Week 4 (Memory, Cognition and Dementia)

Question 1

Cognitive deficits

Answer 1

Affect >10% of population

Associated with other health problems (neuro and psych disorders too)

Many causes, and have range of treatments

Question 2

Dan Schacter’s “7 sins of memory”

Answer 2

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

Question 3

What happens if you block NMDA receptors?

Answer 3

If NMDA receptors are blocked, you have no LTP and no spatial learning

Note: LTP required for learning, but LTP does not equal memory

Question 4

Two major divisions of memory

Answer 4

Non-declarative (implicit): don’t have direct conscious access to it (learning to ride a bike)

Declarative (explicit): facts and events

Question 5

Different brain regions and what type of memory they are involved in

Answer 5

Temporal lobe/hippocampus: spatial learning

Amygdala: emotional memory

Cortico-striatal system: procedural memory

Cerebellum: motor learning

Question 6

Multiple phases of memory

Answer 6

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

Question 7

When we find mutations that enhance learning and memory, what else do we notice?

Answer 7

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

Question 8

What is happening during LTP when you’re potentiating synapses?

Answer 8

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

Question 9

Memory extinction for something like phobia or PTSD

Answer 9

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

Question 10

Neurofibromatosis 1

Answer 10

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!

Question 11

Coma

Answer 11

State of eyes closed unresponsiveness

Profound unresponsiveness, in which the subject cannot be aroused

Sleep wake cycles are usually absent

Question 12

Vegetative state

Answer 12

State of eyes-open unresponsiveness

Unawareness of the self and the environment

Sleep-wake cycles frequently persist

Question 13

Whole brain death

Answer 13

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)

Question 14

Minimally conscious state

Answer 14

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

Question 15

Levels of altered mental status

Answer 15

Delirium: awake but confused

Obtundation: lethargic and confused

Stupor: awakens only with painful stimulus

Coma

Question 16

Anatomic lesions causing coma

Answer 16

Mass lesions: increased intracranial pressure, brainstem compression

Severe diffuse brain injury (hypoxia, carbon monoxide poisoning)

Acute bilateral cortical or thalamic lesions

Brainstem lesions

Question 17

Etiologies of coma approximate mortalities

Answer 17

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

Question 18

Glasgow coma scale

Answer 18

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)

Question 19

What determines prognosis of coma?

Answer 19

Etiology

Age

GCS

Question 20

Causes of coma that are result of encephalopathy vs. neurosurgical emergency

Answer 20

Encephalopathy: toxic, metabolic, anoxic, infectious, degenerative

Neurosurgical emergency: mass lesion, hemorrhage, tumor, trauma, increased pressure

Question 21

Neurological exam

Answer 21

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

Question 22

Decorticate vs. decerebrate

Answer 22

Decorticate: flexion; occurs in upper brainstem lesions

Decerebrate: extension; occurs in lower brainstem lesions

Question 23

Metabolic coma-frequent signs

Answer 23

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?)

Question 24

New syndromes impacting psychiatry and neurology

Answer 24

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

Question 25

Delirium

Answer 25

**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

Question 26

Examples of disturbances in consciousness ("A" criterion)

Answer 26

**Reduced clarity/awareness** of environment **Difficulty focusing**, sustaining, or shifting attention **Easy distractibility**

Question 27

Examples of cognitive deficits ("B" criterion)

Answer 27

**Memory** impairment (acute; recent) **Visuospatial** difficulty **Disorientation** (time, place) **Language** disturbance (dysarthria/dysnomia/dysgraphia) Perceptual disturbance (misinterpretation/illusion/**hallucination**)

Question 28

Commonly associated features of delirium

Answer 28

**Sleep/wake disturbance** Abnormal **psychomotor** activity: hypoactive vs. hyperactive (Lipowski) Atypical **emotion** Non-specific neurologic findings: **tremor**, **myoclonus**, **asterixis**, abnormalities of **reflexes** and tone

Question 29

Prevalence of delirium in specific patient populations

Answer 29

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%

Question 30

Underlying conditions commonly associated with delirium

Answer 30

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

Question 31

Substances that can cause delirium through intoxication or withdrawal

Answer 31

**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)

Question 32

Natural history of delirium

Answer 32

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**

Question 33

Neurophysiology of delirium

Answer 33

Acute deficits in **ACh** neurotransmission Acute **DA** excess **Hypoperfusion** **Cytokines**/inflammatory responses

Question 34

Complications of delirium

Answer 34

**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)

Question 35

How to assess delirium

Answer 35

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)

Question 36

Diagnosis of delirium

Answer 36

Delirium symptom interview (DSI) Confusion assessment method (CAM; \>90% sens/spec; good IRR) Delirium scale (Dscale) Saskatoon delirium checklist (SDC)

Question 37

Severity rating of delirium

Answer 37

Delirium rating scale (DRS) Memorial delirium assessment scale (MDAS)

Question 38

Other tests to assess delirium

Answer 38

**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)

Question 39

Principles of delirium treatment

Answer 39

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)

Question 40

Should we use benzodiazepines in delirium?

Answer 40

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**

Question 41

Side effects of antipsychotics in delirious patients

Answer 41

**Akathisia** **Hypotension** **Arrhythmia** (QT prolongation/ torsades) **Neuroleptic malignant syndrome**

Question 42

Drugs that show promise or are under investigation

Answer 42

NMDA antagonists: **ketamine** Alpha 2 agonists: **dexmedetomidine**

Question 43

Patient HM with bilateral surgical removal of hippocampus and medial temporal lobe

Answer 43

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

Question 44

Mammillary bodies

Answer 44

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**

Question 45

What do you lose in late Alzheimer's disease?

Answer 45

Lose **neuropil** and **neuronal cell bodies** Brain atrophy causes **enlargement** of ventricles (which can cause **hydrocephalus ex vacuo**)

Question 46

Progression of damage in Alzheimer's disease

Answer 46

First affects **entorhinal** cortex, then **hippocampus** then **limbic** cortex then widely across **neocortex**

Question 47

DSM-IV criteria for Dementia of the Alzheimer's Type

Answer 47

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**

Question 48

In AD, get loss of these functions associated with cerebral cortex

Answer 48

**Memory** **Cognitive function** **Object** or **person recognition** **Social skills** **Reading** and **writing skills** **Language skills** **Motor functions** **Circadian regulation**

Question 49

Primary sensory and primary motor cortex

Answer 49

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**

Question 50

Association cortex

Answer 50

Does not contain body map, but is viewed as having either **motor** **or sensory** function

Question 51

Dorsal and ventral pathways from primary cortex to neighboring association cortices

Answer 51

**Dorsal** pathway = **where** = **visual-spatial** orientation **Ventral** pathway = **what** = **object** recognition

Question 52

Different layers of the cerebral cortex

Answer 52

**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**

Question 53

Brodmann areas

Answer 53

Specific functions map to cortical areas with histological sub-specialization **Primary motor = 4** **Primary visual = 17** **Primary auditory = 41, 42**

Question 54

Which two glutamate receptors are linked to ion channels?

Answer 54

**NMDA**: Mg2+ blockade must be removed, lets **Ca2+** in (does LTP) **AMPA**: lets **Na+** in

Question 55

How is Ca2+ involved in LTP?

Answer 55

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)

Question 56

Ampakines

Answer 56

**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

Question 57

Memantine

Answer 57

**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)

Question 58

Will blocking NMDA receptors also slow neurodegeneration?

Answer 58

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**

Question 59

Glutamate excitotoxicity

Answer 59

**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

Question 60

Theory for rapid death of neurons and oligodendrocytes during ischemia (stroke)

Answer 60

**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

Question 61

ACh activation of the cortex

Answer 61

**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**

Question 62

ACh and Alzheimer's disease

Answer 62

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**

Question 63

Aricept (Donepezil)

Answer 63

**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

Question 64

Coincident activity in accumbens pathways leads to "reward" sensation

Answer 64

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

Question 65

Mechanisms other than fast acting (on/off) neurotransmission in higher brain function

Answer 65

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

Question 66

Oxytocin

Answer 66

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**

Question 67

Neurodegenerative diseases

Answer 67

**Alzheimer's** disease (SDAT) **Parkinson's** disease Amyotrophic lateral sclerosis (**ALS**/MND) **Frontotemporal lobar degeneration**

Question 68

Clinical and pathological manifestation of neurodegenerative disorders

Answer 68

**Clinically**: **dementia** +/- **sensorimotor** abnormality **Pathologically**: **neuron loss**, **astrocytic proliferation**, **"inclusions"** (usually neuronal)

Question 69

Alzheimer's disease/senile dementia Alzheimer's type

Answer 69

Age \> 65: 5-10% Age \> 80: 20-40% Familial (various genes: **APP**, **PS-1**, **PS-2**, **ApoE4**): 2-4% (FA says 10%)

Question 70

Causes of senile/presenila dementia

Answer 70

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)

Question 71

Histologic findings in Alzheimer's disease

Answer 71

**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

Question 72

Progression and deficits of AD at different stages

Answer 72

First, **entorhinal** cortex and **hippocampus**: amnestic **mild** cognitive impairment only Widely distributed in **neocortex**: patient becomes very **demented**

Question 73

APP metabolism

Answer 73

**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!

Question 74

Relationship of APP, amyloid, A-beta

Answer 74

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

Question 75

A-beta

Answer 75

**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

Question 76

Braak and Braak staging for AD

Answer 76

Stage I and II: **transentorhinal** Stage III and IV: **hippocampal** Stage V and VI: **neocortical**

Question 77

Fundamental abnormality in AD/SDAT

Answer 77

**Failure** of synaptic **transmission** **Loss** of **synapses**/synaptic proteins

Question 78

Frontotemporal lobar degeneration spectrum

Answer 78

**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)

Question 79

Tau gene

Answer 79

**6 tau isoforms** generated by alternative mRNA splicing of exons 2,3,10 (352-441 AA length)

Question 80

Proteins important in FTLDs

Answer 80

**Tau** **Ubiquitin** **TDP-43** (TAR-DNA binding protein 43)

Question 81

Pick's disease

Answer 81

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)

Question 82

Alpha synuclein

Answer 82

Aggregates to form insoluble fibrils in **lewy bodies** Abnormal in **Parkinson's disorder** (autosomal dominant PARK 1+4)

Question 83

Declarative memory (explicit)

Answer 83

**Semantic** **memory**: facts about the world **Episodic** **memory**: capacity to re-experience past events Involves **medial temporal lobe, diencephalon**

Question 84

Non-declarative memory (implicit)

Answer 84

**Skills** and **habits**: striatum Priming and **procedural** learning: neocortex **Classical** **conditioning**: amygdala (emotion), cerebellum **Non-associative learning**: reflex pathways

Question 85

Hippocampus in learning

Answer 85

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**

Question 86

Dorsolateral prefrontal cortex in memory

Answer 86

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**

Question 87

Causes of loss of memory

Answer 87

**Alzheimer's disease** **Lewy Body Dementia** **Frontotemporal dementia** **Stroke** **Multi-infarct,** or **vascular dementia** **Parkinson's disease**

Question 88

Does cell loss occur in the brain as we age?

Answer 88

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

Question 89

Age-related changes in NT systems

Answer 89

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

Question 90

Changes in brain blood flow with age

Answer 90

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

Question 91

Changes in brain connectivity during life

Answer 91

**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

Question 92

Neuropsychological domains and commonly used tests to assess

Answer 92

**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

Question 93

Neuropsychology of normal aging

Answer 93

**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

Question 94

Older adults and regulation of affect

Answer 94

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

Question 95

Neural connections and activity in older brains

Answer 95

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

Question 96

Cognitive disorders late in life

Answer 96

**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**

Question 97

Dementia and aging

Answer 97

**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

Question 98

Etiology and type of dementia

Answer 98

**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

Question 99

Workup of dementia

Answer 99

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)

Question 100

Treatment of dementia

Answer 100

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

Question 101

Treatment of delirium in an older person

Answer 101

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**

Question 102

Complications in late-life depression

Answer 102

**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

Question 103

Treatment of late-life depression

Answer 103

**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

Question 104

Inflammatory disorders of the CNS that do not have a known causal pathogen

Answer 104

Rasmussen encephalitis causing seizures **MS** **ADEM** (acute disseminated encephalomyelitis)

Question 105

Microbial agents that may cause CNS inflammation, necrosis, neuron loss and gliosis

Answer 105

Bacteria Fungi Viruses Rickettsiae Parasites (cysticercosis, amebae) Prions?

Question 106

Bacterial, fungal, viral meningitis

Answer 106

**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)

Question 107

Distinguishing between delirium, dementia and depression in older people

Answer 107

**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

Question 108

How do microorganisms get into CNS/CSF to cause meningitis?

Answer 108

**Cardiopulmonary** system **Nasopharynx** and sinuses Middle **ear** Traumatic **skull** **lesions** Along **nerves** Note: immunosuppressed patients are particularly susceptible

Question 109

Complications of meningitis

Answer 109

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

Question 110

Predisposing factors for brain abscess

Answer 110

**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**

Question 111

Viral infections of CNS

Answer 111

In healthy people: **herpes simplex** encephalitis Immunocompromised: **PML** from papovavirus, **CMV** encephalitis, worse HSV encephalitis

Question 112

Viral encephalitis

Answer 112

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

Question 113

How do you diagnose a specific viral infection in encephalopathy?

Answer 113

**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

Question 114

Where does HIV like to go?

Answer 114

**Microglia** and **lymphocytes** NOT neurons, oligodendrocytes, astrocytes, or epithelium

Question 115

Progressive multifocal leukoencephalopathy (PML)

Answer 115

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**)

Question 116

HIV-related CNS/PNS pathology

Answer 116

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**

Question 117

CNS opportunistic infections in HIV

Answer 117

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)

Question 118

Neoplasms in HIV

Answer 118

**Lymphoma** (B cell, PCNSL?) can present as mass lesion **Kaposi sarcoma** (rare)

Question 119

Transmissible spongiform encephalopathies (TSE)

Answer 119

**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