9 Neurodegenerative Diseases

Key Characteristics of a neurodegenerative disease

• Insidious onset, gradual progressive degeneration of structure and function of nervous system

• Incurable

• Sarts in one or two locations and spreads based on disease

• Accumulation of misfolded proteins

What is the prion hypothesis?

Pathological seeds cause misfolding of physiological proteins. The misfolded proteins aggregate and form into filaments

What is alzheimer’s caused by?

Pathogenic misfolded proteins that cause plaques and tangles

What proteins are misfolded in Alzheimer Disease?

Amyloid beta and Tau

What proteins are misfolded in Parkinson Disease?

alpha Synuclein

What proteins are misfolded in Huntington Disease?

Huntingtrin

What proteins are misfolded in Creutzfeldt-Jakob Disease?

Prion Protein (PrP)

What proteins are misfolded in Chronic Traumatic Encephalopathy (CTE)?

Tau (different location and spreading compared to Alzheimer)

What proteins are misfolded in Amyotrophic Lateral Sclerosis (ALS) ?

Superoxide Dismutase 1

Tests for neurodegenerative diseases often involve what?

Vision and perception

What is the difference between Dementia and Alzheimer’s?

Dementia is a clinical presentation, not a disease. It is an acquired memory loss that causes significant impairment.

Alzheimer’s Disease is a specific disease that can present with dementia. It is the most common cause of dementia.

What are some dementia-causing disease?

• Alzheimer disease

• Vascular dementia

• Parkingson Disease

• Huntington disease

• Creutzfeldt-Jakob disease

• Chronic traumatic encephalopathy

• Frontotemporal dementia

What is the most common neurodegenerative disease?

Alzheimer disease, has an average onset at 65 with 50% having it at 80.

What are some characteristics of Alzheimer disease?

• No effective diagnostic tool

• No single effective medication to halt or significantly slow neurodegenerative disease in most people

Stages of Alzheimer disease

• Stage 1= Preclinical/Presymptomatic

  • May have difficulty with word-finding

  • Misplacing objects

• Stage 2 = Mild Cognitive Impairment (MCI)

  • Difficulty with normal daily tasks

  • Getting lost d/t visual issues

  • Difficulty reading books/watching shows

  • Anxiety/ depression common/ anger

• Stage 3 = Dementia due to AD

  • may have residual saying and become increasingly less communicative

  • Does not remember others or self

What are some vision related clinical presentations of AD?

• Sleep disturbances

• Contrast Sensitivity

  • Tasks difficult with inadequate light

  • Driving after dusk and before dawn

• Losing self and others

  • Environmental agnosia: lost in familiar surroundings

  • Difficulty with figure-ground discrimination: foreground/background confusion

  • Prosopagnosia: inability to recognize faces

• RNFL thinning: glaucoma/glaucoma-like

• Convergence insufficiency

• Hemispatial neglect

How is AD diagnosed?

Brain atrophy via MRI and cognitive tests.

MRI shows enlarged ventricles, deeper sulci, and hippocampal atrophy

Congitive tests: Mini-mental state examination (MMSE) used to diagnose MCI and dementia

What cognitive impairments must be present for a diagnosis of MCI or Dementia, as assessed by the MMSE?

• Memory and learning

• Complex thinking and executive function

• Language

• Visuospatial abilities

With impairments in 2 of the areas of cognitive function

What is the pathogenesis of AD?

1. etiological factors

2. damage to Gut-Brain axis starts in gut

3. Damage to brain: microglia, BBB, Metabolism, inflammation, etc

4. Misfolding of amyloid, spreading of misfolded amyloid, and induces a misfolding of Tau. Tauopathy spreads

What is the etiology of AD?

• Non-modifiable factors:

  • Genes like APOE4

  • Aging

• Modifiable lifestyle factors:

  • Diet: ultra processed foods

    • High Carb diet (diabetes)

    • Low short chain fatty acids

    • High Trimethylamine N-oxide (TMAO)

    • Low Vitamins

      • Curcumin

      • Omega-3

    • Alcohol

  • Low Physical Activity

  • Poor sleep

  • Poor stress management and trauma

How do neurodegenerative diseases start?

1. Disruptions in the gut microbiome and/or tight junctions in the gut cause inflammation.

2. Leaky gut leads to a breakdown of the blood-brain barrier (BBB), allowing toxins, bacteria, and harmful molecules to enter the brain's extracellular fluid (ECF), which induces protein misfolding.

3. Amyloid-β42 plaques form due to improper cleavage of amyloid precursor protein (APP) by secretases. (A hallmark of neurodegenerative disease, but not necessarily the direct cause).

4. Tauopathy occurs when misfolded tau proteins form neurofibrillary tangles (NFTs). This is highly pathogenic and is exacerbated by misfolded Aβ42.

Is Alzheimer disease transmittable?

Yes, EyeBank does not allow corneal transplants from patients with AD.

What are the treatments for AD?

No Rx that stops the disease. Only Rx for symptomatic relief and delay of cell death.

Acethycholinesterase inhibitors (Aricept) compensates for loss of cholinergic neurons.

Memantine (Namenda) are NMDA blockers

What does Parkinson Disease affect?

It affects the initiation of intentional behavior = hypokinetic = difficult to move w/ tremors

What is Huntington Disease affect?

It affects the suppression of unwanted behaviors = hyperkinetic

What is the second most common neurodegenerative disease?

Parkinson Disease, with an average age of onset at 60 yrs old. There is no cure.

What is Parkinson Disease defined as?

A GROUP of movement diseases

What are the typical presentations associated with Parkinson Disease?

• Bradykinesia

• Rigidity

• Resting tremor

• Gait and Balance

• Loss of smell

• Sleep disorder

• Constipation

• Low blink rate

What are some visual and visuospatial presentations of Parkinson’s Disease?

• Motility Issues

• Visuospatial problems

• Hallucinations: late in disease

What are some motility issues patients with PD present?

• Ocular Surface irritation: 2/3 have KCS or Dry eye disease

• Convergence insufficiency (80% of patients with early PD)

• Freezing Gait; can be alleviated with external cues

What are some visuospatial issues patients with PD present?

• Environmental agnosia

• Prosopagnosia: inability to recognize the faces of familiar people

• Recognition of movement in periphery decreases

What are the hallucinations patients with PD present?

Occurs in 9-44%. Can have passage or complex hallucinations.

What are passage hallucinations?

A type of visual hallucination where a person sees a fleeting figure or object moving in their peripheral vision. It is often brief and non-detailed.

What are complex hallucinations?

Detailed and vivid hallucinations that often involve people, animals, or objects in full form. It can be stationary or moving and may include multiple sensory modalities. Typically much more detailed and scary compared to passage hallucinations.

What does a primary motor problem in Parkinson’s disease (PD) suggest?

In early stage PD, predominant motor symptoms are less likely to have a significant memory impairment

What does a primary sensory problem in Parkinson’s disease (PD) suggest?

In early-stage PD, predominant sensory symptoms (e.g., pain, tingling, or loss of smell) may indicate a non-motor presentation of the disease. Non-motor dominant PD may be associated with a higher risk of cognitive decline over time.

Pathogenesis of Parkinson Disease

1. Triggers

2. Begins in gut and/or olfactory bulb

3. Misfolding of alpha synuclein: loss of smell/constipation; can see misfolded proteins in retina

4. Travels to brain via Vagus or CN1

5. Damages Dopaminergic Substantia Nigra Pars Compacta

6. Causes a patterned spread

What are some Parkinson Disease triggers?

• Genetic mutation in alpha synuclein gene

• Chronic pesticide and herbicide exposure (~250x increased risk)

• Pollution

• Infection with certain gut bacteria

• Low SCFA

How long does it take for the misfolded alpha synuclein to travel to the brain?

~10-15 years

How long does it take for the patient to show symptoms from the misfolded alpha synuclein entering the brain?

~10-15 years

How does PD spread once in the brain?

It spreads to the Dorsal Motor Nucleus (DMX) of Vagus, then to the midbrain. Eventually, it affects the substancia nigra pars compatca of the midbrain

When the substancia nigra pars compacta of the midbrain is affect, what happens?

Lewy Bodies form and are made of misfolded alpha synuclein. There is also a loss of dopaminergic neurons, causing hypokinetic presentaions. Treatement usually begins at this point.

What are the treatments for PD?

• Increase dopamine:

  • Levodopa with carbidopa

  • Inhibition of clearance nezymes

    • MAO B inhibitors

    • COMT inhibitors

  • D2 agonists

• Other:

  • Memantine (namenda) to decrease excitotoxicity

  • Cholinergics (Aricept) to improve brain activity

• Surgery: Deep brain stimulation (DBS); involve putting electrodes into the brain

What are the side effects of the oral medications for PD?

If there is too much Rx, there is an increase in unwanted movement = Dyskinesia (abnormal movements)

What are some key characteristics for Huntington Disease?

• Hyperkinetic: involuntary movements from damaged basal ganglia (unable to suppress unwanted movements)

• AD huntingtin protein

• Incurable

• Autosomal Dominant disease

What are the clinical presentation of Huntinton’s Disease?

• Chorea: purposeless dance-like movements

• Athetosis: snake-like movements of hands

• Abnormal eye movements: Saccades

• Severe Dementia

What is the pathology of Huntington’s Disease?

Misfolded proteins accumulates in the basal ganglia, affecting the caudate and putamen (responsible for inhibiting unwanted movements) and enlarge ventricles

What is Creutzfeldt-Jakob Disease?

A neurodegenerative disease caused by prions.

What is the clinical presentation of Creutzfeldt-jakob disease?

• Rapid deterioration

• Ataxia

• Dementia

• Impaired motor:

  • speech

  • swallowing (dysphagia)

  • Sudden jerky movement

• Die within a year of diagnosis

How does the brain appear histologically from CJD?

spongy appearance

What is Chronic Traumatic Encephalopathy?

A progressive neurodegenerative disease caused by repeated head injuries/concussions.

What is the epidemiology of Chronic Traumatic Encephalopathy?

• athletes

• military

• traumatic brain injury

What are the presentations of chronic traumatic encephalopathy?

• Emotional dysregulation: judgement, anger, impulse control

• Dementia

What is the pathogenesis of chronic traumatic encephalopathy?

• Multiple concussions: coup and countercoup, rotation causes axonal shearing between cortex and white matter and within white matter

• Tau misfolding induced by inflammation: amygdala