Patho Lecture 12 (CNS I: Neurodegenerative diseases)

What are the 2 neurodegenerative diseases covered?

- Alzheimer's disease

- Parkinson's disease

In Neurodegenerative diseases, what happens to neurons?

Neurons degenerate (deteriorate) in these diseases

Glial cells: What are the main glial cells found in the CNS vs. the PNS?

CNS: Ependymal cells, Astrocytes, Microglia, Oligodendrocytes

PNS: Schwann cells, Satellite cells

Glial cells: What do ependymal cells do?

- Form barriers between brain compartments

- Serve as a source of neural stem cells

Glial cells: What are the main roles of astrocytes?

- Take up K+, water, neurotransmitters

- Secrete Neurotrophic factors

- Help form the Blood-brain barrier

- Provide energy substrates for ATP production

Glial cells: What is the job of microglia?

Act as scavengers -- clean up dead cells and debris in the CNS

Glial cells: What is the difference between Oligodendrocytes and Schwann cells?

- Oligodendrocytes (CNS): Form myelin sheaths around multiple axons

- Schwann cells (PNS): Form myelin sheaths around a single axon and release neurotrophic factors

Glial cells: What do satellite cells do in the PNS?

Support neuron cell bodies

Neurodegenerative diseases: Alzheimer's disease

Region: Hippocampus and neocortex

Function: Memory, learning, behavior, language

Neurodegenerative diseases: Parkinson's disease (also Huntington's disease)

Region: Basal ganglia

Function: Voluntary movement

Neurodegenerative diseases: Ataxias

Region: Cerebellum

Function: Coordination and balance

Common pathological processes for Neurodegenerative diseases?

- Accumulation of protein aggregates (amyloidosis)

- Mechanisms of toxicity

- Neuroinflammation

What occurs in Amyloidosis (the accumulation of protein aggregates) for Neurodegenerative diseases?

- Mutations in the aggregated protein

- High expression

- Damage to proteins via oxidative stress

What occurs in Mechanisms of toxicity for Neurodegenerative diseases?

- Misfolded intermediates display toxicity

- Gain of toxic function and loss of normal function

What are the Protein inclusions/deposits for Dementia (Alzheimer's disease)?

> Alpha-beta plaques

> Tau (Tangles)

What are the Protein inclusions/deposits for Hypokinetic movement disorder (Parkinson's disease)?

> alpha-synuclein

Dementia

An umbrella term for the impaired ability to remember, think, or make decisions that interferes with everyday activities

What types of Dementia diseases fall under the Dementia umbrella?

- Alzheimer's (60%)

- Vascular dementia (20%)

- Lewy body dementia (15%)

- Frontotemporal dementia (5%)

- Other dementia

Alzheimer's disease: epidemiology (incidence)

- 6th leading cause of death in the US

- 6.5 M people with Alzheimer's disease

- 1 in 9 people over 65

- Increases with age

- More common in women

- The number of people with Alzheimer's disease is increasing

What are the characteristics of Early Onset Alzheimer's disease (familial)?

*Age of onset is (less than)

What are the characteristics of Late Onset Alzheimer's disease (sporadic)?

*Age of onset (greater than) ≥65 years of age

- (greater than) ≥95% of AD cases

- Most common type

- Can be familial

- Complex genetics with multiple genetic risk factors (disease-associated SNPs)

Genetic risk factors for Alzheimer's disease: Genetics of early-onset Alzheimer's disease

- APP (Amyloid precursor protein), PSEN1, PSEN2 (Presenilin1 and Presenilin2): Autosomal dominant, HIGH penetrance (genes expressed in phenotype)

- Trisomy 21 (Down syndrome)

Genetic risk factors for Alzheimer's disease: Risk alleles for late-onset Alzheimer's disease

- APOE

- Other risk alleles, including tau-related genes

Risk factors for Alzheimer's disease: What INCREASES your risk for Alzheimer's disease?

- Hypertension (high blood pressure)

- Diabetes

- Obesity

- Hypercholesterolemia

- Smoking

Risk factors for Alzheimer's disease: What decreases your risk for Alzheimer's disease?

- Statins

- Estrogens

- NSAIDs

- Mediterranean diet

- Vitamin C or E intake

- Moderate alcohol intake

- Exercise

- Cognitive reserve

What are Alzheimer's disease symptoms described as?

Progressive declines that are different than typical age-related changes

What are some clinical symptoms of Alzheimer's disease?

- Memory loss

- Challenges in planning or solving problems

- Difficult completing familiar tasks

- Confusion about time or pace

- Visual and spatial problems

- New problems with speaking or writing

- Misplacing items and inability to retrace steps to find them

- Decreased or poor judgment

- Social withdrawal

- Changes in mood, personality, and behavior

What are the different levels of clinical symptoms of Alzheimer's disease?

- Preclinical AD: No symptoms but possible biological changes in the brain

- Mild Cognitive Impairment due to AD: Very mild symptoms that may not interfere with everyday activities

- Dementia due to AD Mild: Symptoms interfere with SOME everyday activities

- Dementia due to AD Moderate: Symptoms interfere with MANY everyday activities

- Dementia due to AD Severe: Symptoms interfere with MOST everyday activities

What is the Gross anatomy of Alzheimer's disease?

- Decrease in overall brain weight

- Cortical atrophy

- Degeneration of neurons in the hippocampus and neocortex, loss of acetylcholine

- Loss of pigmented neurons in the locus coeruleus

- Areas preserved

What is Cortical Atrophy in Alzheimer's disease?

- Widening of sulcal spaces and narrowing of gyri

- Degeneration in the temporal, parietal, and frontal lobes

What Areas are preserved in Alzheimer's disease?

- Pigmented neurons in the substantia nigra

- Occipital lobe

- Cerebellum

What are the Pathological hallmarks required for diagnosis in Alzheimer's disease?

- Amyloid plaques

- Neurofibrillary tangles

Amyloid plaques

Aggregates of amyloid fibrils outside neurons, amyloid beta (Aβ)

Neurofibrillary tangles

Accumulation of hyperphosphorylated tau protein inside neurons, tau (microtubule-associated protein tau)

What are the Pathological hallmarks for Neuronal Loss in Alzheimer's disease?

- Glutamatergic pyramidal neurons in the entorhinal cortex and hippocampus

- Cholinergic neurons in the basal forebrain

- Noradrenergic neurons in locus coeruleus

Alzheimer's disease: APP cleavage: What is the normal cleavage pathway for APP and does it produce amyloid-B?

- APP is normally cleaved by alpha-secretase (then y-secretase)

- This pathway does NOT produce amyloid-B, so no plaques form

Alzheimer's disease: APP cleavage: What abnormal pathway leads to amyloid plaque formation in Alzheimer's disease?

- APP is abnormally cleaved by beta-secretase (followed by y-secretase)

- Produces amyloid-B (AB) peptides that accumlate into plaques

Alzheimer's disease: APP cleavage: What causes INCREASED amyloid-B production?

- Mutations in APP or presenilin genes (PSEN1/PSEN2) increase B-secretase or y-secretase activity

- Leads to excessive Ab and amyloid plaque formation

Alzheimer's disease: Tau pathology: What is the role of Tau protein in a "Normal" (healthy) brain?

- Microtubule-associated protein that plays a crucial role in maintaining the stability and structure of microtubules

- Allows proper neuronal function

Alzheimer's disease: Tau pathology: What happens to Tau protein in Alzheimer's disease?

- Tau becomes hyperphosphorylated, falls off the microtubules

- Forms Neurofibrillary tangles

Alzheimer's disease: Tau pathology: How do tau tangles damage neurons in Alzheimer's disease?

- Loss of Tau causes microtubule collapse

- Blocking intracellular transport and leading to neuronal dysfunction and death

Alzheimer's disease: Affected regions in the brain: Which pathology appears first in Alzheimer's disease -- amyloid plaques or tau tangles?

- Amyloid plaques appear first

- Accumulate silently in the preclinical phase

Alzheimer's disease: Affected regions in the brain: Where does tau pathology begin, and why is that clinically important?

- Tau tangles start in entorhinal cortex and hippocampus (memory centers)

- Tau spread correlates with symptom severity and cognitive decline

Alzheimer's disease: Affected regions in the brain: Which pathology correlates more strongly with clinical symptoms in Alzheimer's disease?

- Tau pathology correlates MORE with the symptoms and neuronal dysfunction (amyloid does NOT)

Alzheimer's disease: Affected regions in the brain: In what stage of Alzheimer's disease do patients typically show symptoms: preclinical AD, MCI due to AD, or AD dementia?

- Symptoms start in MCI due to AD

- Worsening as tau spreads

- Amyloid is usually already present

Characteristics of Alzheimer's disease neuroinflammation

- Activated microglia and astrocytes

- Dysregulated neuroinflammation is bad for neurons!

In Alzheimer's disease, neuroinflammation, what are the characteristics of Activated microglia and astrocytes?

- Triggered by aggregates

- Also leads to aggregation

In Alzheimer's disease neuroinflammation what results from dysregulated neuroinflammation?

- Increased tau phosphorylation

- Oxidative stress

- Abnormal pruning of synapses

What are the current FDA-approved treatments for alzheimer's disease?

- Symptomatic: Cognitive (memory and thinking) symptoms

- Disease-modifying: monoclonal antibodies against Aβ

What are some Symptomatic drugs that treat Alzheimer's disease?

- Aricept® (Donepezil): acetylcholinesterase inhibitor

- Razadyne® (Galantamine): acetylcholinesterase inhibitor

- Exelon® (Rivastigmine): acetylcholinesterase inhibitor

- Namedna® (Memantine): NMDA antagonist

- Namzaric (Memantine + Donepezil)

What are some Disease-modifying drugs that treat Alzheimer's disease?

- Aducanumab (Aduhelm) - discontinued

- Lecanemab (Leqembi)

- Donanemab (Kinsula)

Parkinson's disease: epidemiology (incidence)

> Age of onset: Typically 60s-70s (~95%); Early onset: before 50 (~5%)

> 90,000 new cases each year

>1-2% of the population over 65

> 1.2 M people in the US living with Parkinson's disease by 2030

> More common in men in the US

> Fastest growing neurological disease

Environmental risk factors for Parkinson's disease: What INCREASES your risk for Parkinson's disease?

- Exposure to specific types of pesticides and industrial toxicants

- Exposure to heavy metals

- Head injury

Environmental risk factors for Parkinson's disease: What decreases your risk for Parkinson's disease?

- Cigarette smoking

- Caffeine consumption

- Physical activity

Genetic risk factors for Parkinson's disease: Familial Parkinson's disease (5-10%)

- SNCA (α-synuclein)

- LRRK2

- GBA1

SNCA (α-synuclein)

- Protein found in Lewy bodies

- one of the pathological hallmarks of disease

Genetic risk factors for Parkinson's disease: Sporadic Parkinson's disease (90%)

- SNCA (α-synuclein)

- LRRK2

- GBA1

- HLA genes

What are the medical risk factors of Parkinson's disease?

- Constipation

- REM sleep behavior disorder

- Depression

- Hyposmia

- Excessive daytime sleepiness

- Diabetes

- High plasma urate (decreased risk)

Clinical symptoms of Parkinson's disease: Cardinal motor symptoms?

- Bradykinesia (slow movement)

- Rigidity (stiffness)

- Tremor (at rest)

- Postural instability

Clinical symptoms of Parkinson's disease: NON-motor symptoms?

- Constipation

- RBD

- EDS

- Loss of sense of smell

- Mood disorders

- Sexual dysfunction

Parkinson's disease vs. Essential tremor: What are some characteristics of Parkinson's disease?

- Resting tremor

- Unilateral onset

- Primarily hands and legs

- Other common symptoms

- L-DOPA responsive

Parkinson's disease vs. Essential tremor: What are some characteristics of Essential tremor?

- Action tremor

- Bilateral onset

- Hands, legs, head, and voice

- Typically, ONLY tremor

- NOT responsive to L-DOPA

Parkinson's Disease: Prodromal phase: What happens during the prodromal phase (pre-motor) phase of Parkinson's disease?

- Non-motor symptoms like constipation, REM sleep behavior disorder, loss of smell, depression and fatigue appear years before diagnosis

- Motor symptoms like tremor and bradykinesia appear later when enough dopamine neurons are lost

What are the Pathological hallmarks required for diagnosis in Parkinson's disease?

- Nigrostriatal degeneration

- Lewy bodies

Nigrostriatal degeneration

Degeneration of pigmented dopaminergic neurons in the nigrostriatal pathway

Lewy bodies

Aggregates of α-synuclein protein and other cellular components inside neurons of the substantia

What are the Pathological hallmarks required for Extra-nigral and peripheral pathology in Parkinson's disease?

- Lewy pathology in other regions of the central and peripheral nervous systems

What are the affected regions in Parkinson's disease?

- Enteric nervous system

- Olfactory bulb, brain stem

- Substantia nigra

- Neocortex

What is the role of the Basal ganglia in the brain?

*Controls voluntary movement

- Output to motor cortex

- Motor cortex sends info to muscles via the corticospinal tract

How is the Basal ganglia affected in Parkinson's disease?

- Loss of dopaminergic neurons in the SN decreases the activity of the motor cortex

- Decreased voluntary movement

What are the Molecular mechanisms of Parkinson's Disease?

- Mitochondrial dysfunction: MPTP, rotenone

- Autophagic and lysosomal dysfunction: LRRK2

- Neuroinflammation: NLRP3 inflammasome

Current FDA-approved treatments for Parkinson's disease: Symptomatic (motor symptoms) therapies

- Deep brain stimulation (DBS)

- Levidopa/carbidopa (most common treatment)

- Focused ultrasound

Current FDA-approved treatments for Parkinson's disease: DA replacement

- Levidopa/carbidopa: Sinemet, Dhivy, Duopa, Inbrija, Parcopa, Rytary

- Levodopa/carbidopa and entacapone: Stalevo

Current FDA-approved treatments for Parkinson's disease: Prevent breakdown of DA

- COMT inhibitors: Comtan (entacapone), Ongentys (opicapone), Stalevo (levodopa/carbidopa and entacapone), Tasmar (tolcapone)

- MAO-B inhibitors: Azilect (rasagiline), Xadago(safinamide), selegiline

Current FDA-approved treatments for Parkinson's disease: Mimic the action of DA

DA agonists: Apokyn (injectable apomorphine, Kynmobi(sublingual apomorphine), Mirapex, Mirapex ER(pramipexole), Neupro (rotigotine), Requip, Requip XL(ropinirole)