35.5 Nervous System Disorders

Neurodegenerative and Neurodevelopmental Disorders

Neurodegenerative Disorders: Causes and Treatments

Neurodegenerative disorders involve the progressive loss of neurons in specific brain regions. As neurons die, patients lose the functions those regions control. Two of the most studied examples are Alzheimer's disease and Parkinson's disease.

Alzheimer's Disease

Alzheimer's is the most common cause of dementia. It causes progressive memory loss and cognitive decline over months to years. Patients develop difficulty with language, problem-solving, and spatial orientation that increasingly impairs daily life.

At the cellular level, two hallmark changes drive the damage:

• Amyloid plaques build up between neurons. These are clumps of misfolded amyloid-beta protein that disrupt cell-to-cell signaling.
• Neurofibrillary tangles form inside neurons. These are twisted fibers of a protein called tau that collapse the neuron's internal transport system, eventually killing the cell.

Causes:

• Genetic mutations in the APP (amyloid precursor protein), PSEN1 (presenilin 1), and PSEN2 (presenilin 2) genes increase risk, especially for early-onset forms.
• Environmental and lifestyle factors such as head trauma, cardiovascular disease, diet, and exercise levels may influence when the disease appears and how fast it progresses.

Treatments:

• Cholinesterase inhibitors (donepezil, rivastigmine, galantamine) slow the breakdown of acetylcholine, a neurotransmitter important for memory. This can temporarily improve cognitive function.
• Memantine, an NMDA receptor antagonist, regulates glutamate activity to slow cognitive decline. Excess glutamate can overstimulate neurons and cause damage, so blocking some of that activity is protective.
• Non-pharmacological approaches like cognitive stimulation (puzzles, games) and regular physical exercise (walking, swimming) may help maintain quality of life.

Parkinson's Disease

Parkinson's primarily affects motor function. The core symptoms are tremors, rigidity, bradykinesia (abnormally slow movement), and postural instability. These arise because dopamine-producing neurons in a brain region called the substantia nigra progressively degenerate. With less dopamine available, the brain can't properly coordinate smooth, voluntary movement.

Another hallmark of Parkinson's is the presence of Lewy bodies, which are abnormal clumps of alpha-synuclein protein found inside affected neurons.

Causes:

• Mutations in genes like SNCA (alpha-synuclein), LRRK2 (leucine-rich repeat kinase 2), and PRKN (parkin) increase risk.
• Environmental exposures, particularly to certain pesticides (paraquat, rotenone) and repeated head trauma, may also contribute.

Treatments:

• Levodopa is the most effective treatment. It's a chemical precursor to dopamine that can cross the blood-brain barrier. It's given with carbidopa, which prevents levodopa from being converted to dopamine outside the brain (where it would cause side effects without helping symptoms).
• Dopamine agonists like ropinirole and pramipexole directly stimulate dopamine receptors, mimicking dopamine's effects on motor circuits.
• Deep brain stimulation (DBS) is a surgical option for advanced cases. Electrodes are implanted in specific brain areas (subthalamic nucleus or globus pallidus) to deliver electrical pulses that regulate the abnormal signaling causing motor symptoms.

Autism vs. ADHD: Symptoms and Causes

Both autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD) are neurodevelopmental disorders, meaning they arise during brain development in childhood and have strong genetic components. Despite some overlap, they affect different domains of behavior.

Autism Spectrum Disorder (ASD)

ASD is defined by two core features:

• Persistent deficits in social communication and interaction. This can look like difficulty with back-and-forth conversation, reduced eye contact, limited facial expressions, and trouble understanding social cues.
• Restricted, repetitive patterns of behavior, interests, or activities. Examples include repetitive motor movements (hand flapping), strong insistence on routines, and unusually intense or narrow interests.

Symptoms are typically present before age 3 and impair everyday functioning across social, academic, or occupational settings.

Potential causes:

• Genetics play a major role. Mutations in genes like FMR1 (associated with fragile X syndrome), MECP2 (associated with Rett syndrome), and SHANK3 have been linked to ASD.
• Environmental factors such as advanced parental age (over 35) and prenatal exposure to certain medications (e.g., valproic acid) may increase risk.

Attention Deficit Hyperactivity Disorder (ADHD)

ADHD involves three symptom categories:

• Inattention: difficulty sustaining focus, high distractibility, poor organization
• Hyperactivity: excessive talking, fidgeting, difficulty sitting still
• Impulsivity: interrupting others, blurting out answers, making hasty decisions without thinking through consequences

Potential causes:

• Genetic variations in dopamine receptor genes (DRD4) and norepinephrine transporter genes (NET) are associated with ADHD, pointing to disrupted catecholamine signaling.
• Prenatal exposure to tobacco or alcohol and low birth weight (under 2500 g) may increase risk.

Comparing ASD and ADHD

Neurobiological Mechanisms in Nervous System Disorders

Several shared biological processes underlie many nervous system disorders. Understanding these mechanisms helps explain why different disorders can share symptoms and why certain treatments work across conditions.

• Neurotransmitter imbalances disrupt signaling between neurons. For example, dopamine deficiency drives Parkinson's motor symptoms, while serotonin dysregulation is implicated in depression and OCD.
• The blood-brain barrier controls which substances can enter the brain from the bloodstream. This is why drug design for neurological conditions is so challenging: a medication must be able to cross this barrier to be effective. Levodopa crosses it; dopamine itself does not.
• Neuroplasticity is the brain's ability to reorganize its connections. This can aid recovery (e.g., after stroke), but maladaptive plasticity can also reinforce harmful patterns in some disorders.
• Neuroinflammation involves immune activation within the brain. Chronic inflammation damages tissue and worsens symptom progression in conditions like Alzheimer's and Parkinson's.
• Synaptic dysfunction disrupts normal communication at the synapse, contributing to both neurological and psychiatric conditions.
• Neurotoxicity from exposure to toxic substances (pesticides, heavy metals, drugs of abuse) can damage or kill neurons, impairing brain function.

Mental Illnesses and Treatment Approaches

Mental Illnesses: Types and Treatments

Mental illnesses are disorders that affect mood, thinking, and behavior. They are extremely common and have well-established biological underpinnings, often involving neurotransmitter imbalances. Most are treated with a combination of medication and psychotherapy.

Depressive Disorders

The two main types are major depressive disorder (intense episodes lasting at least two weeks) and persistent depressive disorder (chronic, lower-grade depression lasting two years or more). Symptoms include persistent sadness, loss of interest in activities, changes in sleep and appetite, fatigue, and thoughts of death or suicide.

Treatments:

• SSRIs (e.g., fluoxetine) selectively block serotonin reuptake, increasing serotonin availability in the synapse. SNRIs (e.g., venlafaxine) do the same for both serotonin and norepinephrine.
• Cognitive-behavioral therapy (CBT) helps patients identify and change negative thought patterns. Interpersonal therapy focuses on improving communication skills and relationships.

Anxiety Disorders

Common types include generalized anxiety disorder, panic disorder, and specific phobias. Symptoms involve excessive worry, restlessness, irritability, and physical responses like increased heart rate and sweating. These physical symptoms result from overactivation of the sympathetic nervous system.

Treatments:

• Benzodiazepines (e.g., alprazolam) enhance the effect of the inhibitory neurotransmitter GABA, producing rapid anxiety relief. Buspirone is a slower-acting alternative that works on serotonin receptors.
• CBT is highly effective, often using exposure techniques where patients gradually confront feared stimuli in a controlled way to reduce the anxiety response over time.

Bipolar Disorder

Bipolar disorder is characterized by alternating episodes of mania (elevated mood, increased energy, impulsive behavior) and depression. The cycling between these extremes distinguishes it from unipolar depression.

Treatments:

• Mood stabilizers like lithium and valproic acid help regulate mood fluctuations and prevent both manic and depressive episodes.
• Antipsychotic medications (e.g., quetiapine) may be added to manage manic or mixed episodes.
• Psychotherapy, including CBT (to identify triggers) and psychoeducation (helping patients understand their disorder and recognize early warning signs), supports medication management.

Schizophrenia

Schizophrenia involves two categories of symptoms:

• Positive symptoms (added to normal experience): delusions, hallucinations, disorganized speech and behavior
• Negative symptoms (subtracted from normal function): diminished emotional expression, avolition (lack of motivation), social withdrawal

Treatments:

• Antipsychotic medications like risperidone and olanzapine primarily target positive symptoms by blocking dopamine receptors. This is consistent with the dopamine hypothesis, which proposes that excess dopamine activity contributes to psychotic symptoms.
• Psychosocial interventions, including CBT (reality testing) and social skills training, help improve daily functioning.

Obsessive-Compulsive Disorder (OCD)

OCD involves two linked components: obsessions (recurrent, intrusive, unwanted thoughts that cause anxiety) and compulsions (repetitive behaviors or mental acts performed to reduce that anxiety). For example, a person might have obsessive fears about contamination and compulsively wash their hands dozens of times a day.

Treatments:

• SSRIs (e.g., fluoxetine) and clomipramine (a tricyclic antidepressant) help regulate serotonin levels. OCD often requires higher SSRI doses than depression does.
• Exposure and response prevention (ERP) therapy is the gold-standard psychotherapy for OCD. Patients are gradually exposed to anxiety-triggering stimuli while refraining from performing compulsions, which over time weakens the obsession-compulsion cycle.