Neurological Disorders: Parkinson's, Huntington's, Alzheimer's, ALS

What is Parkinson's Disease (PD)?

A long-term degenerative disorder affecting the CNS, first described by James Parkinson in 1817, characterized by gradual development of motor abnormalities.

What is the life expectancy after a Parkinson's Disease diagnosis?

Ranges from 7 to 14 years.

What age group is primarily affected by Parkinson's Disease?

Mainly affects people over 60 years old, often referred to as a 'disease of the elderly'.

What was the incidence rate of Parkinson's Disease found in a 2022 study of people over 65?

108-212 per 100,000.

What are the four main motor symptoms of Parkinson's Disease?

Tremor (resting), Rigidity, Akinesia (specifically bradykinesia), and Postural instability (TRAP).

What is the most common presenting symptom of Parkinson's Disease?

Resting tremors.

Describe the characteristics of resting tremors in Parkinson's Disease.

Typically occur at a slow velocity (3-5 Hz), are asymmetrical, and can affect various body parts like the chin, jaw, arms, and hands.

What is rigidity in the context of Parkinson's Disease?

Increased resistance to movement, occurring in over 90% of patients, often described by the cogwheel phenomenon.

What is bradykinesia and its significance in Parkinson's Disease?

It is the most characteristic clinical feature present in every case, causing slowness in daily activities and loss of spontaneous movement.

What is postural instability and when does it typically occur in Parkinson's Disease?

Loss of postural reflexes leading to impaired balance and increased fall risk, generally occurring in late-stage PD.

What are some non-motor symptoms associated with Parkinson's Disease?

Psychiatric disturbances (depression, anxiety, apathy), autonomic disturbances (constipation, sexual dysfunction), cognitive impairments (executive function deficit, dementia), and sleep disturbances.

What are the main nuclei of the Basal Ganglia?

Dorsal striatum (caudate and putamen), Globus Pallidus (externa and interna), Substantia nigra (pars compacta and pars reticula), and Subthalamic nucleus.

What is the function of the Basal Ganglia?

It sets the overall tone or motivation for action, integrating sensory input to determine the likelihood of movement occurring.

What is the role of the dorsal striatum in the Basal Ganglia?

It serves as the input nuclei, receiving information.

What are the output nuclei of the Basal Ganglia?

The Interna (Gpi) and Pars reticula.

What are intrinsic nuclei in the Basal Ganglia?

The Externa (Gpe), Pars compacta, and subthalamic nucleus, which relay information between input and output.

What is the significance of the Basal Ganglia loops?

They are organized to receive information, send it out, and get feedback, integrating information across different regions.

What are some speech abnormalities associated with bradykinesia in Parkinson's Disease?

Monotonic and hypophonic dysarthria, characterized by reduced intonation and loudness.

What is the cogwheel phenomenon in Parkinson's Disease?

A jerky movement observed during passive movement of limbs due to increased muscle tone.

What is the typical posture of a person with advanced Parkinson's Disease?

A forward tilt due to loss of postural reflexes.

What are common causes of falls in Parkinson's Disease patients?

Postural instability and freezing gait.

How does Parkinson's Disease affect facial expressions?

It can lead to hypomimia, resulting in a blank facial expression and decreased blinking.

What are some cognitive impairments associated with Parkinson's Disease?

Executive function deficits, dementia, and hallucinations.

What are the four main loops that control cognitive function and movements?

Cognitive Loop, Visual/Oculomotor Loop, Affective Loop, Motor Loop.

What functions does the Cognitive Loop control?

Execution functions, working memory, task switching, and priority setting.

What is the role of the Visual/Oculomotor Loop?

It responds to visual stimuli in the environment and aids in spatial recognition.

What is the primary function of the Affective Loop?

It helps regulate emotions, including desire, impulse, and empathy.

What does the Motor Loop help decide?

It helps decide whether to move or not and involves the putamen, globus pallidus (GP), and substantia nigra (SN).

How do the basal ganglia (BG) loops function in relation to the cortex?

They loop back around to the cortex after going to the thalamus to relay motor information.

What is the main pathological finding in Parkinson's Disease (PD)?

Massive cell death in the Substantia Nigra.

What percentage of dopamine neurons are lost in PD at the onset of motor symptoms?

Approximately 70%.

How does dopamine depletion affect the basal ganglia motor loop in PD?

It leads to dysfunction of the BG motor loop, causing motor symptoms such as tremors, rigidity, and bradykinesia (TRAP).

What role does dopamine play in the basal ganglia motor circuit?

Dopamine from the SN modulates activity, activating striatum neurons and stimulating the motor cortex through the direct motor pathway.

What are the compensatory mechanisms that mask early symptoms of PD?

Enhanced dopamine synthesis, increased dopamine release in the striatum, and increased activity in the SNc.

What is the function of the direct motor pathway?

It influences actions by inhibiting the GPi, increasing thalamus activity, and stimulating movement through projections of glutamate to the cerebral cortex.

What is the function of the indirect motor pathway?

It prevents actions by exciting inhibitory GPi neurons, leading to decreased thalamus activity.

How does a lack of dopamine affect the indirect pathway in PD?

It causes more inhibition of the thalamus, leading to decreased activity of the motor cortex.

What is dopamine, and what are its key roles?

Dopamine (DA) is a catecholamine neurotransmitter essential for processes such as reward and movement.

How is dopamine synthesized?

Dopamine is synthesized from tyrosine and packaged into vesicles through the vesicular monoamine transporter (VMAT).

What are the two types of dopamine receptors and their functions?

D1-like receptors activate cellular effects (turn on), while D2-like receptors inhibit cellular effects (turn off).

What types of neurons are found in the striatum, and what are their functions?

Medium spiny neurons (MSNs) include D1 type (excitatory, glutamatergic) and D2 type (inhibitory, GABAergic).

What happens to the indirect pathway when dopamine is released?

The D2 medium spiny neurons are inhibited.

What happens to the direct pathway when dopamine is released?

The D1 medium spiny neurons are activated.

Is dopamine the only neurotransmitter affected in Parkinson's Disease?

No, other neurotransmitter systems such as noradrenergic, serotonergic, and cholinergic are also affected.

What are some non-motor symptoms associated with PD progression?

Urinary infrequency, erectile dysfunction, sleep disturbances, and constipation.

What are the stages of Parkinson's Disease progression?

Stage 1: Olfactory bulb (loss of smell); Stage 2: Locus coeruleus (norepinephrine release); Stage 3: Substantia nigra (motor symptoms appear); Stage 4: Cortex (communication issues, increased falls).

When do the first clinical symptoms of PD typically appear?

When around 70% of neurons are lost.

What is the typical duration of symptoms progression in Parkinson's Disease (PD)?

Symptoms progress over 10 to 15 years.

What phenomenon occurs in the later stages of Parkinson's Disease?

The wearing off phenomenon and random fluctuations in symptoms.

What is the primary cause of Parkinson's Disease?

PD is considered idiopathic, with unknown causes influenced by environmental and genetic factors.

Name two environmental factors that may contribute to Parkinson's Disease.

Toxins and pollutants (like pesticides) and head injuries (such as boxing).

What percentage of patients with Parkinson's Disease have a first-degree relative with the condition?

Only 15% of patients with PD have a first-degree relative with PD.

What genetic mutation is associated with early-onset Parkinson's Disease?

Mutations in genes related to alpha-synuclein production (SNCA) are associated with 5-10% of cases.

What is the main pathological feature of Parkinson's Disease?

The formation of Lewy Bodies inside neurons.

What causes the formation of Lewy Bodies in Parkinson's Disease?

Abnormal aggregation of alpha-synuclein proteins.

Where are Lewy Bodies first located in the brain?

In the olfactory bulb, medulla oblongata, and pontine tegmentum.

How does alpha-synuclein pathology spread in the brain?

It is hypothesized to begin in the gut, travel up the vagus nerve to the brainstem and olfactory bulb, then spread throughout the brain.

What is the role of full truncal vagotomy in Parkinson's Disease risk?

Full truncal vagotomy reduces the risk of developing Parkinson's Disease.

How is Parkinson's Disease diagnosed?

There is no specific test; diagnosis is clinical, based on medical history, symptoms, and progression.

What is the Unified Parkinson's Disease Rating Scale (USDRS) used for?

To assess motor symptoms and track the progression of Parkinson's Disease.

What is Levodopa (L-DOPA) used for in Parkinson's Disease treatment?

It is a dopamine precursor that temporarily improves motor symptoms.

What are the potential side effects of long-term L-DOPA use?

Dyskinesias, hallucinations, and agitation.

What are COMT and MAO-B inhibitors used for in Parkinson's Disease?

They are used to increase the total available dopamine and provide symptomatic relief.

What is the function of dopamine agonists in Parkinson's Disease treatment?

They bind to dopamine receptors and activate striatum neurons to reduce motor symptoms.

What non-pharmacological treatment is recommended for Parkinson's Disease?

Exercise, which helps combat symptoms and acts as a preventative measure.

What is Deep Brain Stimulation (DBS) in the context of Parkinson's Disease?

A surgical option where electrodes are implanted in specific brain regions to relieve motor symptoms.

What is Huntington's Disease?

A rare progressive genetic hereditary disorder caused by a defect of a gene on chromosome 4.

What genetic feature characterizes Huntington's Disease?

CAG repeats in the encoding region of the gene.

What type of gene is the huntingtin gene?

It is a dominant gene.

How many copies of the mutated allele are needed to cause Huntington's Disease (HD)?

One copy is enough to cause the disease.

What is the prevalence of Huntington's Disease from 2011-2022?

4.88 per 100,000.

What was the prevalence of Huntington's Disease from 1985-2010?

2.17 per 100,000.

What is the overall prevalence of Huntington's Disease?

3.92 per 100,000.

What is the risk of developing Huntington's Disease in Canada?

1 in 7000 people have HD, 1 in 5500 are at risk, and 1 in 1000 are affected.

What is the typical age range for the onset of Huntington's Disease?

Between 35 and 55 years of age.

Is Huntington's Disease sex-linked?

No, it is not sex-linked and affects both males and females equally.

What percentage of Huntington's Disease cases are juvenile?

Juvenile cases account for only about 10% of cases.

What is the nature of the symptoms of Huntington's Disease?

Symptoms are gradual, progressive, and typically appear in late adulthood.

What are the main clinical features of Huntington's Disease?

Movement disorder, cognitive disorder, psychiatric disturbances, and psychological pressure.

What is the main motor symptom of Huntington's Disease?

Hyperkinesia (excessive movement), which can include involuntary movements (chorea) and dystonia.

What cognitive symptoms are associated with the progression of Huntington's Disease?

Difficulty organizing tasks, lack of mental flexibility, poor impulse control, slower cognitive processing, and dementia.

What is the most common psychiatric disturbance in Huntington's Disease?

Depression, with rates approximately twice that of the normal population.

What are some other psychiatric symptoms associated with Huntington's Disease?

Irritability, apathy, social withdrawal, and fatigue/loss of energy.

How many stages are there in the progression of Huntington's Disease?

Three stages: early, middle, and late stage.

What characterizes the early stage of Huntington's Disease?

Minor movement issues, subtle loss of coordination, some intellectual issues, and possibly depression.

What happens during the middle stage of Huntington's Disease?

Motor and intellectual symptoms progress, making it difficult to live independently, with prominent chorea and difficulties in swallowing and balance.

What occurs in the late stage of Huntington's Disease?

Patients require assistance with daily living, experience severe chorea replaced by dystonia, and have difficulty communicating and eating.

What is the typical duration from the onset of symptoms to death in Huntington's Disease?

Death occurs 13-15 years after the onset of symptoms.

How does Huntington's Disease pathology compare to Parkinson's disease?

HD affects the basal ganglia similarly to Parkinson's disease.

What are the four main nuclei of the basal ganglia?

Dorsal striatum, caudate, putamen, globus pallidus (externa and interna), substantia nigra (pars compacta and pars reticula), and subthalamic nucleus.

What are the input nuclei of the basal ganglia?

Dorsal striatum, caudate, and putamen, which receive information from the cortex.

What are the output nuclei of the basal ganglia?

Interna (GPi) and pars reticula, which send information to the thalamus.

What are the intrinsic nuclei of the basal ganglia?

Globus pallidus externa (GPe), pars compacta, and subthalamic nucleus, which relay information between input and output.

What are the two main types of medium spiny neurons (MSN) in the striatum?

D1 MSN, which excite the direct motor pathway, and D2 MSN, which excite the indirect motor pathway.

How does the direct pathway of the basal ganglia influence action?

It inhibits the GPi, leading to increased thalamic activity.

How does the indirect pathway of the basal ganglia prevent action?

It releases GABA to GPe, increasing transmission in STN, which excites GPi to release inhibitory neurons, decreasing thalamic activity.

What is the effect of Huntington's Disease (HD) on the basal ganglia?

HD causes damage to the basal ganglia, leading to motor symptoms and loss of D2 MSN, resulting in decreased inhibition and increased excitatory output.

What percentage of D2 MSN are typically lost by late-stage Huntington's Disease?

Approximately 95%.

What genetic mutation causes Huntington's Disease?

An expansion of CAG repeats in the huntingtin (HTT) gene.

What is the normal range of CAG repeats in the huntingtin gene?

10-25 CAG repeats; more than 36 repeats indicates Huntington's Disease.