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Alzheimer's disease new drugs, 2017
1.
2.
3. ◘ Cognition is a group of mental processes
by which the individual acquires and
process information allowing him to
perform day to day functions.
◘ No single part of the brain stands alone in
cognition control but different areas
work together
4. ◘ Dementia is a collective term that describes
several organic brain diseases characterized
by persistent decline in the cognitive
functions in one or more cognitive domains
(memory, language, complex attention,
learning, executive functions, spatial ability
and social cognition) enough to interfere
with the person’s performance of the usual
daily activities.
5. 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).
11. ◘ AD is the most common neurodegenerative
disorder characterized by progressive memory
decline and persistent cognitive impairment
enough to interfere with the person’s
performance of the usual daily activities.
◘ Despite AD is an age related disorder yet it is not
an accelerated aging process but it is a disease
with distinct neuro-pathological changes
including amyloid plaques deposition, NFTs
accumulations, synaptic loss and neuronal death
with gross brain atrophy.
12. ◘ In 1901 A. Alzheimer described manifestations of a
51-years-old female named Auguste Deter who
experienced marked memory decline, fear of
people and became jealous of her husband. Later,
the patient developed severe behavioral
abnormalities, delusions, disorientation of time
and place, hallucinations and severe language
difficulties.
◘ In 1906, Auguste died, and her autopsy revealed
gross brain atrophy and microscopically increased
silver staining by using Bielschowsky method
which later named amyloid plaques and NFTs.
Auguste Deter (1850 – 1906)
Alois Alzheimer (1864 – 1915)
13. ◘ What is your name? Auguste.
◘ Family name? Auguste.
◘ What is your husband's name?
- She hesitates, finally answers: I believe ... Auguste.
◘ Your husband? Oh, So!
◘ How old are you? Fifty-one.
◘ Where do you live? Oh, you have been to our place.
◘ Are you married? Oh, I am so confused.
◘ Where are you right now?
- Here and everywhere, here and now, you must not think badly of me.
◘ Where are you at the moment? We will live there.
◘ Where is your bed? Where should it be?
14. ◘ What are you eating? Spinach (she was chewing meat)
◘ What are you eating now? - First I eat potatoes and then
horseradish.
◘ Write a '5’.? She writes: A woman
◘ Write an '8’? She writes: "Auguste" (While she is writing she
repeatedly says, "I have lost myself, so to say.
Auguste D. ate pork and cauliflower
15. ◘ Alzheimer concluded that she had no sense of time or place.
◘ She could barely remember details of her life and frequently gave answers
that had nothing to do with the question and were incoherent.
◘ Her moods changed rapidly between anxiety, mistrust, withdrawal and
'whininess’.
◘ They could not let her wander around the wards because she would accost
other patients who would then assault her.
16. ◘ > 50 million people have dementia worldwide,
35 million of them have AD (5.5 million in
USA) and this number is expected to double
every 20 years due to increased life
expectancy.
◘ AD is the most common cause of dementia
accounting for about 60–80% of late onset
dementia either as pure or mixed form.
◘ It is one of the commonest causes of prolonged
disability in old age, the 6th cause of death in
USA globally and 5th for old aged people.
17.
18. ◘ AD typically presents by episodic memory impairment (conscious
recollection of specific events) which gradually progresses to interfere
with the usual daily activities.
◘ Later, other cognitive domains are affected depending on the pattern of
cortical progression including apathy, loss of interest in hobbies, sleep
disturbances, impaired spatial and temporal navigations, inability to
solve problems due to executive dysfunction, behavioral changes,
difficulty in using common instruments due to apraxia, language
difficulties, incontinence and high dependency on others.
19. (1) Immediate memory (1 – 3 seconds).
(2) Recent memory: free recall, cued recall & recognition memory (seconds to 1 – 2 minutes).
(3) Long term memory:
◘ Explicit (declarative memory):
- EPISODIC (AUTOBIOGRAPHIC) MEMORY: conscious recollection of specific events
- Semantic memory: Person’s general knowledge about the world, facts, concepts …
◘ Implicit (procedural) memory: change in behavior that occurs as a result of prior experience, skills
or procedures .
◘ The processes by which the individual encodes, stores, and retrieves information.
20. (2) Dysexecutive variant.
(3) Parietal dominant variant.
(4) Frontal dominant variant.
(1) Logopenic aphasic variant.
Start by non-amnestic manifestations but have the same AD pathological hallmarks
MRI acquisition of cortical thickness
21.
22. - Slight difficulty with time relationships.
- Slight impairment in solving problems and in understanding
similarities/differences between things or ideas (e.g., understanding that
a trumpet and guitar are both musical instruments).
- Slight impairment in community activities and affairs.
- Life at home, hobbies and intellectual interests are slightly impaired.
- Fully capable of completing self-care tasks (e.g., bathing, dressing)
◘ Forgetfulness and possibly one or more of the following:
23. - Only highly learned materials are retained.
- Usually disoriented to time, often to place.
- Severely impaired in handling problems and in understanding
similarities/differences.
- Social judgment is usually impaired.
- Loss of independent functioning at home.
- May retain ability to perform simple household duties.
- Requires assistance in dressing, hygiene, and keeping of personal effects.
◘ Severe memory loss especially new ones :
24. - Knows self and oriented to himself only
- Disoriented to both time and place.
- Unable to make judgments or solve problems.
· No pretense of independent function outside the home. Appears too ill
to be taken to functions outside the family home.
- No significant function in terms of either home activities or hobbies.
- Requires much help with personal care tasks. Frequent incontinence is
common.
◘ Severe memory loss – only fragments remain:
25.
26. 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.
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).
Minor Neurocognitive Disorders (DSM-V)
27. ◘ SCD is defined as person's concern of worsening in his memory or
cognitive performance in the absence of objective impairment in
standardized cognitive neuropsychological tests.
◘ SCD is a growing area of research to determine the factors resulting in
its subsequent progression or passing a stationary course.
◘ Many neurologists consider it as the first symptomatic stage of AD
preceding the MCI while others questioned this relationship.
28.
29.
30.
31.
32.
33.
34.
35. ◘ It is well known that, the density of β-amyloid deposition is not
proportional with the severity of AD cognitive decline making the
amyloid hypothesis alone is not sufficient to explain the whole AD
pathological cascade and in turn the possible role of additional
pathogenetic factors including neuroinflammation and vascular
amyloidosis.
36. ◘ The neuroinflammatory theory were supposed after identification of
activated microglia within the vicinity of the amyloid plaques which
number was proportional with the size of the plaques.
◘ At the same time, several microglial expressed genes were associated
with AD predisposition including TREM2, CD33, CR1, CLU, CD2AP,
EPHA1, ABCA7 and INPP5D. Under normal circumstances, microglial
activities are modulated by several neuroimmune regulatory proteins
including insulin-like growth factor–1, brain derived neurotrophic
factor, transforming growth factor–b and nerve growth factor which
help in slowdown and resolving the inflammatory process.
37. ◘ Microglia have no role in Aβ production however they act as Aβ scavengers as
they play major roles in its clearance.
◘ This imbalanced microglial function result in aberrant synaptic pruning,
pathological synaptic stripping, neuronal loss, enhancing the endothelial
response to hypoxia with impaired blood brain barrier (BBB) stability, disturbed
Aβ clearance, increased levels of phosphorylated tau protein, promoting NFTs
accumulation and consequently cognitive decline.
◘ Microglia, also transport amyloid and tau from one brain area to another thus
they play a major role in spatial AD progression.
38. ◘ Vascular risk factors (diabetes, hypertension,
smoking and heart diseases) are associated with
increases risk of AD which is a good
explanation why aging is a high AD risk and
why ischemic events may provoke AD
progression.
◘ Cerebral amyloid angiopathy (CAA) is present
in more than 75% of autopsy confirmed AD
brains especially in mixed AD/vascular
dementia where the vascular risk factors
predominate.
39. ◘ CAA represents imbalanced Aβ production
and clearance with consequent deposition
within the basement membrane of the
leptomeningeal vessels, intracerebral arteries
and arterioles, and less frequently in
capillaries and veins.
◘ Amyloid deposition in and around the blood
vessels wall (cogophilic angiopathy) impairs
its endothelial integrity and disturbs the BBB
leading to Aβ trapping in the CSF and its
diminished clearance to the venous
circulation.
40. ◘ Responsible for cognitive manifestations of AD before manifest neuronal loss
takes place and at the time of clinical onset there are:
(1) Extensive serotonergic denervation in the hippocampus and neocortex.
(2) Depletion of the cholinergic neurons in the basal forebrain.
(3) Loss of > 70% of noradrenergic locus coeruleus neurons.
(4) Reduction of dopamine, dopamine metabolites, and dopamine receptors.
(5) Histaminergic tuberomammillary nucleus degeneration.
(6) Impaired melatonin secretion and action in the pineal body and suprachiasmatic
hypothalamic nucleus respectively.
41.
42. ◘ Glutamate is a non-essential amino acid, but it is one of the most
important excitatory synaptic neurotransmitter as most of the CNS
myelinated axons are glutamatergic. AD patients show aberrant increase
in extracellular glutamate which enhances tau pathology and enhances
glutamate receptors expressed oligodendroglia to transport tau from one
brain area to another leading to AD spatial progression.
43. ◘ There is a reciprocal relationship between glutamate and Aβ as soluble
amyloid oligomers as well as insoluble Aβ deposits, increases the
extracellular glutamate concentration resulting in AMPA (α-amino-3-
hydroxy-5-methyl-4-isoxazolepropionate) and NMDA (N-methyl-D-
aspartate) receptors dysfunction, disturbed synaptic pruning and
impaired synaptic plasticity with promotion of long term synaptic
depression and inhibition of long term synaptic potentiation leading to
cognitive decline especially memory domain.
44. ◘ At the same time, NMDA receptor inhibition promotes amyloidogenic
γ-secretase activities and inhibits non-amyloidogenic α-secretase with
the resultant increase in Aβ production and accumulation and vice
versa. Many studies revealed protective effects of sex hormones against
glutamate induced neurotoxicity through inhibition of glutamate release
by reducing the activities of lactate dehydrogenase, inhibiting
intracellular Ca2+ influx, exerting antioxidant action and enhance
mitogen-activated protein kinase action.
46. (1) Memory loss that disrupts daily life.
(2) Challenges in planning or solving problems.
(3) Difficulty completing familiar tasks.
(4) Confusion with time or place.
(5) Trouble understanding visual images and spatial relationships.
(6) New problems with words in speaking or writing.
(7) Misplacing things and losing the ability to retrace steps.
(8) Decreased or poor judgment.
(9) Withdrawal from work or social activities.
(10) Changes in mood and personality.
47.
48.
49. ◘ It is generally accepted that AD pathological changes begin decades before the
appearance of dementia symptoms and this leads to the introduction of the
term preclinical AD which is defined as biomarker evidences of AD
pathological changes in a cognitively healthy individual.
◘ The current challenge is to develop reliable biomarkers for early pre-
dementia AD diagnosis to maintain longer patients' independence and
prepare the floor for the discovery of disease modifying agents including
hormonal replacement therapy before irreversible neural damage take place.
50.
51. ◘ The ADNI–2 (Alzheimer Disease Neuroimaging Initiative – 2) established CSF biomarkers include:
(1) Reduced CSF Aβ–42.
(2) Elevated total and phosphorylated tau–181 which are very accurate in
prediction of MCI/AD conversion with 85% sensitivity and 90% specificity.
(3) Novel but still non-approved CSF biomarkers include high Aβ oligomers and
neurogranin levels.
52. ◘ Blood biomarkers include:
(1) High plasma homocysteine.
(2) High serum angiotensin converting enzyme activities.
(3) Low plasma levels of the obesity-related hormone leptin.
(4) Other ongoing research biomarkers include prostate-specific antigen
complexed to α 1-antichymotrypsin, pancreatic prohormone, clusterin and
fetuin B.
53.
54. ◘ The imaging biomarkers that can predict MCI/AD conversion are usually
directed to measure the neural and synaptic densities in the commonly affected
cortical areas.
(1) Volumetric MRI, manual and/or automated techniques can detect hippocampus
and entorhinal cortex atrophy with concomitant dilatation of the temporal
horns of the lateral ventricle.
(2) Task-free functional MRI (measures network failure quotient).
(3) Diffusion tensor imaging (DTI) MRI.
(4) Functional imaging include SPECT, FDG-PET, amyloid PET and tau PET.
55.
56.
57.
58.
59.
60. ◘ Increase the levels of acetylcholine in the brain, which plays a key role
in memory and learning.
◘ This kind of drug postpones the worsening of symptoms for 6 to 12
months in about half of the people who take it.
◘ Cholinesterase inhibitors most commonly prescribed for mild to
moderate Alzheimer's disease include Aricept (donezepil HCL), Exelon
(rivastigmine), and Razadyne (galantamine).
61. ◘ Acts on regulation of glutamate action in the brain, which plays a key
role in processing information.
◘ This drug is used to treat moderate to severe Alzheimer's disease and
may delay the worsening of symptoms in some people.
◘ It may allow patients to maintain certain daily functions a little longer
than they would without the medication.
62.
63. ◘ AD pathological changes start decades before the onset of clinical
manifestations which make its treatments trials of limited benefits as
irreversible damage had already happened to a big sector of neurons.
◘ There are 105 agents in the AD treatment development pipeline; 70%
are disease-modifying therapies (DMTs), 14% are symptomatic cognitive
enhancers, 13% are symptomatic agents addressing neuropsychiatric
and behavioral changes and 2% have undisclosed mechanisms.
64.
65.
66. ◘ Phase I human trials are generally conducted in healthy volunteers unless
they are assessing immunotherapies where the potential long-term
modification of the immune system makes participation of normal
controls impermissible.
◘ 2017 Phase I AD drug pipeline includes 25 agents in 29 trials; 12 were
amyloid-related targets (include 8 immunotherapies), 3 were tau related, 5
had other disease modifying therapy mechanisms, 4 symptomatic
cognitive enhancers and 1 agent with non-revealed mechanism of action.
67. ◘ The goal of phase I trials is to assess the safety, doses, tolerability and
document the pharmacokinetics (PK) of the drug (e.g., half-life, time to
maximum serum concentration [T-max], maximum serum concentration
for each dose [C-max], bioavailability, dose-blood level linearity, etc.),
establish the sex and age specific PK, drug-drug interactions and food
effects on drug absorption.
68.
69.
70.
71. ◘ Also named learn trials which aim to establish preliminary efficacy based on a
biomarker outcome, a clinical measure, or a combination of both.
◘ Of the 68 trials in phase II of the AD pipeline, 21 included patients with prodromal
or prodromal and mild AD, 26 were trials for mild-moderate AD, one included
patients with prodromal or mild-moderate AD, and one trial was for mild-
moderate or severe AD. Of the symptomatic trials, 10 were for mild-moderate AD
and six were for mild-moderate or severe AD.
72. ◘ Of the 52 agents in the 68 trials, there were 36 DMTs (14 amyloid targets, 4 tau-
related targets, 1 had both amyloid and tau-related targets, and 17 had other
MOAs e.g., stem cell programs, metabolic, or anti-inflammatory), 8 cognitive
enhancers, 7 for behavioral symptoms, and 1 with an unknown MOA.
◘ DMTs include six immunotherapies (4 amyloid and 2 tau).
◘ Of the drugs with amyloid targets, there were 3 β-site amyloid precursor protein
cleaving enzyme (BACE) inhibitors, four immunotherapies, and 8 anti-aggregation
agents.
73.
74.
75.
76.
77.
78. ◘ Also called confirm trials which is intended to confirm effects observed in
phase II in larger populations treated for longer periods of time. In
addition provide exposure data on larger numbers of patient-days essential
to establishing the safety and tolerability of the candidate therapy.
79. ◘ Of the 28 agents in the 42 trials, there were 18 DMTs (15 amyloid targets, tau-
related target, and 2 had a metabolic MOA), three cognitive enhancing agents, and
seven drugs for behavioral symptoms.
◘ The DMTs include six immunotherapies (all addressing amyloid).
◘ Of the drugs with amyloid targets, there were five BACE inhibitors, six
immunotherapies, and four anti-aggregation agents. Table 3 shows the agents
currently in phase III of AD drug development. Fig. 3 shows the MOAs of agents
in phase III and Fig. 4 shows an illustration of the drug mechanism of phase III
agents and the proposed biology of AD.
80. ◘ Among the DMT trials, there were five prevention trials enrolling
cognitively normal participants at high risk for developing AD in the
course of the trials; 14 trials of patients with prodromal AD (those with
minimal cognitive symptoms and a biomarker indicative of AD-related
brain changes) or prodromal/mild AD; and nine trials of patients with
mild-moderate AD.
