3-30 Dementias

Question 1

What is the definition of dementia?

Answer 1

Deterioration of cognition, or higher intellectual processes, resulting from an organic disease of the brain

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

A progressive and likely IRREVERSIBLE DECLINE from premorbid functioning, and not a temporary decline due to delirium, especially acute medical/surgical illness or psychoactive drugs, or depression (pseudodementia)

Question 2

What is the relationship between dementia and delirium?

Answer 2

Patients with pre-existing dementia are more likely to develop delirium, and sometimes this is the initial presentation of dementia

Question 3

What is the clinical definition of dementia?

Answer 3

The loss of the “higher functions,” including memory, awareness, insight, judgement, executive function, abstract reasoning, visuospatial and construction skills, reasoning ability, social skills, use of meaningful language

Question 4

What 5 diseases constitute the majority of cases of dementia?

Answer 4

1. Alzheimer’s Disease @60 – 70%
2. Lewy Body Dementia/Parkinsons @10 – 15%
3. Multi-infarct/Vascular Dementia @5 - 10%
4. Fronto-temporal Dementia @5- 10%
5. Alcoholism/Vitamin B12 deficiency @5 %

Question 5

How can depression sometimes manifest in the elderly?

Answer 5

Depression, or “pseudodementia,” in the elderly

Question 6

What are the ‘plaques’ in Alzheimer’s made up of?

Answer 6

dead neurons and amyloid

Question 7

What are the tangles in Alzheimer’s made up of?

Answer 7

Tau-containing microtubules inside neurons

Question 8

What is the best known function of tau?

Answer 8

Tau has other cellular functions, but is best known for this protein’s ability to assemble and maintain proper structure in microtubules in cells - heavily phosphorylated

Question 9

What is the theory of pathogenesis of Alzheimer’s disease?

Answer 9

1. Accumulation of beta-amyloid, AB42 in plaques

a. Produced from amyloid precursor protein (APP) by multiple secretases, yielding AB42 (toxic) and AB40 and other fragments(nontoxic?)

2. Accumulation of phosphorylated tau, a protein which assembles microtubules

3. Cell death, apoptosis, particularly in the temporal and parietal lobes, from genetic or environmental signals

4. Slightly hereditary, but it is mostly a sporadic disease

a. But nearly universal in Down syndrome patients who reach the 50s or 60s, so Chromosome 21 must play a role, and it is thought to code for APP

5. Loss of acetylcholine, but also many other transmitters are lost eventually

Question 10

Is tau more important than amyloid in Alzheimer’s pathology?

Answer 10

Numerous drugs which effectively lower amyloid levels in the brains of patients have FAILED to reduce the symptoms of Alzheimer’s Disease, although an amyloid monoclonal antibody was recently useful in a phase 2 study

Pharmaceutical companies have spent over $15 billion on failed studies of anti-amyloid drugs for Alzheimer’s Disease

Phosphorylated tau accumulates in large amounts in AD, and is known to be crucial in many other forms of dementia: the “tauopathies”

Microtubule changes may cause severe changes in neuronal shape and then functions such as axonal transport

Tau may also be crucial in synaptic transmission at the plasma membrane

In the “War of the BAP-tists (beta amyloid) versus the TAO-ists (tau)” over causation of Alzheimer’s Disease, the Tauists are winning at this time

Question 11

What is the prevalence of AD, according to age?

Answer 11

Under 65: < 1%

At age 65: @ 5 – 10%

At age 80 and older: @10 – 25 %

These figures are found all over the world

Question 12

In addition to age, what else are important risk factors for AD?

Answer 12

Slightly more common in women

Poorly educated or mentally inactive people, victims of head trauma, people homozygous for the e4 allele of Apo E are also more prone to Alzheimer’s Disease

Question 13

What is the clinical course of AD in terms of recall, speech, management of daily affairs?

Answer 13

Almost always begins with a LOSS OF MEMORY for recent information or events, including appointments

Objects are misplaced, important items not found

Trouble recalling names of more distant friends and relatives

Some questions are repeated many times, as are old stories

Recent conversations with friends/family soon forgotten

Speech is restricted, with limited content or meaning, repetition of some simple phrases, inability to complete a sentence, can’t name some objects

Trouble in managing day-to-day affairs: shopping, paying bills, writing a check or using a credit card, cooking or cleaning at home

Question 14

What is the clinical course of Alzheimers in terms of visuospatial reasoning, gait, and mood?

Answer 14

Visuospatial decline, due to disease of the nondominant hemisphere: patients get lost walking or driving, stop by the roadside or at an intersection, wander the neighborhood, pace in a nursing home

Gait disorder is common, with dizziness and shortened steps, rigidity, poor posture especially extension

Depressed mood, boredom, lack of social inhibitions, irritability at first, sometimes leading to paranoia and denial of relationships “You’re not my wife, child, etc”

Occasionally violent, more often agitated or anxious, or simply inflexible (“set in his ways”)

Sundowning: more confusion and agitation at night

Question 15

What is apraxia?

Answer 15

the loss of some relatively simple actions, in spite of preserved gross motor and sensory functions; due to loss of connections between cortical sites

1. Inability to button or put on clothing, difficulty taking a shower or bath, brushing the hair or teeth, operating simple equipment or even opening a door, inability to enjoy hobbies such as painting, cooking, working on cars

Question 16

What is aphasia like in AD?

Answer 16

the content of speech declines, and sometimes quite late in the course of the disease patients are mute

Question 17

What is agnosia like in AD?

Answer 17

inability to recognize abnormalities in themselves and their environment, inability to recognize people and familiar places

Question 18

What levels of care and independence are consistent with mild AD?

Answer 18

¡patient is safe at home, requiring some help with activities of daily living; not a threat to himself, and can be left alone for a day

Question 19

What levels of care and independence are associated with moderate AD?

Answer 19

patient is kept at home only with great effort; full or nearly full-time caregiver, assistance with most ADLs is needed

Question 20

What are the levels of care and independence associated with severe cases of AD?

Answer 20

patient must go to a nursing home or assisted living for round-the-clock supervision, or would otherwise be in danger

Question 21

Is a Dx of AD in patients generally clinical or pathological? Accuracy?

Answer 21

This remains a clinical diagnosis, but with a high rate of accuracy

a. It is very rare that a brain biopsy or autopsy is the only way to diagnose the disease now; studies have shown that clinicians are correct > 80 % of the time when they diagnose patients with Alzheimer’s disease

Question 22

What are some physical signs of AD in living patients?

Answer 22

There may soon be diagnostic “tests,” including a current test for amyloid deposition in the brain, using a PET scan and injection of the Pittsburgh compound, PiB

a. PiB binds to beta-amyloid, allowing a quantitative measurement of the extent of amyloid deposition in the brain

Cerebrospinal fluid levels of beta amyloid and tau protein are often altered, also

1. Tau levels usually rise in the CSF, while beta amyloid levels usually fall

Brain MRIs show increased amount of atrophy in the medial temporal lobes, but this is not specific for Alzheimer’s Disease

Question 23

When making a Dx of AD, what else should you do clinically? How should you treat family and caregivers?

Answer 23

Exclude other diagnoses by history, examination, course, CT or MRI scan, laboratory tests including renal and hepatic function, B-12 level, thyroid functions

Consider the feelings of the patient and her family: don’t be too negative or pessimistic, but give some sense of the seriousness of this fatal disease; or to paraphrase the country song: “Break it to them gently!”

Be confident of the diagnosis with patient and/or caregiver, or reevaluate the patient in a few months, or get help from a neurologist, psychiatrist or neuropsychologist

Information on likely course, safety, management and concern for caregivers: The 36 Hour Day, by Folstein

Question 24

What class of drugs are helpful in potentially treating AD?

Answer 24

Cholinesterase inhibitors

Question 25

How do cholinesterase inhibitors help with AD? What can you expect with these meds?

Answer 25

• Relief of memory impairment, agitated behavior, and poor concentration presumably by raising acetylcholine levels
• Modest gains in Mini Mental State Exam at first, then slower decline; no major differences in treated and untreated patients by two – three years

Question 26

What are 3 drugs that can help AD? What are the ADRs?

Answer 26

1. Donepezil (Aricept) Most widely used, well-tolerated, fewest systemic adverse effects, once daily
2. Rivastigmine (Exelon) Strongly cholinergic effects, including vomiting and diarrhea, as a capsule, but now available as a skin patch to limit adverse effects
3. Galantamine (Razadyne) Similar to rivastigmine, extended release form is available

Question 27

In addition to 3 cholinesterase inhibitors, what other drug can help with AD? How does it work?

Answer 27

Memantine (Namenda)

1. Antagonizes glutamate at the N-methyl-D-aspartate receptor
2. May prevent cell death from glutamate activity
3. Used alone or with an AChE for moderate or severe AD, but memantine is seldom very effective

Question 28

In addition to cholinesterase inhibitors and memantine, what drugs can be used to alleviate some symptoms of AD?

Answer 28

Antidepressants are often needed, especially early in disease

There is often the use of antipsychotics to control agitation, anxiety; but studies show increased falls and earlier death

Question 29

What lifestyle modifications can help with AD?

Answer 29

Keep the patient mentally and physically active, and prevent him from seeking social isolation

Future therapies, which limit production of beta amyloid, or hyperphosphorylation of tau, must do much more!

Question 30

What is the percursor to AD? How does it manifest?

Answer 30

MILD COGNITIVE IMPAIRMENT

This is seen increasingly in patients who have very limited problems with memory or cognition, perhaps a bit more than would be expected for their age

They still function fairly well in social and even some occupational roles

So they do not meet the requirements for Alzheimer’s Disease

Question 31

How many people with mild cognitive impairment go on to develop AD?

Answer 31

Perhaps half or more of them will eventually develop Alzheimer’s Disease, at a rate of approximately 10 % per year

Question 32

How well known is Lewy Body dementia? How common is it?

Answer 32

Not well known to the public or to many physicians

One fifth as common as Alzheimer’s Disease, which means there are about one million Americans who do have Lewy Body Dementia

Question 33

What is the clinical presentation of Lewy Body Dementia?

Answer 33

The patients present with symptoms and signs of dementia and often agitated behavior, but have decreased facial animation, slowness and imbalance,

but mild or no tremor, suggesting a case of early Parkinson’s Disease,

except for the EARLY dementia and agitation, which are usually LATE problems in Parkinson’s Disease

A little more common in men than in women

Question 34

What are the SSXs of Lewy Body dementia?

Answer 34

A combination of cognitive decline with mild or moderate Parkinsonian features:

1. DEMENTIA, progressive, but FLUCTUATING or variable from day to day
2. VISUAL HALLUCINATIONS, sometimes complex and sometimes delusions
3. PARKINSONISM, with falls and rigidity, slowness in moving, but seldom have prominent tremor
4. BAD RESPONSE TO ANTIPSYCHOTIC DRUGS, with increased agitation or increased motor problems
5. Patients may improve with the AChE drugs used for Alzheimer’s Disease.

Question 35

What is the pathology behind Lewy body dementia?

Answer 35

Originally called Diffuse Lewy Body Disorder, DLBD, because Lewy bodies were found not just in the substantia nigra or brainstem, but throughout the brain, including the cerebral hemispheres and brainstem.

Other than this more widespread distribution of Lewy Bodies, Lewy Body Dementia has a very similar appearance in autopsies to Parkinson’s Disease, despite the major clinical differences.

Lewy bodies contain the protein ALPHA-SYNUCLEIN and have the senile plaques and neurofibrillary tangles found in AD.

However, it is one of the few dementias NOT known to be a tauopathy, possibly a low rate of dopamine reuptake at synapses with prominent involvement of the autonomic nervous system.

Question 36

What is the clinical course of Lewy Body dementia?

Answer 36

More rapid decline than in Alzheimer’s Disease, with death occurring quite often in 5 to 7 years

Psychotic behavior, fluctuating nature and complex visual hallucinations often lead to admission to psychiatry wards, or an early admission to a nursing home; may have had prior REM behavior disorder

May be injured or killed by falls or visual hallucinations

Agitation may be impossible to control, and unresponsive or made much worse by antipsychotic drugs, such as olanzapine, risperidal, haloperidol, etc.

Often incorrectly diagnosed as having Parkinson’s disease, or depression, or late life psychosis

Question 37

How is the Dx of Lewy body dementia made?

Answer 37

can only be made by clinical observation, formerly by brain biopsy

Question 38

How is Lewy Body Dementia treated?

Answer 38

The diagnosis can only be made by clinical observation, formerly by brain biopsy

The acetylcholinesterase inhibitors, originally developed for Alzheimer’s Disease, are somewhat effective

Be cautious in using antipsychotics

Depression and agitation often need some treatment

Occasionally low doses of levodopa can be added safely IF the parkinsonian symptoms of rigidity, imbalance and mild tremor should worsen

Question 39

What is multi-infarct dementia? How does PMH contribute?

Answer 39

Dementia from a known clinically history of strokes, including hemorrhagic ones, not just CT or MRI findings; however these scans must show some ischemic changes

Patients and their families recall PRIOR STROKES, and note a STEP-LIKE, downhill course, not a slowly progressive one

Question 40

What do patients with multi-infarct dementia show on exam? What diseases do they tend to have?

Answer 40

Patients have “focal” findings on exam, including aphasia, dysarthria, hemiparesis, spasticity, visual field cuts

Seizures more common than in other dementias

Likely concurrent coronary artery disease, peripheral vascular disease and carotid stenosis, which may be seen with ultrasound

Question 41

How common is multi-infarct dementia?

Answer 41

Becoming much less common in clinical practice due to control of risk factors for stroke

Question 42

What are the risk factors for multi-infarct dementia?

Answer 42

Patients have the typical risk-factors, sometimes under poor control:

1. Hypertension
2. Diabetes
3. Hyperlipidemia
4. Obesity, inactivity
5. Smokers, often alcoholics
6. Known coronary artery disease, atrial fibrillation

Question 43

How is multi-infarct dementia treated?

Answer 43

control of risk factors, aspirin and other inhibitors of platelet aggregation, and sometimes antic-coagulants (warfarin, etc.)

Question 44

What is fronto-temporal dementia?

Answer 44

A FAMILY of multiple disorders with dementia

The patients have problems with DECLINE IN BEHAVIOR AND/OR SPEECH

Question 45

What pathology can be seen with fronto-temporal dementia?

Answer 45

Autopsies and some MRIs show a visible degeneration of the frontal lobes and anterior temporal lobes

Increases of TAU protein

Degeneration of these two lobes in contrast to the temporal-parietal degeneration of AD, but usually the decline is asymmetric: more severe in either the left or the right hemisphere

Question 46

Is fronto-temporal dementia genetic? What is the age of onset?

Answer 46

May be familial in a minority of patients, equal in men and women

Onset at younger ages than AD; typically in the 50s and early 60s, rarely as early as the 20s

First described by Arnold Pick in the 1870s, who found inclusion bodies in demented patients

A. The disease was named for him, but is now known as FTD

Question 47

How is FTD Dx’ed?

Answer 47

NOT an easy diagnosis to make at this time

Most patients have either the behavior dominant form, or less commonly, the language predominant form

A psychiatric problem is often suspected at first, especially for the younger patients

Brain MRIs are not always helpful

No effective treatments now; but somewhat helped with antidepressants, and often antipsychotics

Question 48

What are the clinical features of FTD?

Answer 48

MOST PATIENTS HAVE THE BEHAVIORAL DOMINANT FORM:

Major personality changes, often with inappropriate actions, apathy, loss of sexual inhibitions, no concern with appearance, shoplifting or other crimes, no insight any more, no ability to plan their activities

Become obsessed with certain subjects, sing one song over and over, clap their hands inappropriately due to uncontrolled emotions

Overeating and overdrinking, often of sweet, fried or “junk food”¡Occasionally become weak, due to involvement of the adjacent motor areas of the frontal lobes

A. This kind of dementia may occur in patients with amyotrophic lateral sclerosis (ALS)

Memory loss may occur but usually later in the disease

FTD patients don’t get the auditory and visual hallucinations of Alzheimer’s

About equal in incidence in men and women

Question 49

What are the clinical features of the language-predominant form of FTD?

Answer 49

Primary progressive aphasia is a slow form of aphasia somewhat like Broca’s aphasia

The left frontal and temporal lobes have more atrophy than the right hemisphere

Sentences become shorter and shorter, with progressive inability to name, and read and write

Patients are quite aware of their deficits, and are very frustrated

They don’t get the behavioral problems of the behavior dominant form of FTD

Question 50

What are the clinical features of CJD?

Answer 50

CREUTZFELDT-JAKOB DISEASE, after the two physicians who published the first reports of patients

1. Fairly RAPID DEMENTIA over just a few months, or even week, with only rare patients living one year
2. Prominent MYOCLONIC JERKS eventually which can be provoked by staring at or touching the patients
3. Loss of balance and coordination, loss of visual fields, and sometimes cerebellar signs, and confusion and agitation. Patients may soon become mute.

Question 51

What parts of the brain tend to be affected in CJD?

Answer 51

The disease can be in any part of the brain, but often is toward the posterior portions, including the parietal and occipital lobe, and the cerebellum

Question 52

How is CJD Dx’ed?

Answer 52

Diagnosed by this very rapid downhill course

EEG shows triphasic waves, diffuse periodic wave pattern

CSF usually shows high levels of a 14-3-3 protein, which may be fragments of a longer protein of unknown function, but this test may take many weeks to perform, and is not completely specific to CJD

MRI shows rapidly accumulating subcortical deposits in the cerebral hemispheres, and cerebellar deposits sometimes

Question 53

What does CJD look like at autopsy? Is it common?

Answer 53

Brain biopsy or autopsy will show large holes in the brain, called SPONGIFORM, with enormous loss of neurons

Fortunately it is a very rare disorder, 1 -2 per million

Question 54

Why is normal pressure hydrocephalus important?

Answer 54

Important because it is one of the most treatable dementias, although probably no more than 1 or 2 % of dementias

Question 55

What causes normal pressure hydrocephalus?

Answer 55

Caused by insufficient reabsorption of cerebrospinal fluid by the arachnoid villi

Question 56

What changes happen in the brain as a result of normal pressure hydrocephalus?

Answer 56

Eventually the choroid plexi of the ventricles produce no more CSF than is reabsorbed into the veins, so the intracranial pressure goes back to normal, but the ventricles are very large

The sulci remain normal in size, unlike most dementias

Question 57

How does normal pressure hydrocephalus cause symptoms?

What is the TRIAD?

Answer 57

This distortion of the frontal lobes apparently causes the TRIAD of

1. Gait disorder 2. Dementia 3. Urinary incontinence

Question 58

What’s this?

Answer 58

Normal on top, normal pressure hydrocephalus on bottom

Question 59

What is the clinical picture of normal pressure hydrocephalus?

Answer 59

The disease begins with a GAIT DISORDER which is variable, and sometimes intermittent

Patients have difficulty controlling their legs, and have trouble with stairs or curbs on streets

The steps become shorter, and eventually it is hard to raise the feet off the ground at all, called a MAGNETIC GAIT

There are unexpected falls, while at other times the gait seems normal

They may even have trouble simply rolling over in bed

Patients say their legs are weak or heavy, but on clinical exam they seem to have normal strengths

Question 60

What behavior and mood changes happen with NPH?

Answer 60

The dementia is more of a behavioral change than the loss of cognition in most dementias

Patients are apathetic, uncaring, indifferent, lacking judgement, and may only have a slight loss of memory

There may be depression or personality changes

They respond very slowly when speaking, although they are not really aphasic

Question 61

Why is there incontinence with NPH?

Answer 61

The urinary incontinence is not always present, or occurs much later, and is poorly understood

Sometimes there is bowel incontinence, too

Patients don’t seem to sense they have a full urinary bladder, or don’t care anymore if they are incontinent, or perhaps they find it very difficult just to walk to the bathroom eventually

Question 62

How is NPH treated?

Answer 62

May respond dramatically to ventriculo-peritoneal shunting, and the gait disorder and the dementia disappear nearly completely

Diagnosis can be strongly supported by the removal of 30 cc of CSF by a lumbar puncture This procedure may produce a temporary clinical improvement for a few days, or even weeks, suggesting permanent shunting may be helpful

Shunts may stop working eventually because of infection or blockage, or the patient develops other serious illnesses