxiety, schizoaffective disorder (schizophrenia + depression) Impulsivity Disruption of striatal neurons to the brainstem, pineal gland sleeping difficulties, insomnia, autonomic instability Huntington’s Disease, Management Pharmacologic Management: Tetrabenazine Prevents dopaminergic effects via two mechanisms: 1) preventing dopamine packaging into pre-synaptic vesicles (meaning that it can’t be released from the neuron); II) competitive antagonism of dopamine receptors on the post- synaptic neuron, resulting in decreased responsivity to dopamine Why would tetrabenazine aid in the management of Huntington’s Chorea? Decrease in dopamine decreased D2 binding of dopamine in the striatum decreased indirect pathway activity (i.e., decreased inhibition of Gpe increased activity of subthalamic nucleus increased Gpi activity, resulting in increased GABA release increased inhibition of thalamus+cortex) decreased hyperkinetic features (chorea, athetosis) Because it primarily affects the indirect pathway not as useful for late stage Huntington’s! CAN increase risk of suicidal ideation; use with caution! Neuroleptics/Antipsychotics Can aid in management of agitation and choreiform movements; also aid with sleep Olanzapine/Quetiapine blocks dopamine (D2) and serotonin (5-HT2A) receptor Late Stage Management (Bradykinesia, rigidity) Levodopa/Carbidopa, Amantadine Genetic Counseling should be discussed! Amyotrophic Lateral Sclerosis, General Amyotrophic lateral sclerosis (ALS), or Lou Gehrig’s Disease, is a unique cause of progressive neurodegenerative disease. Unlike Huntington’s Disease and Parkinson’s Disease, ALS typically results in upper motor neuron (neurons in the brain) and lower motor neurons (those deriving from the spinal cord/brainstem and projecting to other tissues). Very little has yet to be elucidated regarding the exact pathophysiologic mechanism, though many models have been proposed. Epidemiology: 90-95% of cases are sporadic (random); more commonly affects Caucasian males in their 70’s; slightly more common in those who have histories of working in construction/electrician jobs, military, or around strong electromagnetic fields/nuclear plants Amyotrophic Lateral Sclerosis, Pathophysiology Proposed mechanisms of ALS development: Glutamate Toxicity Mitochondrial Dysfunction with increased oxidative stress Axonal Transport Dysfunction Hyperactivation of microglial cells secondary to increased pro-inflammatory cytokine expression Amyotrophic Lateral Sclerosis, Pathophysiology Glutamate Toxicity due to increased expression of NMDA receptors that bind glutamate Increased binding of glutamate by NMDA receptors increased calcium influx into the neuron calcium induces mitochondrial damage, organelle dysfunction, and can activate pro- apoptotic enzymes resulting in neuronal death Mitochondrial Dysfunction due to mutations in the SOD1 gene, resulting in decreased expression of functional superoxide dismutase 1(SOD1) + misfolded protein aggregates of nonfunctional SOD1 Under normal conditions superoxide dismutase 1 (SOD1) destroys free radicals, thus reducing oxidative stress and oxide-mediated destruction of cellular proteins and organelles Due to inactivating mutations of the SOD1 gene decreased expression of functional SOD1 promotes increased free radical and ROS (reactive oxygen species) presence, resulting in mitochondrial dysfunction MOREOVER the dysfunctional SOD1 (due to the mutation) can aggregate, forming units of neurotoxic aggregates which can further destroy neurons Axonal Transport Dysfunction Axonal transport requires ATP, which is primarily produced at the level of the mitochondrion; mitochondrial dysfunction secondary to oxidative stress decreases axonal transport and action potential propagation, which can affect large portions of the CNS Increased Microglial Cell Activation secondary to Pro-Inflammatory Cytokines Amyotrophic Lateral Sclerosis, Pathophysiology Clinical Phenotype: both upper motor neuron and lower motor neuron symptoms! Upper Motor neuronal symptoms Hyperreflexia, increased spasticity (stiffness/tightness of muscles), Uncontrollable laughing/crying Lower Motor neuronal symptoms Muscle atrophy (due to gradual denervation secondary to neuronal death), muscle twitches due to abnormal discharges from damaged neurons, muscle weakness which evolves to complete muscle paralysis, gradual loss of reflexes (areflexia) Other symptoms (usually seen in late stages) slurred speech which evolves to a complete loss of vocalization, difficulty swallowing, tongue atrophy with fasciculations, various cognitive difficulties Most common cause of death: Respiratory Failure (and consequences of respiratory failure) Amyotrophic Lateral Sclerosis, Management Pharmacologic Management: Riluzole blocks glutamate transmission via two mechanisms: 1) Stabilizes the voltage- gated sodium channels on glutamatergic neurons, preventing depolarization of these neurons and, therefore, release of glutamate onto NMDA receptors; and 2) serves as a NON-competitive antagonist of the NMDA receptor post-synaptically Why does this work? Decreased release of glutamate + decreased binding of glutamate to NMDA receptors = decreased free radical formation, decreased mitochondrial damage, promotes neuronal survival Survival benefit! Prolongs survival by 4-6 months and reduces the progression to respiratory failure Edaravone exact mechanism is unknown, but known to be a fantastic free-radical scavenger; by destabilizing free radicals and ROS, reduces oxidative damage to neurons EXCELLENT adjunctive therapy with riluzole! Tofersen ONLY USED IN SOD1-ASSOCIATED ALS! Functions by decreasing protein synthesis of abnormal SOD1, resulting in decreased accumulation of dysfunctional SOD1 aggregates and, therefore, decreased neuronal death