"It is clear, though, that inflammation has moved to center stage in neurodegeneration," says Kevin spelman, rh(aHG), MCPP Chair - Clinical Division Tai Sophia Institute. Inflammation leads to functional changes in the body's signaling system that increase inflammatory mediators and cut across many disparate diseases.
"It is clear, though, that inflammation has moved to center stage in neurodegeneration," says Kevin spelman, rh(aHG), MCPP Chair - Clinical Division Tai Sophia Institute. Inflammation leads to functional changes in the body's signaling system that increase inflammatory mediators and cut across many disparate diseases.
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"It is clear, though, that inflammation has moved to center stage in neurodegeneration," says Kevin spelman, rh(aHG), MCPP Chair - Clinical Division Tai Sophia Institute. Inflammation leads to functional changes in the body's signaling system that increase inflammatory mediators and cut across many disparate diseases.
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Attribution Non-Commercial (BY-NC)
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Скачайте в формате PDF, TXT или читайте онлайн в Scribd
Neurodegeneration,
The inflammation link
‘The Body from the Brain's Perspective
* Inflammation leads to functional changes
inthe body's signaling system that
increase inflammatory mediators and cut
‘across many disparate diseases as
Pl
Kevin Spelman, RH(AHG), MCPP
Chai - Clinical Dion
“Tai Sophia Instituto
eee ee eee A Common Etiology
Inflammatory conditions are
Inflammation explains why epidemiological
evidence associates the use of specific
ant-inflammatories over periods of time
with lowered incidence of certain
degenerative diseases in age, such as
‘neurodegeneration or cardiac-related
‘dysfunction
Spbiaeaets aaa involved in nearly all chronic,
180 degenerative, age-related
pe diseases
~ Secondary signs of diabetes
Corporate Awareness! "
Corporate Awareness! Neurodegeneration
“tis clear, though, that inflammation
has moved to center stage in
neurodegeneration...”
Robert SapolskyThe Web of Physiology
‘er Preeti main sansa eg A
‘naa ea
Some anatomists have advocated
rewriting textbooks that treat the
The Web
‘neuropeptide receptors occur on mobile
‘cells of the immune system; monocytes
‘can chemotax to numerous
neuropeptides. Neuropeptides and their
‘eceptors thus join the brain, glands,
immune a systems a aan oa
neuroimmunoiogy as a single competion Brain! boxy,
interacting system ae 9 the biochem
The Web
oir Wong 188. Ma Pena 86831727
interleukin-1B and IL-1 receptor
antagonist appear to play a role in
the biology of major depression
Proinflammatory Cytokines
eta fr eee oe
Sinn Jiao a a
* Its now generally accepted that inflammatory
mediators, including la-derived cytokines such
‘ [L-1b and reactive oxygen species such as
nitric oxide ean contribute to damage in
neurological diseases including
multiple sclerosis
Parkinson's disease
= Stroke
Alzheimer's disease
The Microglia
[=
Microglia are mediators of the
production of inflammatory cytokines
and contribute to degenerative
disease by increasing the risk of
oxidative stress of neurons and
apoptotic cell Seah, premature cellEtiology
=
Sty Mee ew foment
* Along ist of conditions can increase neuronal
oxidative stress and mediators of inflammatory
conditions in the brain due to accumulated
‘damage over decadas,qulving:
~ acohel coneumsnon
heavy metal oun exposure
chron eueee
~ suboptimal B-vtamin nd anondart nun
~ ecsonta fay aoc ineicencies
= exposure to ionizing rection
= egarete eeking
4 areas ofthe etiology of
Alzheimer's disease, in part, is urodegenerative disease
"elated to inflammation of the
rain through the release in ~'OxidatWe'sireaé:
neurons of inflammatory
mediators like interleukin-2, * Mitochondrial dysfunction
interleukin-6, and tumor necrosis + Excitotoxicity
factor alpha * Inflammation
Lifestyle Factors
Lifestyle Factors
Fr
* The initiation of an inflammatory
response by allergens, toxins, or
‘emotions can clearly increase the
oxidative stress burden
~upregulating the HPA axis and
creating a more oxidant
environment
Habituation
‘Sin 2 Herr err 892127
‘One of the most consistent findings
in anxious depressed patients is
elevated levels of cortisolLifestyle Factors
Se Seen hc oy Ass Nt
‘oes
Glucocorticoids can lead to the
premature apoptotic cell death of
neurons we associate with
increased risk of
neurodegeneration or brain aging
‘tess Hormone Level and Suielce
TWPRRHRTERSRLE Es
nda Sac
Lifestyle Expense
(oF, ALM a 20 Nespeepamasny 2409708
* Constant environmental demand requiring
sustained arousal invokes a biological
transformation or brain signature that may
be long lasting
* With continued sustained arousal the
hippocampus may undergo atrophy
* Additionally, various endocrine and
systemic disorders (eg elevated insulin,
increased blood pressure) may also.
manifest
The Physiology of Adaptation
‘Sesh RL 203, uacensal Rao 2019) 17- 172
* Under circumstances in which stress impairs
‘hippocampal Long Term Potentiation, it
facitates amygdaloid LTP
* Under circumstances in which stress causes
atrophy of denaitic processes in the
hippocampus, the samo stressor causes
‘extension of processes by neurons in the
‘amygdala and in the bed nucleus of the stria
terminalis, an amygdaloid projection site central
to amity
How?
‘eons pen no
aan
Mitochondrial DNA injuries can
modify cognition and produce
dysfunction at what is called
the “intelligence level”
pe
Leading to Inflammation
Pe 0.5 Pn cn
*+ Because of decreased ATP production,
the NMDA receptor becomes sensitized,
‘and when glutamate stimulates it, it allows
€n influx of calcium into the neuron, which
begins this progressive feed-forward cycle
that utimately leads to progressive
degeneration and, ultimately, cell desth
* This links together excitotoxicity &
mitochondrial disordersLiteral Bumout
‘stan eon Soe wetseie te
The NMDA pathway is an
excitatory pathway for neuronal
activity; when it is overstimulated,
the result can be "neuronal
burnout”
eg. Oat name tl Aer nanan
‘ilocos anemetsdusah sand Pe Sans
opie omc: vous aware ote Br Na
‘pienso
There is a substantial overlap
between AD and other
neurodegenerative conditions
Alzheimer's Disease
eget nays cornomnenr ees oa pee
‘ron cose nay Asam) ahs arses
* Alzheimer's disease (AD), accounts for
about 70% of the dementia cases
* Neuropathologically characterized by
‘dense and neuritic amyloid plaques and
‘cerebral intraneuronal neurofibrillary
tangles
~ nelther plaques nor tangles correlate strongly
Alzheimer's Disease
Ss ee Dene Nie ae
* Alzheimer’s disease presently afflicts
some 4 milion people in the Ur
States. The Census Bureau projects
that by the year 2050, 79 million
Americans will be 65 or older, and
almost 18 million of them will be 85 or
With the degree of dementia, loss of synapses older and at risk for Aizheimer's
{nd nourone, and abnormalities of he elssese!
cytoskeleton
Alzheimer’s Disease Alzheimer's Disease
Inonte Tat cand aeons
eee aoe sein a
* Alzheimer’s disease (AD) represents the
third leading cause of death in the U.S.
and the leading cause of dementia in the
elderly population
‘+ In 1999, this disorder accounted for
‘approximately 170,000 deaths in the
United States, placing it in third piace
(7.1% of total deaths)
Ipc fst da nema pi th es
Sa Ne heed Seema
* The yearly cost of AD in the United States
is estimated to be $100 bilion
* The cost of treating each patients
estimated to be $195,000, with a
significant amount ofthis cost being
attributed to loss of productivity of the
Patient and caregiver and to costs
sustained by the familyAlzheimer's Disease
‘Stree ke hl nets =
From an anatomic point of view, AD is
characterized by an atrophy of the
cerebral cortex and by a massive loss
of cortical neurons and cholinergic
projections made by the nucleus
basalis towards the cortex
Alzheimer’s Disease
Saeeesoumet sen emma ra canna ne
From a histopathologic point of
view, there is a diffuse presence
of extracellular and perivascular
neuritic plaques and intracellular
neurofibrillary tangles in the
cerebral parenchyma
How?
eat enn Denon ad been te
aspen noes Morons rT ee.
* In AD, the amyloid plaque is the focus
of a microglial inflammatory response
which increases cytokines, inducible
NO synthase, complement, and acute
phase proteins.
Amyloid beta (AB) induces
inflammatory responses in microglia
il
How?
‘Sonepat cons acne owt als PTS
pempeneqpemnemeet erty tascy oe
seat
* Inflammatory mechanisms and more
specifically activated microglia may
contribute to the neurodegenerative
process of Ads.
not only as a purely secondary
Phenomenon
but also as a possible primary
source of its clinical pathology
When?
Pen Ma 6. Toen ne pr nnd
‘Fetinad inert ono ks hse SSS
+ Annual neurological assessment of 62
initially nonsymptomatic individuals in the
ppre-AD age bracket with post-mortem
pathological changes in their brains of
functional neurological signs and
symptoms found a close association
between the early-stage onset of these:
‘symptoms and the existence of neocortical
plaques
When?
Ps Moe Tange an pei nama ag
el ote ry arr
The data suggest that the early
loss of cognitive function may be
@ predictor of the onset of
Alzheimer’sEtiology, Genetics?
Aeron enn fal Ah me
Se See
The apoE4 genotype is more
‘susceptible to brain inflammation
Etiology, Genetics?
ae
‘The apoE4 genotype is more
susceptible Alzheimer's disease
Etiology, Genetics?
* HIV-infected subjects who have
an apoE4 allele had excess
dementia and peripheral
neuropathy
* Those with an apoE4 carriage
had higher incidence of
Alzheimer's disease
Etiology, Genetics?
S05 nano
cmc Panta he Up May, 8.
+ ApoE4 genes, either single or double
‘@poEé alleles, mark and track against
both cardiovascular disease risk and
neurodegeneration
—Hypethomocysteinemia?
‘sete fete osm thc ety
‘iow Davo oe Can Sarees a
* Increases in vascular risk factors, serum
homocysteine, apoE4 load, and
neuroimaging pathology were found not
‘only in dementia but also in dysmentia and
in patients with only subjective symptoms.
‘+ Homocysteine levels correlated inversely
with cognitive performance.
Etiology, Genetics?
* "itis also important to emphasize that
many people who carry the apoE allele
do not develop Alzheimer's, so there must
'be other genetic andlor environmental
factors involved. ... The hope for the future
‘must be that biochemical studies will
reveal how apoE is involved in the
processes that go awry. ...”
aaThe Context of Life
ope R208 Aan i Med FAT,
Gene environment interaction is
Disease as Multifactorial
{Cooper RS. 2008 Aan intern Med! 139457-40,
‘The genetic component of all complex
described as Context dependency traits, such as hypertension, arthritis,
~ conditional nature of the and cognitive function, is influenced
2 whence by a broad range of effects spread
Seen ee ce eres, ‘across many single nucleotide
polymorphisms in many genes
What do we expose our DNA to? Genetics
DNA methylation-related processes
are involved with atherosclerosis,
diabetes, cancer, and
neurodegeneration
We are no longer peas in
Mendel’s garden
Therapy
‘Attempts to Heal
Acetyicholinesterase Therapy?
‘Sez eof ae Met a mao iat
‘Semen orem ter aw ao
‘The consistent loss of cholinergic
markers (choline acatyransierase,
acetyicholinesterase, and pi ic
Tuscarinic receptors) in the AD brain
has prompted the development of
acetyicholinesterase inhibitors with
the aim of increasing acetylcholine
levels in the brainAcetylcholinesterase Therapy?
‘Sorenson Nr sss
This approach has been
consistently shawn to produce
symptomatic effects but has not
had a significant impact on the
natural history of the disorder
Antiinflammatories, A Therapy?
RGAe an wp stage ame anyway Nar
‘Soccer
There is 2 reduced incidence of
Alzheimer's disease in patients
who take either NSAIDs or H2
receptor antagonists regularly
Antiinflammatories, A Therapy?
Sere
Almost 20 retrospective studies
have already shown the
protective effect of nonsteroidal
anti-inflammatory drugs (NSAIDs)
in populations with a long history
of NSAID consumption which
would reduce the AD prevalence
by 50% and delay its onset by 5—
Zvears
Antiinfiammatories, A Therapy?
‘sre sont s asa me an ant
Soop corer sonmnoepy esas 2 a
Sean
* Other studies with antiinflammatories
(diclofenac, hydroxychioroquine) or
nimesulide did not demonstrate a
Positive effect on AD progression
* This possibly indicates that
influencing this neuroinfiammation
should be done in an early stage and
maybe for a prolonged period of time
Antiinflammatories, A Therapy?
‘aM, Fans DL sre ae ecto ee
oe ear nu Reet ar 8a 8,
‘There are compelling epidemiological
data demonstrating that a subset of
NSAIDs provide protection in AD, and
long-term use is accompanied by
‘significant reduction in activated
microglia
Antiinflammatories, A Therapy?
ela, Fete DL Epes an tne ce nie
‘See yan owes a 08440 8.
+ The precise mechanisms responsible for
NSAID protective effects are not yet clear.
* Because ibuprofen and indomethacin also
bind to and activate PPAR, ithas been
‘suggested that the protective effects of
NSAIDs may be mediated, in part, by
activation of PPARAntiinflammatories, A Therapy?
‘Snhaet moe Vassum te ONC
* Antiinflammatorys activate peroxisome
proliferator-activated receptors (PPARs), in
Particular the PPARc isoform, whose ligands
include thiazolidinediones and some NSAIDs.
* The mechanisms subserving anti-
inflammatory effects ot PPARc agonists are
‘not conclusively established
effects on |jB could contribute to their
therapeutic effects in disease
Modes of Degeneration
Mechanisms
‘SBosyemmestnooaos Rant har ea Spe
Several studies have suggested
that transcription factor NF-jB
plays a role in the etiology of
AD pathogenesis
Mechanisms
‘ent MT Fei OL. Erect and cn ite i
‘eyes prt Nea hrs OAS,
* Despite an increasing understanding
of the roles that NF-jB activation plays
in inflammatory responses and cell
damage in neurologic disease and
trauma, studies of its regulatory
factors, namely the JB proteins, re
limited
Mechanisms
otea hie DL. Epona cto nti oe
ae pun Ror a 8 Ha
* Microglial phagocytosis is
inhibited by NO and increased
by NOS inhibitors, suggestin
that anti-inflammatories whi
reduce NOS2 expression
might enhance amyloid
removal
Mechanisms
Herala MT, Fein OL fapnsn a fo te
‘Sees n oven. Near! hr 204 140
* In glial cells, increased levels of HSPs,
including that ofthe Ba protein, provide
‘antiinflammatory effects, yet increased
HSPs have been shown to increase
amyloid phagocytosis
* Thus, itis possible that PPARc agonists,
rather than reducing, could enhance
microglial phagocytosis as a consequence
of reduced iNOS and increased HSP
‘expression
10Mechanisms.
‘erat MT Fontan Lx sino nel he
(canes now I ewaemonl har F305 ae Ie
PPAR agonists may represent a class
of agents able selectively to reduce
NF-jB-dependent inflammatory
expression without reducing their anti-
Mechanisms
‘tent Fermin DL. Exxeneen ana incon of cin ae
‘Seton nous Jnl Mar SC a
Rapid induction of {ja occurs in
response to NF-jB activation,
providing an autoregulatory loop to
limit inflammatory gene expression
* However, the BBB is a selective
barrier
inflammatory responses
=
Mechanisms
A call for research of herbal eee
remedy affects = SB is Leg bone connected
— to the thigh bone
Bi i ie A Causative Factor, Cytokines
oe oie ae aaa
* The construct of the BBB as an oe *
absolute barrier has kept bodily enaeenceinmapaemense:
pathophysiology mostly apart fhe cies manfestaione of dcoase
from neurology Transcriptional, translational and other
‘molecular control mechanisms protect
the host from excessive cytokine
production
1‘A Causative Factor, Cytokines
Sms vinwe has ts nome datnt
* Autonomic dysfunction has been
associated with human inflammatory
diseases including rheumatoid arthritis,
diabetes and sepsis; whether this
dysfunction results from the inflammatory
‘component of these diseases, or is
‘actually an underlying cause, is not clear
The Liver, Site of Fire/Heat
“my 0) Tie oe ao 4,
+ Recently, vagal connections tothe liver have
been identified as involved in an “inlarnmatory
reflex” are
+ The ver is tho largest ste of fixed macrophages
‘and the brain regulates inflammatory (stress)
‘oytokine production inthis pathway
+ The nervous system reflexvely regulates the
inflammatory response in real time, just as it
‘controls heart rate and other vital functions
‘The ‘cholinergic ant-inflammatory pathway’
in canine 5 Atom me
‘oun nom ate
* The inflammatory reflex - the autonomic
nervous system detects the presence of
inflammatory stimuli and modulates
‘cytokine production
~Afferent signals to the brain are
transmitted via the vagus nerve, which
activates a reflex response that
culminates in efferent vagus nerve
signaling (remember the gut (2:1)
Catecholamines
Increased catecholamines with
increased oxidation can be
associated with
neurodegeneration
“The ‘cholinergic ant-nflammatory pathway’
Ses heten eae momma
* The ‘cholinergic anti-inflammatory
pathway, efferent activity in the vagus
nerve releases acetylcholine (ACh) in
the vicinity of macrophages within the
reticuloendothelial system
~ACh can interact with macrophage
nicotinic ACh receptors, leading to
cellular deactivation and inhibition of
cytokine release
The Second Brain
12Beyond The Brain
Spc andor sys maa aes tcc ah
‘Soe sry ws Se
‘A trigger for inflammation: antigenic insults
+ Headache and central nervous system
white matter abnormalities (measured by
MRI) were associated with gluten
sensitivity
‘* When gluten was removed there was
‘symptomatic response and improvement
in their MRIs
rain Mf ofa patient with gluten ataxle showing rapid onset
‘of eerebela atrophy over a period of 15 months beore the
lagnosis of gluten ataxia.
Beyond The Brain
"an ton un nny prin
* There is @ very high statistical correlation
between nonspecific gluten enteropathy
and early-stage dementia
* The authors propose a causal link
between low-level gluten sensitivity and
dementia
Beyond The Brain
eda Mra RA, Dnderones Gh Git say:
{eyes her Bal Tosaarete Tt
* Patients with neurological dysfunction of obscure
etiology demonstrated a high prevalence of
circulating antigliadin antibodies (@, IgA, or
bot in 57 % vs. § % in neurological controls
812% in normal controls)
+ There is neatly a tenfold increase in tis
neurological dysfunction or dementia in gluten-
‘sensitive individuals compared to those are not
luton sensitive
=
Beyond The Brain
aso Dec hn snip el
‘ner iaua!ogaraes
* This link may be created through
activation of the gut-associated
lymphoid tissue (GALT)
~ increased release of
proinflammatory markers from the
GALT like IL-2 and TNF
Beyond The Brain
‘Sei Ge hese Caen srr sce ch
‘im emir oes.
This result points to connections
‘among the gut, the immune system,
the gut-associated-lymphoid-tissue
(GALT), and the blood/brain barrier
transference of that information
through inflammatory mediators.
a
13Beyond The Brain
hE ae
* 42% of pts with Crohn's disease and
46% of pts with ulcerative colitis have
‘small white-matter lesions on
magnetic resonance imaging
* These changes were found in only 16
percent of healthy controls
Beyond The Brain
SSDS NRA atemere
+ Thar is an inerrlaionsip between
ateraton in mtochonealuncton sun
resistance, and lowered energy production
(mitochondrial uncoupling).
+ As much as 40% educton can be
cbservedin mitochondlendatve and
Dhosphenlation acy nnn
resistance
Beyond The Brain
SSSA en
Metabolic syndrome is
associated with the risk of
cognitive decline
Beyond The Brain
Monit mre Th eines a a a!
‘tro irnwenso ie eee
* Alterations of the cysteine-to-sulphate
ratio may also be an
assessment/prognostic indicator of
alteration and detoxification that
tracks back to potential risk to
Neurodegeneration
* Low sulphate-to-creatine ratios are
associated with poor detoxification
Speculation
‘Although unproven, scientifically, common
Sense dictates that the strategies always
Used by phytotherapists may be
Particularly useful in at least the delay of
‘onset of neurodegenaration
= Improving the dit
= Cooling the iver
Enhancing digestion
~ Balancing the system
= Enhancing “organ reserve”
14Nutritional Affects
Genes respond to the
environment (informational
input)
Hippocrates
“Let food be thy medicine and
medicine be thy food”