neurodegenerative diseases

how are neurodegenerative diseases characterized?

• by the abnormal aggregation of proteins

• degeneration of neurons

what are the pathophysiological characteristics of neurodegenerative diseases?

• which protein aggregates

• where aggregates occur

• which cells degenerate

what are the cells of the nervous system?

glial cells

what are neurodegenerative diseases in the hippocampus and neocortex?

• function: memory, learning, behavior, language, higher cognitive functions
• symptoms: Alzheimer's disease, memory loss, deficits in higher cognitive functions

what are neurodegenerative diseases in the basal ganglia?

• function: voluntary movement
• symptoms: problems with voluntary motion, tremor, loss of balance, Parkinson's disease (too little movement), Huntington's disease (too much movement)

what are neurodegenerative diseases in the cerebellum?

• function: coordination and balance
• symptoms: loss of coordination and balance, ataxias

what are the common pathological processes of neurodegenerative diseases?

• accumulation of protein aggregates (amyloidosis)
• neuroinflammation

what is accumulation of protein aggregates (amyloidosis)?

• mutations in the aggregated protein
• high expression
• damage to proteins via oxidative stress

what are the clinical patterns and protein inclusions/deposits of Alzheimer's disease (AD)?

• clinical pattern: dementia
• protein inclusions/deposits: Aβ (plaques), tau (tangles)

what are the mechanisms of toxicity?

• aggregates or misfolded intermediates
• gain/loss of function
• unclear which is the trigger and which one comes first

what are the clinical patterns and protein inclusions/deposits of Parkinson's disease (PD)?

• clinical pattern: hypokinetic movement disorder
• protein inclusions/deposits: ⍺-synuclein

what are the clinical patterns and protein inclusions/deposits of Huntington's disease (HD)?

• clinical pattern: hyperkinetic movement disorder
• protein inclusions/deposits: huntingtin (polyglutamine repeat expansions

what is dementia?

• an umbrella for the impaired ability to remember, think, or make decisions that interferes with everyday activities
• major diseases that can cause dementia: alzheimer's, cardiovascular disease
• depression, sleep apnea, lyme disease, thyroid problems, excessive alcohol use, etc.

what is the epidemiology of alzheimer's disease?

• 6th leading cause of death in the US
• 6.5 million people with AD
• 1 in 9 people over 65
• increases with age
• more common in women (almost double risk)
• number of people with AD is increasing
• doesn't occur with normal aging

what is early-onset AD?

• familial
• age of onset <65 yrs of age
• <5% of AD cases
• mendelian genetics: autosomal dominant inheritance
• 3 known genes (PSEN1, PSEN2, APP)

what is late-onset AD?

• sporadic
• age of onset >65 yrs of age
• >95% of AD cases
• can be familial
• complex genetics with multiple genetic risk factors (disease-associated SNPs)

what are the genetic risk factors of early-onset AD?

• APP (amyloid precursor protein, PSEN1, PSEN 2 (presenilin1 and presenilin2): autosomal dominant, high penetrance
• trisomy 21: APP is on the chromosome (high expression of APP)

what are the genetic risk factors of late-onset AD?

• APOE: E4 allele, E2 allele
• other risk alleles, including tau-related genes (increase/decrease risk of disease, doesn't cause it)

what are the decreased modifiable risk factors of AD?

statins, estrogens, NSAIDs, mediterranean diet, vitamin C or E intake, moderate alcohol intake, exercise, cognitive reserve

what are the increased modifiable risk factors of AD?

hypertension, diabetes, obesity, hypercholesterolemia, smoking

what are the clinical symptoms of AD?

• memory loss
• challenges in planning/solving problems
• difficult completing familiar tasks
• confusion about time/pace
• visual and spatial problems
• new problems with speaking/writing
• misplacing items and inability to retrace steps to find them
• decreased/poor judgment
• social withdrawal
• changes in mood, personality, and behavior

what is the process of development of symptoms of AD?

→ 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 AD?

• decrease in overall brain weight
• cortical atrophy: widening of sulcal spaces and narrowing of gyri; degeneration in temporal, parietal, and frontal lobes
• degeneration of neurons in the hippocampus and neocortex, loss of ACh
• loss of pigmented neurons in the locus coeruleus
• areas preserved: pigmented neurons in the substantia nigra, occipital lobe, cerebellum

what are the pathological hallmarks of AD required for diagnosis?

• amyloid plaques: aggregates of amyloid fibrils outside neurons, amyloid beta
• neurofibrillary tangles: accumulation of hyperphosphorylated tau protein inside neurons, tau (microtubule-associated protein tau)

what are the pathological hallmarks of AD regarding neuronal loss?

• glutamatergic pyramidal neurons in entohinal cortex and hippocampus
• cholinergic neurons in basal forebrain
• noradrenergic neurons in locus coeruleus

what is the process of APP cleavage?

normal cleavage of APP:
→ APP cleaved by ⍺-secretase
abnormal cleavage of APP leading to excess amyloid accumulation:
→ APP mutations increase β-secretase cleavage
→ PSEN1/PSEN2 mutations increase 𝛾-secretase activity
→ Aβ peptide
→ amyloid plaque

what is the Tau pathology in AD?

• Tau protein tangle
• neurofibrillary tangle
• disintegrating microtubule
• diseased neuron

what does Tau do?

• stabilizes microtubules
• disintegrate tracks of microtubules

what occurs with neuroinflammation in AD?

• activated microglia and astrocytes: triggered by aggregates and lead to aggregations
• dysregulated neuroinflammation is bad for neurons: increased tau phosphorylation, oxidative stress, abnormal pruning of synapses

what are the symptomatic FDA-approved treatments of AD?

• cognitive (memory and thinking) symptoms
• focused on restoring pathways

what is the process of

what are the disease-modifying FDA-approved treatments for AD?

monoclonal antibodies against Aβ

what is the epidemiology of parkinson's disease?

• typical age of onset: 60s-70s (~95%)
• early onset: before 50 (~5%)
• 90,000 new cases each year
• 1-2% of the population over 65
• 1.2 million peopls in the US living with PD by 2030
• more common in men in the US (1.5x more)
• fastest growing neurological disease

what are the environmental factors of increased risk of PD?

• exposure to specific types of pesticides and industrial toxicants
• exposure to heavy metals
• head injury

what are the environmental factors of decreased risk of PD?

• smoking cigarettes
• caffeine consumption
• physical activity

what are the genetic risk factors of familial PD?

• 5-10%
• SNCA (⍺-synuclein): protein found in Lewy bodies, one of the pathological hallmarks of disease
• LRRK2
• GBA1

what are the genetic risk factors of sporadic PD?

• ~90%
• SNCA (⍺-synuclein)
• LRRK2
• GBA1
• HLA genes: involved in making Ab

what are the medical risk factors of PD?

• constipation
• REM sleep behavior disorder
• depression
• hyposmia
• excessive daytime sleepiness
• diabetes
• high plasma urate (decreased risk)

what are the cardinal motor symptoms of PD?

• bradykinesia (slow movement)
• rigidity (stiffness)
• tremor (at rest)
• posutral instability

what are the non-motor symptoms of PD?

• constipation
• RBD
• EDS
• loss of sense of smell
• mood disorders
• sexual dysfunction

what is the prodromal phase of PD?

by the time people are diagnosed 50% of cell bodies lost 80% of input lost

what are the characteristics of a parkinson's tremor?

• resting tremor
• unilateral onset
• primarily hands and legs
• other common symptoms
• L-DOPA responsive
• not sensitive to alcohol consumption

what are the characteristics of an essential tremor?

• action tremor
• bilateral onset
• hands, legs, head, and voice
• typically only tremor
• not responsive to L-DOPA
• temporarily reduced by alcohol consumption

what are the pathological hallmarks of PD required for diagnosis?

• 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 of PD regarding extra-nigral and peripheral pathology?

lewy pathology in other regions of the CNS and PNS

what can be seen with nigrostriatal degeneration?

loss of pigment and DAT expression in striatum (can confirm diagnosis)

what are the affected regions of PD?

enteric nervous system → olfactory bulb, brain stem → substantia nigra → neocortex

what are the regions affected in the presymptomatic phase?

enteric nervous system, olfactory bulb, brain stem, substantia nigra

what are the regions affected in the symptomatic phase?

enteric nervous system, olfactory bulb, brain stem, substantia nigra, neocortex

what is the importance of basal ganglia in PD?

• controls voluntary movement: output to motor cortex, which sends info to muscles via the corticospinal tract
• loss of dopaminergic neurons in SN decreases activity of motor cortex
• decreased voluntary movement

what are the molecular mechanisms of PD?

• mitochondrial dysfunction: MPTP, rotenone
• autophagic and lysosomal dysfunction: LRRK2
• neuroinflammation: NLRP3 inflammasome

what are the symptomatic FDA-approved treatments for PD?

• deep brain stimulation (DBS): intraperative effects of STN DBS on essential tremor; effects of STN DBS on PD symptoms after surgery
• levidopa/carbidopa (most common)
• focused ultrasound

what are the mechanisms of FDA-approved treatments for PD?

• DA replacement: levidopa/carbidopa and entacapone
• prevent breakdown of DA: COMT and MAO-B inhibitors
• mimic the action of DA: DA agonists

what is the process of the mechanism of action of drugs against PD?

→ DA replacement: levidopa in cerebral vessel
→ AADC inhibitors: release dopamine in cerebral vessel
→ COMT inhibitors (peripheral): release 3-OMD in cerebral vessel
→ specific MAO-B inhibitors: release DPAC in CNS
→ COMT inhibitors (central): release 2MT in CNS
→ amantadine stimulates dopamine in synapse
→ dopamine receptor agonists stimulate dopamine receptor