Neuropathology: Common neurocognitive disorders Flashcards
NEurodegenerative disorders:
Progressive loss of neurons with associated secondary changes in white matter tracts.
-Selective, affecting one or more groups of neurons while leaving others intact.
(sometimes neurons next to degenerative ones are completely normal)
Finding common to many are protein aggregates that are resistant to degradation through the ubiquitin-proteasome system. (form inclusions within neurons)
Some of these disorders are extremely common: Parkinson’s, & Alzheimer’s
What is dementia?
early: mild neurocognitive disorder
Late: major neurocognitive disorder
-Generalized, progressive impairment of cognitive function, accompanied by impairment in ADL’s
-Not impaired level on consciousness
-Executive function, memory, and attention can be affected.
ADLs/iADLs:
Activities of daily living vs. instrumental activities of daily living:
-iADLs: things you do every day to take care of yourself and your home. One way to measure how you can live on your own. (require more complex planning)
-ADLs: basic self-care tasks like bathing
Classifying severity of Dementia:
Mild neurocognitive disorder:
-ADLs not significantly impaired
-Reduction in function of one (or more) major cognitive domain noted. (complex attention, executive function, learning and memory, language, perceptual-motor, or social cognition)
-Often the patient is aware (and frustrated by deficit)
Major neurocognitive disorder:
-ADLs & iADLs are affected
(often iADLs are affected first: shopping, food preparation, finances, and medication management)
-Larger impairment of one or more major cognitive domains
-Often patient is relatively unaware of cognitive deterioration
Alzheimer’s disease:
Most common cause of dementia in the elderly:
-prevalence of 1 in 8 in older populations, 40% in those in the 80–90-year-old group
-6th leading cause of death
General pathological findings:
-neurofibrillary tangles
-beta-amyloid plaques
-cerebral atrophy
-often loss of widely distributed cholinergic neurons in the nucleus basalis of meynert
Alzheimer’s pathology:
Neurotic plaques (beta-amyloid):
-focal, spherical collections of dilated, tortuous, neurotic processes (dystrophic neurites)-Often around the amyloid core, which may be surrounded by clear halo
Amyloid core contains several abnormal proteins:
-Aβ, a peptide derived through specific processing events from a larger molecule, amyloid precursor protein (APP)
-Other proteins are present in plaques in lesser abundance, including components of the complement cascade and pro-inflammatory cytokines
Neurotic plaques (beta-amyloid) cont:
Range in size from 20-200um in diamter
-Microglial cells and reactive astrocytes are present at their periphery
-Plaques are found in the hippocampus, amygdala, and neocortex. (primary motor and sensory cortices tend to be spared)
Neurofibrillary tangles:
-bundles of filaments in the cytoplasm of the neurons that displace or encircle the nucleus
-basophilic fibrillary structures with H&E staining
-Commonly found in cortical neurons: especially in the entorhinal cortex, pyramidal cells of the hippocampus, amygdala, basal forebrain
-Insoluble and resistant to clearance in vivo: a major component of many “tangled filaments’ is abnormally hyperphosphorylated forms of the protein tau
Tau=axonal microtubule-associated protein that enhances microtubule assembly
-Other components include MAP2 (another microtubule-associated protein) and ubiquitin
Alzheimer’s disease pathophysiology:
What is APP for?
-membrane-associated protein that is thought to be a receptor for an as yet unidentified ligand
-Is cloven as part of the abnormal breakdown of cellular proteins: depending on where it is cut, it can either be soluble or insoluble/ insoluble forms accumulate in the extracellular space and is thought to be important in the pathogenesis of Alzheimer’s disease.
-Aggregates of beta-amyloid are directly neurotoxic and also active microglia and astrocytes, resulting in chronic inflammatory injury to neurons
-It is thought that accumulation of beta-amyloid is responsible for neurofibrillary tangles within neurons
Genetic factors for AD:
Presenilin 1 & presenilin 2:
-Associated w/ severe early-onset AD
-Variants in a normal gene whose protein is very important in regulating neuronal intracellular calcium levels in association w/ LTP (long-term potentiation)
-Interestingly, same protein is also involved in cleaving APP (performs similar function as secretase)
Apolipoprotein E4:
-One of the 4 subtypes of apolipoproteins that help transport cholesterol throughout the CNS
-Those that are heterozygous for E4 have approximately double the risk of late-onset AD (LOAD) (about 25% of the Caucasian population): those that are homozygous have a 16X increased risk of LOAD/ Apo E4 positivity is not as strongly “causative” of AD as presenilin mutations that increase risk of AD
The infectious theory of Alzheimer’s disease (less accepted, will likely be abandoned):
APP may be a primitive component of the innate immune system:
-seems to cause death of bacteria and viruses
-What virus is getting into the brain?
Herpes family: HSV-1, HHV-6, & HHV-7.
HHV 6 & 7: viruses that cause benign skin infections in kids, however, the virus seems to be able to migrate into the CNS & remain dormant.
-In some Alzheimer’s patients, the amyloid accumulation may lead to chronic inflammation instead of performing a virus-fighting role.
Insulin resistance & AD:
Type II diabetes: The most common disorder of glucose metabolism
-Due to genetic and lifestyle factors, the diabetic patient develops insulin resistance. (Fewer receptors. Downregulation of intracellular signaling linked to the insulin receptor)
You already know that insulin:
-Increases “storage” of glucose: glycogenesis in the liver
-Decreases “new production” of glucose: gluconeogenesis in the liver
-Inhibits lipogenolysis
-Insulin also increases the transport of glucose from the bloodstream into liver & muscle
-Therefore, type II diabetics have long-term increased blood levels of: glucose, free fatty acids
DM II as a causative factor in AD:
Insulin resistance seems to be an important component of AD pathophysiology in a large component of the population.
-AD is much more common in those with type II diabetes mellitus than in those w/out
Why?
-Insulin resistance likely reduces synaptogenesis.
Insulin seems to have a role in normal neuronal physiology and synaptic plasticity.
As resistance in insulin builds due to long-term hyperglycemia, then the intracellular signaling cascades are downregulated=> decreased plasticity
Insulin resistance increases the levels of circulating pro-inflammatory cytokines.
(May lead to glial activation=> neuronal damage)
Insulin resistance is linked (partially caused) by long-term hyperglycemia.
-As blood glucose increases, it becomes non-enzymatically linked to the basement membrane of brain capillaries => a “leaky” blood-brain barrier
-An extracellular protein whose function is altered by high levels of glucose binding to it=AGE (advanced glycation end-product)
Systemic pro-inflammatory cytokines can then leak through into the brain => maladaptive glial activation and neuronal damage.
Insulin resistance is linked to elevated levels of free fatty acids (FFA) in blood.
-Decreased insulin activity=> increased triglyceride breakdown=> increased circulating FFAs
-High levels of FFAs can cause microglial activation=> neuronal damage
Alzheimer’s disease clinical features:
Slow development of impaired cognition:
-short term memory and executive dysfunctions (planning, logic) impaired relatively early
(personality changes and loss of normal inhibitions can follow sometime after)
-Language deficits and loss of learned motor skills tend to result from more advanced disease
-Incontinence and impaired ambulation result from severe disease. (impaired mobility related to development of pneumonia and sepsis)
4 A’s and 1 D:
-Anterograde
-Aphasia
-Apraxia-difficulty with motor planning to perform tasks or movements
-Agnosia- difficulty recognizing/identifying objects, persons, or sounds although sensation is intact
-Disturbance in executive function
Anterograde amnesia + at least one of the other criteria are used to help make the diagnosis
Dementia w/ Lewy bodies:
Genetically-determines disorder:
-tau protein is mutated (results in aggregation of tau protein, or alteration of how tau interacts w/ microtubules
-Frontal and temporal lobes show more marked atrophy
Parkinson-like movement disorder:
-Temor, rigidity, bradykinesia
-typically, the dementia antecedes (come before) the movement symptoms, or presents early with the movement disorder
Dementia that usually pre-dates the diagnosis of Parkinson’s: presence of Lewy bodies in neurons: likely aggregates of misfolded alpha-synuclein
0.1-5% of general elderly population
Clinical features of Dementia w/ lewy bodies:
Fluctuations in cognitive function with varying levels of alertness and attention. (AD tends to be more constant)
Visual hallucinations that are vivid (other hallucinations may be present/ AD rarely involves hallucinations)
Parkinsonian motor features (usually later or close to the same time as the onset of dementia)
Anterograde memory loss: usually less prominent than that found in AD
More prominent executive function deficits.
Psychosis:
impairment in reality testing: characterized by delusions and hallucinations.
