6. DSM-IV
• The general description of dementia was that
of a condition “characterized by the
development of multiple cognitive deficits
(including memory impairment) that are due
to the direct physiological effects of a general
medical condition, to the persisting effects of a
substance, or to multiple etiologies .”
7. • The cognitive effects needed to represent a
decline from a previous level of functioning,
and had to be severe enough to cause
significant impairment in social or
occupational functioning.
8. The neurocognitive disorders cluster
• In DSM-5, the cluster of neurocognitive disorders is
characterised by the presence of cognitive deficits that
are the most prominent and defining features of a given
condition.
• For the purpose of classifying neurocognitive disorders,
the Neurocognitive Work Group agreed on six principal
domains of cognitive function:
complex attention, executive function,
learning and memory, language,
perceptual–motor function, and social cognition .
9.
10. • The newly included domain of social cognition is
particularly important , as it recognizes the fact
that, in some neurocognitive disorders, socially
inappropriate behaviour can manifest as a
prominent feature.
• These symptoms can take the form of reduced
ability to inhibit unwanted behaviour, recognize
social cues, read facial expressions, express
empathy, motivate oneself, alter behaviour in
response to feedback, or develop insight.
• Deficits in social cognition were usually referred
to as personality change in previous diagnostic
criteria.
11. Subdividing the cluster
• The neurocognitive disorders cluster comprises
three syndromes, each with a range of possible
aetiologies:
• Delirium,
• Mild neurocognitive disorder (MCI)and
• Major neurocognitive disorder.(Dementia)
12. I.Delirium
• This neurocognitive disorder is characterised by disturbance
in attention that makes it difficult for the individual to direct,
sustain and shift their focus.
• The individual is, therefore, likely to have reduced
orientation to their environment, and at times to oneself.
• This symptom has sometimes been referred to as ‘reduced
level of consciousness’ or confusional state, although
disturbance in awareness is a more accurate description.
• Delirium can be caused by an underlying medical condition,
substance intoxication or withdrawal, exposure to toxins, or a
combination of these factors
13. II. Mild neurocognitive disorder
• The use of the diagnosis of MCI has become
commonplace in clinical practice, partly
because many patients with cognitive decline
now seek treatment earlier in the course of the
disease, before a diagnosis of dementia is
justified .
14.
15.
16.
17. III.Major neurocognitive disorder
• The introduction of major neurocognitive
disorder as an alternative term to dementia in
DSM-5 was prompted by a number of reasons.
18. DSM-5
• We expect that ‘dementia’ will continue to be
used for elderly patients and in many clinical
settings owing to familiarity and historical
continuity, but we also expect that major
neurocognitive disorder will be a more
suitable diagnosis for many
younger patients.
19. • The DSM-5 criteria for major neurocognitive disorder
have some noteworthy differences from the DSM-IV
criteria for dementia.
• First, substantial decline in only one cognitive
domain is sufficient for the diagnosis if the other
criteria are met. As a consequence, the DSM-IV
category of ‘amnestic disorder’ is now covered by
major neurocognitive disorder.
• Second, memory impairment is not essential for the
diagnosis. This change was made in recognition of the
fact that many individuals with dementia not due to
AD can have relatively intact memory, as is seen in
patients with cerebrovascular disease, frontotemporal
degeneration and some other conditions.
20. • Third, the functional criterion has been
revised to reflect that the threshold for
diagnosis of major neurocognitive disorder
emphasizes
loss of independence in daily living,
in comparison with the DSM-IV requirement of
impairment that
“significantly interferes with work or social
activities or relationships with others.”
21. • The determination of “significant” cognitive decline—
that is, impairment sufficient to diagnose major
neurocognitive disorder—is based on concern
expressed by an individual or by an informant or
clinician who knows the individual, and also on the
demonstration of substantially impaired performance
on an objective cognitive measure.
•
• If such an assessment is available, the performance
typically falls at least 2 SD below the normative mean
(or below the third percentile) on the test administered.
22. Aetiological subtypes
• The diagnosis is made in two steps:
• A syndromal diagnosis is made first, and then
• Potential causative factors are examined to
attribute aetiology.
• Mild and major neurocognitive disorders are
therefore subtyped according to aetiology.
23. The aetiological subtype
(the same for both mild and major NCD)
• Alzheimer disease
• Frontotemporal lobar degeneration
• HIV infection
• Huntington disease
• Lewy body disease
• Parkinson disease
• Prion disease
• Substance and/or medication use
• Traumatic brain injury
• Vascular disease
• Another medical condition
• Multiple aetiologies
• Unspecified
24.
25. • Incidental memory is memory for non-
intentional memory - memory for information
people are not asked to remember.
• In tests for incidental memory, people see/hear
some information (often secondary to another
task that the person is performing) and are then
asked to recall (or recognize) the information
despite the lack of prior effort made to
memorize the information.
• Tests of incidental memory are often used to
examine the Levels-of-processing effect
26. • What is enriched encoding?
• The process of actively relating new
information to knowledge that is already in
memory.
• Visual Imagery. visual representations created
by the brain after the original stimulus is no
longer present
27.
28.
29. Neurocognitive disorder due to AD
• AD is a neurodegenerative disorder with an insidious
onset and gradual progression of cognitive deficits.
• In a typical case, decline in learning and memory is an
early and predominant feature, and the decline is
progressive, without extended plateaus.
• For the DSM-5 diagnosis of major neurocognitive
disorder due to AD, decline in at least two cognitive
domains is necessary, one of which should be learning
and memory;
• For mild neurocognitive disorder due to AD, the
learning and memory deficit is sufficient for
diagnosis, although the characteristic profile of
insidious onset and gradual progression is necessary.
30. • Biomarkers of AD have received much attention
recently.
• The presence of the ε4 variant of apolipoprotein E is
a risk factor for AD but not a diagnostic marker.
• Other markers include the demonstration of
1-amyloid deposition in the brain using PET,
2-reduced levels of amyloid-β42 and elevated levels
of phosphorylated tau and total tau in the
cerebrospinal fluid,
3-hippocampal and temporoparietal atrophy on MRI,
4- temporoparietal hypometabolism on
18 F- fluorodeoxyglucose PET.
31. • Alzheimer's disease (AD) , and
vascular disease, are the most common
diseases that cause dementia both in the
elderly and in younger patients.
32.
33.
34. DM & Alzheimer`s disease
• Type 2 DM which cause increased
formation of free radicals may have a
role in development of cortical atrophy
and memory loss which may develop
because of damage to the hippocampus.
35.
36. Type 3 diabetes mellitus (T3DM) corresponds to a
chronic insulin resistance
plus
insulin deficiency
state that is largely confined to the brain.
T3DM
represents a major pathogenic mechanism of
AD neuro-degeneration.
37. • There was evidence that
tau gene expression and phosphorylation are
regulated through
insulin and insulin-like growth factor (IGF)
signaling cascades.
(Rivera et al.2005) .
38. Targeting Metabolic Disorders
• Drugs targeting insulin signaling may promote
cognitive improvement in models of AD.
• Therefore, insulin signaling seems to be a
novel therapeutic target for AD
39. • Several studies have linked obesity and energy
regulation with AD .
• Reducing caloric intake and adhering to a
“Mediterranean diet” appear to improve cognitive
health
The MINDdiet
• It uses aspects of the
DASH diet
(Dietary Approaches to Stop Hypertension)
&
Mediterranean diet.
40. Blueberries and strawberries, in particular, have
been used for their brain benefits.
Blueberries are vitamin-rich berries with high
content of antioxidants, specifically flavonoids.
41. • It consists of 15 dietary components:
10 "brain-healthy food groups" and
five unhealthy food groups.
42. • Green leafy vegetables, other vegetables,
nuts , berries, beans, whole grains, fish,
poultry, and olive oil make up
the brain-healthy foods
• while red meats, butter and stick margarine,
cheese, pastries and sweets, and fried or fast
food are the food groups that
should be limited.
• Unlike the DASH and Mediterranean diets - in
which high consumption of all fruits is
recommended –
the MIND diet focuses specifically on berries .
46. The Cholinergic Hypothesis
• The cholinergic hypothesis is the first and most studied
approach that describes AD pathophysiology.
• AD is a primary degenerative process capable of
selectively damaging groups of cholinergic neurons
in
the hippocampus, frontal cortex, amygdala,
nucleus basalis, and medial septum,
regions and structures that serve important
functional roles in
conscious awareness, attention, learning & memory,
(Terry and Buccafusco ,2003)
47. • The cognitive effects of acetylcholine are
mediated via the muscarinic M1 receptor.
• Non-selective and selective muscarinic
agonists have shown to improve learning and
memory.
• Selective M1 muscarinic agonists are a pivotal
target that link major hallmarks of AD.
48.
49.
50. (MAPK ) mitogen-activated protein kinase...,
(ERK) the extracellular signal-regulated kinase
MEK (MAPK/ERK) : (mitogen extracellular kinases)
Transcription facrors
51. • The M1 selective muscarinic agonists
AF102B [Cevimeline], AF150(S) and AF267B :
elevated αAPPs,
decreased Aβ levels & tau hyperphosphorylation
via M1 mAChR-modulation of kinases
(e.g. PKC, and GSK3β);
.
54. • Cholinergic hypothesis was reinforced
through Immunohistochemical &
neuroimaging, that revealed:
• 1- A reduced expression of
α3, α4, α7 and B2 subunits at
cortex and hippocampus,
• 3-A decline in the binding ability of
α7 hippocampal & α4 cortical receptors.
• Recent studies have shown that
amyloid β interacts with cholinergic
receptors affecting their function.
56. • Because the cholinergic and glutamatergic
systems significantly interact during
neurotransmission,
alterations in the glutamatergic signaling
has been associated with
cholinergic disruptions found in AD .
• Acetylcholine and its receptors, especially (α7)5
are considered as neuroprotective by modulating
glutamate-mediated neuronal excitability
57. • In AD abnormalities in glutamatergic
neurotransmission is initially observed at the
entorhinal cortex (EC),
followed by further neurotransmission defects in
the hippocampus, amygdala, frontal cortex, and
parietal cortex
58. • The physiological glutamatergic neurotransmission in the
hippocampus produces
a cytosolic calcium signal, which
mediates synaptic plasticity phenomena
such as
long-term potentiation (LTP),
encouraging learning and memory consolidation
•A sustained increase in calcium, sodium, and
chloride ions as a result of
the hyperactivation of NMDA glutamate receptors
has been associated with
excessive depolarization of the postsynaptic membrane,
&
onset neurodegenerative processes and cell death
59. • Memantine it is the first approved AD
drug to target (NMDA) receptor and
glutaminergic pathways (2003) .
(noncompetitive NMDA receptor antgonist)
• Accordingly, riluzole an inhibitor of
glutamate release and postsynaptic
glutamate receptor signaling, is in
a phase II trial in mild AD patients.
63. Amyloid cascade hypothesis
• The amyloid cascade hypothesis postulates
that the build up of Aβ in the brain causes
damage to neurons, and the clinical
phenotype of the amnestic dementia ofAD.
64. • The plaques may cause neuron degeneration and death
&
stimulate an inflammatory process
around the nerve cell.
• The nerve cell damage results in decreased
amounts of neurotransmitter substances, especially
the presynaptic cholinergic
neurons in the cerebral cortex
65. • This aggregation is the result of an
abnormal APP cleavage by β- and γ-
secretases .
APP is a transmembrane glycoprotein that
can undergo cleavages by secretases.
66. No accumulation of the
peptide
An insoluble form
Cleaved by α- secretase
A soluble fragment
APP
Cleaved at the β and γ sites
Aggregates in senile plaques
67. • A series of abnormalities in the process and
secretion of the amyloid precursor protein
(APP), where an inequality between
production and clearance of amyloid β
is the triggering event and
responsible for other
abnormalities observed in AD
(Doody and Clark, 2007)
68. • Amyloid β is a peptide with high resistance to
proteolytic degradation. It consists of 37–43 amino
acids, in which the isoforms 1–40 and
1–42 are the most common
(Deane et al.,2009)
The 1–42 amyloid peptide isoform is the most
hydrophobic and is considered to
have the greatest toxicity
it shows a greater tendency to aggregate and form
the core of the amyloid plaque .
(Leão et., 2012).
70. • BACE1(B-secretase ) expression can be
modulated by frequently seen situations in
neurodegenerative diseases and aging such as
OS, ischemia, inflammation, hypoxia, and
trauma.
71. • γ-secretase, consisting of a heteromeric complex
of 4 subunits called:
1 -Presenilins (PSEN1 and PSEN2),
2-Nicastrin (NCSTN),
3-APH-1, (anterior pharynx defensive phenotype 1)
(APH-1a and APH-1b) &
4-PEN – 2 (PS-enhancer-2) (preseniline enhancer -2)
.
73. Amyloid
1-Modulation of
Amyloid β Production.
2-Increasing Amyloid β
Degradation:
The Defective-Clearance
Hypothesis.
3-Inhibiting Protein
Aggregation:
The Role of Molecular
Chaperones.
4-The transport of
amyloid β through
the BBB.
74. 1-Modulation of Amyloid β Production
• Modulating Aβ production has proven difficult, in part
because of the complexity of the γ-secretase complex.
• Each of its four subunits is regarded as a potential
therapeutic target:
Nicastrin (NCSTN), presenilin (PEN-1), anterior pharynx-
defective 1 (APH-1), and presenilin enhancer 2 (PEN-2) .
• Because γ-secretase complex is now known to cleave up
to 50 different type 1 transmembrane protein substrates
besides APP, the identification of a selective and specific
inhibitor, ideally for only APP processing, represents a
tremendous drug-development challenge.
75. • Among its numerous downstream effects, γ-secretase
plays a key role in controlling the proteolysis of the
transmembrane domain of the Notch receptors,
with critical consequences for many different kinds of
cell differentiation events and eventually the
expression of genes that control cell fate.
• The effects of γ-secretase inhibitors on Notch
proteolysis can lead to toxic effects, including
gastrointestinal bleeding and immunosuppression.
• The interaction with Notch is among the reasons why
numerous γ-secretase inhibitors have failed
advanced-phase clinical trials
76. • A new generation of γ-secretase inhibitors and
modulators, including some nonsteroidal anti-
inflammatory drugs (NSAIDs), are designed to
reduce Aβ42 selectively, with little or no effect
on physiological Notch cleavage.
• Currently in a phase II trial, EVP-0962
(FORUM Pharmaceuticals, Inc.) is a γ-
secretase modulator that reduces the
production of Aβ42 by shifting the APP
cleavage toward the production of
shorter and less toxic Aβ peptides,
without affecting Notch cleavage.
77. • After the apparent failure of early γ-secretase-
based drug candidates,
β-secretase
namely β-site APP cleaving enzyme 1 (BACE1)
became the
favored target
for Aβ-centered therapeutics.
78. • They failed because of low oral bioavailability
and low blood–brain barrier penetration.
• The second-generation BACE1 inhibitors were
supposed to be more lipophilic and to reach
the BACE1 active site
• However, many compounds failed advanced-
phase clinical trials because of liver toxicity.
79. • An alternative immunotherapy approach consists of
site-directed Abs that
affect the BACE-APP complex
by targeting
the β-secretase cleavage site of APP.
• Therefore, anti-APP Abs would preserve BACE
activity directed toward non-APP substrates and
selectively interfere with the BACE-APP complex,
inhibiting Aβ formation
81. 2-Increasing Amyloid β Degradation:
The Defective-Clearance Hypothesis
• Aβ is constantly metabolized, and its net content
in the brain results from the equilibrium between
overall rates of production and clearance.
Numerous peptidases and proteinases, known
collectively as Aβ-degrading proteases (AβDPs),
affect Aβ levels.
• Increased Aβ levels may be caused not only by
elevated production but also by diminished
degradation .
82. • Dugs that enhance Aβ degradation
directly by
stimulating the expression of AβDPs
or
indirectly by
inhibiting the endogenous inhibitors
that regulate AβDPs.
83. Immunotherapy to IncreaseAmyloid β Clearance
significantly reduced Aβ
plaque formation and
prevented memory
deficit in AD animal
passive immunization
with systemic
infusion of
monoclonal Abs
(mAbs) directed at
Aβ
active immunization
achieved by using synthetic
full-length Aβ42, human Aβ42
high specificity and
affinity toward
their antigen, low
toxicity
1999
6% of the patients
developed severe
meningoencephalitis
halted
As a
consequence of
this failure
vasogenic cerebral
edema.
84. • Gantenerumab (Chugai Pharmaceutical Co., Ltd.,
Roche) is the first fully human anti-Aβ IgG.
• It seems to be well tolerated and is currently in a
phase III trial for AD and
in a phase II/III trial for dementia prevention.
85. • Finally, produced through
a “reverse translational medicine” approach,
aducanumab (Biogen, Inc.) is a fully human
IgG1 mAb obtained from a screen of healthy
advanced-age donors with normal cognition
who are hypothesized to harbor naturally
developed mAbs against Aβ.
• Reduces amyloid deposition and slows
cognitive decline.
• Aducanumab is currently in a phase III
trial
88. Inhibiting Protein Aggregation:
The Role of Molecular Chaperones
Molecular chaperones
Proper protein
folding
Assure physiological
protein conformation
during cellular stress
Chaperones mediate
the transfer of
misfolded proteins to
the proteasome for
degradation
molecular chaperones might modulate the
aggregation of amyloid proteins
and therefore play a key protective role in
neurodegenerative diseases characterized by
protein misfolding.
clusterin and
several heat
shock proteins
HSP 70-90
89. • Chaperones and chaperone-like molecules are
potential tools to prevent and/or inhibit early
aggregates of Aβ.
• Although still in the preclinical research phase,
the use of endogenous chaperones or
engineered recombinant versions represents a
Novel approach to the potential treatment of
AD and other neurodegenerative diseases.
(Autophagy)
91. • The transport of amyloid β through the BBB
is mediated by receptors, the passage of the
peptide from the brain to the blood occurs by
interaction with
LRP-1 receptors
(Lipoprotein receptor-related protein-1)
•Increased levels of amyloid β and aging,
decrease of the expression of LRP-1
receptors
results in an accumulation of amyloid peptide in
the central nervous system (CNS).
92. • The transit of amyloid β peptide into the brain
through the blood-brain barrier also occurs via
receptors, primarily through multi-ligand AGE
(advanced glycation end products ) receptors
or RAGE.
• In contrast to the
expression decrease of LRP-1 receptors due to
high levels of amyloid β in the brain,
RAGE increases the expression under these
conditions (Aisen 2009)
93. • Since RAGE interaction with amyloid β causes:
1-Inflammatory responses at the endothelium level,
2-Endothelial cell apoptosis,
3- Decreased cerebral blood flow, and
4-OS
RAGE may play a role in the development of
neurovascular changes observed in AD .
94. • Azeliragon is a small-molecule inhibitor of
receptor for advanced glycation end products
(RAGE).
• In animal models, azeliragon treatment showed
decreased brain Aβ levels and improved
cognitive performances.
• Azeliragon is currently in phase III trials.
96. The Tau (τ) Protein
• The production and accumulation of
amyloid β peptide as
the beginning of the disease process;
does not completely explain the
etiopathogenesis of AD.
• The τ protein arises as a
secondary pathogenic event
that subsequently causes neurodegeneration .
97. • Amyloid β induces τ- alterations .
mainly
increased phosphorylation
and
often linked to neurodegeneration .
(Stancu et al,2014)
98. • The τ protein is a highly soluble protein
that relates to the microtubules and its
function under normal conditions consists
of stabilizing them.
• These microtubules provide support for
structural changes,
axonal transport, and
neuronal growth.
99. • Hyperphosphorylated τ protein presents
aberrant
aggregation with the cytoskeletal proteins;
with the consequent
malfunction of axonal transport.
100. Roles of glycogen synthase kinase 3 B
(GSK3 ß )in Alzheimer's disease.
There is Critical role of GSK-3 in AD pathogenesis such as
1-Beta-amyloid (Aβ) production and accumulation.
2-The formation of neurofibrillary tangle (NFT) and
3- Neuronal degeneration.
GSK-3 could play a critical role in Aβ production via:
A- Enhancing β-secretase activity.
B- GSK-3 may downregulate α-secretase through inhibiting
protein kinase C (PKC)
101. Considering that active GSK-3 induces
the hyperphosphorylation of tau and
NF lesions,
GSK-3 is a possible linking between
Amyloid plaques & NFT pathology.
Preclinical and clinical studies have supported that
GSK-3β inhibitors could be useful in the treatment of
AD.
102. Neurofibrillary Tangles as Drug Targets
• Restabilize the microtubules to preserve
neuronal health and axonal transport.
• Epothilone D stabilize microtubules has been
shown to reduce transport deficits and protect
from cognitive impairment in tau transgenic
mice .
• Epothilone D has been evaluated in a phase I
trial.
103. Targeting Tau Aggregates
• Derivatives of methylene blue have been shown
to disrupt the aggregation of tau, thereby
{reducing oxidative stress, preventing
mitochondrial damage, and preserving cognitive
function in mice} .
• The clinically applied derivative, Rember TM
(TauRx Therapeutics Ltd.), showed some
significant improvement of AD-related symptoms,
although there were side effects.
• A second-generation version, TRx0237 (TauRx
Therapeutics Ltd.), is currently in a phase III
trial.
104. Immunization
Active immunization
against
phosphorylated tau
Passive immunization
activation of the
immune system and
production of high-
affinity Abs against the
target
Two active
immunization
vaccines
Clearance of total tau or
fragments of tau may
have therapeutic value
The targets of these Abs can be:
hyperphosphorylated tau,
fragments of tau, and total tau.
108. Autophagy
• Autophagy is an intracellular process of
‘self-eating’,
which provides homeostatic maintenance
through the capture and degradation of
aggregate-prone proteins,
misfolded proteins
& dysfunctional
organelles.
• Excessive OR insufficient autophagic activity in
neurons leads to altered homeostasis and
influences their survival rate, causing
neurodegeneration.
109. •
Autophagy is normally suppressed by
amino acids and insulin ..
•
activated under stress conditions:
nutrient deprivation.
Mitochondrion
(mitophagy)
110. mTOR
• The mammalian Target Of Rapamycin (mTOR) is a highly
conserved serine/threonine kinase that can sense
environmental stimuli such as growth factors, energy state,
and nutrients, regulating many physiological processes.
• It is essential for cell growth, proliferation, and
metabolism, but dysregulation of mTOR signaling pathway
is also associated with a number of human diseases.
• There is sufficient evidence for the relationship between
the mTOR signaling pathway and Alzheimer's disease (AD)
111. • Upregulation of mTOR signaling pathway is
thought to play an important role in major
pathological processes of AD.
• The mTOR inhibitors such as Rapamycin have
been proven to ameliorate the AD-like pathology
and cognitive deficits effectively in a broad range of
animal models.
116. Rapamycin, a drug that keeps the immune system from
Attacking transplanted organs, may have another exciting
use: fighting Alzheimer's disease.
117.
118.
119. Oxidative stress (OS)
• OS is a condition in which the balance
between production of active reactive oxygen
species (ROS) and the level of antioxidants is
significantly disturbed,
resulting in cell damage.
• ROS chemically interact with biological
molecules such as nucleic acids, proteins and
lipids, and cell organelles.
120. • The presence of extensive OS is a
characteristic of AD brains.
-The accumulation of free radical ;
alterations in the activities or expression of
antioxidant enzymes such as
superoxide dismutase and catalase
are also present in AD patients .
121. • Abnormal accumulation of amyloid β is
capable of promoting the formation of ROS
through a mechanism that involves the
activation of NMDA receptors.
• OS may augment amyloid β production and
aggregation as well facilitate
tau phosphorylation and polymerization,
forming a vicious cycle that promotes the
initiation and progression of AD
amyloid β ROS amyloid β
122. • Mitochondria are quite vulnerable to OS,
which may directly disrupt its functions
generating a further
increase in ROS levels
that finally produce
cell death by
caspase activation and apoptosis
