ICL 10.7: Alzheimer's and Other Dementias

Question 1

what is dementia?

Answer 1

“the development of multiple cognitive deficits that are sufficiently severe to cause impairment in occupational or social functioning”

must involve memory and other cognitive domains (aphasia, apraxia, or agnosia), and must be a decline from premorbid function

so it’s important to know what their baseline premorbid function because someone might already have a cognitive condition

Question 2

what are the 5 categories of dementia?

Answer 2

1. degenerative
2. vascular
3. infectious
4. metabolic
5. structural/traumatic

Question 3

which conditions classify as degenerative dementia?

Answer 3

1. Alzheimer’s
2. Pick’s
3. Huntington’s
4. Parkinson’s
5. Lewy body disease
6. Multiple sclerosis
7. Primary progressive aphasia

Question 4

which conditions classify as vascular dementia?

Answer 4

1. multi-infarct vascular dementia

2. amyloid angiopathy

Question 5

which conditions classify as infectious dementia?

Answer 5

1. Creutzfeld-Jakob disease (prion disease)
2. HIV-related
3. neurosyphilis
4. PML (JC virus)

Question 6

which conditions classify as metabolic dementia?

Answer 6

1. Wilson’s disease
2. Wernicke-Korsakoff syndrome
3. deficiency states
4. renal failure

Question 7

which conditions classify as structural/traumatic dementia?

Answer 7

1. normal pressure hydrocephalus
2. subdural hematoma
3. tumor
4. abscess

Question 8

what is the most common type of dementia?

Answer 8

alzheimer’s = degenerative dementia

currently, alzheimer’s disease is the 6th leading cause of death in the US and by 2050, 14 million people are projected to have AD

Question 9

in what gender is dementia more common?

Answer 9

more common in women but we don’t know why….

prevalence also increases with age

Question 10

what is the general characteristics of Alzheimer’s?

Answer 10

1. gradual, progressive decline; begins with symptoms of forgetfulness (this is the first symptom!)
2. usually presents in the 60s (some in their 50s or 40s with DS patients since they have 3 copies of the APP!)
3. memory loss is for newly acquired information rather than old events from the past

depression is only in 5-8% so it’s uncommon

5. agitation and psychosis is a late development in 20% so it’s not a presenting symptom)
6. late stage aphasia, visual-spatial orientation, abstract thinking, judgement, personality, etc.

eventually, end-stage patients become mute, incontinent, bedridden

Question 11

what is the progression of the symptoms of AD?

Answer 11

symptom onset of forgetfulness then diagnosis won’t be till 3 years later

3-6 years is forgetfulness, loss of skilled activities (apraxia), declining personal care

by 10 years they have severe dementia and require 24/7 care

Question 12

what is the pathology of alzheimer’s?

Answer 12

1. amyloid beta plaques formed from APP
2. tau tangles

phosphorylated tau can no longer bind to the microtubules and you lose cell transport so the cell gets sick and dies –> you’ll find intracellular filamentous inclusions made up of poorly soluble hyperphosphorylated tau protein in the cell bodies and proximal dendrites that impairs neuron function

Question 13

what are the microscopic findings you see in Alzheimer’s patients?

Answer 13

1. amyloid plaques

2. tombstone ghost neurons due to neurofibrillary tangles in the cells

Question 14

what gross changes do you see in an Alzheimer’s patient

Answer 14

1. ventricular enlargement –> leads to hydrocephalus ex vacuum (compensatory)
2. severe hippocampus atrophy

Question 15

what is the clinical presentation of Alzheimer’s?

Answer 15

1. amnesia that presents as gradually progressive forgetfulness; e.g. appointments, misplaced objects
2. speech changes and dysnomia like initial word-finding difficulty, speech and vocabulary changes, hesitant speech with pauses – much later there is a loss of fluency and patients might constantly repeat questions
3. visuospatial disorientation in the middle stages so patients will have problems with copying, parking the car, setting the table
4. paranoia and personality changes are a later development – they may include imposter syndrome, psychosis, false accusations, delusions
5. executive dysfunction such as difficulty coordinating and planning tasks and following complex conversations or instructions – patients may stop participating in social activities and become withdrawn. poor driving, confusion during hospitalization (delirium) is common; poor calculation leads to problems with financial management
6. other features include apraxias (ideational and/or ideomotor) and agnosias (prosopagnosia, tactile, auditory, verbal…)

Question 16

how do we diagnose Alzheimer’s?

Answer 16

1. dementia defined by clinical examination, MMSE, or similar mental status examination (there’s not a blood test or anything)
2. patient older than age 40 years
3. deficits in 2 or more areas of cognition and progressive worsening of memory and other cognitive functions, such as language, perception, and motor skills (praxis) – MOCA exam
4. absence of disturbed consciousness (can’t diagnose AD during an acute delirium)
5. exclusion of other brain diseases

Question 17

what are the risk factors of Alzheimer’s disease?

Answer 17

1. increasing age
2. female gender
3. head Trauma
4. genetics: hereditary forms are RARE; most AD is sporadic!!

Question 18

what genetic mutations would increase the risk of developing Alzheimers?

Answer 18

1. mutations in amyloid precursor protein gene (APP) –> this is related to Down’s syndrome

there are only 20 families worldwide that have an AD inheritance of a mutated APP gene

2. mutations in presenilin gene: presenilin1 (Ch 14) and presenilin2 (Ch 1)
3. apolipoprotein E (cholesterol-binding protein in blood and it also shuttles amyloid beta into the cortex)

ApoE binds to amyloid plaques in AD brains

ApoE4 is found in increased amounts in Alzheimer’s patients but it’s not a cause of Alzheimer’s

Question 19

how do treat Alzheimer’s?

Answer 19

1. family support and education
2. adult day care if financially plausible – keeps patients active and engaged
3. symptomatic treatments for sleep disturbance, behavioral agitation, depression
4. medications

Question 20

which medications can be used to treat Alzheimer’s?

Answer 20

1. acetylcholinesterase inhibitors = Donepezil, galantamine, rivastigmine

GI side effects most common

2. glutamate inhibitors = memantine

dizziness, headache, constipation and confusion are the side effects

these medications don’t make memory better but what they do is stabilize for a short time, a person’s memory so it doesn’t decline as quickly – eventually though this effect wears off and it only lasts about a year

Question 21

what are the clinical stages of Alzheimer’s?

Answer 21

1. normal aging
2. mild cognitive impairment
3. Alzheimer’s

Question 22

how do you diagnose mild cognitive impairment?

Answer 22

MCI is like the middle stage that is pre-Alzheimer’s where people are having some memory and cognitive problems but it’s not full on AD

1. change in cognition noted by the patient or an informant
2. impairment in 1 or more cognitive domains like executive function, attention, language, visual spatial skills etc. (does NOT have to include memory loss; this is the big difference)
3. preservation of independence in functional abilities – they can still pay their bills, cook, drive, ADLs etc.
4. not demented (no significant impairment in social or occupational function)

Question 23

what was the first pathological change of people who eventually died from Alzheimer’s?

Answer 23

amyloid beta deposits!

this was then followed by phosphorylated tau

changes in brain structure like atrophy didn’t happen till later on

Question 24

what is the clinical presentation of someone who is in the mild/early stages of AD?

Answer 24

1. problems coming up with the right word or name
2. trouble remembering names when introduced to new people
3. challenges performing tasks in social or work settings
4. forgetting material that one has just read
5. losing or misplacing a valuable object
6. increasing trouble with planning or organizing (executive function problems)

so this sounds a lot like MCI but they’re also having memory and executive function problems which is why it’s considered early stages of AD

Question 25

what is the clinical presentation of someone who is in the moderate stages of AD?

Answer 25

this is the longest stage of AD and at this point, symptoms will be noticeable to others and may include:

1. forgetfulness of events or about one’s own personal history
2. feeling moody or withdrawn, especially in socially or mentally challenging situations
3. being unable to recall their own address or telephone number or the high school or college from which they graduated
4. confusion about where they are or what day it is
5. the need for help choosing proper clothing for the season or the occasion
6. trouble controlling bladder and bowels in some individuals
7. changes in sleep patterns, such as sleeping during the day and becoming restless at night
8. an increased risk of wandering and becoming lost
9. personality and behavioral changes, including suspiciousness and delusions or compulsive, repetitive behavior like hand-wringing or tissue shredding

Question 26

what is the clinical presentation of someone who is in the late stages of AD?

Answer 26

1. need around-the-clock assistance with daily activities and personal care
2. unable to use common household objects, apraxia (e.g., eating utensils)
3. lose awareness of recent experiences as well as of their surroundings
4. experience changes in physical abilities, including the ability to walk, sit and, eventually, swallow
5. have increasing difficulty communicating, not in full sentences or sometimes they don’t respond at all
6. become vulnerable to infections, especially pneumonia because they don’t move around a lot and they become more susceptible (they’re not immunocompromised)
7. social graces lost
8. psychosis may develop paranoia, hallucinations, and delusions
9. terminal: mute, bedridden, and incontinence

Question 27

72 y/o woman with word-finding problems. widowed, formerly able to do all ADL/IADLs, now needs assistance with the checkbook. has not paid bills on time, family is concerned. pt denies any problem, states she is just “getting old”. called her daughter 3x in the same day to ask when her grand-daughter’s graduation party was to be held. difficulty using the new microwave (apraxia). likes to knit, but did not know how to use a special set of knitting needles she formerly used and she didn’t even recognize them (apraxia and agnosia)

Exam: No focal deficits.
MMSE 22/30

CT: Normal

Follow-up 1 year: pt now is moved into assisted living because she lost weight (did not prepare herself food), wrecked her car, BP uncontrolled due to forgetting her meds

Diagnosis?

Answer 27

Alzheimer’s

memory deficits, visual spatial disorientation, agnosia, apraxia

Question 28

what are the symptoms of vascular dementia?

Answer 28

1. step-wise decline in function: amnesia, cognitive slowness**, apathy, social function, motor symptoms

cognitive slowness in their speech, action, and responses is the hallmark of vascular dementia

we don’t see motor symptoms in AD like we do in vascular dementia who might have righty and tremors

2. men > women
3. may present first with focal deficits or urinary changes
4. history of HTN, CHF, DM, peripheral vascular disease…all are a risk for stroke
5. gradual onset, early mental deterioration

Question 29

what would a brain scan of vascular dementia look like?

Answer 29

bunch of white patches within the parenchyma of the brain caused by vascular disease (it’s not a just a stroke!)

dementia symptoms occur when the brain is damaged because of problems with the supply of blood to the brain

Question 30

what parts of the brain are effects in Alzheimer’s vs. vascular dementia?

Answer 30

alzheimer = more of a cortical disease

vascular dementia = more of a subcortical disease

Question 31

what is the difference between subcortical and cortical dementia?

Answer 31

aka vascular vs. alzheimer’s essentially

VASCULAR (subcortical)
1. amnesia may or may not be present

2. VERY slow cognitive speed; it will take them forever to answer
3. recall is aided by cues = filing cabinet is in disarray
4. apathy is present/severe
5. depression is common
6. motor symptoms are common; tremor, registry, bradykinesia
7. apraxia and agnosia are uncommon
8. pathology is in the basal ganglia, striatum, midbrain and thalamus
9. vocabulary is spared
10. attention is poor

ALZHEIMER’S (cortical)
1. amnesia is more severe

2. cognitive speed is normal!!
3. recall is not aided by cues; this is because AD effects the hippocampus more and the information has never been transferred into long term memory for it to be recalled in the first place = filing cabinet is empty
4. apathy is present
5. depression is uncommon
6. motor symptoms are absent
7. apraxia and agnosia are very common!
8. pathology involves cortical association areas
9. vocabulary is affected
10. attention is sometimes preserved

Question 32

what are the core vs. supportive clinical criteria of Lewy Body dementia?

Answer 32

CORE CRITERIA
1. fluctuating cognition, attention and arousal, including behavioral inconsistency, incoherent speech, variable attention, staring

2. REM behavior disorder
3. visual hallucinations
4. Parkinsonism

triad = psychosis, dementia, EPS (extrapyramidal signs)

SUPPORTIVE CRITERIA
1. hypersomnia

2. hyposmia
3. transient unresponsiveness; people look like they’re asleep
4. severe neuroleptic sensitivity

Question 33

what are the indicative biomarkers of lewy body dementia?

Answer 33

1. DAT scan will show decreased uptake of dopamine
2. myocardial scintigraphy will show reduced MIBG uptake (target is post-ganglionic sympathetic cardiac innervation)
3. polysomnogram: if + for REM behavior disorder AND the pt has dementia it’s >90% predictive of LBD, even w/o clinical features

Question 34

what would an MRI, PET scan and EEG show for Lewy body dementia? (supportive biomarkers)

Answer 34

1. MRI would show preserved hippocampal volume on MRI
2. PET/SPECT would show low occipital FDG uptake on PET and posterior cingulate island (preserved metabolism)
3. EEG would show prominent posterior slow waves

Question 35

what is the criteria for diagnosing someone with probable Lewy body dementia?

Answer 35

probably DLB can be diagnosed if:

1. > 2 clinical features of DLB +/- biomarkers

OR

2. 1 core clinical feature + indicative biomarkers

probable DLB should not be diagnosed on the basis of biomarkers alone

Question 36

what is the criteria for diagnosing someone with possible Lewy body dementia?

Answer 36

possible DLB can diagnosed if:

1. 1 clinical feature of DLB is present, without an indicative biomarker

OR

2. > 1 indicative biomarker is present with no core clinical features

Question 37

what is the pathology of Lewy body dementia?

Answer 37

1. Lewy bodies are inclusions of ubiquitin and synuclein (main component) – synuclein is also found in the inclusions associated with Parkinson’s disease
2. diffuse involvement of cortical neurons with Lewy-body inclusions and by an absence or inconspicuous number of neurofibrillary tangles and amyloid plaques

Question 38

HPI: 76 y/o man (former accountant who still works part-time) presents with sleep disturbance. Wife has moved out of the bedroom because she gets kicked, awakened by pt acting out his dreams.

Exam: normal

MMSE: 29/30

Dx: REM behavior disorder

6 months later: Pt has visual hallucinations: sees people without faces in his bathroom at night. Wife thinks he is depressed

1 year later: Rigidity, masked facial expression, no tremor.

Diagnosis?? Differential diagnosis?

Answer 38

Lewy Body dementia

differential might include vascular dementia or Parkinson’s

Question 39

what is frontotemporal dementia?

Answer 39

mean age of onset is in the 50s ):

patients will have preserved perception, spatial skills, praxis and memory

there are 3 variants = behavioral, progressive non-fluent aphasia and semantic dementia

may be autosomal dominant ): ): there is no treatment either…..

Question 40

what are the 3 variants of frontotemporal dementia?

Answer 40

1. behavioral variant FTD = prominent behavior change
2. progressive non-fluency aphasia = prominent speech/language disruption
3. semantic dementia/progressive fluent aphasia = prominent speech/language disruption

Question 41

what is the clinical presentation of the behavioral frontotemporal dementia?

Answer 41

personality changes

Abulia

Apathy

social withdrawal

Disinhibition

Impulsivity

lack of insight

poor hygiene

stereotyped or ritual behaviors

change in eating patterns or preferences

new artistic ability

emotional blunting

loss of empathy

mental rigidity

Distractibility

Impersistence

Perseveration

impaired organizational and executive skills

bizarre affect

eating disorders

general disengagement
+/- euphoria

Repetitive or compulsive behaviors

Joviality

Question 42

what is the clinical presentation of progressive non-fluent frontotemporal dementia?

Answer 42

1. early anomia
2. word-finding difficulty
3. effortful speech
4. preserved comprehension early
5. increasing dysfluency
6. behavior and social interactions normal until late stage

Question 43

what is the clinical presentation of the semantic frontotemporal dementia?

Answer 43

1. temporal variant
2. progressive speech disturbance
3. impaired comprehension
4. preserved fluency!
5. paraphasic errors
6. anomia

Question 44

what are the microscopic findings of frontotemporal dementia?

Answer 44

Pick bodies = made of tau

Pick’s disease is a form of FTD and would have many similar symptoms – people aren’t diagnosed with Pick disease until biopsy

Question 45

what is Wernicke-Korsakoff Syndrome?

Answer 45

a neurological disorder caused by thiamine deficiency –> Wernicke’s encephalopathy and Korsakoff’s psychosis are the acute and chronic phases, respectively, of the same disease

triad = gait ataxia, oculomotor palsy, and encephalopathy

often seen in chronic alcoholics and malnourished people

Question 46

what causes Wernicke-Korsakoff Syndrome?

Answer 46

it’s due to the B1 (thiamine) deficiency

it’s associated with lesions in the mamillary bodies and mediodorsal thalamus

Question 47

what is Korsakoff syndrome?

Answer 47

it’s a late sequelae of Wernicke’s encephalopathy

1. both anterograde and retrograde amnesia
2. inability to form new memories leads to confabulation (making stuff up)
3. some dysinhibition, inappropriate behavior, hypersexuality – may be confused with FTD

Question 48

what gross changes do you see in the brain of a Wernicke-Korsakoff syndrome?

Answer 48

1. microhemoragic lesions

2. not a lot of atrophy or hippocampus loss

Question 49

HPI: 64 y/o woman with social withdrawal, formerly lively and independent. Last month bought a new refrigerator, even though she didn’t need one. Seems uninterested in family, though that was never true before. Not interested in her appearance.

MMSE: 29/30

Exam: Jovial, hyperactive in exam room, frontal release signs (primitive reflexes like rooting and sucking)

6 months later: In a nursing home, incontinent, has crawled into bed with other residents. Does not answer questions, sparse speech. Still hyper-jovial, and seems to obsess about the small parts of objects.

Dx??

Answer 49

behavioral variant of frontotemporal dementia

Question 50

what is normal pressure hydrocephalus?

Answer 50

normal pressure hydrocephalus (NPH) is an accumulation of cerebrospinal fluid (CSF) that causes the ventricles in the brain to become enlarged, sometimes with little or no increase in intracranial pressure (ICP)

in most cases of NPH, the cause of blockage to the CSF absorptive pathways is unclear

patients will have hydrocephalus without excessive cortical atrophy!!

Question 51

what are the symptoms of normal pressure hydrocephalus?

Answer 51

“wet, wobbly, wacky”

1. urinary incontinence
2. ataxia; “magnetic gait’
3. cognitive decline; psychomotor slowing, apathy, amnesia

1st gait change –> amnesia –> incontinence

Question 52

how do you treat normal pressure hydrocephalus?

Answer 52

CSF shunting if done early enough in the disease

so NHP is curable!! it’s the only dementia we’ve talked about that is curable (:

Question 53

what are the risk factors of developing normal pressure hydrocephalus?

Answer 53

1. CHI
2. SAH
3. meningitis

Question 54

how do you diagnose normal pressure hydrocephalus?

Answer 54

lumbar puncture or drain showing normal opening pressure, followed by improvement in gait, and memory

Question 55

what will the CT scan of normal pressure hydrocephalus look like?

Answer 55

GINORMOUS ventricles

not a lot of cortical atrophy!

Question 56

what is Creutzfeldt-Jakob Disease?

Answer 56

most common form of prion disease that is due to a transmissible pathogen that is a proteinaceous infectious particle that is devoid of nucleic acid

Question 57

what is the pathology of Creutzfeldt-Jakob Disease?

Answer 57

patients develop spongiform encephalopathy = lots of vacuoles and degeneration that make the brain look like a sponge

widespread neuronal loss and gliosis accompanied by a striking vacuolation or spongy state of the affected regions

+14-3-3 protein in CSF

Question 58

what are the symptoms of Creutzfeldt-Jakob Disease?

Answer 58

1. rapidly progressive profound dementia = 100% of patients will have memory loss
2. diffuse myoclonic jerks (78% of people)
3. variety of neurologic abnormalities; mainly visual or cerebellar

Question 59

what is new variant Creutzfeldt-Jakob Disease?

Answer 59

aka mad cow disease in England!

vCJD was transmitted by infected meat (mad cow disease)

patients were often younger onset (20’s) and manifested with psychiatric and sensory symptoms as the first sign of illness

no EEG changes, as seen in the usual CJD

Question 60

what does an MRI of Creutzfeldt-Jakob Disease look like?

Answer 60

hyperpigmentation of the cortex and basal ganglia

Question 61

what is the treatment for Creutzfeldt-Jakob disease?

Answer 61

there is no treatment ):

life expectancy: 6-12 months

you also can’t use their organs for transplants because you could transmit the “infectious protein”