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Neuro SKS > Basal and Degenerative > Flashcards

Basal and Degenerative Flashcards

0
Q

Extrapyramidal system

A 
Anatomically diverse, all connected
Basal ganglia
 - striatum = caudate and putamen nuclei
 - globus pallidus - medial and lateral
Substantia nigra (midbrain) - pars compacta and pars reticulata
Subthalamic nucleus
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1
Q

Overview of basal ganglia

A

Part of extra-pyramidal system
- initiation and planning of movement (prior to movement)
- posture, muscle tone
- many other functions
Regulates cortex - topographic input and output via cortex
- cortical feedback loops regulated by dopamine

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2
Q

Striatum anatomy

A

Caudate nucleus - follows lateral wall of lateral ventricle
- long body and tail curve into cortex
Putamen - anterior to thalamus, inf to internal capsule
- merges with caudate anteriorly = nucleus accumbens
Globus pallidus - medial to putamen
+ putamen = “lentiform nucleus” - useless term

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3
Q

Claustrum

A

Grey matter between putamen and insular cortex
Unknown function?
- reciprocal connections to all sensory cortices
-> rhythmic cortical activity?

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4
Q

Connections of basal ganglia

A

Feeback loop! Cortex -> ganglia -> thalamus -> cortex
Input:
- all areas of cortex (except primary visual, auditory)
- substantia nigra pars compacta -> dopamine
Output:
- substantia nigra pars reticulata
- external globus pallidus -> subthalamic nuclei ->
-> internal globus pallidus -> ventroantero (VA)/ventrolateral (VL) nuclei of thalamus -> cortex (mostly premotor)

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5
Q

Direct pathway

A

Dysinhibition -> inhibition of tonically active -> facilitation

Direct pathway -> facilitates movement

  • cortex -excites> medium spiny neurons of striatum
    • tonically inhibit> internal globus pallidus -inhibit> VA/VL
  • > dysinhibition of thalamus, cortex -> movement
  • dopamine via D1 -> spiny neurons -> facilitates movement
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6
Q

Basal ganglia subcircuits

A

Segregated pathways to/from regions of motor, premotor, supplementary
-> map onto putamen, globus pallidus, subthalamic, VA/VL
-> feedback onto same cortical area
Body -> putamen -> lateral globus pallidus -> VA/VL

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7
Q

Convergence

A

Every cortical area projects except primary visual, auditory

  • prefrontal dorsolateral loop -> executive fx
  • prefrontal orbital/medial loop = limbic -> emotions, mood

Convergence -> fewer neurons
cortex -> striatum (75 million) > globus pallidus (700K)
- spiny neurons = integrate, very long dendrite with many spines

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8
Q

Basal ganglia function

A

Indirect pathway -> tonic inhibition
Direct -> selects and excites movements
- superimposed on indirect (center-surround)

Abnormalities - too much, too little, random

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9
Q

Striasomes

A

Patches of regulatory interneurons - distinct neurotransmitter

  • Ach
  • enkephalin
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10
Q

Ventral striatal system

A

aka limbic system

Limbic cortex -> ventral striatum (nucleus accumbens) ->
-> ventral pallidum -> mediodorsal nucleus -> cortex
Dopamine from ventral tegmental area -> D3, D4
- mesolimbic dopamine reward system (DA from ventral tegmental -> nucleus accumbens)

Ventral striatum/accumbens = anterior, ventral junction of putamen and caudate
Ventral pallidum = ventral to globus (across ant commissure)

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11
Q

Indirect pathway

A

Indirect pathway -> inhibits movement

  • cortex -excites> striatum -tonically inhibit> external globus pallidus -inhibit> subthalamic nuclei -excites> internal globus pallidus -inhibit VA/VL
  • > net inhibition of VA/VL, cortex
  • dopamine via D2 -> decreases inhibition -> facilitates movement
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12
Q

Oculomotor pathway

A

Eye cortex -> caudate -> globus pallidus -> VA, mediodorsal

second pathway -> substantia nigra pars reticulata -> superior colliculus

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13
Q

Prefrontal (dorsolateral) pathway

A

Executive function
Prefrontal dorsolateral cortex -> anterior caudate
-> internal globus pallidus and substantia nigra pars reticulata
-> VA, mediodorsal

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14
Q

Hyperkinesia syndromes

A

aka Dyskinesia

Chorea-athetosis - usually together, pt’s pretend purposeful movement
- chorea - quick, irregular, proximal, “dancing”
- athetosis - smooth, writhing, distal
Dystonia - twisting of neck, trunk
Ballismus - violent, proximal, throwing or flinging - can be hemi
Tics - fleeting, usually repetitive/stereotyped
Tremor - resting vs action

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15
Q

Hypokinesia syndromes

A

Bradykinesia - slowed, trouble initiating
-> slowed postural reactions, mask facies
-> akinesia, freezing
Rigidity - smooth resistance to movement (vs clasp knife spasticity)
- cogwheel - rigidity + tremor

16
Q

Differential dx of chorea-athetosis

A

V cerebrovasc of basal
I infection - encephalitis
N mass lesion of basal
D rugs - chronic neuroleptics (metoclopramide), Levodopa, amphetamines, Li+, INH
I
C congenital - cerebral palsy, Huntington’s, Wilson’s
A autoimmune - SLE, Sydenham (strep pyogenes)
T trauma, toxins - CO, Hg
E endocrine - gravidarum, hypo or hyperthyroid, hypoCa, hypoglyc
D egeneration - Alzheimer’s, senile

17
Q

Huntington’s disease

A

Trinucleotide repeat (separate path card)
Age 35-40 -> 15 yrs mortality
- Chorea - worse with Parkinson’s meds
- Dementia -> vegetative
- Behavior change -> psychosis
- high incidence of suicide, legal/psych presentation

Tx = symptomatic

  • psych, chorea -> old neuroleptics (DA block) - haloperidol, perphenazine -> risk of tardive dyskinesia
  • some use DA depletors (reserpine, tetrabenzine -> severe depression), Ach agonists (not effective)
  • palliative care…
18
Q

Essential tremor

A

Strong familial - autosomal dom with incomplete penetrance
-> 25-55 yo
Postural + motion/intention tremor, fast, symmetrical
- b/l upper extremities + face, voice sim to spasmodic dysphonia
- improves with EtOH
- slowly progressing

Tx: surprisingly effective
- beta blockers - ex propanolol
- consider barbituates (Mysoline), neuroleptics (Neurontin, topiramate)
- Valproate not effective
- DBS -> ventral interstitial nucleus (thalamus)
(- thalamotomy, botox for vocal cords)

19
Q

Parkinson’s presentation

A

Insidious, unilateral -> progressive
Tremor - static/resting, pronation/supination, improves with movement
- unliateral arm or leg -> progresses rapidly
- slow (4-6 Hz)
Bradykinesia
- micrographia, hydrophonia, dysphagia, masked facies
- small, shuffling steps, flexed posture, freezing or halting
Rigidity - constant vs spasticity - can have “cogwheel” + tremor
Cognitive - depression common, 50% dementia (half Alz, half Lewy)

20
Q

Parkinson’s pathology

A

Loss of pigmented neurons (DA producting) in substantia nigra
- degree correlates with bradykinesia - 50-70% symptoms, 90% death
- also locus ceruleus -> cognitive, mood?
Lewy body inclusions - in remaining DA neurons
- synuclein -> folded beta sheets
-> dense, spherical, peripheral fibrils (Ab stain can’t penetrate)
- can be found through brain -> Lewy body dementia, asymptomatic

Env’t - age, rural/pesticides (trichloroethane), heavy metals, trauma, etc
Genetic - 11 different loci, present earlier with more dystonia

21
Q

Parkinson’s treatment

A

Morbidity approx 15 yrs
- due to falls, dementia (20-30%) -> PNA, UTI, PE, fractures
- worse if progressive supranuclear palsy or multi-system atrophy
Tx: decreases mortality
- sinemet = levodopa (crosses BBB) + carbidopa (preserves levo)
-> oxide radicals -> damage DA receptors
- also sensitize receptors to increases in DA - “lose middle ground”
-> minimize L-dopa dose
- adjuncts (not as effective) - DA agonists, MAOb-inhibitors, COMT-i
- anticholinergics - suppress tremor, lots of systemic s/e
- amantadine - effective, also helps prevent dyskinesias

  • surgery - thallotomy (vs tremor), pallidotomy (brady, rigid)
  • DBS - subthalamic nucleus, globus pallidus internus - reversible!
  • stem cell replacement?
22
Q

Parkinsonism differential

A

85% idiopathic Parkinson’s disease
Neuroleptic - high acute doses vs chronic tardive dyskinesia
Vascular - vs basal ganglia
Trauma, post-encephalitis (1918 flu -> Tau), Mn fumes (welder), CO
MPTP - synthetic street Demerol -> astrocytes -MAO> MPP+ (radical) -> inhibits mitochondrial complex 1 -> low ATP -> neuron death

Parkinson “plus” - don’t respond to tx, may worsen

  • suspect if no tremor, no tx response, symmetrical, autonomic, hallucinations, cerebellar, UMN, LMN signs, vertical EOM palsy
  • multisystem atrophy - glial cytoplasmic inclusions
  • Shy-Drager syndrome - autonomic -> bladder, orthostasis
  • striatonigral degen - extrapyramidal - hyperreflexia, Babinski
  • olivopontocerebellar degen - cerebellar sx’s
  • progressive supranuclear palsy
  • Lewy body dementia - ubiquitin/synuclein granules -> hallucinations, confusion, dementia -> respond to newer antipsych (quetiapine, clozapine), anticholinergic
  • corticobasal ganglionic degen
  • Park-dementia-ALS of Guam (Al toxicity?)
23
Q

Tics

A

Spectrum of simple -> complex movements, usu repetitive
Can be suppressed, worse with stress

Tourettes - multiple motor + verbal (snort, sniff, coprolalia)

  • often comorbid with ADHD, OCD
  • fluctuates 5-18 yrs -> often resolves in adulthood
  • tx not needed - can use neuroleptics (DA antag), clonidine
24
Q

Classification of degenerative diseases

A

Classify by location:

  • cortex - Alz, Pick’s, fronto-temporal, diffuse Lewy, corticobasal
  • striatum - Huntington’s
  • midbrain - Park and similar, multi-system atrophy, progress supranuc
  • spinocerebellar - Friedreich’s, spinocerebellar ataxia
  • motor - ALS, spinomusc atrophy

Classify by pathology:

  • beta amyloid plaques - Alz (also Tau tangles)
  • Tau (hyperphos -> tubules -> blocks axonal transport)
    • fronto-temp-park (FTDP-17), Picks, corticobasal, prog supranuc
  • synuclein - Park, multi-system atrophy, dementia with cort Lewy, Lewy dysphagia (dorsal vagus nucleus in medulla)
  • TDP-43 - ALS, fronto-temp lobar degen (FTLD)
  • trinucleotide repeat - Huntington’s, spinocerebellar, Friedreich’s
25
Q

Alzheimer’s pathology

A

Rare biopsy, strict criteria only used for research or borderline cases
- neither plaques nor tangles are pathognomonic (found in all senile)

Gross - general cortical atrophy, often spares occipital
- big ventricles (hydroceph ex vacuole), sulci
Beta-amyloid plaque + astrocytes, nuclear processes - extracellular
- amyloid precursor (APP) - chrom 21 -> secretases
- alpha -> gamma -> soluble, functional
- beta -> gamma -> AB42, insoluble -> neurofibrils
- Bodian stain
Tau neurofibrillary tangles - hyperphosphor, intracellular

Genetic correlates - most are sporadic!

  • beta-APP, presenillin 1, 2 (catalytic enzyme of gamma secretase)
  • Apo E (4 bad, 2 good) - post AB42 processing
  • Tau not associated with Alz (other tauopathies)
  • trisomy 21 (extra APP gene)
26
Q

Alzheimer’s clinical

A

Presentation:
Usu post 65, increasing incidence
Memory - short term, word finding
Cognitive - disorientation (time, place), numerical, lack of initiative

Tx:
Symptomatic - does not halt progression
- anticholinesterases -> inc Ach
- NMDA antag (Memantine) - prevent excitotoxicity
AB42 vaccination = disaster (autoimmune encephalitis)
Gamma secretase block = disaster (also needed for Notch in CNS)
Statins?

27
Q

Non-Alzheimer’s dementia

A

Need to rule out, especially reversible/treatable

Reversible
- metabolic
- infectious
- psychiatric
Vascular - small vessel or multi-infarct
Degenerative fronto-temporal dementias
- often social/behavioral, non-fluent aphasia (difficulty naming), preserved comprehension, problem solving, memory
- tau -> FTDP-17, Pick’s, progressive supranuclear palsy, corticobasal
- synuclein - Parkinson’s, diffuse Lewy body
- TDP43 - fronto-temp lobar degen (FTLD)

28
Q

Pick’s disease

A

Clinical:
- frontotemporal degen - almost identical presentation to Alzheimers
Path:
- gross - frontal and ant temp degen, preserved occipital, parietal
- swollen neurons - basophilic Pick bodies = agglutinated Tau
- stain silver (Bodian, Boch), anti-tau, neurofil, tubule
- cortex, hippocampus, subcortical, brainstem (ex locus ceruleus)
Molecular:
- sporadic - Tau 3-repeat, missing 10 (10-) -> smaller 55, 64

29
Q

Corticobasal degeneration

A

Clinical: >60yo,
- assym UE or LE stiff, clumsy -> rhythmic myoclonus -> alien limb
- frequent sensory, executive (comorbidity?)
Path:
- gross - fronto-parietal atrophy, path in basal ganglia (pigmented SN)
- swollen ballooned neurons (NOT Pick), microvacuolation
- Tau aggregates in glial cells (more diffuse)
Molecular:
- sporadic - Tau 4-repeat, 10+ exon -> larger 64, 69

30
Q

Progressive supranuclear palsy

A

Clinical:
- parkinsonism (gait, dysarthria), vertical ophthalmoplegia (rostral midbrain), retrocollis, dysphagia, emotional, personality
Path:
- gross - loss of pigment in SN, locus ceruleus, normal above mesenceph
- intranuclear globose tangles (“ball of wool”) in basal ganglia, thalamus, brainstem
Molecular:
- sporadic Tau 4-repeat, 10+ exons -> 64, 69

31
Q

multiple system atrophy

A

Family of synuclein disorders

  • glial cytoplasmic inclusions - not prominent Lewy bodies
  • profound, localized atrophy

Striatonigral degeneration - lose neurons in SN, striatum - no Lewy
Olivo-ponto-cerebellar atrophy -> paralysis
Shy-Drager syndrome - sympathetic intermedio-lateral column of spinal cord -> orthostatic

32
Q

TDP43 - opathies

A

transactive response DNA binding protein

  • escorts RNA, DNA to rough ER
  • abnormal C terminal is ubiquitinated, hyperphos -> inclusions (vs localization to nucleus) -> death of motor neurons and glia

fronto-temporo-lobar degeneration with ubiquitinated inclusions
(aka FTLD-U)
- inclusions in neocortex, hippocampus
ALS - upper and lower motor neuron disfunction -> paralysis
- most sporadic but genetic cases from TDP43 or superoxide dismutase

33
Q

Trinucleotide repeat diseases

A

Autosomal dominant

  • CAG repeats (>40) -> polyglutamate sequence -> disease
  • suspect if multiple systems, family hx, atrophy on MRI

Huntington’s -> caudate and putamen -> chorea and dementia
- complete penetrance, few sporadic from expansion
Spinocerebellar ataxia -
- early adult -> progressive ataxia (extremities, trunk, speech), nystagmus, parkinsonism, dysautonomia, cognitive -> death
Friedreich’s ataxia - dorsal columns, spinocerebellar, corticospinal
- GAA repeat -> dec expression of frataxin (mitochondrial Fe metab)
- preadolescent, hyporeflexia (+ Babinski), cerebellar (ataxia, nystagmust, dysarthria, scoliosis)
- also dilated cardiomyopathy -> 50% of deaths

Neuro SKS (19 decks)

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