Psychopharmacology 3e Chapter 20 Summary

Neurodegenerative Diseases

 

Parkinson’s Disease and Alzheimer’s Disease

Parkinson’s Disease

  • Parkinson’s disease is a chronic, progressive neurodegenerative disorder.
  • The primary symptoms of PD are motor disturbances that result in a visible resting tremor and slowing of movement (bradykinesia). Other motor symptoms of the disorder include rigidity and postural instability.
  • Nonmotor effects of the disorder start with loss of the sense of smell and include REM behavior disorder and mood disorders.
  • Cognitive disturbance can be a result of PD and is called Parkinson’s disease dementia (PDD). The slowing of thought and verbal responses (bradyphrenia) is a cardinal symptom.
  • These motor and cognitive symptoms are traced to loss of dopaminergic neurons in the substantia nigra, a major input pathway to the basal ganglia.
  • Onset of PD is most commonly a sporadic event, although about 10% of cases have an inherited genetic cause.
  • Pathology in PD is likely due to mitochondrial dysfunction and resulting oxidative stress. Additionally, protein aggregation in cells causes the formation of Lewy bodies, which trigger apoptotic cell death.
  • Several animal models of PD allow investigation of various aspects of PD pathology, including the MPTP model, 6-OHDA lesions, and administration of the pesticide rotenone or the drug reserpine.
  • The primary therapies in PD aim to increase DA signaling and include l-DOPA, a DA precursor, MAOIs, COMT inhibitors, and DA agonists such as pramipexole, ropinirole, and rotigotine.

Alzheimer’s Disease

  • Alzheimer’s disease is a dementia disorder that affects increasing numbers of people in the United States.
  • The onset of AD is preceded by neurocognitive disorder (NCD), but not all cases of NCD develop into AD.
  • Early symptoms of AD include forgetfulness and impairment in other cognitive functions, including language, thinking, and judgment. Physiological changes include difficulty swallowing and disrupted sleep. Psychiatric difficulties come in the form of delusions, hallucinations, depression, and agitation. As the disease progresses, communication becomes increasingly difficult because of reading, writing, and verbal communication problems.
  • Two pathological findings hallmark disease progression in AD: amyloid plaques and neurofibrillary tangles (NFTs). Amyloid plaques are formed by accumulation of Aβ (primarily Aβ42) after production by secretase cutting of the amyloid precursor protein (APP). NFTs are composed primarily of abnormally phosphorylated tau, a microtubule-associated protein, and other proteins like ubiquitin. Accumulation of NFTs results in disruption of cellular processes and eventually apoptotic cell death.
  • Risk factors for development of AD include advancing age and poor cardiovascular health. Previous head injury or psychopathology can also increase risk.
  • Several genes are associated with the development of autosomal dominant Alzheimer’s disease (ADAD) and include the genes for APP, presenilin-1, and presenilin-2.
  • Several other genes impart increased risk for AD, including the APOEe4 allele, A2M, UBQLN1, and SORL1.
  • Because of the location of risk genes on chromosome 21, AD has a strong association with Down syndrome (trisomy 21).
  • AD generally is not diagnosed until after death, although newer imaging technologies may allow earlier diagnosis in the future.
  • Animal models for AD include transgenic mice with alterations in the genes listed above, a natural aged-beagle model, and a cholesterol-fed rabbit model.
  • Current treatments for AD are primarily cholinesterase inhibitors and an NMDA receptor modulator.
  • Research indicates that Aβ antibodies, chemotherapy drugs, and perhaps even antibiotics may be effective treatments that will become available in the future.

Other Major Neurodegenerative Diseases

Huntington’s Disease

Amyotrophic Lateral Sclerosis

Multiple Sclerosis

  • Huntington’s disease (HD) is an inherited, single-gene, neurodegenerative disorder that leads to significant motor, cognitive, and psychiatric symptoms.
  • The huntingtin gene contains a CAG trinucleotide repeat, and HD is tied to an abnormal number of repeats (generally 40 repeats).
  • Motor function deficits are characterized by choreic movements, which are jerky, writhing movements that are present during waking hours. Additionally, speech, swallowing, and gait problems are noted in patients. Psychiatric symptoms associated with HD include OCD, bipolar disorder, depression, and mania.
  • No disease-modifying treatments are available for HD, but one drug, tetrabenazine, is approved for treatment of the excessive movement found in HD. Tetrabenazine works by decreasing monoamine vesicle packaging, thereby reducing dopamine signaling. The decreased DA signaling, however, can bring about depressive and Parkinsonian side effects.
  • Amyotrophic lateral sclerosis (ALS) is a degenerative disorder that affects motor function but spares most other cognitive and mood function.
  • Degeneration of upper and lower motor neurons results in a progressive loss of motor function that generally starts with the far extremities and moves “inward” until muscles of breathing are finally affected. Some motor groups are spared, including bladder and bowel function and eye movements. A strange side effect of this degeneration is an exaggeration of emotional behavioral responses, including laughing and crying.
  • The mechanism of degeneration of the motor neurons is still poorly understood but seems to involve protein aggregation in the cells and inflammation. These processes cause the triggering of apoptotic cell death pathways.
  • Two FDA-approved therapies are available for ALS: riluzole has modest disease-modifying effects, generally increasing life expectancy by about 2 to 3 months, and may delay reliance on mechanical breathing support; Radicava is a disease-modifying drug that slows progression of motor symptoms.
  • Multiple sclerosis is widely believed to be the result of an autoimmune attack on central nervous system myelin.
  • Four subtypes of MS are defined by their course: relapsing-remitting MS, primary progressive MS, secondary progressive MS, and progressive-relapsing MS.
  • Symptoms of MS vary widely and are largely unpredictable. Depending on the location of the immune attack, symptoms may include motor, sensory, gait, emotional, cognitive, or vision problems. Depression is often comorbid with MS, at rates that are not explained entirely by the stress of having a neurological disorder.
  • MS is diagnosed by MRI, neurological exam, and evidence of neuroinflammation.
  • Immunological, environmental, infectious, and genetic contributors may play a role in the development of MS, but no clear-cut cause has been identified.
  • Treatments fall into disease-modifying and symptomatic categories.
  • Disease-modifying treatments include several interferon drugs (Avonex, Rebif, Betaseron, and Extavia), Copaxone (a protein that stimulates myelin basic protein), Novantrone (a cancer drug), Tysabri (an antibody that prevents immune cells from entering the brain), Gilenya (a drug that keeps immune cells from leaving the lymph system), and Aubagio (which inhibits immune cell function). Recently, Ocrevus was approved for treatment of both RRMS and PPMS; it is the first available therapy for the progressive form of the disease.
  • Symptomatic treatments include corticosteroids for treating acute exacerbations, antidepressants, drugs for bowel and bladder function, and Ampyra (a drug that treats gait and walking dysfunction).