Week 4 (Memory, Cognition and Dementia) Flashcards
Cognitive deficits
Affect >10% of population
Associated with other health problems (neuro and psych disorders too)
Many causes, and have range of treatments
Dan Schacter’s “7 sins of memory”
1) Transience: time weakens memory
2) Absent-mindedness: lack of attention weakens encoding
3) Blocking: similar or related memories can compete during recall
4) Misattribution: remembering a piece of information but forgetting its source
5) Suggestibility: new information (suggestions) during recall can change stored information
6) Bias: our biases at the time of storage or recall can change memory
7) Persistence: inappropriate persistent and strength of traumatic memories can lead to or be associated with psychiatric conditions such as phobias, PTSD, etc
What happens if you block NMDA receptors?
If NMDA receptors are blocked, you have no LTP and no spatial learning
Note: LTP required for learning, but LTP does not equal memory
Two major divisions of memory
Non-declarative (implicit): don’t have direct conscious access to it (learning to ride a bike)
Declarative (explicit): facts and events
Different brain regions and what type of memory they are involved in
Temporal lobe/hippocampus: spatial learning
Amygdala: emotional memory
Cortico-striatal system: procedural memory
Cerebellum: motor learning
Multiple phases of memory
Acquisition: induction of LTP; Ca2+ enters through NMDA receptors in CA1 region of hippocampus –> kinases (PKA, PKC, MAPK, CaMKII) activated –> CaMKII phosphorylates glutamate receptors containing GluR1 subunit which increases numbers of these receptors at the synapse –> this strengthens synapse
Cellular consolidation: long-term storage of information/late phase LTP; activation of CREB and other TFs by kinases activated during acquisition (PKA, MAPK) –> transcription of specific genes required for synaptic growth and stabilization –> co-transcriptional recruitment of trans-acting factors such as exon junction complex –> assembly of transport granule to be transported along MTs into dendrites by molecular motors –> activation of NT receptors and voltage-gated ion channels engages intracellular second messenger cascades like mTOR that promote translation of some mRNAs near synapse
Systems consolidation: brain structures involved in permanent storage of memory differ from those required for initial storage; hippocampus has temporary role in storage and then memory becomes more dependent on sites in the cortex
Reconsolidation: recall and retrieval of stored info can trigger memory acquisition and consolidation; shares some molecular and cellular mechanisms with acquisition (NMDA receptors) and consolidation (CREB) but also has unique mechanisms (cannabinoid receptor 1 and L-type voltage-gated Ca2+ channels); if reconsolidation blocked then previously stored memory can be weakened/erased
Extinction: active process of reversing learned information; create new memory that competes with extinguished memory
Allocation: determine which cells in circuit become involved in a given memory; two closely related memories are stored in overlapping populations of neurons and recall of one is likely to trigger recall of the other; involves CREB
When we find mutations that enhance learning and memory, what else do we notice?
95% of these mutations that enhance learning and memory also enhance stable long-lasting change in synaptic function
However, doesn’t go the other way because mutations that enhance stable long-lasting change in synaptic function can produce harm elsewhere that can have negative cognitive effects
What is happening during LTP when you’re potentiating synapses?
Once NMDA receptors open to let Ca2+ in, this triggers a cascade that ultimately adds AMPA receptors
This is important because as you add glutamate (NMDA or AMPA) receptors, you strengthen the synapse
Strengthening synapse means that you increase the chance of having depolarization and increased chance that soma will see that depolarization and fire to release NTs/signal
Memory extinction for something like phobia or PTSD
Exposure to conditioned stimulus (CS) in absence of unconditioned stimulus (US)
Does not necessarily erase memory of CS-US association, but instead creates memory that CS does NOT predict (is not associated) with US
D-cycloserine (NMDA agonist) may be useful in facilitating extinction based therapies
Neurofibromatosis 1
NF1 is inherited disorder that causes benign tumors and is associated with cognitive deficits (in learning and memory)
NF1 encodes Ras-GAP and when NF1 is mutated, it can no longer inactivate Ras so you have a constitutively activated Ras
Enhanced Ras/MAPK in CA1 –> enhanced GABA release in CA1 –> deficits in CA1 plasticity –> deficits in hippocampal learning
Recently found that statins can reverse this increase in Ras signaling and restore cognitive function!
Coma
State of eyes closed unresponsiveness
Profound unresponsiveness, in which the subject cannot be aroused
Sleep wake cycles are usually absent
Vegetative state
State of eyes-open unresponsiveness
Unawareness of the self and the environment
Sleep-wake cycles frequently persist
Whole brain death
Permanent loss of function of the brain and brainstem
Patient is deeply comatose (lowest level of coma)
EEG is iso-electric (absence of EEG activity)
Minimally conscious state
Defined as condition of “severely altered consciousness”
Is controversial!
Minimal but definite behavioral evidence of self or environmental awareness is demonstrated: follows simple commands, gestural or verbal yes/no, intelligible verbalization, purposeful behavior
Levels of altered mental status
Delirium: awake but confused
Obtundation: lethargic and confused
Stupor: awakens only with painful stimulus
Coma
Anatomic lesions causing coma
Mass lesions: increased intracranial pressure, brainstem compression
Severe diffuse brain injury (hypoxia, carbon monoxide poisoning)
Acute bilateral cortical or thalamic lesions
Brainstem lesions
Etiologies of coma approximate mortalities
Drug OD: mortality 5-10% (one of most common causes though)
Metabolic: mortality 50%
Head trauma: mortality 50%
Anoxia: mortality 90%
Stroke: mortality 80%
Note: prognosis of coma primarily dictated by etiology
Glasgow coma scale
3-15
Eye opening: never, to pain, to verbal, spontaneous (1-4)
Best verbal response: none, sounds, inapp words, disoriented, oriented (1-5)
Best motor response: none, extensor, flexor, withdrawal, localization, obeys commands (1-6)
What determines prognosis of coma?
Etiology
Age
GCS
Causes of coma that are result of encephalopathy vs. neurosurgical emergency
Encephalopathy: toxic, metabolic, anoxic, infectious, degenerative
Neurosurgical emergency: mass lesion, hemorrhage, tumor, trauma, increased pressure
Neurological exam
Vitals: fever, irregular breathing
Examine neck: meningitis, SAH
Examine for signs of trauma: ecchymosis over oribt or mastoid
Papilledema: evidence of increased pressure
Pupils: unilateral dilation and down and out = uncal herniation
Oculo-vestibular response (doll’s eyes): test integrity of brainstem from medulla to midbrain
Decorticate vs. decerebrate
Decorticate: flexion; occurs in upper brainstem lesions
Decerebrate: extension; occurs in lower brainstem lesions
Metabolic coma-frequent signs
Pupils small: narcotic OD (opiates)
Pupils large: TCA or amphetamine OD
Tremor/asterixis: metabolic coma (uremia, hepatic encephalopathy, alcohol induced delerium tremens, Reye’s syndrome?)
New syndromes impacting psychiatry and neurology
Hashimoto’s encephalopathy: anti-TPO antibody; delirium, seizures and psychosis (suddenly psychotic and don’t know where they are)
Paraneoplastic syndromes: anti-NMDA encephalitis (delirium, status epilepticus, psychosis); give IV Ig and completely recover
Delirium
Acute disturbance of consciousness, attention, cognition and perception
Develops over a short period of time (hours to days)
Fluctuating course (waxing and waning)
Common
Life-threatening (indication that disease is going to kill you), with in-hospital mortality rate similar to AMI and sepsis
Examples of disturbances in consciousness (“A” criterion)
Reduced clarity/awareness of environment
Difficulty focusing, sustaining, or shifting attention
Easy distractibility
Examples of cognitive deficits (“B” criterion)
Memory impairment (acute; recent)
Visuospatial difficulty
Disorientation (time, place)
Language disturbance (dysarthria/dysnomia/dysgraphia)
Perceptual disturbance (misinterpretation/illusion/hallucination)
Commonly associated features of delirium
Sleep/wake disturbance
Abnormal psychomotor activity: hypoactive vs. hyperactive (Lipowski)
Atypical emotion
Non-specific neurologic findings: tremor, myoclonus, asterixis, abnormalities of reflexes and tone
Prevalence of delirium in specific patient populations
Hospitalized, medically ill adults: 6-56%
Hospitalized elderly: 10-40%
Hospitalized with AIDS: 30-40%
Post-operative adults: 50%
ICU: 70-90%
“Terminal delirium” 80%
Underlying conditions commonly associated with delirium
Disorders of CNS: head trauma, seizures/post-ictal state, vascular disease (HTNsive encephalopathy), degenerative disease
Metabolic disorders: renal failure/uremia, hepatic failure, anemia, hypoxia, hypoglycemia, thiamine deficiency, endocrinopathy, fluid or electrolyte imbalance, acid-base imbalance
Cardiopulmonary disorders: MI, CHF, arrhythmia, shock, respiratory failure
Systemic illness: substance intoxication or withdrawal, infection, neoplasm, severe trauma, sensory deprivation, temperature dysregulation, postoperative state, dehydration/malnutrition
Substances that can cause delirium through intoxication or withdrawal
Drugs of abuse: alcohol, amphetamines, cannabis, hallucinogens, inhalants, opioids, phencyclidine, sedatives, hypnotics, other
Iatrogenically prescribed: anesthetics, analgesics, antiasthmatics, anticonvulsants, antihistamines and anticholinergics, antihypertensives, antimicrobials, anitparkinsonism agents, corticosteroids, muscle relaxants, immunosuppresives, lithium
Toxins: anticholinesterases, organophosphates, carbon monoxide, carbon dioxide, volatiles (fuels, organic solvents)
Natural history of delirium
When delirium is manifestation of underlying medical illness, course of medical illness often dictates course of delirium
Duration of delirium episode averages around 7-10 days
Neurophysiology of delirium
Acute deficits in ACh neurotransmission
Acute DA excess
Hypoperfusion
Cytokines/inflammatory responses
Complications of delirium
Aspiration/pneumonia
Decubiti
Falls/fractures/subdural hematoma
Seizures
Long-term disability
Death (if develop delirium during hospitalization, have 25-33% chance of dying during hospitalization; if survive hospital stay, 25% mortality in 6 months following)
How to assess delirium
H&P (emphasis on neuro)
Vitals
Review medical records, meds, time course, correlation with behavioral change
Mental status exam (clock face, digit span, trailmaking, etc)
Diagnosis of delirium
Delirium symptom interview (DSI)
Confusion assessment method (CAM; >90% sens/spec; good IRR)
Delirium scale (Dscale)
Saskatoon delirium checklist (SDC)
Severity rating of delirium
Delirium rating scale (DRS)
Memorial delirium assessment scale (MDAS)
Other tests to assess delirium
Lab tests: chem, TSH, CBC, ECG, CXR, pulse ox or ABG, urinalysis, urine culture/sensitivity, tox screen, VDRL, heavy metal screen, B12/folate, ANA, urinary porphyrins, serum ammonia, HIV, blood culture, therapeutic drug monitoring, lumbar puncture
Neuroimaging: CT or MRI (if focal neuro signs, hx trauma, fever and AMS), EEG (gold standard)
Principles of delirium treatment
Make diagnosis
Identify/address reversible causes
Support/protect patient from new morbidities associated with delirium: remove dangerous items, reduce risk for falling, familiar objects, visible clock, family present, day/night distinction
Educate patient/family
Somatic interventions: pharmacologic to reduce agitation, psychotic sx, affective abnormalities, normalize sleep/wake cycle (haloperidol, droperidol, risperidone, olanzapine, ziprasidone, quetiapine)
Should we use benzodiazepines in delirium?
In most cases, no because will make delirium worse (disinhibition, worse cognition, increased risk for falls)
However, can use if alcohol or benzo withdrawal, if akathisia, or to raise seizure threshold
Side effects of antipsychotics in delirious patients
Akathisia
Hypotension
Arrhythmia (QT prolongation/ torsades)
Neuroleptic malignant syndrome
Drugs that show promise or are under investigation
NMDA antagonists: ketamine
Alpha 2 agonists: dexmedetomidine
Patient HM with bilateral surgical removal of hippocampus and medial temporal lobe
HM cound not retain any new declarative memories for more than a few min
Early childhood memories were intact
No effect on personality, attention, intelligence, nondeclarative (implicit) forms of memory
Mammillary bodies
Involved in memory, so damage to mammillary bodies can cause memory disturbances
Mammillary bodies can degenerate in obstructive sleep apnea, chronic alcoholism with Wernicke-Korsakoff syndrome
What do you lose in late Alzheimer’s disease?
Lose neuropil and neuronal cell bodies
Brain atrophy causes enlargement of ventricles (which can cause hydrocephalus ex vacuo)
Progression of damage in Alzheimer’s disease
First affects entorhinal cortex, then hippocampus then limbic cortex then widely across neocortex
DSM-IV criteria for Dementia of the Alzheimer’s Type
A) Development of multiple cognitive deficits manifested by both memory impairment (impaired ability to learn new info or to recall previously learned info) AND one or more of following cognitive disturbances: aphasia, apraxia, agnosia, disturbance in executive functioning
B) Cognitive deficits in criteria A1 and A2 each cause significant impairment in social or occupational functioning and represent a significant decline from previous level of functioning
C) Course characterized by gradual onset and continuing cognitive decline
D) Cognitive deficits in A1 and A2 not due to other CNS conditions, systemic conditions, or substance-induced conditions
E) Deficits do not occur exclusively during course of delirium
