Neurodegenerative diseases Flashcards
neurodegenerative disorders
characterized by progressive dysfunction and death of neurons
- Abnormal accumulations of specific proteins in the brain
degeneration repercussions
often affects specific systems, implying selective vulnerability ⇒ not all brain regions are the same and some may be affected by certain toxins or not
pathophysiology of neurodegenerative diseases (3)
- Aging is generally the most important risk factor
- Interaction between genetic and environmental factors ⇒ Parkinson’s and MS
- Genetic and sporadic forms
prevalence
proportion of people in the population affected by each disease
incidence
rate or frequency of the disease
what % of neurodegenerative disease is AD?
75% followed by parkinson’s and MS
types of neurodegenerative diseases (2)
- cognitive
- motor
cognitive disorders
degeneration affects the cerebral cortex, leading to dementia
- Alzheimer’s disease (AD), frontotemporal dementia (FTD), Pick’s disease
motor disorders (4)
- Degeneration affects motor neurons leading to motor weakness
- Amyotrophic Lateral Sclerosis (ALS) aka Lou Gherigs disease, spinal muscular atrophy (SMA) - Degeneration affects cerebellum and tracts leading to Cerebellar ataxia
- Spinocerebellar ataxias (SCA) - Degeneration affects substantia nigra and basal ganglia leading to akinetic and rigid movements
- Parkinson’s disease (PD), progressive supranuclear palsy (PSP) => akinetic - Degeneration affects basal ganglia leading to hyperkinetic movements
- Huntington’s disease (HD) => hyperkinetic
Ataxia
lack of voluntary coordination of muscle movement and ability to maintain proper gait when standing and walking ⇒ can translate into speech abnormalities
Akinetic
Akinetic
hyperkinetic
high tuned and sometimes uncontrolled muscle movements
brain structures affected in Huntingtons
caudate nucleus, striatum, and frontal cortex
brain structures affected in AD
hippocampus, entorhinal, and frontal cortex
brain structures affected in frontotemporal dementia
frontal and temporal cortex
brain structures affected in PD
substantia nigra
brain structures affected in cerebellar ataxia
cerebellum neuron loss
- all brain cells may express mutant proteins but certain brain regions will degrade first
brain structures affected in Amyotrophic lateral sclerosis
motor neurons
protein aggregates
occur within cells (protein inclusions) and occur outside the cells in extracellular space (plaque)
- There can be misfolded proteins that form aggregated inside and outside of cells
- there are both neuron and glial inclusions in the disorders
how does inflammation work in neurodegenerative diseases?
we often see inflammation due to the substances which the body will attack as if it is foreign
- protein aggregates will form in cells and the neurons will be harmed as they become larger
- The neurons will release molecules called DAMPS ⇒ damage associated molecular patterns
DAMPS
molecules that can activate certain receptors in immune cells
- Microglia share same origin as immune cells which express pattern recognition receptors that sense the presence of DAMPS to start immune response
- This triggers an inflammation cascade
- Particularly in areas where the blood brain barrier is compromised ⇒ macrophages will invade the brain and contribute to further information which creates worse symptoms
Alzheimer’s disease
progressive neurodegenerative dementia, whose duration (death) of the disease can vary from 3 years to 20 years ⇒ after clinical manifestation
- Most common type of dementia in the elderly ⇒ decline in mental ability severe enough to interfere with daily life
- Difficult to perform activities of daily living
ow many Americans have dementia in 2024
7 million
classifications of AD (% genetic)
- 98% sporadic ⇒ late onset AD
- 2% familial ⇒ early onset AD (as early as 24)
genes in AD (3)
- APP ⇒ chromosome 21 (Amyloid Precursor Protein)
- PSEN1 ⇒ chromosome 14 (Presenilins)
- PSEN2 ⇒ chromosome 1 (Presenilins)
histological features of AD (4)
- Gyri are smaller and sulci are larger (loss of 30%)
- the lateral ventricles are larger and so is 3rd ventricle
- hippocampus is mostly gone and the surrounding enteral cortex is also gone
- extracellular accumulation of amyloid-beta (Abeta) in amyloid plaques (brown) and intracellular accumulation of tau inclusions forming neurofibrillary tangles (black)
MCI AD; characterization?
mild cognitive impairment which leds to AD ⇒ characterized by neuronal death (first phase)
Preclinical AD
misfolding and aggregation of ABeta and Tau leading to plaques and NFT’s
- 2-3 decades long ⇒ can tell us there may be identifiable signs
clinical presentation of Alzheimers early on (3)
- Memory loss that disrupts daily life
- Confusion with time or place
- Trouble with visual and spatial
clinical presentation of Alzheimers later on (4)
- Challenges in planning or solving problems
- New problems with word finding and speaking
- Decreased or poor judgment
- Changes in mood or personality (second phase)
Apolipoprotein E (APOE4)
depending on how many copies your risk will increase for AD
- 2, 3, or 4 copies
- 2 copies makes you 12x more likely
- 1 copy makes you 3x more likely
symptomatic treatments for AD (2)
- Cholinesterase inhibitors ⇒ the original brain area that degenerates characteristically has cholinesterase
- Donepezil (Aricept)
- Rivastigmine (Excelon)
- Galantamine (Razadyne) - NMDA receptor antagonists ⇒ prevent neuron loss
- Memantine-HCl (Namenda)
disease modifying agents for AD
Aggregated ABeta antibodies ⇒ antibodies targeting ABeta only for those in MCI stage
- Donanemab (Kisunla)
- Lecanemab (Lequembi)
what happens to some people taking the ABeta antibodies?
may have swelling/bleeds in the brian which can cause seizures and other symptoms (rare)
- APOE4 carriers are at greater risk of complications
- only for MCI and mild AD with relatively modest effects of 20%
Parkinson’s disease
belongs to a group of conditions called motor system disorders which are the result of the loss of dopamine-producing brain cells in the substantia nigra (>50-70%)
- Named after physician James Parkinson
classifications of PD (% genetic)
- 95% sporadic and occurs late onset PD
- 5% familial for early onset PD
genes for PD (5)
- SNCA (alpha-synuclein)
- Parkin
- DJ-1
- PINK1 (PTEN-induced kinase 1)
- LRRK2 (Leucine-Rich repeat kinase 2)
Sporadic PD
associated with risk factors, notably aging (>50 years) and exposure to pesticides (rotenone) or herbicides (Agent orange) ⇒ why midwest has a lot of cases particularly
histological features of PD
loss of neurons in Substanta nigra
- Lewy bodies and Lewy neurites are intracellular aggregates of alpha-synuclein in the soma and neurites respectively
symptoms of PD (4)
- Tremor: trembling in hands, arms, legs, jaw, and face ⇒ resting tremor
- Rigidity: stiffness of the limbs and trunk
- Bradykinesia: slowness of movement ⇒ patients usually cannot turn while walking
- Postural instability: impaired balance and coordination
PD onset symptoms that are non-motor (5)
- Sleep disorders
- Autonomic function
- Sensation
- Mood disorders
- Cognitive impairment
→ in the advanced stages of the disease, cognitive and behavioral problems may arise, with dementia commonly occurring ⇒ 30-80% of subjects with PD
symptomatic treatments of PD (3)
- L-Dopa ⇒ complement the loss of dopamine cells
- Dopamine receptor agonist (loss dop cells)
- Deep brian stimulation (DBS) ⇒ UMN does this which introduces a pacemaker in the brain to stimulate regions of specific neurons
Note: there is currently no cure but treatments exist to drastically relieve motor symptoms
Multiple Sclerosis
chronic, inflammatory, demyelinating and neurodegenerative disease of the central nervous system (CNS) ⇒ likely affecting glial cells
- MS is a heterogenous, multifactorial, immune mediated (autoimmune) disease that is caused by complex gene environment interactions
- Immune cells attack the glial cells myelinating in the CNS
4 clinical courses of MS
- Relapsing remitting MS (RRMS) ⇒ 85%
- Secondary progressive MS (SPMS) ⇒ 85%
- Primary progressive MS (PPMS) ⇒ 10-15% (gradually progressive)
- Progressive relapsing MS (PRMS) ⇒ rare
symptoms of MS (4)
Immune mediated inflammatory demyelinating disease of the CNS
- Optic neuritis (early)
- Clumsiness and muscle weakness
- Paresthesias ⇒ abnormal feeling in skin
- Lhermitte sign ⇒ discharge feelings when you do movements of your neck
treatment options of MS (3)
- corticosteroids
- Beta interferons 1A and 1B
- glatiramer acetate
pathological features of MS (6)
- white matter ⇒ myelin pathology (blue arrowheads) by antibody labeling (brown) or by MRI
- Retina ⇒ thinning of the peripapillary retinal nerve fiber layer
- grey matter ⇒ myelin pathology (blue arrowheads) by antibody labeling (brown) or by MRI
- meninges ⇒ vascular pathology (blue arrowheads) by MRI or by histology staining pink
- optic nerve ⇒ myelin pathology by MRI (pink circle) and antibody labeling (brown)
- thalamus and pons ⇒ myelin pathology (blue arrowheads) by antibody labeling (brown) or by MRI
pathological hallmarks of MS plaques (4)
- Inflammation
- Demyelination
- Oligodendrocyte death
- Axon degeneration
symptomatic treatments for MS (2)
- Corticosteroids
- Reduce inflammation - Plasma exchange
- Slows down functional decline (breathing)
Disease modifying treatments for MS
- Ocrelizumab (Ocrevus)
- For primary progressive MS and only FDA approved disease modifying therapy ⇒ those receiving the treatment are slightly less likely to progress than untreated people - Many treatment options available
- For relapsing remitting Ms, several disease modifying therapies are available - New treatments soon possibly
- For secondary progressive MS there is tolebrutinib (Sanofi) which is a BTK inhibitor ⇒ 30% delay in onset of disability progression
