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Stephen A Berman MD PhD
University of Central Florida
College of Medicine
Clarifying some basic terminology
Dementia is a general term for loss of cognitive
functions, i.e. thinking abilities.
Alzheimer’s Disease, as routinely used in the medical
literature, is a particular type of
dementia.
Alois Alzheimer
b. 6/14/1864
First Known Case of
Alzheimer’s Disease
Auguste D.
Alois Alzheimer
b. 6/14/1864
• “Auguste D.”, a 51 y/o woman.
• Delusions that her husband was having an affair.
• Soon followed by rapidly progressive memory loss,
losing her way in the apartment, carrying/hiding
household objects, worsening paranoia.
Alzheimer’s Disease
NFT’s
(silver stain)
Cortical atrophy
Plaque
(silver
stain)
Tangle
(silver
stain)
1898 Recent studies on dementia senilis and brain disorders caused by
atheromatous vascular disease: by A. Alzheimer
1901-1906 Alzheimer treated and followed Auguste D.
1906 Lecture on Auguste D.’s case
1910 Emil Kraepelin coins term Alzheimer’s Disease
(both Alzheimer’s and Kraepelin had reservations concerning whether
it was a “disease” or just a premature aging of the brain.
1970’s Alzheimer’s disease recognized but considered relatively rare.
1975- Dr. Robert Butler—NIA. Alzheimer’s is the major cause of cognitive impairment in
the Elderly. With sufficient application of money, we can cure it in 5 years!
1981-Ann Neurol. 1981 Aug;10(2):122-6.
Alzheimer disease: evidence for selective loss of cholinergic neurons in the nucleus
basalis. Whitehouse PJ, Price DL, Clark AW, Coyle JT, DeLong MR.
Donepezil (Aricept): all stages of Alzheimer's.
Rivastigmine (Exelon): mild to moderate Alzheimer's.
Galantamine (Razadyne): mild to moderate Alzheimer's.
2014-
Alzheimer’s Disease: the Scientific Holy War
Amyloid Plaque
(beta amyloid protein or
BAP)
Neurofibrillary Tangle
(tau protein)
• BAPtists: The accumulation of a fragment of the beta amyloid
precursor (BAP) protein or APP (the amyloid beta 42 residue
fragment or Ab-42) leads to the formation of plaques that
someone kill neurons.
• TAUists: Abnormal phosphorylation of tau proteins makes them
“sticky,” leading to the break up of microtubules. The resulting
loss of axonal transport causes cell death.
Ann Neurol. 1981 Aug;10(2):122-6.
Alzheimer disease: evidence for selective loss of cholinergic neurons in the nucleus
basalis. Whitehouse PJ, Price DL, Clark AW, Coyle JT, DeLong MR.
Most of what we call Alzheimer’s Disease is essentially aging of the brain.
Some people’s brains age faster in this manner…others age slower.
Numerous factors influence this process including general health, cardiovascular
health, sleep, exercise, relaxation vs. stress, diet, and heredity.
Some tests may measure certain substances that correlate with or predict this process but
that does not prove we are dealing with a singular disease—or even a multifactorial
disease as we usually think about it.
Myth
Closer to Reality
Alzheimer’s is a disease
Alzheimer’s is a complex cluster of multi-factorial, multi-level brain
problems typically seen with aging
“AD ravages the brain”
“Brain aging creates age-associated cognitive challenges”
“AD leads to a loss of
self”
“Brain aging creates a change in self”
“Alzheimer's is a slow
death”
Even WITH a diagnosis of AD, “Aging persons can still be vital
contributors”
We must declare war on
Alzheimer’s
We should better understand the aging process, particularly as
applied to the nervous system
So what is Alzheimer’s disease?
Short answer: I don’t know
Longer answer: A word describing a cluster of multiple problems at
multiple levels of the nervous system which can give rise to a gradual
decline in our ability to think.
If you want, you may call that a disease, but if so it probably is not a
disease that will respond to a single type of treatment.
Anti-Alzheimmab
Berman Pharmaceuticals
Ltd
Alzheimer’s: A Multi-level Multi Factorial Problems Associated with Aging ?
Cell types
Proteins
Intracellular
Structures Affect
Supracellular
structures Affected
Other bodily
systems
Neurons
(beta) amyloid
Mitochondria
Data Streams
Cardiovascular
Tubulin
Lysosomes
Networks
Endocrine
Proteases (calpains)
Proteasome
Connectome (or
parts thereof)
Ubiquitin
Glia, and
Microglia
Proteases (calpains)
Mitochondria
Ubiquitin
Lysosomes
Neurofilament
protein
Proteosomes
teleomeres
Weakness With Aging
Muscle Disease—Adult Muscular Dystrophies, Myasthenia Gravis, Polymyositis, etc.
Nerve Disease---Diabetic, Hereditary (e.g. Charcot-Marie-Toothe Disease), etc.
Nerve Root Injury---Disc problems, infections
Spinal Cord Problems
Weakness due to aging per se
Thinking Problems With Aging
Strokes
Hereditary Diseases—Huntington’s, Lewy Body Disease, Fronto-Temporal Dementia, Normal
Pressure Hydrocephalus, Progressive Supranuclear Palsy, Corticobasilar atrophy
Brain trauma
Brain tumors
Effects of Aging on the brain =? Alzheimer’s Disease ?
Neurodegenerative
Disorders - Part 2
Neurodegenerative disorders, Oriented toward
Dementia/neurocognitive disorders (e.g.
Alzheimer’s disease)
Stephen Berman MD PHD
Professor of Neurology UCF
Spongiform changes of the brain
Spongiform changes
Amyloid
plaque
INCLUSIONS
Disease
Inclusions
Protein
Associated proteins
Parkinsons
Lewy body
α-synuclein
?
Lewy Body Disease
Lewy body
α-synuclein
?
Alzheimers
Amyloid Plaque, NF
Tangle
β- amyloid
fragments ,
abnormal Tau
APP, presenilin,
secretases,
Tau positive glial
inclusions
Tau
Tau
Fronto Temporal
Dementia, (also
Progressive Supranuclear
Palsy, Corticobasilar
Degeneration)
Huntington’s
Nuclear and
Huntintin
cytoplasmic inclusions
Huntintin
SCA
Ataxin
Ataxin
ALS
SOD1
NF-H
Prion
Prion
CJD
Amyloid plaque,
spongiform changes
Objectives
• The objectives of this session are to understand
and learn about concepts, ideas, and facts related
to neurodegenerative diseases. These include the
following:
•
•
•
•
General features
Pathological hallmarks
Genetic and molecular biological factors
Biochemical Mechanisms
DEMENTIA
Causes
 Alzheimer's disease*
 Vascular dementia*
 Fronto-temporal dementia
 Parkinson's disease with dementia
 Lewy body dementia
 Progressive supranuclear palsy (PSP)
 Normal pressure hydrocephalus
 Creutzfeldt-Jacob Disease
 Huntington's disease
 Others
* We will focus on the problems marked with an asterix
Working Definition of Dementia




Acquired disorder
Decline from premorbid baseline
Affects at least 2 cognitive functions
Is a syndrome more than a diagnosis
 Some forms of dementia leave memory intact
 Previously called “hardening of the arteries” or “senility”
DSM IV Diagnosis of Dementia
 Memory impairment [insidious onset, gradual
progression] AND
 Impairment in at least 1 other cognitive domain
 Affecting social or occupational function
(“activities of daily living” – ADLs)
 Represents a decline from pre-morbid ability
DSM-5: Minor Neurocognitive disorder
Diagnostic Criteria
A. Evidence of modest cognitive decline from a previous level of performance in one or more
cognitive 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 mild decline in cognitive function; and
2. A modest impairment in cognitive performance, preferably documented by standardized
neuropsychological testing or, in its absence, another quantified clinical assessment.
B. The cognitive deficits do not interfere with capacity for independence in everyday activities
(i.e., complex instrumental activities of daily living such as paying bills or managing medications
are preserved, but greater effort, compensatory strategies, or accommodation may be
required).
C. The cognitive deficits do not occur exclusively in the context of a delirium.
D. The cognitive deficits are not better explained by another mental disorder (e.g., major
depressive disorder, schizophrenia).
DSM-5: Major Neurocognitive disorder
Diagnostic Criteria
A. Evidence of significant cognitive decline from a previous level of performance in one
or more cognitive 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. A 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 activities (i.e., at a
minimum, requiring assistance with complex instrumental activities of daily living such
as paying bills or managing medications).
C. The cognitive deficits do not occur exclusively in the context of a delirium.
D. The cognitive deficits are not better explained by another mental disorder (e.g.,
major depressive disorder, schizophrenia).
Important Issues
Dementia is an important public health problem
that is increasing.
The diagnosis of dementia is still clinical but new
methods are emerging.
Etiology is probably related to toxic beta amyloid
fragments, neurofibrillary tangles and problems
caused by other proteins.
Acetylcholine is especially affected in Alzheimer’s
disease and Lewey Body Disease.
Current treatments are effective, but palliative.
First line: acetylcholinesterase inhibitors.
Alzheimer’s Disease: the Scientific
Holy War
The Baptists vs. The Tauists
• BAPtists: The accumulation of a fragment of the beta amyloid
precursor (BAP) protein or APP (the amyloid beta 42 residue
fragment or Ab-42) leads to the formation of plaques that
someone kill neurons.
• TAUists: Abnormal phosphorylation of tau proteins makes them
“sticky,” leading to the break up of microtubules. The resulting
loss of axonal transport causes cell death.
Amyloid Hypothesis
1. The amyloid precursor protein (APP) is broken down by “secretases”
2. A nonsoluble fragment of the APP protein (mostly Ab-42) accumulates
and is deposited outside the cell.
3. The “sticky” nature of Ab-42 helps other protein fragments
(including apoE) to gather into plaques.
4. These plaques and/or the migration of the Ab out of the cell causes
neuronal injury and death
5. PSEN1 & PSEN2 genes  subunits of g secretase.
Amyloid precursor protein (APP) is membrane protein that sits in the membrane extending outward.
It is though to be important for neuronal growth, survival, and repair.
From: Sww.niapublications.org/pubs/unraveling/01.htm
Enzymes cut the APP into fragments, the most important of which for AD is called b-amyloid (beta-amyloid) or
Ab.
From: www.niapublications.org/pubs/unraveling/01.htm
Beta-amyloid is “sticky” so the fragments cling together along with other material outside of the cell, forming the
plaques seen in the AD brain.
From: www.niapublications.org/pubs/unraveling/01.htm
Neuronal Plaques in Alzheimer’s Disease
From http://www.rnw.nl/health/html/brain.html
Tau Protein
•
•
•
•
•
No tau mutations in AD but some in other “tauopathies.” However, the
burden of abnormal tau accumlations seems to correlate much better with
dementia in AD than does the burden of amyloid or amyloid plaque
accumulation
Tauopathies: Diseases caused, at least partially, by abnormal forms,
configurations, or accumulations of tau protein.
In tauopthathies Tau is generally deposited in hyper phosphorylated form
as paired helical or straight filaments. These usually form neurofibrillary
tangles.
Examples: AD (in part), Pick's Disease, Frontotemporal Dementia with
Parkinsonism Linked to Chromosome 17 (FTDP-17), Corticobasal
Degeneration, and Progressive supranuclear palsy
NFT’s can also be found in dementia pugilistica, myotonic dystrophy, and
prion diseases
Tau Hypothesis
1. Ordinarily, the t (tau) protein is a microtubule-associated protein (MAP)
that
acts as a three-dimensional “railroad tie” for the microtubule, which is the
conduit for axonal transport.
2. Tau phosphorylation causes tau to aggregate into proteins cause “paired
helical filaments” (PHFs) leading to neurofibrillary tangles (NFTs).
3. This process impairs axonal transport causing of cell death.
4. Possibly, tau aggregates may even form “prion” like structures which
promote the spread of the degeneration to adjoining neurons [This is a
recent addition to the hypothesis]
NFT’s
Microtubules are like railroad
tracks that transport nutrition
and other molecules. Tauproteins act as “ties” that
stabilize the structure of the
microtubules. In AD, tau
proteins become tangled,
unstabilizing the structure of
the microtubule. Loss of
axonal transport results in cell
death.
Neurofibrillary Tangles in Alzheimer’s Disease
From http://www.rnw.nl/health/html/brain.html
Alzheimer’s Disease
NFT’s
(silver stain)
SP’s (beta
amyloid
stain)
Cortical atrophy
Plaque
(silver
stain)
Tangle
(silver
stain)
Plaques and neurofibrillary tangles
http://www.hosppract.com/genetics/9707gen.htm
Senile Plaques
• Spherical lesions measuring up to 100 microns
• Neuritic plaques are fully developed senile plaques
– Central core of extracellular amyloid
– Halo of dystrophic neuronal processes with neurofibrillary
degeneration
– Zone around the amyloid core contains reactive astrocytes
and microglia
• In addition to neuritic plaques, beta amyloid can also be
found in diffuse plaques and may not be associated with
dementia (e.g. cerebral amyloid angiopathy)
Drawings of three neuritic (senile) plaques from the brains of patients with dementia.
Goedert M Brain 2009;132:1102-1111
More On Amyloid
• Chromosome 21 contains the gene for the Amyloid Precursor
Protein (APP)
• Trisomy 21 (Down syndrome): 1.5x’s the amt of APP as typical
people. But not clear that they get more AD because to the extent
amyloid might “cause” AD it does so not by overproduction of
APP but by defective processing which produces toxic fragments
rather than normal non-toxic (and/or beneficial) fragment.
Tau Protein
• Tau (the Greek letter) is a microtubule associated
protein, encoded by the gene MAPT gene on 17q21.
Normally, tau is phosphorylated and is present mainly
in axons where it binds and stabilizes microtubules.
• Neurofibrillary degeneration is characterized by
deposition in neuronal body and processes of INsoluble
polymers of OVER-phophorylated microtubule
associated protein tau.
• Tau aggregates as paired helical filaments, affecting
axonal transport and thus nutrition and function of the
cells.
• Is this the primary cause of AD? Some would say “Yes.”
But it’s likely there’s a lot more to this story yet to be discovered….
Nature. 2012 May 2;485(7400):651-5. doi: 10.1038/nature11060.
Prion-like behaviour and tau-dependent cytotoxicity of pyroglutamylated amyloid-β.
Nussbaum JM, Schilling S, Cynis H, Silva A, Swanson E, Wangsanut T, Tayler K, Wiltgen B,
Hatami A, Rönicke R, Reymann K, Hutter-Paier B, Alexandru A, Jagla W, Graubner S, Glabe CG, Demuth HU,
Bloom GS.
Source:Department of Biology, University of Virginia, Charlottesville, Virginia 22904, USA.
AbPeptide
AbPeptide
Pyroglutamate
Tau
Perhaps the Cause is Multi-Factorial (always good
to say when you don’t really know).
• Protein accumulation:  beta amyloid and tau, i.e. plaques &
tangles
•Oxidation
• Inflammation: glia, microglia, cytokines, lymphokines, and
whatever else is around.
•Mitochondrial dysfunction
• Lipid distribution: Lipid membrane site of APP cleavage.
•Mutations in other genes affecting amyloid and tau
•Prions and/or “prion like” proteins (perhaps altered beta amyloid
or tau)
•Proteasome damage
•Impairment of ubiquitin system (cell wastes not cleared properly)
Current gene candidates for AD:
• Changes too rapidly to keep track of.
• Go to http://www.alzgene.org/ for more information
•Actually the above database has gotten behind. Their last
update was 2011. They are working on a new version.
More On Amyloid
• Autosomal dominant AD develops < 65 y/o (presenile
dementia)
– Due to APP gene and presenillin 1 and 2 mutations
(affects secretase activity) on chr 14 and 1
respectively
• Apolipoprotein E (ApoE) genotype (chromosome 19)
– Transports lipids in and out of cell
– 3 forms (ApoE2, ApoE3, ApoE4)
– Genetic risk factor as homozygous ApoE4 allele develop
AD at a mean age of 70 (earlier onset)
How is AD different from
normal aging?
Normal ADL’s
Normal Memory
Normal
Impaired ADL’s
Impaired Memory
AD
Normal Aging
• Rate of learning may slow with age
• Rate of recall may slow with age
• Rate of forgetting does not increase with age
 Significant declines in cognitive function do not
represent normal aging
Vascular dementia
• 2nd most common form of
• Caused by degenerative
• occurs when the blood supply carrying oxygen and
nutrients to the brain is interrupted by a blocked or
diseased vascular system
• Usually occurs in “stepped” declines, whereas the decline
in Alzheimer's Disease is more gradual
• higher in men than in women
• incidence increases with age
Different types of vascular dementia
•
Stroke-related dementia
– Single-infarct dementia
– Multi-infarct dementia
– Hemorrhage less common but possible
•
Small vessel disease-related dementia
– known as sub-cortical vascular dementia
– Binswanger's disease (severe form)
•
Vascular dementia and Alzheimer's disease ,. i.e. mixed dementia. Not
uncommonly seen.
Signs and Symptoms
Behavioral
Physical signs/symptoms
signs/symptoms
•
•
••
••
•
•
Memoryspeech
Slurred
problems;
forgetfulness
Language problems
Dizziness
Abnormal behavior
Leg
or arm weakness
Wandering
or getting lost in
familiar
Lack
of concentration
surroundings
Laughingwith
Moving
or crying
rapid, shuffling
inappropriately
steps
• Loss
Difficulty
of bladder
following
or bowel
instructions
control
• Problems handling money
Risk factors
•
•
•
•
•
•
•
high blood pressure
diabetes
high cholesterol
family history of heart problems
disease in arteries elsewhere in the body
heart rhythm abnormalities
lifestyle factors (overweight/smoking)
Treatment and Prevention
• taking medication to treat any underlying conditions
– control high blood pressure and heart disease
• commitment to a healthier lifestyle
– stopping smoking, taking regular exercise, healthy diet and
drinking alcohol in moderation
• receiving rehabilitative support
– physiotherapy, occupational therapy and speech therapy
• Medications for Alzheimer’s disease may also help a
little
DEMENTIA
Causes
 Alzheimer's disease*
 Vascular dementia*
 Fronto-temporal dementia
 Parkinson's disease with dementia
 Lewy body dementia
 Progressive supranuclear palsy (PSP)
 Normal pressure hydrocephalus
 Creutzfeldt-Jacob Disease
 Huntington's disease
 Others
* We will focus on the problems marked with an asterix
DSM-5: Minor Neurocognitive disorder
Diagnostic Criteria
A. Evidence of modest cognitive decline from a previous level of performance in one or more
cognitive 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 mild decline in cognitive function; and
2. A modest impairment in cognitive performance, preferably documented by standardized
neuropsychological testing or, in its absence, another quantified clinical assessment.
B. The cognitive deficits do not interfere with capacity for independence in everyday activities
(i.e., complex instrumental activities of daily living such as paying bills or managing medications
are preserved, but greater effort, compensatory strategies, or accommodation may be
required).
C. The cognitive deficits do not occur exclusively in the context of a delirium.
D. The cognitive deficits are not better explained by another mental disorder (e.g., major
depressive disorder, schizophrenia).
DSM-5: Major Neurocognitive disorder
Diagnostic Criteria
A. Evidence of significant cognitive decline from a previous level of performance in one
or more cognitive 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. A 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 activities (i.e., at a
minimum, requiring assistance with complex instrumental activities of daily living such
as paying bills or managing medications).
C. The cognitive deficits do not occur exclusively in the context of a delirium.
D. The cognitive deficits are not better explained by another mental disorder (e.g.,
major depressive disorder, schizophrenia).
Important Issues
Dementia is an important public health problem
that is increasing.
The diagnosis of dementia is still clinical but new
methods are emerging.
Etiology is probably related to toxic beta amyloid
fragments, neurofibrillary tangles and problems
caused by other proteins.
Acetylcholine is especially affected in Alzheimer’s
disease and Lewey Body Disease.
Current treatments are effective, but palliative.
First line: acetylcholinesterase inhibitors.
Alzheimer’s Disease: the Scientific
Holy War
The Baptists vs. The Tauists
• BAPtists: The accumulation of a fragment of the beta amyloid
precursor (BAP) protein or APP (the amyloid beta 42 residue
fragment or Ab-42) leads to the formation of plaques that
someone kill neurons.
• TAUists: Abnormal phosphorylation of tau proteins makes them
“sticky,” leading to the break up of microtubules. The resulting
loss of axonal transport causes cell death.
Neuronal Plaques in Alzheimer’s Disease
From http://www.rnw.nl/health/html/brain.html
Neurofibrillary Tangles in Alzheimer’s Disease
From http://www.rnw.nl/health/html/brain.html