PROGRESSIVE & NEURODEGENERATIVE DISORDERS-HUNTINGTON’S & PARKINSON’S DISEASE, DEMENTIA

BASAL GANGLIA: components include striatum (caudate & putamen), globus pallidus; functionally connected to

thalamus, substantia nigra, and subthalamic nuclei

▪ Action control, selection & initiation of action

▪

DISEASES OF THE BASAL GANGLIA:

HUNTINGTON’S disease

▪ Brain disorder that leads to progressive degeneration of nerve cells in the brain that affects movement, cognitive

functions, and emotions.

▪ Cause: Genetically based, usually starts in late 30s – early 40s; caused by the defective, short

arm of chromosome 4. The changed form kills neurons in the striatum, particularly in the

anterior caudate nucleus.

▪ Symptoms:

▪ Motor: too much motion, which is often inappropriate; chorea (rapid, jerky movements

that appear to be well coordinated bur are performed involuntarily and ceaselessly);

other motor difficulties in initiating and executing movement.

▪ Cognitive: Executive control dysfunction: Initiation, selection, switching, perseveration, inflexibility; Spatial

processing; Memory problems (much better at recognition than recall).

▪ Emotional: Depression, Irritability, Apathy, Impulsivity, Aggressivity, Emotion lability, Psychotic

symptoms.

▪ Behavioral: Socially inappropriate behavior; Lack of awareness of own deficits across the emotional and

cognitive domains.

▪ Diagnosis: Physical examination; Family medical history; Neuropsychological and psychiatric assessment:

evaluates Motor symptoms (reflexes, muscle strength and balance), Sensory symptoms (sense of touch, vision and

hearing), and Psychiatric symptoms (mood and mental status); Standardized tests to check patient’s Memory,

Reasoning, Mental agility, Language skills, and Spatial reasoning; Genetic testing; Brain imaging: CT, MRI, fMRI,

PET

▪ Treatment:

▪ Medications: to control movement (tetrabenazine) - Deplete dopamine from synaptic vesicles. Side effects;

Antipsychotics (haloperidol). Dopamine antagonists; Other medications.

▪ Psychotherapy

▪ HD Stages - Average time from onset to death is 10-30 years

▪ Early Stage: individuals are largely functional and may continue to work, drive, handle money, and live

independently. Symptoms may include minor involuntary movements, subtle loss of coordination, difficulty

thinking through complex problems, and perhaps some depression, irritability, or disinhibition.

▪ Middle Stage: individuals lose the ability to work or drive and may no longer be able to manage their own

finances or perform their own household chores, but will be able to eat, dress, and attend to personal hygiene

with assistance. Chorea may be prominent, difficulty with voluntary motor tasks increases. There may be

problems with swallowing, balance, falls, and weight loss. Problem solving becomes more difficult because

individuals cannot sequence, organize, or prioritize information.

▪ Late Stage: individuals require assistance in all activities of daily living. Although they are often nonverbal

and bedridden in the end stages, it is important to note that people with HD seem to retain some

comprehension. Chorea may be severe, but more often it is replaced by rigidity, dystonia, and bradykinesia.

Psychiatric symptoms may occur at any point in the course of the disease but are harder to recognize and

treat late in the disease because of communication difficulties.

PARKINSON’S disease

▪ Brain disorder that causes unintended or uncontrollable movements, such as shaking, stiffness, and difficulty with

balance and coordination.

▪ Cause: damage to the cells of the subtantia nigra, which stops producing the neurotransmitter dopamine (due to

genetics, toxins, trauma, inflammation).

▪ Symptoms:

• Motor: Tremors at rest; Muscular (“cogwheel”) rigidity; Akinesia; Posture disturbances (have difficulty

counteracting the force of gravity - head may drop).

• Neuropsychological: Impairments in Executive processes; memory retrieval (but not retention); emotional

functioning

▪ Diagnosis: Physical and neurological examination; Neuropsychological assessment; Blood tests; Note: Brain

imaging not particularly helpful, but may be used to help rule out other disorders

Treatment: L-Dopa (precursor to dopamine that can cross the blood-brain barrier), to try to offset the dopamine

deficiency. Can improve at least some of the cognitive deficits but has side effects (dyskinesias, hallucinations), and

looses efficacy over time. Other dopamine agonists are now preferred for early stages of the disorder when they are

effective, with L-dopa reserved for later stages. Deep brain stimulation via an implanted electrode in the subthalamic

nucleus, globus pallidus and thalamus.

DEGENERATIVE DISORDERS: DEMENTIA

Dementia: Gradual loss of higher cognitive function due to changes in the brain caused by disease or trauma.

• Reversible dementia: Symptoms mimic those of dementia, but caused by effects from medications, depression,

delirium, thyroid problems, excessive use of alcohol, certain vitamin deficiencies.

• Irreversible dementia: Caused by an incurable condition (e.g., Alzheimer's disease); Progressive and

degenerative; Patients are eventually unable to care for themselves and require round-the-clock care

Types of Dementia

Based on the brain region most affected:

• Cortical dementias (e.g., Alzheimer’s disease)

• Subcortical dementias (Huntington’s, Parkinson’s disease)

• Mixed-variety dementias, which encompass both cortical and subcortical damage (Vascular dementia)

Based on the suspected cause:

• Accumulation of defective proteins=> Alzheimer’s Dementia (AD)

• Vascular disorders => Vascular dementia

• Brain atrophy => Frontotemporal dementia

Greatest risk factor is advanced age (1% incidence at 65, doubling every 5 years). Other causes: Inheriting the

genes associated with Alzheimer's or Huntington's disease (the epsilon 4 variant of the apolipoprotein E

(ApoE4); Untreated infectious and metabolic disease, substance abuse.

ALZHEIMER'S DISEASE (AD)

The most common form of dementia, characterized by IRREVERSIBLE and PROGRESSIVE

DETERIORATION of areas in the brain essential for learning and memory. Episodic memory loss is the most

prominent symptom of AD,

AD hallmarks: accumulation of amyloid plaques between neurons in the

brain. Amyloid is a general term for protein fragments that the body produces normally,

which are broken down and emilinated in a healthy brain; Neurofibrillary tangles, consist

primarily of a protein called tau, which is part of a microtubule (structural support and

transport functions). In AD the tau protein is abnormal and the microtubule structures

collapse => loss of synapses and neurons, athrophy and loosening of the gyri.

Stages of AD

AD Diagnosis: No specific physiological test in living people. Probable diagnosis based on cognition and

behavior.

AD Treatment: There are currently no cures for AD.

- Medication (Acetylcholinesterase inhibitors and NMDA glutamate receptor antagonists) can slow the course of

AD, but they cannot stop their progression (they do not address directly the core pathology of AD, the formation

of plaques and tangles).

-Nonpharmalogical prevention: diet, exercising, smoking, and degree of mental activity are all predictors of

developing the disease.

VASCULAR Dementia (VD)

The 2nd most common cause of dementia, caused by brain damage from impaired blood flow to the brain.

Creates both cortical and subcortical lesions. Specific cognitive domains affected depend on stroke location.

Deficits in attention and executive function are common. More common in men over 50 years old.

VD Stages: has a relatively abrupt onset (due to a stroke), is accompanied by a stepwise rather than gradual

course (because the effects are compounded by each additional stroke), and is not restricted to onset in later

years. Also, because VD is associated with stroke, the pattern of impairment can fluctuate, being worse initially

and then improving.

VD Diagnostic:

- Medical history (problems with arterial hypertension, etc)

- Brain imaging (MRI scans can reveal previous infarcts)

- Neuropsychological testing

VD Treatment: no cure for the condition or a way to reverse the damage that's already happened. Goal: treat the

underlying cause of vascular dementia and help stop it getting worse.

- Medication ( to reduce High blood pressure, High cholesterol, to reduce risk of blood clots and further

strokes)

• Problems with word-finding

• Trouble remembering recent

information

• Planning/organizing becomes

challenging

Mild Alzheimer’s Disease

• Confusion with time and place

• Changes in behavior

• Experience greater memory loss

Moderate Alzheimer’s

Disease

• Require round-the-clock care

• Lose the ability to communicate

• Decline in physical abilities

Severe Alzheimer's Disease

• Plaques and tangles begin

forming in areas associated

with learning/memory and

thinking/planning

• Spread to regions involved

with language/speech, and

visual-spatial processes

• Thinking/planning regions

accumulate more plaques and

tangles

• Cortex shrinks dramatically,

widespread damage

• Individuals can no longer care

for themselves or recognize

family

- Lifestyle changes: healthy, balanced, losing weight for those who might be overweight, stop smoking,

getting fit, cutting down on alcohol.

FRONTOTEMPORAL Dementia

A type of dementia that primarily affects the frontal and temporal lobes of the brain, which are generally

associated with personality, behavior and language.

- Caused by progressive brain atrophy. Earlier onset than AD (56-58 years olds). Strong genetic component.

Symptoms: first symptoms are in social-emotional functioning (difficulty modulating social behavior, lack of

inhibition, impulsivity, outbursts of frustration); Repetitive and routinized behavior; some patients loose the

ability to use language properly; Mood changes (trending toward depression and anxiety).

DEMENTIA DIAGNOSIS

Thorough medical history: Underlying treatable condition; Onset, duration, and progression of symptoms

Any possible risk factors for dementia (e.g., , family history of the disorder or other neurological disease);

History of stroke; Alcohol or other drug (prescription or over-the-counter) use. Don’t rely on patient report!

Two generally accepted criteria for the diagnosis of dementia:

1. Evidence for erosion of recent and remote memory

2. Evidence of impairment in one or more of the following cognitive functions: memory (amnesia),

language (aphasias), motor activity (apraxia), recognition (agnosia), and executive function.

Differential Diagnosis!!!

The process of differentiating between two or more conditions which share similar signs or symptoms.

Different conditions with different etiologies could have similar symptoms, but very different effective

treatments

Identify and look for signs, symptoms, or characteristics that are unique to a particular disorder or disease!

- Test for episodic memory loss, and imaging of the medial temporal lobe structures that are responsible for

episodic memories can help differentiate AD from other types of dementia.

- Delirium: transient, acute mental disturbance that manifests as disorganized thinking and a decreased ability to

pay attention to the external world. Caused by infectious disease, brain tumor, poisoning, drug or alcohol

intoxication or withdrawal, seizures, head trauma, metabolic disorders - life-threatening or progressive if left

untreated.

- Pseudodementia - set of symptoms that mimic those of dementia, but there is typically no degeneration in the

brain. Common- severe depression that occurs mostly in elderly people - slow motor movements and thinking,

deficits in working memory.

- Blood tests can help differentiate AD (ApoE4 gene) from other conditions such as Huntington’s disease,

anemia, hypoglicemia, liver disease, and others.

- Imaging tests (CT or MRI scan) can detect structural or physical, changes in the brain caused by stroke, blood

clots, Huntington's disease, tumors, head injury, or hydrocephalus.

DEMENTIA TREATMENT

NO cure, aim is to slow down development

• Drugs: Cholinesterase inhibitors and an NMDA receptor antagonist

• Therapy: Targeting vascular system, glucose metabolism, and inflammation.

• Lifestyle interventions

Lifestyle interventions: Regular exercise and diet

Behavioral approaches: Social engagement, Support