Neurodegenerative Diseases Pt. 1 Flashcards
What are the 3 poles of the cerebral cortex?
- Frontal
- Temporal
- Occipital
What are the 6 layers of the neocortex?
- Molecular layer
- External granular layer
- External pyramidal layer
- Internal granular layer
- Internal pyramidal layer
- Multiform layer
What are the primary cortices?
- Somatosensory
- Motor
- Visual
- Auditory
What is the difference between unimodal and heteromodal association cortices?
- Unimodal: concerned with integration of function from a single area
- Heteromodal: higher order information processing: integration of function from multiple sensory and/or motor modalities
What is Papez circuit?
Limbic structures: Cingulate to hippocampus to fornix to mammillary bodies to thalamus
What are the Outer Core-Cortical Components of the brain? (what functions do they serve?)
- Cingulate cortex (emotional and motor; visual spatial and memory)
- Orbital frontal lobe (personality, behavior)
- Temporal lobe (memory)
What are the inner core subcortical components? (what function do they serve)
- Hypothalamus (pleasure center, autonomic, endocrine integration)
- Amygdala (preservation of self behaviors)
- Septum (preservation of species behaviors - sex)
Lesions in hippocampus, dorsal medial nucleus of the thalamus, mammillary nuclei alone or in combination can lead to _______ states
Amnestic
What are the two parts of declarative memory (hippocampus)?
- Episodic - personal events in one’s life, actively remembered
- Semantic - facts, known rather than actively remembered
What are the two forms of longterm memory?
Explicit (declarative)
Implicit (nondeclarative)
What are the functions of the following brain regions?
- Frontal cortex:
- Hypothalamus:
- Frontal cortex:
- Highest cognitive functions; emotional control
- Hypothalamus:
- Primitive emotional responses
What two different types of output neurons (dopamine receptors) in the striatum are affected by dopamine?
- Neurons with D1 dopamine receptors (excite direct pathway and facilitate movement)
- Neurons with D2 dopamine receptors (inhibit indirect pathway → disinhibition; facilitate movement)
What is the difference between the direct and indirect nigrostriatal pathway in terms of thalamus function?
- Indirect pathway: thalamus is inhibited
- Direct pathway: Thalamus is disinhibited (excited)
Fill in the blanks
What are common features of Neurodegenerative diseases?
- Selective vulnerability of specific neurons and systems
- Misfolded and/or aggregated proteins
- Sporadic and familial forms
What are characteristics of gray matter diseases? (Selective vulnerability)
- Progressive loss of neurons
- Groups of neurons and associated fiber tracts
- Functionally related and relatively symmetric
What are common cellular hallmarks in many degenerative diseases? (Misfolded or aggregated proteins)
- Resistance to normal degradation processes (ubiquitin proteosome system)
- Often form inclusions
- Cytotoxic to neuron
What are possible etiologies of neurodegenerative diseases?
- Genetic mutations
- Genetic polymorphisms
- Aging
- Environmental toxins
What are the cellular mechanisms of neurodegenerative diseases?
- Oxidative stress (ROS)
- Inflammation
- Disruption of axonal transport and synaptic function
- Dysfunctional waste clearance
- Mitochondrial dysfunction
- Programmed cell death (apoptosis)
What are the three main causes of neurodegeneration?
Environmental toxins
Neuronal metabolism
Aging
How can ROS, oxidative stress, and exitotoxicity lead to cell death?
- DNA damage
- Lipid peroxidation
- Protein damage
How does cell membrane damage arise from dysfunctional mitochondria?
- Toxins and aging lead to loss of mitochondrial function
- Inefficient mitochondrial electron transport “leaks out” electrons; oxygen radicals
- Complex 1 is vulnerable to injury in response to free radicals
- Free radicals → lipid peroxidation → loss of membrane integrity
What reactive molecules cause oxidative stress?
Hydrogen peroxide and superoxide
How does superoxide perpetuate excitotoxicity (damage of neurons)?
Superoxide → **Persistent activation of NMDA receptors **→Excess intracellular calcium → ATP depletion (so cells can’t get rid of calcium) → Cell death → excess glutamate → Persistent activation of NMDA receptors
What mechanisms does the cell have to deal with oxyradicals?
- Ascorbate
- Glutathione
- Superoxide dismutase
- Catalase (inactivated hydrogen peroxide)
What is the most common form of dementia?
Alzheimer’s Disease
What is the clinical definition of Alzheimer’s Disease?
Gradual and progressive decline in cognitive funciton with impairments in recent memory and one additional cognitive domain that is not due to other medical or psychiatric illness, and results in a functional impairment socially or occupationally
What Cognitive Domains can be affected in Alzheimer’s disease?
- Memory
- Language
- Abstract thinking and judgment
- Visuo-spatial or perceptual skills
- Praxis
- Executive function
What are the diagnostic criteria for:
- Definite DAT (dementia of Alzheimer type):
- Probable DAT:
- Definite DAT (dementia of Alzheimer type):
- Criteria for Probable DA and Histopathalogic evidence
- Probable DAT:
- Dementia
- Two areas of cognitive impairment
- Progression over time
- Normal sensorium
- Age of onset between 40-90 years
- No other disease causing the dementia
What are the diagnostic criteria for Possible DAT?
- Atypical onset, presentation, or progression without known etiology
- Systemic or other brain disease capable of producing dementia
- Gradually progressive decline in a single intellectual function in the absence of any other cause
What is seen in Stage 1 of DAT? What is the duration
1-3 years
- Memory (new learning defective)
- Visuospatial skills (topographic disorientation)
- Language (poor wordlist generation, anomia – inability to name 17 things in a category)
- Psychiatric features (depression/apathy and delusions)
What is seen in Stage 2 of DAT? What is the duration?
2-10 years
- Memory (recent and remote recall more severely impaired)
- Visuospatial skills (poor construction; spatial disorientation)
- Calculation (acalculia)
- Psychiatric features (delusions)
What is seen in Stage 3 of DAT? What is the duration?
8-12 years
- Intellectual funcitons severely impaired
- Sphincter control - urinary and fecal incontinence
- Motor - limb rigidity and flexion posture
What are the two types of senile plaques associated with Alzheimer’s disease?
- Diffuse plaque (senile plaques) – extracellular accumulation of β-amyloid protein
- Neuritic plaque – extracellular accumulation of Aβ protein and tau containing neurites (frontal cortex → temporal cortex → neocortex)
What gross changes can be seen in the brain with Alzheimer’s disease?
- Atrophy of gyri and widening of sulci
- Increased size of lateral ventricles
Which type of senile plaque is more closely associated with cognitive decline?
Neuritic plaque
How do you stain a cerebral amyloid angiopathy (almost always found in AD)?
Congo red stain
What are Neurofibrillary tangles (NFT)? Are they unique to AD?
- NFT: Intraneuronal accumulation of an abnormally phosphorylated form of tau (normal microtubule associated protein)
- Not unique to AD – also found in degenerative diseases
What is the biggest risk factor for AD?
What are the current factors used in the pathological diagnosis of AD?
- What is the biggest risk factor for AD?
- Age
- What are the current factors used in the pathological diagnosis of AD?
- Density fo neuritic plaques
- Staging scheme for neurofibrillary tangles
What are the three patterns of inheritance for Alzheimer’s Disease? What is the prevalence of each?
- Sporadic (75%)
- History of affected relatives (20-25%)
- Prominent family history – usually autosomal dominant (1-5%)
What are the differences between early onset and late onset AD?
- Early onset:
- <60-65 years old
- Often autosomal dominant mutation - highly penetrant
- Late onset
- >60-65 years old
- No Mendelian pattern of inheritance
What is Amyloid precursor protein?
How is it related to Down Syndrome?
- Amyloid precursor protein (APP) – transmembrane glycoprotein (on chromosome 21)
- Normal functions not fully understood
- Amyloid plaques (senile plaque) derived from APP
- Older individuals with Down’s syndrome develop AP in late 30s
What are the two ways in which Amyloid Precursor Protein is processed?
APP processing: two pathways
- α secretase cleaves Aβ sequence; no Aβ produced
- Cleavage at β and γ sites of APP: Aβ produced, β secretase enzyme identified, γ secretase enzyme unknown
What genetics are associated with AD?
-
Presenilin 1 (PSEN1 gene) on chromosome 14 (complete penetrance)
- Most common genetic mutation at this time (50% of familial AD)
- Amyloid precursor protein (APP gene) on chromosome 14 – rare
- Presenilin 2 (PSEN2 gene) on chromosome 1 (very rare)
How do Apolipoprotein E and the APOE gene contribute to AD? What is their normal function?
- Established genetic risk factor for late-onset AD
- Three alleles at gene locus on chromosome 19: ε2, ε3, ε4
- Code three protein isoforms, E2, E3, and E4
- Apo E protein involved in cholesterol transport, metabolism, and storage
How does the ε4 allele of the APOE gene modify genetic risk?
- Dose-dependent: people with one ε4 allele have approx. 3x increased risk of AD, people with two ε4 alleles have approx. 15x increased risk of AD
- Association robust but not specific
- Presence of ε4 necessary but not sufficient
What types of dementia are associated with Cholinergic signaling deficiency?
- Alzheimer’s disease
- Dementia with Lewy bodies
- Vascular Dementia
What are the four approved centrally acting cholinesterase inhibitors for treating Dementia?
- Tacrine (not used much - worst side effects)
- Donepezil
- Rivastigmine
- Galantamine
What is an NMDA channel blocker with some efficacy in slowing AD disease progression?
Memantine
