Schizophrenia Symptoms Quiz

BMS 200 - Week 6 Cardiology E-learning

• Cardiomyopathies and atherosclerosis pathogenesis is the focus of this session.
• Outcomes include: epidemiology, pathogenesis, clinical features, and prognosis of cardiomyopathies (hypertrophic, dilated, restrictive).
• Pathogenesis of atherosclerosis and unstable plaque formation, with a focus on lipoprotein A (Lp(a)) biology, metabolic syndrome, and plaque instability factors.

The Cardiomyopathies

• Cardiomyopathies target cardiac myocytes or the extracellular tissue in the myocardium.
• Major cardiomyopathies include dilated cardiomyopathies (caused by genetic deficits in sarcomere proteins, and acquired from infections, inflammation, or toxic agents).
• Hypertrophic cardiomyopathy (genetic deficits in sarcomere proteins).
• Restrictive cardiomyopathy (related to abnormal deposition of extracellular material).

Hypertrophic Cardiomyopathy

• Often abbreviated as HOCM ("O" for obstructive).
• The septum is usually thickened, restricting blood flow to the left ventricle.
• The entry to the aorta is blocked by the septum.
• One of the more common autosomal dominant disorders.
• Prevalence is approximately 1 in 500.

Hypertrophic Cardiomyopathy (General Pathogenesis)

• If sarcomere proteins, such as myosin, are implicated, mutations can lead to gain-of-function mutations.
• The mechanism of hypertrophy isn't fully understood.
• Myocytes are disorganized in orientation.
• Diagram B shows septal overgrowth (diagram A).

Hypertrophic Cardiomyopathy (Clinical Features)

• Many individuals are asymptomatic. This makes diagnosis difficult; it can be life threatening.
• A major cause of sudden cardiac death or arrest. This can occur due to abnormal heart rhythms.
• As the patient ages, angina, shortness of breath, and syncope may be more prevalent.
• Syncope is sudden loss of consciousness due to global impairment of blood flow to the brain.
• Over time, HFpEF (heart failure with preserved ejection fraction) may develop.

Dilated Cardiomyopathy

• Most common cardiomyopathy. However, it's not a fair evaluation since many are involved.
• Toxicities include alcohol use, excessive catecholamines (including situations that create a strong stress response), and cancer therapies.
• Peripartum cardiomyopathy is a specific genetic form.
• Genetic causes, in general, include autosomal and sometimes X-linked mutations in proteins supporting the sarcomere (dystrophin, titin, actinin) or related to contraction (tropomyosin, troponins, myosin).
• Inflammatory causes, including infections and sarcoidosis, which is discussed further in BMS 250.

Dilated Cardiomyopathy (Clinical Features)

• Patients can be asymptomatic until heart failure symptoms appear.
• Typical heart failure symptoms include fatigue, shortness of breath, and swelling in the lower extremities.
• Severe ventricular enlargement can obstruct the mitral valve.
• Palpitations and syncope (brief loss of consciousness) can occur due to dysrhythmias.
• Acquired conditions of DCM can sometimes reverse if the initial insult is removed. If the underlying cause cannot be resolved, the prognosis is more serious; DCM is a frequent indication for heart transplantation.

Dilated Cardiomyopathy (Echocardiography)

• The heart is massive (up to 2 or 3 times the weight of a healthy heart).
• Ventricles are usually more dilated than atria.
• Heart wall appears weak.
• Dilated ventricles can cause leakage at the atrioventricular valves (AV valves).

Restrictive Cardiomyopathy

• The least common of the three cardiomyopathies.
• Markedly higher mortality.
• Typically isolated diastolic dysfunction; stroke volume is often normal.
• The cause is poorly understood, but many are autosomal dominant mutations.
• Secondary causes include conditions extrinsic to the heart system itself, such as amyloidosis and hemochromatosis.

Restrictive Cardiomyopathy (Pathogenesis)

• Some are related to autosomal dominant mutations, and the contribution to the pathogenesis isn't well understood.
• Most are secondary conditions extrinsic to the heart system.
• Amyloidosis - protein accumulation in various tissues.
• Other factors discussed include beta-pleated sheet accumulation from liver or abnormal antibody fragments from myeloma proteins, reducing ventricular compliance.
• Hemochromatosis - iron accumulation in cardiomyocytes.
• Sarcoidosis - chronic condition with granulomatous inflammatory reaction.

Atherosclerosis - Pathogenetic Mechanisms

• A multifaceted disorder.
• Unique across individuals based on environmental and genetic factors.
• The contributions of systemic and local inflammation, dyslipidemia, higher levels of lipoprotein A (Lp(a)), and metabolic syndrome and diabetes and hypertension.

Atherosclerosis - Review

• Progression from a fatty streak through deposition, migration, and activation of macrophages.
• Formation of foam cells and cholesterol accumulation.
• Increased extracellular matrix deposition under the intima.
• Construction within the lumen of the artery, impairing blood flow.

Atherosclerosis - Risk Factors

• Smoking increases endothelial damage.
• High blood pressure increases endothelial damage.
• Oxidative stress increases endothelial damage.
• Lp(a) is likely to increase endothelial damage.
• Diabetes and dyslipidemia are linked to higher likelihood and accelerated formation.
• LDL is more easily incorporates into the intima if there are advanced glycocation end-products (AGEs) in the endothelium.
• AGEs can further increase general inflammation and lead to increased oxidative stress.

More on Lp(a)

• Everyone has some Lp(a).
• Liver produces it.
• Increases with acute phase responses, such as from factors such as inflammation cytokines (IL-6 and others).
• Women tend to make more than men.
• High Lp(a) levels (2 to 3 times the normal amount) are associated with higher risk of heart problems (IHD, stroke, and calcific aortic stenosis).
• Thyroid hormone may reduce elevated Lp(a)
• Lp(a) closely resembles LDL.

More on Plaque Types

• Unstable plaques have unstable fibrous caps; they are prone to rupture.
• Rupture releases pro-coagulant molecules into the bloodstream.
• Factors increasing plaque stability include the amount of collagen in the fibrous cap.
• Activated platelets can promote collagen production and deposition.
• Activated macrophages degrade collagen, reducing the structural integrity of the fibrous cap and plaque, decreasing stability.
• Inflammation decreases plaque stability.

Unstable Plaques and ACS

• Harrison's video and Atlas of Atherosclerosis chapter are references for this concept.

More on Plaque Types (FYI)

• Plaque erosion can occur, which is different from rupture.
• Eroded plaques have a more stable fibrous cap and underlying thrombus, along with higher NET deposition.
• Plaque erosion is responsible for up to 50% of acute coronary syndromes (ACS), but less well understood than plaque rupture.

Diabetes and the Metabolic Syndrome

• Elevated VLDL and increased circulating LDL.
• Increased hypertension.
• Visceral obesity and insulin resistance, leading to increased free fatty acids (FFAs) and pro-inflammatory cytokines.
• Insulin resistance contributes to the production of advanced glycation end-products (AGEs).

Possible Mechanisms

• Pro-inflammatory cytokines are increased in migraines; they sensitize afferent nerve endings and induce visceral pain.
• Gut permeability increases; LPS leakage, and pro-inflammatory cytokine release are common.
• Bacterial strains metabolizing tryptophan affect local serotonin metabolism.

Schizophrenia - DSM V Criteria

• Two (or more) of the following signs or symptoms.
• At least one must be delusions, hallucinations, or disorganized speech or behavior.
• Active symptoms (delusions, hallucinations, or disorganized speech or behavior) need to be present for 6 months.
• Function in the areas of work, school, relationships, and self-care is substantially impacted.
• The condition is not due to another underlying condition.

Schizophrenia - Definitions

• disorganized speech: the speech pattern is less coherent and logically sound due to thought blocking, derailment, poverty of speech, tangentiality, neologisms, loosening associations, clanging, and/or echolalia.
• Catatonia: catatonia presents as abnormal motor behavior presenting as psychomotor disturbances, and can manifest as motor immobility, stupor, rigidity, or excessive activity or posturing.
• Negative Symptoms: negative symptoms can manifest as decreased social activity, reduced emotional response, loss of motivation, and/or decreased communication and speech;

Schizophrenia- Negative Symptoms

• Communication, emotion/affect, social activity, motivation, and psychomotor activity are substantially reduced.

Schizophrenia - Onset/Pathogenesis

• Onset typically in puberty and early 20s/30s.
• Affects approximately 1% of the population.
• Pathogenesis is not fully understood, but thought to involve dysregulation in dopaminergic systems and neurological basis for cognitive symptoms.
• Problems with working memory, attention, and executive function are possible due to cognitive symptoms.
• Difficulties with socializing, interpersonal cues and relationships is often part of the condition.

Dopamine and Schizophrenia

• There is a believed hyper-responsiveness of the dopaminergic system, which is thought to be involved in schizophrenia.
• Antipsychotic medications block dopamine D2 receptors.
• Drugs that increase dopamine (L-dopa, amphetamines) can worsen symptoms.
• GABA interneurons are incorporated last in the developing brain; likely the most vulnerable to developmental insults.
• This region appears to be highly susceptible to damage from oxidative stress and glutamate-ergistic drive during the first few years of life after birth.

Dopaminergic System

• What is the "dopaminergic system"? Diffusely-projecting monoamine systems (discussed in BMS 150)
• Dopamine (and other monoamines) are involved.
• Most dopamine-producing neuronal cell bodies in the midbrain.
• Projections include to nucleus accumbens and ventral striatum (reward/motivation), substantia nigra/striatum (motor function), and VTA/dorsal substantia nigra (executive function/many cortical areas).

Dopaminergic System (Details)

• Dopamine neurons fire in a slow, pacemaker-like fashion.
• Tonic firing is a slow and sustained firing rate of dopamine neurons.
• Reticular activating system is thought to be important for detecting stimuli, leading to glutamate release, which activates a firing burst, and phasic firing of dopamine neurons.
• This pattern of tonic and phasic firing is involved in the response to stimuli and is notable during chronic stress.

Dopaminergic System and Schizophrenia

• All known antipsychotic medications block D2 receptors; however, the use of L-dopa and amphetamines can cause dopamine to "leak" into the synaptic cleft further worsening positive symptoms;
• In schizophrenia, there is evidence that hippocampal regions demonstrating tonic activity are hyperactive.
• These regions are thought to be inappropriately stimulated and abnormally functioning.
• This hyperactive dopamine activity is thought to contribute to cognitive symptoms and negative symptoms like delusions/hallucinations.

Dopaminergic System and Schizophrenia (Stress)

• Stressing during early childhood and adolescence seems to be a risk factor for schizophrenia.
• There are also theories that posit a loss of inhibitory GABA-ergic neurons in the hippocampus, which may coincide with activation of the amygdala.

Inflammation and Schizophrenia

• General inflammation may be linked to schizophrenia but the "how" is poorly understood.
• Elevated pro-inflammatory cytokines (TNF-alpha, IL-6, and IL-1 beta) relate to schizophrenia but normalize with treatment.
• Kynurenic acid is a metabolite of tryptophan and blocks neurotransmission in the NMDA receptor, increasing likelihood of psychosis.
• Activation of microglial cells may be linked to volume loss and cognitive impairment.

Migraine - Pathophysiology

• Key pain pathway is meningeal vessels, trigeminal ganglion, and trigeminovascular complex (TCC).
• Important modulation from midbrain nuclei (dorsal raphe nucleus, locus coeruleus, nucleus raphe magnus) involves modulation of pain sensation and modulation of pain.
• Possible causes of dysfunction include vascular dilation and constriction; this region is complex and under investigation.
• Medications such as 5-HT1 receptors and CGRP can be impacted via this pathway.
• Theories posit that a primary neural dysfunction, resulting in spreading depression, might be the root cause.

Central Sensitization

• Pro-inflammatory cytokines from mast cells likely trigger nerve growth factor (NGF).
• NGF triggers an increase in BDNF release, causing increased excitability of the "pro-pain" dorsal horn networks and C fibre transmission.

Neurogenic Inflammation

• Action potentials can move in both directions along pain fibers.
• Substance P (and CGRP) released into peripheral tissues can trigger mast cell degranulation, vasodilation, and edema.
• This phenomenon is known as neurogenic inflammation.

Migraines and Gut Microbiome

• Some evidence suggests that H. pylori eradication can lead to some improvement in migraine symptoms.
• H. pylori can trigger CGRP release, which might sensitize nerves.
• IBS is frequently reported in migraine sufferers and is characterized by visceral hypersensitivity; there is an increased association of migraines between the two conditions.
• Foods that trigger intolerance can possibly be linked to the formation of migraines.
• Some pharmaceuticals that modify serotonin receptors are used against both conditions.

Possible Mechanisms (Migraines)

• Pro-inflammatory cytokines (IL-1Beta, IL-6, IL-8, TNF-alpha, and interferon) are increased in migraine sufferers, which may sensitize afferent endings and cause visceral pain.
• Increased permeability of the gut and leaky gut, causing pro-inflammatory cytokine release.
• Several strains of bacteria can metabolize tryptophan; this correlates to possible alterations in serotonin metabolism.

Test your knowledge of the symptoms and behaviors associated with schizophrenia. This quiz covers various aspects such as disorganized speech, behavior, and specific terms related to mental health disorders. Challenge yourself to see how well you understand these complex concepts.