Neurodegen disorders (1) Flashcards
What ares of brain are most susceptible to stroke?
III: external pyramidal layer
V: interal pyramidal layer
Primary cortices of cerebral cortex
: somatosensory, motor, visual, and auditory
Association cortices:
– _______: Concerned with integration of function from a single area
–______: Higher order information processing: integration of function from multiple sensory and/or motor modalities
Unimodal
Heteromodal
What makes up the limbic system of the brain?
Papez’s circuit: Cingulate to hippocampus to fornix to mammillary bodies to thalamus
Outer Core Cortical Compoments:
Cingulate cortex
Orbital frontal lobe
Temporal lobe: hippocampus, parahippocampus, entorhinal cortex
Key for emotions and motor
this part for visual spatial and memory
Cingulate cortex
Rostal: emtions and motor
caudal = visual spatial and memory
in charge of personality, behavioral control adn self awareness (key for alzeihmers path)
Orbital frontal lobe
Key for memory
temporal lobe (hippo)
Key INNER core subcortical components
Hypothalamus
Amygdala
septum
Pleasure center, autonomic and endocrine integration
neurons from here project to pituitary to regulate ACTH and TSH secreation
*key for maternal behavior, BP, feeding, temp regulation and immune
HYpothalamus
“preservation of self” emotion, social behavior, aggressin and defense response, sexual behavior, affective visual stimuli, affect of faces, affective regulation
Amygdala (part of inner core)
Preservation of SPECIES, sexual behvior, personality
Septum
Lesion here can lead to amnestic states ro memory impairments and are key in declaritive memory
Hippocampus, dosral medial nucleas of thalamus, mammillary nuclie
Crucial for formaiton of episodice memories in humans (record of personal events)
HIppocampus
Difference of episodic and semantic memory
Explictic or delcaritive memory of facts(semantic) and events(episodic) are examples of long term memory stored in:
Medial temporal lobe
IN charge of highest cognitive functions adn emotional control
Frontal cortex
In charge of primitive emtional responses
Hypothalamus
Key for storage of emotional memories
Amygdala
Storage of emtional memories and actived and inhibited by emotionality
hippocampus
Structal organization of the basal ganglia
be familiar with structre
What makes up corpus STriatum?
Caudate nucleus, Putamen and Globus Pallidus
Putamen + Globus pallidus =
CN + putamen =
Lentiform/lenticulate
Striatum/neostritum
What structures are int he GP?
GPe = external
GPi= internal or medial segment
What is located in the substantia nigra
pars compacta (SNc; dopaminergic)
pars reticulata (SNr: GABAergic)
What affect does dopamine have on the D1 receptors in the striatum?
D1 = EXCITE direct to facilitate MOVEMENT
Neurons with D2 dopamine receptors will:
_______ indirect pathway with the goal to ______ movement
INHIBITS indirect path (which fnx to inhibit movement)
Understand Direct pathway in thalamus
Thalaus is DISinhibited or EXCITED
movement is facilitated
via G1 path
Understand indirect pathways of thalamus
thalamu is Inhibited
movement is inhibitied
Understand the selective vulnerability of specific neurons and systems that is common to neurodegenerative diseases
Gray matter diseases: progressive loss of neurons, groups of neurons, associated fiber tracts, usually functionally related (rather than physically contiguous) & relatively symmetric
– Leading to progressive decline in nervous system function
List of more grey matter diseaes that lead to progressive decline of NS fnx
Parkinson’s disease: extrapyramidal system
Alzheimer’s disease: cerebral cortex (higher order association cortices and limbic system)
Huntington’s disease: extrapyramidal system
Amyotrophic lateral sclerosis: pyramidal system
Understand how misfolded or aggregates of proteins lead to neurodegenerative diseases
• Misfolded and/or aggregated proteins
– Common cellular hallmark in many degenerative diseases
Resistant to normal degradation processes (ubiquitin- proteosome system)
Often form inclusions (traditionally used to diagnose disease at autopsy)
Cytotoxic to neuron +/or marker of disease presence
Examples of neurodegenerative disease d/t misfolded proteins or aggregates
• Alzheimer’s disease: amyloid-B and tau
- Parkinson’s disease: alpha-synuclein
- Frontotemporal lobar degeneration: tau, ubiquitin, TDP-43
• Huntington’s disease: polyglutamine
Forms of neurodegen diseases are sporadic and familial with ____ being more common especially in Alzeihmers, Parkinsons, and AML while ___ more common in Huntingtons
sporadic
familial
What is useful about familial degenrateive disease when we study them?
amilial forms of disease
– Genetic linkage studies make candidate genes and proteins easier
to identify
– Aid in deciphering mechanisms (often applicable to both sporadic and familial disease types)
– Aid in development of animal models (transgenic)
Etiology of Neurodegen disease
– Genetic mutations
– Geneticpolymorphisms(risk factors)
– Aging
– Environmental toxins
Understand list of cellular mechanisms responsible for pathogenesis seen in neurodegenerateive disease
– Oxidative stress and generation of ROS
– Inflammation
– Disruption of axonal transport and synaptic function
– Dysfunctional waste clearance: Inhibition of ubiquitin proteosome system and Autophagy
– Mitochondrial dysfunction
– Programmed cell death (apoptosis)
Some neurons are more vulnerable to toxic insults than others: _______
This is true even when the gene responsible is widespread (eg. Huntington’s Disease)
These basic observations along with other data have lead to the idea that neurodegeneration occurs because of :
“selective vulnerability”
a combination of events, not a single factor
How do Envi toxins/neuronal metabolism/aging contribute to neurodegenerative disease?
Insults that can induce neurodegeneration
** Environmental toxins**
– Reduce mitochondrial function; decrease ATP production, increased oxidative stress
• Neuronal metabolism– Is oxidative
• Aging
– Affects mitochondrial function
– L_oss of protective e_nzymes and molecules – _Progressive hits _
Describe how free radical oxidation leads to neurodegenerative disease
Can arise from dysfunctional mitochondria
Toxins, aging lead to loss of mitochondrial function
Inefficient mitochondrial electron transport “leaks out” electrons; oxygen radicals
In particular, complex 1 is vulnerable to injury in response to free radicals
Free radicals cause **lipid peroxidation; loss of membrane integrity **
Describe how oxidative stress plays a role in neurodegenerative disease
- Hydrogen peroxide and superoxide
- Oxygen is easily converted to these reactive molecules by the same enzymes that utilize oxygen as fuel; “leaky, inefficient”
- A precipitating factor for both excitoxicity and mitochondrial dysfunction; also results from both excitotoxicity and mitochondrial dysfunction
Excess GLUTAMATE and SUPEROXIDE both lead to persistant acitivation of _____
which resluts in _____
persistant activation of NMDA receptor
excess intracellular calcium
Persistant activaiton of NMDA receptors lead to excess intracellular calcium, why is this an issue?
See ATP depletion and which leads to cell death which causes excess glutamate and cycle continues
How do cells deal with oxyradicals?
•Ascorbate
- Glutathione
- Superoxide dismutase
- Catalase (inactivates hydrogen peroxide)
***Degeneration occurs when the cells either produce too many radicals or l**ose the ability to detoxify them **
Autosomal dominant disorder
Progressive motor, cognitive and behavioral domains
Prevalence 4 to 8 per 100, 000 person
Symptoms present in the 4th and 5th decade
Symptoms generally progress over several decades with complete motor disability and dementia approximately 20 years after symptom onset
Huntingtons disease
– _______ are predominant at the onset of HD in 60% of cases
•_____ being the characteristic feature
Motor symptoms
Chorea
– _____ symptoms may occur at or before the onset of
motor symptoms in pts with Huntingtons
• As the disease progresses patients eventually become______
–_______ symptoms are exhibited in 98% of patients
• Over 10% of patients with HD have attempted suicide
Cognitive
demented
Neuropsychiatric
Huntingtons: Mutation on ______
– Expanded trinucleotide repeat in gene (CAG) causes structural abnormalities in huntingtin protein
huntingtin gene on chr.4
• Higher number of repeats associated with early age of onset
_________: earlier age of onset in subsequent generations, found when mutated gene passed to offspring from father
• Anticipation
Role of Huntingtin gene
– Function of Huntingtin protein is unknown
– Hypothesized that gene expansion causes a toxic gain of function in the huntingtin protein
What happens when huntingtin gene is mutated?
Mutation causes protein aggregation
• Formation of intranuclear inclusions in basal ganglia
• Direct pathway to cellular injury is not understood
What causes the motor and cognitive changes we see in Huntingtons
– Loss of medium striatal neurons in the caudate and putamen (these modulate motor activity): Loss results in increased motor output-chorea
– Neuronal loss in c_erebral cortex – cognitive changes _
What will we see on MRI in pt with Huntingtons
Atrophy of caudate & putamen, ventricular enlargment Mild to moderate atrophy of gyri
What is the reason for chorea in pt with Huntingtons
Increased inhibition of the subthalamic nucleus
results in decreased excitation to the Globus pallidus and SnPr
overall decrease inhibition to thalamus = OVER stimulation
What is recommended for tx of Huntingtons
Treat the symptoms, not disease
Focus on depression, delusions and movement control
Fluoxetine for depression
antiphyschotics for delusion + paranoia
Terabenzine for mvmt control
Etiology for Amyotropic Lateral sclerosis (ALS)
Amyotrophic lateral sclerosis (ALS)
Occurs in all parts of the world, 1-5 cases/100,000
About 23,000 cases in U.S.
Males>females
Typical age of ALS onset is 60 years, rare <35
Most cases are sporadic: only 5-10% of ALS cases are believed to be familial
ALS is defined by Widespread degeneration of
upper and lower motor neurons
Results of Lower motor neuron degeneration seen in ALS
Lower motor neuron degeneration:
– Muscle atrophy, weakness and fasciculations (“Amyotrophy”)
– Due to degeneration of the a**nterior horn cells and axons **
Features seen in ALS dt
Upper motor neuron degeneration:
– Spastic tone, hyperreflexia and Babinski signs
– Degeneration of the cortico spinal tracts in lateral column of spinal
cord (“Lateral sclerosis”)
Why do pts with ALS have issues with swallowing and speaking?
Bulbar dysfunction (involvement of the brainstem motor cranial nerves): dysarthria, dysphagia
Weakness progresses, sensation intact
– Pt. loses ability to move, eat, speak and breathe
progression of ALS
What do we see on
MRI
LP
in pt with ALS
CSF normal
MRI normal
Mean survival 3-5 years (death from respiratory failure)
Familial ALS
Genetic mutations: 14 different genes have been described
Most often, ______ inheritance
- Most common mutation: ________
- TDP-43 accumulations and gene mutations are also found in a subset of ALS
autosomal dominant
superoxide dismutase 1 gene (SOD1)
ALS pathogenesis
– SOD1 mutations
- ?Decreased ability to detoxify free radicals
- ?Misfolded proteins trigger injurious cellular reaction (called unfolded protein response)
- Environmental agent? (higher incidence in Guam)
Pathology of ALS
athology
– Anterior (motor) roots of spinal cord are atrophic
– Primary motor cortex (cerebrum) may show atrophy
– Reduced numbers of anterior horn cells
– Loss of corticospinal tract axons and myelin
– Brainstem motor cranial nerves may be affected (Hypoglossal, motor trigeminal, etc.)
What would look different in gross pathology of pt with ALS in spinal cord?
ATROPHIC ANTERIOR SPINAL ROOTS (MOTOR ROOTS)
What do we see on histology in pt with ALS in cross section of spinal cord?
Loss of anterior horn cells and degeneration of lateral corticospinal columns
(loss of anterior corticospinal tract)
MOA for Riluzole
Riluzole
Mechanism: inhibitor of NMDA channels, inhibits glutamate release; increases uptake
Has modest but genuine effects on ALS Increases life span 2-3 months
What drug inhibits NMDA channels to inhibit glutamate release and inhibit uptake to increase lifespan of ALS pts for up to 2-3 months
Riluzole
