2. Dementia affects some 300 million people worldwide.
There are many types of clinical dementia but
Alzheimer's disease represents 60-75% of cases of
dementia.
Clinically, dementia presents with progressive decline
in cognitive function, including impaired memory,
learning, attention span, executive functions and
personality.
Dementia
3. COMMON SIGNS & SYMPTOMS
DEMENTIA
-MEMORY LOSS
-IMPAIRED JUDGEMENT
-DIFFICULT WITH
ABSTRACT THINKING
-FAULTY REASONING
-INAPPROPRIATE
BEHAVIOUR
-LOSS OF COMMUNICATION SKILLS
-DISORIENTATION TO PLACE & TIME
-GAIT, MOTOR & BALANCE PROBLEMS
-NEGLECT OF PERSONAL CARE & SAFETY
-HALLUCINATIONS,PARANOIA &
AGITATION
A Progressive Deterioration Of Intellect, Behaviour &
Personality due to diffuse disease Of Cerebral
Hemisphere, maximally affecting the
Cerebral Cortex & Hippocampus.
4. RISK FACTORS FOR DEMENTIA
AGE (ABOVE
65)/ SEX
(MALE)/
GENETIC
OVER WEIGHT/
DRUG/SMOKI
NG/ ALCOHOL
BLOOD
PRESSURE/
BLOOD SUGAR/
CHOLESTEROL
DEPRESSIO
N/ STRESS
HEART DISEASES/
DIABETES/
VASCULAR
DISEASES
HEAD INJURY/
INFLAMMATORY
STRESS/ TUMOR
HIV
INFECTION/
SOME
IMMUNOLOGIC
AL DISORDERS
POOR EDUCATION/
LOW PHYSICAL
ACTIVITY/
POOR NUTRITION
5. • SYMPTOM RATHER THAN A SINGLE DISEASE ENTITY.
• OCCURS IN ANY AGE,MORE COMMON IN ELDERLY AGE (ABOVE 65
YEARS).
• IF OCCURRED UNDER 65, IT IS TERMED AS PRE-SENILE DEMENTIA.
• INCIDENCE RATE: 187/100,000 PERSONS.
• ACCELERATED BY CHANGE OF ENVIRONMENT, INTERCURRENT
INFECTIONS, SURGICAL PROCEDURES.
6. INTEROSPECTIVE:
UNSURE OF SELF
DIFFICULTY IN
COPING WITH
WORK & DAILY
ROUTINE
(RETAINED
INSIGHT)
LOSS OF INSIGHT,
BEHAVIOURAL
CHANGES, LOSS OF
INHIBITION
LONG TERM CARE;
CAN’T BE
UN-ATTENDED
MUTISM
INCONTINENCE,
DEATH.
DEVELOPMENT OF SYMPTOMS
7. CLASSIFICATION -BASED ON CAUSE
1) ALZHEIMER’S DISEASE (60% OF ALL CASES)
2) CEREBRO VASCULAR DISEASES (20% OF ALL CASES)
- MULTI INFARCT (ATHEROSCLEROTIC) DEMENTIA
- SUBCORTICAL VASCULAR DISEASE ( BINSWANGER’S DISEASE)
3) NEURO DEGENERATIVE - PICK’S DISEASE ; HUNTINGTON’S CHOREA ; PARKINSON’S DISEASE
4) INFECTIONS- CREUTZFELD-JACKOB’S DISEASE ; HIV(AIDS DEMENTIA COMLEX) ; VIRAL
ENCEPHALITIS ; PROGRESSIVE MULTIFOCAL LEUCOENCEPHALOPATHY
5) NORMAL PRESSURE HYDROCEPHALUS
6) NUTRITIONAL-WERNICKE KORSAKOFF (THIAMINE DEFICIENCY); B12 DEFICIENCY; FOLIATE
DEFICIENCY
7) METABOLIC- HEPATIC DISEASE; THYROID DISEASE; PARATHYROID DISEASE; CUSHING’S
SYNDROME
8) CHRONIC INFLAMMATORY – COLLAGEN VASCULAR DISEASE & VASCULITIS, MULTIPLE
SCLEROSIS
9) TRAUMA – HEAD INJURY; PUNCH-DRUNK SYNDROME
10) TUMOR - eg: SUBFRONTAL MENINGOMA
SOME CASES ARE TREATABLE ; 10-15% ARE REVERSIBLE.
8. CLASSIFICATION -BASED ON SITE
# FRONTAL
PREMOTOR
CORTEX.
#BEHAVIOURAL
CHANGES,
LOSS OF INHIBITION,
ANTI-SOCIAL
BEHAVIOUR,
FACILE &
IRRESPONSIBLE
#Eg: NORMAL
PRESSURE
HYDROCPHALUS,
HUNTINGTON’S
CHOREA,
METABOLIC DISEASE
ANTERIOR POSTERIOR
#PARIETAL &
TEMPORAL
LOBES.
#DISTURBANCE OF
COGNITIVE
FUNCTION
(MEMORY &
LANGUAGE)
WITHOUT MARKED
CHANGE IN
BEHAVIOUR.
#Eg: ALZHEIMER’S
DISEASE.
SUB-CORTICAL CORTICAL
#APATHETIC
#FORGETFUL &
SLOW, POOR
ABILITY TO USE
KNOWLEDGE
#ASSOCIATED
WITH OTHER
NEUROLOGICAL
SIGNS &
MOVEMENT
DISORDERS.
#Eg: PARKINSON’S
DISEASE,
AIDS DEMENTIA
COMPLEX.
# HIGHER
CORTICAL
ABNORMALITIES
#DYSPHASIA,
AGNOSIA,
APRAXIA
#Eg:
ALZHEIMER’S
DISEASE
9. Pathology of dementia
1. Accumulation of insoluble proteins within cells, especially
neurons
Tau (microtubule associated protein), synuclein, TDP-43
2. Accumulation of insoluble proteins in the extracellular
spaces of the brain
Amyloid beta (Aβ), prion proteins, cystatin etc
3Cerebrovascular disease with cerebral infarction resulting in
Vascular Dementia
4 Mixture of Alzheimer's disease and vascular dementia
10. Type of Dementia Intracellular
inclusions
Extracellular
deposit
Infarcts
Ageing Tau + Aβ + +
Vascular
Dementia
Tau + Aβ + ++++
Alzheimer’s
Disease 85%
Tau ++++ Aβ ++++ +/++
Lewy Body
Dementia
Synuclein ++ Tau
++
Aβ ++ +
Creutzfeldt-Jacob
Disease
Prion Protein
(PrP) ++++
+
Huntington’s
Disease
Huntingtin in Basal
Ganglia
+
Fronto- temporal
Dementia
Tau ++++ TDP-43
Ubiquitin ++
Aβ +/- +
Pathology of Dementias
11. Causes of dementia
1overproduction of intercellular and extracellular proteins due
to genetic mutations
2failure of elimination of intracellular and extracellular proteins
with age
3 ageing of the vascular system
a. failure of blood supply and infarction
b. failure of elimination of extracellular amyloid proteins.
Therapy
Immunotherapy for Alzheimer's disease
13. Alzheimer’s disease:
• Most common type of dementia; accounts for an estimated
60 to 80 percent of cases.
Symptoms:
Difficulty remembering names and recent events is
often an early clinical symptom.
apathy and depression are also often early symptoms.
Later symptoms include impaired judgment,
disorientation, confusion, behaviour
changes and difficulty speaking, swallowing
and walking.
Brain changes:
=>Hallmark abnormalities are deposits of the protein
fragment beta-amyloid (plaques) and twisted
strands of the protein tau (tangles) as well as evidence
of nerve cell damage and death in the brain.
14. Level
of
Disabilty
and
Dependence
Severe
Minimal
Presymptomatic Mild Moderate Severe
Mild
Cognitive
Impairment
Memory
loss
Impaired
driving, meal
preparation,
paying bills
Cannot
manage
independently
Irritability,
agitation
Needs assistance
with bathing,
dressing,
toileting
Alzheimer’s disease
- - - - Dementia - - - - -
David Knopman Ch 8
21. A Tribute to Professor Felix Cruz Sanchez
1956-2011
International
Argentina, Spain, Germany, England
Scientist
140 papers 1983-2011
Organiser and Facilitator
First Brain Bank in Spain
Energy and Enthusiasm
A Dear and Entertaining
Friend
22. J Neural Transm. 2011 November ; 118(11): 1651–1657. doi:10.1007/s00702-011-0690-x.
Spatial patterns of FUS-immunoreactive neuronal cytoplasmic inclusions (NCI) in neuronal intermediate
filament inclusion disease (NIFID)
Richard A. Armstrong,
Vision Sciences, Aston University, Birmingham B4 7ET, UK
Marla Gearing,
Department of Pathology and Laboratory Medicine and Centre for Neurodegenerative Disease, Emory
University School of Medicine, Atlanta, GA, USA
Eileen H. Bigio,
Department of Pathology, Northwestern University Medical School, Chicago, IL, USA
Felix F. Cruz-Sanchez,
Institute of Neurological and Gerontological Sciences, International University of Catalonia, Barcelona,
Spain
Charles Duyckaerts,
Laboratoire de Neuropathologie, Hôpital de la Salpêtrière, AP-HP, 75651 Paris, France
Ian R. A. Mackenzie,
Department of Pathology and Laboratory Medicine, Vancouver General hospital, Vancouver, BC, Canada
Robert H. Perry,
Department of Neuropathology, Newcastle General Hospital, Newcastle-upon-Tyne NE4 6BE, UK
Kari Skullerud,
Department of Pathology, Rikshospitalet, N-0027 Oslo, Norway
Hideaki Yokoo, and
Department of Pathology, Gunma University School of Medicine, Maebashi, Japan
Nigel J. Cairns
Charles F. and Joanne Knight Alzheimer's Disease Research Center, Washington University
2011
24. Clinical Aspects of
Neurodegenerative Diseases
Development of Imaging – Pathology in Vivo
MRI and functional MRI
Positron emission Tomography (PET)
Clinical testing
Biochemical markers
26. PET Scans
Cognitively Normal Alzheimer’s disease
Deoxyglucose PET
showing
hypometabolism in
Alzheimer’s disease
Pittsburgh
compound B PET
for Amyloid
David Knopman Ch 8
27. Specimen in end stage AD demonstrating
severe global atrophy.
The images show FDG-PET and axial FLAIR images
of a normal subject and of patients with AD and
FTD.
In AD there is a decreased metabolism of the parietal
lobes (yellow arrows), whereas in FTD, there is
frontal hypometabolism (red arrows).
Presenile AD with normal hippocampus and
severe parietal atrophy
A
D
28. The images show a patient with a strategic PCA
infarction involving the hippocampus.
This type of infarct can result in sudden dementia if
located in the dominant hemisphere.
It will usually not result in dementia if it occurs in the
non-dominant hemisphere.
Vascular Dementia (VaD)
The images are of a patient who had VaD, but the
medial temporal lobe was normal.
MTA in a patient with VaD
29. Cerebro Amyloid Angiopathy showing multiple
peripherally located micro bleeds.
End stage FTLD with striking atrophy of
frontal and temporal lobes. No artophy of
parietal and occipital lobes.
images of the same patient show Fazekas 2
white matter hyprintensities.
Fronto-temporal Lobar Degeneration
Cerebral Amyloid Angiopathy
30. Cerebrovascular dementia:
Previously known as multi-infarct or post-stroke dementia, vascular dementia is
the second most common cause of dementia after Alzheimer's disease.(20% Of all
cases)
Eg:MULTI INFARCT DEMENTIA (ATHEROSCLEROTIC) , SUBCORTICAL VD
(BINSWANGER’S DISEASE-SUBCORTICAL LEUCOENCEPHALOPATHY)
Symptoms:
Impaired judgment or ability to plan steps needed to complete a task is more
likely to be the initial symptom, as opposed to the memory loss often
associated with the initial symptoms of Alzheimer's.
Occurs because of brain injuries such as microscopic bleeding and
blood vessel blockage.
The location of the brain injury determines how the individual's
thinking and physical functioning are affected
Brain changes:
Brain imaging can often detect blood vessel problems implicated in vascular
dementia.
31. Eg: PICK’S DISEASE , HUNTINGTON’S CHOREA , PARKINSON’S DISEASE
Parkinson’s disease
As Parkinson's disease progresses, it often results in a progressive dementia similar
to dementia with Lewy bodies or Alzheimer's.
Symptoms:
Problems with movement are a common symptom early in the disease. If dementia develops,
symptoms are often similar to dementia with Lewy bodies.
RESTING TREMOR, AKINETIC RIGIDITY,BENT POSTURE,HYPOMIMIA
Brain changes:
Alpha-synuclein clumps are likely to begin in an area deep in the brain called the substantia
nigra. These clumps are thought to cause degeneration of the nerve cells that produce
dopamine.
NEURO DEGENERATIVE DEMENTIA:
32. Pick’s disease
presents with impairment of recent memory associated with entorhinal
cortex and hippocampal dysfunction, Pick disease typically affects the
frontal and/or anterolateral temporal lobes.
A TYPE OF FRONTO-TEMPORAL DEMENTIA.
Emotional & behavioral changes, mutism, aphasia, echolalia(repeating whatever
spoken to them), rigidity, apraxia, weakness, memory loss.
BRAIN CHANGES:
Pick disease is defined pathologically by severe atrophy, neuronal loss, and gliosis.
Frequently, Pick disease is accompanied by the occurrence of tau-positive
inclusions.
Swollen (ballooned) neurons (Pick cells) and argentophilic neuronal
inclusions, known as Pick bodies, can disproportionally affect the frontal and
temporal cortical regions. Fewer Pick bodies may be present in these regions
if the primary symptoms are behavioral (behavioral variant), compared with
the primary symptoms of aphasia.
33. Dementia caused by infections
Eg: CREUTZFELD-JACOB DISEASE , HIV INFECTION (AIDS-DEMENTIA COMPLEX) , VIRAL
ENCEPHALITIS , PROGRESSIVE MULTIFOCAL LEUCOENCEPHALOPATHY
CREUTZFELD-JACOB DISEASE
CJD is the most common human form of a group of rare, fatal brain disorders
affecting people and certain other mammals. Variant CJD (“mad cow disease”)
occurs in cattle, and has been transmitted to people under certain circumstances.
Symptoms:
Rapidly fatal disorder that impairs memory and coordination and causes behavior
changes.
Brain changes:
Results from misfolded prion protein that causes a "domino effect" in which prion
protein throughout the
brain misfolds and thus malfunctions.
34. HIV Infection (AIDS-Dementia complex)
A condition that leads to the loss of intellectual abilities such as memory, judgment,
and abstract thinking. It can also cause changes in personality.
AIDS Dementia Complex (or ADC) is a type of dementia that occurs in advanced stages of
AIDS (acquired immunodeficiency syndrome).
These are some of the first signs and symptoms of ADC:
•Short attention span
•Trouble remembering
•Poor judgment
•Slowed thinking and longer time needed to do tasks
•Irritability
•Unsteady gait, tremor, or trouble staying balanced
•Poor hand coordination
•Social withdrawal or depression
In later stages, you may have more severe symptoms:
•Extreme mood swings
•Psychosis
•Loss of bladder and bowel control
35. Normal Pressure Hydrocephalus
Symptoms:
Symptoms include difficulty walking, memory loss and inability to control urination.
Brain changes:
Caused by the build up of fluid in the brain. Can sometimes be corrected with
surgical installation of a shunt in the brain to drain excess fluid.
Nutritional
Eg: WERNICKE-KORSAKOFF (THIAMINE DEFICIENCY),
B12 DEFICIENCY , FOLIC ACID DEFICIENCY
WERNICKE KORSAKOFF SYNDROME
Korsakoff syndrome is a chronic memory disorder caused by severe deficiency of
thiamine (vitamin B-1). The most common cause is alcohol misuse.
Symptoms:
Memory problems may be strikingly severe while other thinking and social skills
seem relatively unaffected.
Brain changes:
Thiamine helps brain cells produce energy from sugar. When thiamine levels fall too low,
brain
cells cannot generate enough energy to function properly.
36. By Metabolic disorders
Eg: HEPATIC DISEASES, THYROID DISEASES, PARATHYROID DISEASES, CUSHING’S
SYNDROME
Chronic inflammatory
Eg: COLLAGEN VASCULAR DISEASE, VASCULITIS, MULTIPLE SCLEROSIS
Trauma
Eg: HEAD INJURY, PUNCH-DRUNK SYNDROME
Punch-Drunk Syndrome
A condition seen in boxers and alcoholics, caused by repeated
cerebral concussions and characterized by weakness in the lower
limbs, unsteadiness of gait, slowness of muscular movements,
hand tremors, hesitancy of speech, and mental dullness.
Boxer's encephalopathy, dementia pugilistica. A syndrome affecting 10–20% of
professional boxers, which is the cumulative result of recurrent brain damage and
progressive communicating hydrocephalus due to extrapyramidal and cerebellar lesions
that translate into dysarthria, ataxia, tremors, pyramidal lesions– causing mental
deterioration and personality changes–eg, rage reaction and morbid jealousy– 'Othello
syndrome'
37. Tumor
Eg: SUBFRONTAL MENINGOMA
Dementia rarely may be due to intracranial tumour, especially
when tumours occur in certain anatomical sites.
Mental or behavioral changes occur in 50-70% of all brain tumours as
distinct from dementia which is associated with frontal lobe tumours,
III ventricle tumours and corpus callosum tumours.
Cognitive impairment also occurs as a non metastatic complication of
systemic malignancy.
38. DEMENTIA CAN OCCUR AS A SYMPTOM OF MORE WIDE SPREAD DEGENERATIVE
DISORDERS
Eg: HUNTINGTON’S DISEASE, DIFFUSE LEWY BODY DISEASE, PROGRESSIVE
SUPRANUCLEAR PALSY, MOTOR
NEURON DISEASE etc.
DEMENTIA WITH LEWY BODY DISEASE (DLB)
Symptoms:
People with dementia with Lewy bodies often have memory loss and thinking problems
common in Alzheimer's, but are more likely than people with Alzheimer's to have initial or
early symptoms such as sleep disturbances, well-formed visual hallucinations, and
muscle rigidity or other parkinsonian movement features.
Brain changes:
Lewy bodies are abnormal aggregations (or clumps) of the protein Alpha- synuclein. When
they develop in the brain cortex, dementia can result. Alpha- synuclein also aggregates in the
brains of people with Parkinson's disease, but the aggregates may appear in a pattern that is
different from dementia with Lewy bodies.
Other causes:
39. Huntington’s Disease
Huntington’s disease is a progressive brain disorder caused by a single defective gene
on chromosome 4.
Symptoms:
Include Huntington’s chorea, dysarthria, dysphagia, facial twitching, chameleon or
trombone tongue a severe decline in thinking and reasoning skills, and irritability,
depression and other mood changes.
Brain changes:
The gene defect causes abnormalities in a brain protein that, over time, lead to
worsening symptoms.
Mixed Dementia
In mixed dementia abnormalities linked to more than one type of dementia
occur simultaneously in the brain.
Brain changes:
Characterized by the hallmark abnormalities of more than one type of dementia —most
commonly, Alzheimer's and vascular dementia, but also other types, such as dementia
with Lewy bodies.
40. HISTORY TAKING
- FROM PATIENT & RELATIVE
NOTE:
1) RATE OF INTELLECTUAL DECLINE
2) IMPAIRMENT OF SOCIAL FUNCTION
3) GENERAL HEALTH & RELEVANT DISORDERS (Eg: STROKE, HEAD
INJURY)
4) NUTRITION STATUS
5) DRUG HISTORY
6) FAMILY HISTORY OF DEMENTIA
TESTS ASSIGNED TO CHECK INTELLECTUAL FUNCTIONS ARE DESIGNED
TO CHECK:
1) MEMORY 2) ABSTRACT THOUGHT 3) JUDGEMENT 4) SPECIFIC HIGHER CORTICAL
FUNCTIONS
IN EARLY / PSEUDO DEMENTIAS, A FORMAL ASSESSMENT FROM A
CLINICAL PSYCHOLOGIST IS ADVISABLE
41. PHYSICAL EXAMINATION
NOTE: FOCAL SIGNS
INVOLUNTARY MOVEMENTS
PSEUDO BULBAR SIGNS
PRIMITIVE REFLEXES
CHECK: POUT REFLEX (Tap lips with a tendon hammer, a pout reflex is
observed)
GRASP REFLEX (Tapping in between eyes, patient can’t inhibit
blinking in response to stimulation)
GLABELLAR REFLEX (Stroking palm induces grip)
PALMOMENTAL REFLEX (Quick scratch on palm induces
sudden contraction of mentalis muscle in face)
42. PHYSICAL EXAMINATION
PRIMITIVE REFLEXES ARE PRESENT IN INFANCY & IN AGED
PEOPLE, AS WELL AS IN DEMENTIA
NEUROPSYCHOMETRIC TEST
-DIAGNOSE EARLY DEMENTIA
-SEPARATE TRUE DEMENTIA FROM PSEUDO DEMENTIA
-MONITOR PROGRESS / TRIALS OF TREATMENT
(ASSESSMENT OF ONE’S COGNITIVE FUNCTIONS SUCH AS MEMORY, CONCENTRATION,
PROBLEM SOLVING SKILLS) IS PERFORMED TO:
48. Normal Brain Huntington’s Disease
Huntington’s Disease is a triplet
repeat disorder involving the
protein Huntingtin.
Pathology: Neuronal loss from
the Caudate Nucleus (arrow),
Putamen (*) and Globus Pallidus
with atrophy and gliosis
* *
*
50. Old cerebral Infarcts
14 months
> 5years
> 5years
Atrophy of
the Cortico-
spinal tract.
Mid-
brain
Infarct
**
Medulla
**
51. Causes of dementia
1overproduction of intercellular and extracellular proteins due
to genetic mutations
2failure of elimination of intracellular and extracellular proteins
with age
3 ageing of the vascular system
a. failure of blood supply and infarction
b. failure of elimination of extracellular amyloid proteins.
Therapy
Immunotherapy for Alzheimer's disease
52. Type of Dementia Intracellular inclusions
Extracellular deposits
Gene defects and
mutations
Alzheimer’s disease Tau Aβ Mutations in the APP and
presenilin genes – processing
of Aβ
Tauopathies Tau Mutations in tau gene Chr
17
Parkinson’s disease synuclein – Lewy bodies Parkin, PTEN-induced kinase
1 (PINK-1), DJ-1 Synphylin
Lewy Body
Dementia
Synuclein ++ Synphylin, synuclein
Creutzfeldt Jakob
disease (CJD)
Prion protein Prion Protein (PrP) gene
Huntington’s disease Huntingtin in nuclei Triplet repeat disorder
Fronto- temporal
dementia/ ALS
Tau TDP-43 Progranulin gene
TDP-43 Vasolin (VCP)
Genetics of Dementias
54. Neurofibrillary tangles
in Alzheimer's disease.
Ubiquitin and
hyperphosphorylated
tau protein.
Failure of
ubiquitin/proteasomal
system
Lewy bodies in
Parkinson's disease
and Lewy body
dementia.
Ubiquitin and
synuclein.
Failure of the
ubiquitin/proteasomal
system
TDP 43. in
Frontotemporal
Lobar
Degeneration
Accumulation of
protein in the
cytoplasm as
entry into the
nucleus fails
Failure of elimination of proteins from cells
– mainly neurons but also glia
55. Aβ
Soluble Aβ– drains
along periarterial
spaces
Insoluble and
fibrillary Aβ – are
deposited as plaques
and in artery walls
(Cerebral Amyloid
Angiopathy) in
Alzheimer’s disease
Amyloid Precursor
Protein (APP) Aβ
APP
Cell
Membrane
56. Balance between Production and Elimination of
Amyloid
Overproduction of
Amyloid or Tau
Familial cases (5%)
with mutations in the
Amyloid Precursor
protein gene
Failure of elimination of
Amyloid and tau
95% of cases of
Alzheimer’s disease
Age is the major risk
factor
Production Elimination
57. A4
Membrane
Cytosol
COOH
NH2
Extracellular Space
NL GQ VI
G
F
X
VMLKK COOH
NH2 VKMDAEFRHDSGYEVHHQKLVFFAEDVGSNKGAIIGLMVGGVVIATVIVITL
-Secretase
“Flemish
mutation”
692
“Swedish
double mutation”
670/671
-Secretase
“Dutch
mutation”
693
“Australian
mutation”
723
“Florida
mutation”
717
“London
mutations
”
716
-Secretase
40 42 43
Genetic Alzheimer’s disease: Mutations in the Amyloid Protein Precursor gene on
Chromosome 21 – overproduction of Aβ
58. Failure of elimination of Aβ from the ageing brain and in
Alzheimer’s disease
Young
Elimination of Aβ
Aβ
Neprilysin**
etc
Fail with Age **
LPR-1**
Capillary and Artery
Perivascular
drainage of
ISF and Aβ**
Arteriosclerosis and
Amyloid Angiopathy
Old
Failure of
Elimination of Aβ
Soluble Aβ
Plaques of Aβ
Targets for
Therapy
59. Drainage to Regional Lymph nodes
Lymphatic Drainage of Bodily Tissues – except the CNS and the Retina
Post-capillary venules
Blood Capillaries
and “Immune cells”
60. Green: Dextran
Red: Laminin in BM
Blue: Dextran +
Laminin in BM
Diffuse Spread
Capillary
Artery
5 minutes
5 minutes
5 mins
Roxana Carare
Dextran (3kDa)
Injection into
Mouse Caudate
Putamen
61. Solutes (Aβ) and ISF
drain along basement
membranes between
smooth muscle cells
Capillary
Artery
Smooth muscle cells
Endothelium
Tunica media
Perivascular (lymphatic) drainage of interstitial fluid and solutes
(Aβ) along basement membranes of capillaries and arteries
Perivascular macrophage
Roxana Carare
Aβ
Basement membranes
not involved in transport
62. Cerebral Amyloid Angiopathy
Aβ in the Basement Membranes of Capillaries and Arteries
Capillaries Arteries
Thioflavin
(Aβ is Brown)
63. Collagen IV Smooth Muscle Actin Aβ Combined
Figure 10. Separated colour channels of leptomeningeal arteries
from a brain with CAA. A-D: Immunocytochemical labelling of collagen
IV (A, blue), SMA (B, green) and Aβ (C, red) and overlayed (D). Note the
absences of Aβ labelling. Note the presence of Aβ surrounding deposits
around the smooth muscles and the ‘lumping’ of the deposits marked by
* in channel C. Scale = 25µm.
Shown with the kind permission of Nimeshi Jayakody: Medical
Student, Faculty of Medicine, Southampton University
64. Figure 12. An oblique section of a leptomeningeal artery with triple
immunofluorescence of AD leptomeningeal arteries. A) Blue colour channels
shows the distribution of Collagen IV in a reticular pattern B) Green colour channels
showing the distribution of SMA spiralling through the tunica media of the artery C)
Red colour channel showing the deposition of Aβ around smooth muscle cells and
within BM. D) The overlayed triple immunofluorescent image. Note the colocalisation
of Aβ with the BM. Scale = 25 µm.
Shown with the kind permission of Nimeshi Jayakody: Faculty of Medicine,
Southampton University
Collagen IV Smooth Muscle Actin Aβ Combined
65. Figure 14. A) An oblique cross section of an artery taken from an AD brain,
showing the interesting observation of the Aβ deposits between the two
layers of basement membranes B) A magnified image of a section of the
artery in image in ‘A’. Note the arrangement of Aβ deposits marked with a * in
between the BM. They do not have a mixture of colours i.e.purple/pink which
shows that they are not colocalised. Shown with the kind permission of
Nimeshi Jayakody: Faculty of Medicine, Southampton University
66. Blood in lumen of
Artery
Endothelium with
its own basement
membrane
Smooth muscle cell
Smooth muscle cell
Soluble Aβ
drains out of the
brain along BM
between smooth
muscle cells
Soluble Aβ forms
insoluble fibrillar
deposits in the
artery wall. Smooth
muscle cells die.
Insoluble fibrillar
Aβ
Pathogenesis of Cerebral Amyloid Angiopathy
67. Age and possession of Apolipoprotein E ε4 allele
are the major risk factors for Alzheimer’s disease.
Both reduce the clearance of solutes – including
Aβ – from the brain along perivascular drainage
pathways
69. Soluble Aβ and other
metabolites fail to clear -
Cognitive Decline
Aβ
Ageing of arteries
70. DIAGNOSTIC APPROACH:
IMAGING : MAINLY INCLUDES MRI, CT-SCAN , SPECT , PET
etc.
LAB STUDIES INCLUDES CBC , ESR , THYROID HORMONE TEST,
VIT-B12 BLOOD TEST , LIVER FUNCTION TEST
(ALT,AST,BLOOD TEST) , HIV TEST, ELECTROLYTE
TEST (TO CHECK KIDNEY FUNCTION),
TOXICOLOGY SCREEN (DRUG) , ANTINUCLEAR
ANTIBODIES (AUTOIMMUNE DISEASE) ,
LUMBAR PUNCTURE (To check some proteins in spinal fluid),
LEAD TEST (to check heavy metals in blood) etc.
CONFIRMATION: USUALLY WITH AUTOPSY,BIOPSY.
71. Differential diagnosis:
Dementia, delirium and depression are the 3 most prevalent mental
disorders in the elderly.
While dementia and depression are prevalent in the community,
hospitals and nursing homes, delirium is seen most often in acute
care hospitals.
The first step is to recognise which of the syndromes is present.
Dementia is defined by a chronic loss of intellectual or cognitive
function of sufficient severity to interfere with social or occupational
function.
Delirium is an acute disturbance of consciousness marked by an
attention deficit and a change in cognitive function.(Hallucinations,
autonomic over reactivity as a consequence of toxic, metabolic or
infective conditions.
Depression is an affective disorder evidenced by a dysphoric
mood, but the most pervasive symptom is a loss of ability to enjoy
usual activities.
These syndromes are not mutually exclusive, as dementia frequently
coexists with delirium and depression.
72. Diagnostic criteria for delirium
- Altered mental status (AMS) not explained by dementia.
-AMS developed over a short period of time (hours to days) and fluctuates
-AMS could be explained by a drug, acute illness or metabolic disturbance
Diagnostic criteria for dementia
-Memory loss, impairment of language, praxis, recognition or abstract thinking
-Chronic and progressive
-Delirium ruled out
Delirium is attention disorder vs. dementia which is a memory disorder.
In alcoholism before leaping into the diagnosis- WERNICKE KORASKOFF
SYNDROME, we should also consider the chance of CHRONIC SUBDURAL
HEMATOMA
73. PREVENTION
PEOPLE WHO HAVE DEMENTIA DUE TO STROKE, MAY BE ABLE TO
PREVENT FUTURE DECLINES BY REDUCING THEIR RISK FOR HEART
DISEASES.
FOR Eg: 1)TREAT OR
PREVENT HIGH BP
2)DON’T SMOKE
3)STAY AT A HELTHY
WEIGHT
(REDUCE RISK OF
DIABETES)
4)KEEP YOUR
CHOLESTEROL
NORMAL RANGE
5)PROPER PHYSICAL
ACTIVITY
6)STAY MENTALLY &
SOCIALLY ACTIVE
74. TREATMENT
# Doctors use medicines to treat dementia in the following
ways:
correct a condition that's causing dementia, such as thyroid
replacement for hypothyroidism, vitamins for lack of vit-
B12, or antibiotics for infections.
To maintain mental functioning for as long as possible
when dementia cannot be reversed.
To prevent further strokes in people who have dementia
caused by stroke (vascular dementia).
To manage mood or behaviour problems, such as
depression, insomnia, hallucinations, and agitation.
75. =>CHOLINESTERASE
INHIBITORS SUCH AS DONEPEZIL
(ARICEPT),GALANTAMINE
(REMINYL), & RIVASTIGMINE
(EXELON) ARE DEVELOPED TO
TREAT PRIMARILY ALZHEIMER’S ,
BUT ARE ALSO USED IN OTHER
DEMENTIAS ESPECIALLY IN
VASCULAR DEMENTIAS.
=>MEMENTINE (NAMENDA) USED
TO TREAT THE SYMPTOMS OF
ALZHEIMERS DISEASE, BUT MAY
ALSO HELP WITH MILD-
MODERATE VASCULAR
DEMENTIA
=> IT IS NOT CLEAR
THAT HOW LONG
THESE MEDICINES
WORK.
# MEDICINES TO HELP MAINTAIN MENTAL FUNCTIONS:
76. # CHANGING WHAT YOU EAT CAN REDUCE DEMENTIA SYMPTOMS & IMPROVE MENTAL
CLARITY
=>Reduce intake of carbs & sugars ; Take enough protein ,
vitamins-C,D,E,B12 , omega 3s fatty acid, zinc @ prescribed amount).
# MEDICINES TO CONTROL MOOD/BEHAVIOUR PROBLEMS
=> ANTI-PSYCHOTIC DRUGS:
SUCH AS RISPERIDONE (RISPERDAL) , OLANZEPINE (ZYPREXIA)
=> ANTI-DEPRESSANTS:
ESPECIALLY SELECTIVE SERETONIN REUPTAKE INHIBITORS
# MEDICINES TO PREVENT FUTURE STROKES
=>DOCTORS PRESCRIBE MEDICINES FOR HIGH BP & CHOLESTEROL
(THESE CAN’T REVERSE EXISTING DEMENTIA;BUT PREVENT FURTHER
BRAIN DAMAGE DUE TO STROKES & HD)
77. Therapy for Alzheimer’s disease
• Cholinesterase Inhibitors
• Immunotherapy – immunizing patients
against Aβ
78. Increase in fluid in
the white matter in
Alzheimer’s disease
Impaired drainage
of CSF?
Impaired drainage
of Intersitial Fluid?
Neuropathology of human Alzheimer’s
disease following immunization with amyloid
β-peptide
James AR Nicoll, David Wilkinson, Clive
Holmes, Phil Steart, Hannah Markham & Roy
Weller
Nature Medicine 2003; 9: 448-452
85. Alzheimer’s Disease: 65-75% of all cases of dementia
Clinical Features: Progressive decline in cognitive
function including impaired memory, learning, attention
span, executive functions and personality.
Effects: Difficulty of care; Financial consequences
Risk factors: Advanced Age; Apolipoprotein E ε4 allele;
In 5% cases there are mutations in Amyloid Precursor
Protein, and Presenilin genes
87. Microscopic Changes in the Brain in
Alzheimer’s Disease
1 Accumulation of waste proteins: Inside cells – mainly neurons
2 Accumulation of waste proteins: Outside cells
(3] Multiple small infarcts – thrombo-embolic disease)
88. Pathogenesis of
Alzheimer’s Disease
• Failure of elimination of Tau - ? Failure
of the Ubiquitin/Proteasome system
• Failure of elimination of Aβ from the
extracelluar spaces of the brain
91. Immunotherapy
1 Results for Alzheimer’s disease
A. Some positive improvement in mice and humans
B.Failure of elimination of Aβ may still be a problem with a rise
in soluble Aβ in the brain and accumulation of Aβ in
perivascular drainage pathways – Cerebral amyloid Angiopathy
2] Removal of Tau and synuclein in mice with some success
94. Pathology
Classification – Molecular Pathology – mainly based on the
proteins that accumulate:
Within cells - Intacellular
In Extracellular compartments
95. Neurodegeneration: the Molecular Pathology of
Dementias and Movement Disorders
1 Introduction: basic mechanisms of neurodegeneration
2Alzheimer's disease and ageing
3] Tauopathies
4] Synucleinopathies: Parkinson’s disease and Lewy body dementia
5] Trinucleotide repeat disorders: eg Huntington’s disease
6 Prion disorders: eg Creutzfeldt Jakob disease
7Frontotemporal lobar degeneration and amyotrophic lateral sclerosis /
motor neuron disease
8 Other neurodegenerative disorders
96. The future
1. Understanding why proteins such as tau (Neurofibrillary tangles)
and synuclein (Lewy bodies) accumulate in the ageing brain
Prevention
2. Understanding why Amyloid (Aβ or Prion Protein) accumulates in
the ageing brain
Devising methods to encourage the elimination of amyloid
3] Understanding the causes of cerebrovascular disease
Prevention
4] Care, management and relief of symptoms for Demented patients
and support for the carers
