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
In AD, get loss of these functions associated with cerebral cortex
Memory
Cognitive function
Object or person recognition
Social skills
Reading and writing skills
Language skills
Motor functions
Circadian regulation
Primary sensory and primary motor cortex
Both contain maps of the body (homonculus)
Tongue is lateral, then face, hand, arm, then trunk is top/middle, then leg, foot, genitals down near ventricles
Association cortex
Does not contain body map, but is viewed as having either motor or sensory function
Dorsal and ventral pathways from primary cortex to neighboring association cortices
Dorsal pathway = where = visual-spatial orientation
Ventral pathway = what = object recognition
Different layers of the cerebral cortex
6 layers of cerebral cortex, based on neuron type and density
From top to bottom:
Output to other cortex
Input from thalamus
Output to brainstem and spinal cord
Output to thalamus
Brodmann areas
Specific functions map to cortical areas with histological sub-specialization
Primary motor = 4
Primary visual = 17
Primary auditory = 41, 42
Which two glutamate receptors are linked to ion channels?
NMDA: Mg2+ blockade must be removed, lets Ca2+ in (does LTP)
AMPA: lets Na+ in
How is Ca2+ involved in LTP?
Activation of NMDA glutamate receptor leads to Ca2+ influx
Ca2+ activates Calmodulin kinase II and PKC which phosphorylate substrates
Phosphorylation causes AMPA receptors to be inserted into postsynaptic membrane
More AMPA receptors in postsynaptic membrane means synapse more sensitive to signal (strengthened)
Note: in certain target neurons, influx of Ca2+ activates phosphatases which dephosphorylate and thus remove AMPA receptors (called LTD)
Ampakines
Glutamate related drug development
Bind to AMPA-type glutamate receptors and enhance LTP and strengthen synapses
Are being developed as cognitive enhancers (in clinical trials) for various conditions
Memantine
Glutamate related approved treatment
Low affinity uncompetitive antagonist (partial blocker) of NMDA-type glutamate receptors
“Dirty” drug with other effects: 5HT, DA, ACh receptors
Approved for Alzheimer’s disease as protector against excitotoxic neurodegeneration and to “balance” activity at glutamate synapses (leads to moderate improvement in function and decrease in deterioration in AD)
Will blocking NMDA receptors also slow neurodegeneration?
AD pathology leads to excessive glutamate signaling, which leads to circuit dysfunction as well as excitotoxicity
Memantine is thought to reduce some of the excess NMDA receptor activation and “balance” signaling as well as protect against excitotoxicity
Glutamate excitotoxicity
Final common pathway for neuronal cell death in many CNS disorders (seizures, ischemia, etc)
Over-activation of NMDA glutamate receptor leads to excess calcium signaling that kills neurons
Theory for rapid death of neurons and oligodendrocytes during ischemia (stroke)
Ischemia leads to lack of ATP and failure of glutamate uptake transporters on astrocytes
During failure of ATPase pumps, the electrochemical gradient may reverse (too much Na+ inside cell?) and glutamate (and Na+?) may be released from astrocytes
ACh activation of the cortex
All cerebral cortical regions, hippocampus, amygdala receive inputs from the basal forebrain cholinergic system
Cholinergic inputs disinhibit small specific regions of cerebral cortex and allow those restricted regions to act in a more easily excitable state without risk of widespread seizure activity
Cholinomimetic drugs (nicotine) promote cognition (attention)
Cholinomimetic drugs are approved for Alzheimer’s disease
ACh and Alzheimer’s disease
Hallmark of AD is progressive and ultimately pronounced loss of cholinergic fibers in the hippocampus and association areas of cerebral cortex as well as the gradual atrophy and eventual death of basal forebrain cholinergic neurons
Aricept (Donepezil)
Acetylcholinesterase inhibitor
Blocks the breakdown of acetylcholinesterase so you get more ACh in the synapse
This drug is approved for AD
Potential drug interactions as would be expected from cholinergic mimetics or inhibitors
Coincident activity in accumbens pathways leads to “reward” sensation
When DA present, accumbens medium spiny neurons become more responsive to glutamate inputs from amygdala, frontal cortex, cingulate cortex and other limbic cortex
Similar cellular mechanisms of coincident activity of glutamatergic signaling and D2 receptor activation in cerebral cortical circuits are thought to be involved in conferring “salience” to specific inputs
Mechanisms other than fast acting (on/off) neurotransmission in higher brain function
Chemical neuromodulators (NOT fast acting neurotransmitters) of various kinds can influence neural activity: cytokines (TNF-a), steroid hormones, many different peptides
Sometimes a single neuromodulator has effects that seem to influence or coordinate complex behaviors
TNF-a acts on certain neurons to increase surface expression of AMPA glutamate receptors
Estrogens increase density of spines, synapses and NMDA receptors in hippocampal pyramidal neurons and modulate LTP (densities fluctuate with cycle!)
Testosterone has similar effects to estrogen too
Oxytocin
Oxytocin may be involved in mediating and coordinating related behaviors
Peripherally induces uterine contractions and milk ejection
Centrally induces maternal behavior and bonding with infants in exerimental animals
Nasal oxytocin spray reduces amygdala activation and perception of fear and promotes trust in gambling games!
Implicated as molecule that promotes social bonding
Neurodegenerative diseases
Alzheimer’s disease (SDAT)
Parkinson’s disease
Amyotrophic lateral sclerosis (ALS/MND)
Frontotemporal lobar degeneration
Clinical and pathological manifestation of neurodegenerative disorders
Clinically: dementia +/- sensorimotor abnormality
Pathologically: neuron loss, astrocytic proliferation, “inclusions” (usually neuronal)
Alzheimer’s disease/senile dementia Alzheimer’s type
Age > 65: 5-10%
Age > 80: 20-40%
Familial (various genes: APP, PS-1, PS-2, ApoE4): 2-4% (FA says 10%)
Causes of senile/presenila dementia
1) Alzheimer disease/senile dementia Alzheimer’s type
2) Fronto-temporal lobar degeneration (FTLD spectrum): 35-50% familial, many genes
3) Lewy body dementia (diffuse Lewy body disease)
4) HIV dementia (HIV-associated neurocognitive deficit)
5) Multi-infarct dementia
6) Multi-system atrophies
7) Huntington disease (autosomal dominant “triplet repeat” disease)
8) Miscellaneous abnormalities (progressive subcortical gliosis, diffusely infiltrating neoplasms, etc)
Histologic findings in Alzheimer’s disease
Senile plaques: extracellular beta-amyloid core containing A-beta (note, normal people have senile plaques too)
Amyloid angiopathy: blood vessel walls have A-beta deposits; can lead to brain hemorrhage because smooth vessel cells replaced by non-flexible amyloid
Neurofibrillary tangles: intracellular, abnormally phosphorylated tau protein
Progression and deficits of AD at different stages
First, entorhinal cortex and hippocampus: amnestic mild cognitive impairment only
Widely distributed in neocortex: patient becomes very demented
APP metabolism
A-beta is cleaved from the larger molecule amyloid precursor protein (APP)
If beta-secretase and gamma-secretase are used, you generate amyloid (A-beta)
If alpha-secretase used, you do not generate amyloid because it is chopped right in the middle!
Relationship of APP, amyloid, A-beta
APP is amyloid precursor protein
APP is cleaved (by beta-secretase and gamma-secretase) to create amyloid
A-beta stands for beta amyloid, which is the type of amyloid present in Alzheimer’s disease
Amyloid protein is composed of many beta sheets
A-beta
Cleavage product of APP encoded on chromosome 21 (implications for Down Syndrome)
Two pathways of APP cleavage (non-amyloidogenic vs. amyloidogenic via alpha, beta, gamma-secretases)
39-43 amino acids (unique vs. other, intra-/extra-CNS amyloids)
Differential deposition of 1-40 vs. 1-42 forms in SPs, CAA
Can be measured in CSF (with ph-Tau) as a biomarker to support the clinical dx of AD/SDAT
Braak and Braak staging for AD
Stage I and II: transentorhinal
Stage III and IV: hippocampal
Stage V and VI: neocortical
Fundamental abnormality in AD/SDAT
Failure of synaptic transmission
Loss of synapses/synaptic proteins
Frontotemporal lobar degeneration spectrum
Frontotemporal dementia (including behavioral variant)
FTD and Parkinsonism linked to chromosome 17 (FTDP-17)
Primary progressive aphasia
Semantic dementia
Pick’s disease (PiD)
Argyrophilic Grain Disease (AGD)
Corticobasal ganglionic degeneration (CBGD)
Progressive supranuclear palsy (PSP)
FTD with motor neuron disease
Dementia lacking distinctive histology (DLDH)
Tau gene
6 tau isoforms generated by alternative mRNA splicing of exons 2,3,10 (352-441 AA length)
Proteins important in FTLDs
Tau
Ubiquitin
TDP-43 (TAR-DNA binding protein 43)
Pick’s disease
One cause of frontotemporal dementia
Selective atrophy of temporal and frontal lobes; spares parietal lobe and posterior 2/3 of superior temporal gyrus
Pick bodies: spherical tau protein aggregates (no A-beta protein)
Alpha synuclein
Aggregates to form insoluble fibrils in lewy bodies
Abnormal in Parkinson’s disorder (autosomal dominant PARK 1+4)
Declarative memory (explicit)
Semantic memory: facts about the world
Episodic memory: capacity to re-experience past events
Involves medial temporal lobe, diencephalon
Non-declarative memory (implicit)
Skills and habits: striatum
Priming and procedural learning: neocortex
Classical conditioning: amygdala (emotion), cerebellum
Non-associative learning: reflex pathways
Hippocampus in learning
Located in medial temporal lobe
Important in declarative memory
Disorders result in profound memory loss for people, places and events
Examples of disorders: Alzheimer’s disease, temporal lobe epilepsy, anoxia from many causes, herpes encephalitis
Dorsolateral prefrontal cortex in memory
Responsible for working memory and “executive functions”
Also responsible for “mental scratch-pad” or very short term memory
Failures of working memory include task perseveration despite evidence that other strategies should be tried
Disorders believed to involve DLPFC deficits include schizophrenia, TBI, frontotemporal and other cortical dementias
Causes of loss of memory
Alzheimer’s disease
Lewy Body Dementia
Frontotemporal dementia
Stroke
Multi-infarct, or vascular dementia
Parkinson’s disease
Does cell loss occur in the brain as we age?
Yes, but most of cortical thinning is due to decreases in synaptic connections
Only minimal cell loss in brain stem nuclei, supraoptic and paraventricular nuclei
10-60% loss in other areas (hippocampus)
Note: brain mass shrinks in 7th and 8th decade (frontal lobe and hippocampus mostly) and ventricular size relative to brain increases
Age-related changes in NT systems
Enzymes: decreased AChE, carbonic anhydrase, choline O-acetyltransferase, glutamic acid decarboxylase; increased COMT, MAO
Receptors: decreased muscarinic and 5HT receptors; increased D2 receptors
NTs: decreased neurotensin, substance P; increased VIP
Changes in brain blood flow with age
Brain blood flow decreases by 20%
Decreases greater with small vessel disease
Sex differences after age 60–women have it worse
Greater decrease in prefrontal area and in gray matter
Metabolism: mitochondrial function declines
Changes in brain connectivity during life
Childhood: brain wiring up
Adolescence: frontal lobe development
Adulthood: neuroplasticity (resource utilization, compensation, adaptation)
Note: older brain can be more efficient, resourceful; can compensate more readily depending on complexity or emotional salience of cognitive task
Neuropsychological domains and commonly used tests to assess
Orientation/global mental status: temporal orientation test; mini-mental status exam; ADAS-cog
Intellect: Wechsler Adult Intelligence Scale
Memory: Wechsler Memory Scale, California Verbal Learning test; CERAD, Rey AVLT
Attention/concentration: serial 7s or 3s; spelling WORLD; digit span (forward/backward)
Executive function: trail making test; Wisconsin Card Sorting Test; Go-No-go; Hand Luria
Visuoperception: Facial recobnition; tests of constructional praxis
Sensorimotor abilities: Grooved pegboard; finger oscillation
Personality and Mood: MMPI; Geriatric Depression Scale; Beck Depression Inventory; PHQ-9; PHQ-2
Neuropsychology of normal aging
Cognitive “decline” after age 50 reflects changes of aging nervous system
Older adults show selective losses in functions related to speed and efficiency of information processing
Older adults and regulation of affect
Older adults have high motivation to regulate affect
Have difficulty remembering negative information
No memory impairment for positive information
If emotional rather than neutral faces, older adults showed decreased medial temporal lobe and increased prefrontal activation compared to younger adults
Neural connections and activity in older brains
Greater frontal lobe and bifrontal lobe activity in older brain
Less synchronization of activity
Declining integrity of frontal-parietal WM tracts relate to problems with working memory and performance
Cognitive disorders late in life
First have changes of normal aging (age-associated memory impairment, age-associated cognitive decline, cognitively impaired not demented
Next have mild cognitive impairment
Last have dementia
Dementia and aging
Aging is greatest risk factor for developing dementia syndrome
Prevalence increases with age: 5% of 65yo and 50% of 85yo
Susceptibility (ApoE4) vs. genetic (PS1, PS2, APP) risk factors which predispose to EARLY onset AD
Etiology and type of dementia
Beta-amyloid = Alzheimer’s disease
Tau = FTD
alpha-synuclein = Parkinson’s
Lewy bodies = Lewy body dementia
Stroke/CVD = vascular dementia
Hydrocephalus - PNH
HIV = ADIS dementia
Syphilis = neurosyphilis
Fungal = cryptococcus
Prion = CJD
Thiamine deficiency = Wernicke’s
B12 deficiency
Endocrinopathies = hypo or hyperthyroidism
Alohol = alcohol dementia
Heavy metal poisoning = substance-induced dementia
Mood = dementia of depression
Psychosis = end-stage schizophrenia
Workup of dementia
Careful clinical history
Review med list
Perform physical and MSE
Basic screening labs
At least once, obtain brain scan (MRI/CT vs. PET)
Consider referral for neuropsychological testing (not always needed)
Treatment of dementia
Directed at addressing underlying cause if determined (reversible deficiencies/toxicities/primary psychiatric illness vs. irreversible AD, PD, FTD, CJD)
For neurodegenerative dementia, cognitive treatment is supportive/palliative (AChE inhibitors, NMDA antagonists)
Behavioral symptoms comorbid
Safety is paramount concern
Long-term care planning is essential
Treatment of delirium in an older person
Assure safety first: falls, strangulation, aspiration
Remove all unnecessary medications (polypharmacy often contributes; many non-psychiatric meds have psycho-active effects)
Correct underlying etiology if found, but often delirium is multi-factorial in elderly
Supportive measures (optimize environment, assure comfort and avoid restraints, increase familiarity, get a sitter)
Meds used only to treat target symptoms or for safety
Complications in late-life depression
Inanition: severe dehydration, weight loss, collapse
Catatonia: disturbances of motor movement, extreme psychological distress, elective mutism, exhaustion
Psychosis: delusions of poverty, extreme guilt, nihilism
Dementia: severe cognitive impairment that can reverse with treatment of mood
Suicide: highest risk group esp old white males, acute risk factors are pain, insomnia, psychosis, bereavement, attempts decrease but successful completions increase
Treatment of late-life depression
Behavioral: exercise, socialization, psychotherapy (individual, group or family)
Somatic: pharmacotherapy, brain stimulation therapy (ECT)
Less severe LLD best treated non-pharmacologically but more severe LLD needs combined approach
Inflammatory disorders of the CNS that do not have a known causal pathogen
Rasmussen encephalitis causing seizures
MS
ADEM (acute disseminated encephalomyelitis)
Microbial agents that may cause CNS inflammation, necrosis, neuron loss and gliosis
Bacteria
Fungi
Viruses
Rickettsiae
Parasites (cysticercosis, amebae)
Prions?
Bacterial, fungal, viral meningitis
Bacterial meningitis: high PMNs (supprative/purulent meningitis), high protein, low glucose; treat right away with antibiotics
Fungal meningitis: high lymphocytes, high protein, low glucose
Viral meningitis: high lymphocytes, high protein, normal glucose; self-limited so don’t need to treat
Granulomatous meningitis: multinucleated cells; due to acid fast bacteria (TB) or fungal infection (crypto, coccidio) or no microorganism (sarcoid); tend to be basal (only involve base of brain)
Distinguishing between delirium, dementia and depression in older people
Delirium: hours to days, abnormal vitals/PE, altered consciousness, inattention, fluctuation, hypo/hyperactive behavior, functional decline, need to review med list
Dementia: weeks to months (unless CVA), normal vitals, usually normal PE, memory plus multiple cognitive deficits, early behavioral findings if FTD or LBD, I-ADLs go before B-ADLs, need to get history
Depression: weeks onset, normal vitals, psychomotor retardation/agitation on PE, subjective cognitive deficits, poor effort, social withdrawal, irritability, anxiety, functional decline out of proportion to what is expected, need to review past psychiatric history
How do microorganisms get into CNS/CSF to cause meningitis?
Cardiopulmonary system
Nasopharynx and sinuses
Middle ear
Traumatic skull lesions
Along nerves
Note: immunosuppressed patients are particularly susceptible
Complications of meningitis
Immediate: cerebral edema, inappropriate ADH secretion (causing decreased Na+), subdural effusion, infarction/necrosis, DIC
Late: seizures, cranial nerve palsy, deafness, vestibular dysfunction, hydrocephalus, decreased IQ
Predisposing factors for brain abscess
Congenital heart disease (esp R –> L shunt because anything in venous system goes directly to L heart then circulation)
Otitis media/paranasal sinusitis
“Metastatic” infection from heart, lungs
Trauma (including iatrogenic: craniotomy)
Congenital skull/CNS anomaly
Immunosuppression
Viral infections of CNS
In healthy people: herpes simplex encephalitis
Immunocompromised: PML from papovavirus, CMV encephalitis, worse HSV encephalitis
Viral encephalitis
Always see:
Perivascular lymphocytic infiltrates (lymphocytes around blood vessels)
Microglial activation (but this is not specific, also see it in MS and other inflammatory disorders)
Neuronophagia (aka single neuron necrosis, piecemeal necrosis) which is neuron being gobbled up by chronic inflammatory cells
How do you diagnose a specific viral infection in encephalopathy?
Anatomic distribution of pathologic change (HSV likes temporal lobes and cingulate gyrus)
Characteristic microscopic pathology (HSV is necrotizing/hemorrhagic)
Viral inclusions (rabies, HSV)
Viral culture/IHC probe studies to visualize virus
PCR of CSF or brain biopsy to determine virus
Where does HIV like to go?
Microglia and lymphocytes
NOT neurons, oligodendrocytes, astrocytes, or epithelium
Progressive multifocal leukoencephalopathy (PML)
Caused by infection with papova virus (JC virus)
One of the most common viral opportunistic infections
Injures white matter/myelinated fibers (but different from MS!) but gray matter is spared
Poorly demarcated gelatinous areas in white matter
See large bizarre/atypical astrocytes
Oligodendroglial inclusions with “effacement” of normal chromatin (entire nucleus is dark/glassy)
HIV-related CNS/PNS pathology
HIV-associated neurocognitive deficit (HAND)
HIV-1 leukoencephalopathy (including pediatric)
Vacuolar myelopathy
Syndromes of neuropathy/myopathy (can be very disabling and meds make it worse)
Cerebrovascular disease
CNS opportunistic infections in HIV
Parasites: toxoplasmosis (can present as mass lesion)
Fungi: cryptococcus, candida, aspergillus, coccidiomycosis
Mycobacteria: MAI, MTB
Spirochetes: treponema pallidum
Viruses: CMV, HSV, VZV, papova (JC virus causing PML)
Neoplasms in HIV
Lymphoma (B cell, PCNSL?) can present as mass lesion
Kaposi sarcoma (rare)
Transmissible spongiform encephalopathies (TSE)
CJD, KURU are transmissible
Prion = proteinaceous infectious particle
Rapidly progressive dementia (3-4 weeks)
Very rare
Turn cortex into spongy appearance
Can have amyloid deposition
