Dementias (Cohen)

Question 1

Dementia; definitions

Answer 1

Deterioration of cognition, or higher intellectual processes, resulting from an organic disease of the brain.
From the Latin, dementia, “madness,” or “senseless”

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

Dementia in clinical practice

Answer 2

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 3

What the psychiatrists have done

Answer 3

no longer Alzheimer’s, they call it MAJOR NEUROCOGNITIVE DISORDER

Evidence of significant cognitive decline from a previous level of performance in one or more areas of congnitive domains (complex attention, executive function, learning and memory, language, perceptual-motor or social cognition) based on:

1. Concern of the individual, a knowledgeable informant or the clinician that there has been a significant decline in cognitive function; and
2. Substantial impairment in cognitive performance, preferably documented by standardized neuropsychological testing or, in its absence, another quantified clinical assessment.

B. The cognitive deficits interfere with independence in everyday actiities

C. The cognitive deficits do not occcur exclusivelyin the context of a delirium

D. The cognitive deficits are not better explained by another mental disorder (e.g. ajor depressive disorder, schizophrenia)

Question 4

Primary causes of dementia

Answer 4

1. Alzheimer’s Disease
2. Lewy Body Dementia/Parkinsons
3. Multi-infarct/Vascular Dementia
4. Fronto-temporal Dementia
5. Alcoholism/Vitamin B12 deficiency
6. Normal pressure hydrocephalus, Progressive Supranuclear Palsy, Huntington Disease, Multiple Sclerosis, Chronic Traumatic Encephalopathy, or no known cause

Question 5

Alois Alzheimer, 1864 - 1915

Answer 5

a German psychiatrist, who reported the clinical and pathological features of a 51 year-old patient with dementia
At the time, considered a rare condition
Patient died at age 55, and Dr. Alzheimer did the brain autopsy; published in 1907
Previous neuropathologists had discovered plaques but Alzheimer possibly discovered these neurofibillary tangles. The eminent psychiatrist Emil Kraepelin later named the disease after Alzheimer

Question 6

Plaques

Answer 6

dead neurons, amyloid

Question 7

Tangles:

Answer 7

Tau-containing microtubules inside neurons

Question 8

Theories of Pathogenesis of Alzheimers (not important)

Answer 8

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?); numerous experimental drugs reducing amyloid deposition have failed to help patients with Alzheimer’s Disease
2. Accumulation of phosphorylated tau, a protein which assembles microtubules and may play a role in synaptic transmission
3. Cell death, apoptosis, particularly in the temporal and parietal lobes, from genetic or environmental signals
4. Mostly a sporadic disease, sometimes familial in younger patients
   a. But nearly universal in Down syndrome patients who live 60 years: 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
6. History of head trauma or multiple head traumas in some patients
7. Possibly a partial loss of the blood brain barrier in middle life?
8. Prior head trauma

Question 9

Epidemiology: Age is the cause?

Answer 9

Prevalence of AD, according to age:
Under 65: < 1%
At age 65: @ 5 – 10%
At age 80 and older: @10 – 25 %
These figures are found all over the world

Slightly more common in women
Poorly educated or mentally inactive people are
more likely to become patients
Lack of exercise?

Question 10

Alzheimer’s Clinical Course

Answer 10

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: dressing, bathing, paying bills, falling victim to financial scams, poor use of checks or a credit card, loss of usual hobbies or interests
Behavioral changes occur, with loss of the usual manners or inhibitions: anger, cursing, inappropriate sexual behaviors: called a LOSS OF COMPORTMENT: personal conduct, behavior, demeanor

Question 11

physical/ mood issues in alzheimers

Answer 11

Visuospatial decline, due to disease of the nondominant hemisphere: patients get lost walking or driving, wander the neighborhood, pace in a nursing home, cannot even find their own bathrooms
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, but more often agitated or anxious, or simply inflexible (“set in his ways”)
Sundowning: more confusion and agitation at night

Question 12

allzheimer’s: apraxia, aphasia, agnosia

Answer 12

APRAXIA: 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

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

AGNOSIA: inability to recognize abnormalities in themselves and their environment, inability to recognize people (prosopagnosia) and familiar places

Question 13

Levels of Alzheimer’s Disease

Answer 13

MILD: 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
MODERATE: patient is kept at home only with great effort; full or nearly full-time caregiver, assistance with most ADLs is needed
SEVERE: patient must go to a nursing home or assisted living for round-the-clock supervision, or would otherwise be in danger

Question 14

Diagnosis of Alzheimer’s Disease

Answer 14

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

  You may hear that a brain biopsy or autopsy is the only way to diagnose the disease BUT studies have shown that clinicians are correct > 80 % of the time when they diagnose patients with Alzheimer’s disease

There are now diagnostic “tests,” including a current test for amyloid deposition in the brain, using a PET scan and injection of the Pittsburgh compound, Pib, which 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 15

What to do when you suspect Alzheimer’s Disease

Answer 15

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 16

Three Cholinesterase Inhibitors

Answer 16

• 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

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 17

Other treatments for Alzheimer’s

Answer 17

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

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

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 18

Mild cognitive impairment

Answer 18

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

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

Question 19

Lewy Body Dementia- presentation

Answer 19

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

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 20

Lewy Body Dementia features

Answer 20

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

1. DEMENTIA, progressive, but FLUCTUATING or variable from day to day, perhaps from fluctuating attention
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 in some patients

Question 21

Clinical Course of Lewy Body Disorder

Answer 21

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

Psychotic behavior, fluctuations, 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 the disease may be 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 22

Lewy Body Dementia Pathology

Answer 22

Similar or perhaps identical to Parkinson’s Disease, yet clinically distinct

Other than a 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

Also 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

Prominent involvement of the autonomic nervous system, also

Question 23

Treatment of Lewy Body Dementia

Answer 23

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 24

Multi-infarct Dementia

Answer 24

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

Question 25

Multi-infarct Dementia risk factors and treatment

Answer 25

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

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

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

Question 26

Fronto-temporal Dementia

Answer 26

Also known as Fronto-temporal Lobar Degeneration

A FAMILY of multiple disorders with dementia
Patients have problems with DECLINE IN BEHAVIOR AND/OR SPEECH
Autopsies and some MRIs show a visible degeneration of the frontal lobes and anterior temporal lobes, and increased tau deposition

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
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 27

Clinical features of FTD

Answer 27

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

Question 28

FTD: MOST PATIENTS HAVE THE BEHAVIORAL DOMINANT FORM:

Answer 28

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 29

FTD: THE LANGUAGE PREDOMINANT FORM:

Answer 29

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 30

Transmissible Spongiform Encephalopathy: CJD

Answer 30

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

1. Fairly RAPID DEMENTIA over just a few months, 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.
4. 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 31

Creutzfeldt-Jakob findings

Answer 31

Diagnosed by this very rapid downhill course
EEG shows triphasic waves
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
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 32

Creutzfeldt-Jakob- discovery

Answer 32

The disease, similar to kuru, which can be transmitted by cannibals in New Guinea, eating the brains of patients with that disease, clearly was transmissible or contagious
But where was the virus, or other organism? Nothing could be found.
Dr. Stanley Prusiner proposed and documented that a protein which humans and other animals synthesize, can become infectious by a simple change in conformation or shape
He coined the term PRION (Pree-on) for an “infectious” protein, and there are at least four diseases now thought to be due to prions
Prusiner won the Nobel Prize for his work

Question 33

Normal Pressure Hydrocephalus

Answer 33

Important because it is one of the most treatable dementias, although probably no more than 1 or 2 % of dementias
Caused by insufficient reabsorption of cerebrospinal fluid by the arachnoid villi
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
This distortion of the frontal lobes apparently causes the TRIAD of
1. Gait disorder 2. Dementia 3. Urinary incontinence

Question 34

Normal Pressure Hydrocephalus findings

Answer 34

The disease begins with a GAIT DISORDER which is variable, and sometimes intermittent
Patients ARE NOT WEAK, but 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
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
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
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 35

Treatment of NPH

Answer 35

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