Date post: | 02-Jun-2018 |
Category: |
Documents |
Upload: | bintari-anindhita |
View: | 222 times |
Download: | 0 times |
of 61
8/10/2019 Neuroregeneration Journal Reading
1/61
JOURNAL READING
Presented by : FK UKI
Supervisor : dr. Sabar Siregar,
SpKJDepartment of Psychiatry Faculty of medicineChristian University of Indonesia,Jakarta
8/10/2019 Neuroregeneration Journal Reading
2/61
ABSTRACT
8/10/2019 Neuroregeneration Journal Reading
3/61
ABSTRACT
In the last years,physiological aging became
a general concept thatincludes all the changes
that occur in organism withold age
One of these majorconcerns is probably
dementia.
Sooner or later, all forms ofdementia lead to learningdeficit, memory loss, low
attention span, impairmentof speech and poor
problem solving skills.
In this review, try tohighlight some of thenewest aspects of
therapeutic strategiesthat can improve natural
neuroregeneration
8/10/2019 Neuroregeneration Journal Reading
4/61
Introduction
8/10/2019 Neuroregeneration Journal Reading
5/61
INTRODUCTION
In developing and developed countries, new health
problems concerning specific needs of older
populations arise. One of the major health concerns
in this aspect is dementia.
Dementia is a clinical term used to characterize a
number of diseases with neuropsychiatricsymptoms, that are not explained by delirium or
major psychiatric disorder
8/10/2019 Neuroregeneration Journal Reading
6/61
INTRODUCTION
All changes that occur in all organs and systems
associated with old age is now generally accepted
as physiological ageing
8/10/2019 Neuroregeneration Journal Reading
7/61
INTRODUCTION
Brain ageing is associated with structures and functionsdecline both is neurons and glia. This is generallyreferred as neurodegeneration
It is a normal process that can lead to reductions incommunication and in memory function but also to poorrecovery after stroke
Neurodegeneration is a progressive process that occursbecause of a decline in the total number of neurons;generally, this process is due to apoptosis and is associatedwith a loss of neuronal structure and function
8/10/2019 Neuroregeneration Journal Reading
8/61
INTRODUCTION
AIMEDand by discussing
contradictory resultsof different
researcher groups
summarizing up
to-date findingsdescribed
evaluated by anumber of
different authors
8/10/2019 Neuroregeneration Journal Reading
9/61
Neuroregeneration and aging
8/10/2019 Neuroregeneration Journal Reading
10/61
AGEING
Physiological ageing is now generally accepted as a concept
that includes all the changes that occur in all organs and
systems associated with old age, characterized by the
declining ability to respond to different types of stress,
homeostatic imbalance and diseases.
The phenomena involved in brain ageing are associated with a
decline of the neuronal and glial structures and functions,
which can lead to reductions in communication and in
memory function and also to poor recovery after stroke
8/10/2019 Neuroregeneration Journal Reading
11/61
NEURODEGENERATION
Neurodegeneration is a process is due to apoptosis
and is associated with a loss of neuronal structure
and function.
Ageingis considered the most important risk factorfor brain degeneration and age-related cognitive
disorders
8/10/2019 Neuroregeneration Journal Reading
12/61
NEUROGENERATION
An increasing susceptibility to poor recovery from brain
injury has been observed in the elderly. Regeneration of
neuronal tissue makes no exception however the pathways for
the cellular processes that characterize these phenomena have
yet to be found.
The concept of neurogeneration can be also defined as the
superposition of three distinctive processes including
neurogenesis, neuroplasticity and neurorestoration
8/10/2019 Neuroregeneration Journal Reading
13/61
However, older organisms, including humans, have reported a
decline in the rate of neurogenesis. Hippocampal neurogenesis
seems to persist also in adult age. With ageing, the
proliferation and differentiation of neural progenitors are
significantly decreased with a higher number of newborndeath neurons.
8/10/2019 Neuroregeneration Journal Reading
14/61
The neural stem cells are enteringin a quiescent state.
Another possibility can be that theexpression of some transcription
factors (Er81 and Dlx2) associatedwith neural development are
reduced in the elderly
Another effect can be thereduction in telomerase activity.
supported by the hypothesis thataged neural stem cells areintrinsically different from theyounger one
A study on adult mice deficient intelomerase activity, reported poorneurogenesis in hippocampal areas,associated with a lower number of
proliferation (Ki67+) or immature(Dcx+) cells
8/10/2019 Neuroregeneration Journal Reading
15/61
Potential mechanisms
responsible for the age-
related decline in
neurogenesis
Artegiani B, Calegari F. Age-
related cognitive decline:
can neural stem cells help
us?. 2012 (1)
A-E :
SCHEMATIC
REPRESENTATION OF
ADULT NEUROGENESIS
IN THE YOUNG (A) AND
OLD (B-E)
8/10/2019 Neuroregeneration Journal Reading
16/61
Nevertheless, extrinsic factors from the local environment
neurogenic niche) can regulate neurogenesis. In old age, lower
levels for different growth factors that can facilitate
neurogenesis (fibroblast growth factor-2, insulin growth
factor-1 or vascular endothelial growth factor) wereregistered in the hippocampal area.
8/10/2019 Neuroregeneration Journal Reading
17/61
Ageing and dementia
8/10/2019 Neuroregeneration Journal Reading
18/61
DEMENTIA
Dementia has many different causes. Dementia is seen as a
clinical term used to characterize a number of diseases such as
Alzheimer's disease dementia, Lewy bodies dementia, vasculardementia, behavior variant frontotemporal dementia, primary
progressive aphasia or any cognitive/behavioral changes with
neuropsychiatric symptoms, that are not explained by
delirium or major psychiatric disorder and interfere with one'sability to function with usual activities
8/10/2019 Neuroregeneration Journal Reading
19/61
Disease such as alzheimer, parkinson, huntington all have in common theformation of aggregates of abnormal proteins in the cells of the brain.
In young individuals,autophagy take care of continually eliminating the
abnormal proteins.
How ever, with age, the reduced activity of autophagy contributes to building
up of these abnormal proteins that eventually intoxicate
8/10/2019 Neuroregeneration Journal Reading
20/61
PREVALENCE
At the moment it isestimated that 35.6
million peopleworldwide arediagnosed with
dementia
It is predicted thatin approximately
20 years thisnumber will
double
triple in the next40 years
8/10/2019 Neuroregeneration Journal Reading
21/61
Based on all the information the scientific community hasgathered, the diagnostic criteria for dementia has becamemore accurate .
Treatment and management of dementia are generated byresearch based on results from studies.
Test subjects are patients with early stages of dementia.
As the population gets older, new criteria for diagnosing oldelderly persons (>75 years old) are needed because theborder between non pathological aged brain and dementiabrain is becoming more unclear with age
8/10/2019 Neuroregeneration Journal Reading
22/61
- Broken line shows
patients that were
included in clinical
research of diagnostic
methods and
theurapeutic trials
- Solid line shows
demented patients age
distribution from the
general population of
the netherlands
8/10/2019 Neuroregeneration Journal Reading
23/61
As one gets older, multiple risk factors varyingfrom:
- childhood IQ ,
- obesity in middle age,- smoking,
- hypertension,
- high cholesterol- diabetes at midlife to stroke
- atrophy in old age
contribute
to dementia in
the elderly
8/10/2019 Neuroregeneration Journal Reading
24/61
Scientific progress has found that a small number ofhighly conserved genes can have a positive effect on thelength of a life span.
These genes act through a number of metabolic processeslike the reactive oxygen species (ROS) representingone of the most incriminated and poorly understoodcontributors to brain ageing.
Acquiring defense from dietary antioxidants canprotect against ROS induced damage
8/10/2019 Neuroregeneration Journal Reading
25/61
Regardless of the risk factors, dementia is still a
consequence of neuronal populations loss that
cannot be compensated. It is unclear as to why
there is such large individual variability in ourpopulation.
8/10/2019 Neuroregeneration Journal Reading
26/61
Studies done on old elderly persons
As people get older harder to distinguishbetween a normal aged brain and a dementiaaffected brain
The only objective and quantifiable diagnosticcriteria still remaining valid is cerebral atrophy
Neuropathological examination can sometimesdetect individual with microscopic features typical
of late-onset Alzheimersbut no clinical history ofdementia.
Other times, individuals diagnosed with late stagedementia during their life can show only mild
pathological features ofAlzheimersdisease
8/10/2019 Neuroregeneration Journal Reading
27/61
Relation between CVD and
dementia
It is still not clear
if cerebrovascular disease induces dementia or..
if both have the same risk factors and thus are
indirectly linked
Studies on cerebrovascular system in elderly
population have found that..The blood brain
barrier permeabilityincreases with
normal age
can lead to theinitiation/worsenign
of cerebralmicrovasculr
disease/dementia
8/10/2019 Neuroregeneration Journal Reading
28/61
An overlap can be found between vasculardementia (VaD) and Alzheimer dementia (AD)
Spontaneous cerebral emboli were detected in43% of AD patients and 45% in VaD cases
Associated with a cognitive and functional decline
within 2 years The patient also had an increase in psychiatric
symptoms
8/10/2019 Neuroregeneration Journal Reading
29/61
Neuropathological findings have shown that
the burden and location of cerebral infarcts
are associated with a cognitive decline
However..No evidence was found that stroke prevention
treatment (esp antihypertensive agents) have any
effect on dementia incidence.
8/10/2019 Neuroregeneration Journal Reading
30/61
The best available neuropathological evidence
and dementia are scarce, suggesting there are
no boundaries between them.
8/10/2019 Neuroregeneration Journal Reading
31/61
Treatment
8/10/2019 Neuroregeneration Journal Reading
32/61
In order to remove various behavioral and
psychological symptoms of dementia
Many studies seek other ways of renewing the
natural cargo of brain neurons
Early onset dementia/ late onset dementia
lead to the patient tobe disoriented in time,
place, and identity
M l l d l ti f RNA
8/10/2019 Neuroregeneration Journal Reading
33/61
Molecular modulation of mRNA
expression
Recombinant DNA vaccine
Composed of multiple specific inhibitorydomains of neurite growth inhibitors (NOIs)
Mechanisms of action immunological,inducing antibodies against the specificdomains
3 good responses wereobserved
Little formation of solubleAoligomer and amyloid
plaques in the co-
transgenic mice brain
Attenuated neuronaldegeneration
Protection againstbehavioral deficits
M l l d l ti f RNA
8/10/2019 Neuroregeneration Journal Reading
34/61
Molecular modulation of mRNA
expression
The modulation of mRNA expression
regarding NOIs was also obtained using
generated channelrhodopsin-mutant
protein expressing microglia
By increasing theintracellular level of the
ioncan control microglial
activation
cause repair/regenerationof neural and
oligodendrocytic damage
8/10/2019 Neuroregeneration Journal Reading
35/61
Zhang H, Wang FW, Yao IL, Hao AJ. Microglia-Friend or Foe. Frontiers in Bioscience. 2011; 3: 869-83
8/10/2019 Neuroregeneration Journal Reading
36/61
Stem Cells Therapy
Stem cells capable of being integrated into adegenerative environment & releasingneurotrophic cytokines may sustain endogenous neurogenesis and/or
activate neuroprotective pathways (for nestin andconnexin 43)
Quantification of these cytokines revealed aneurogenic/angiogenic predisposition of naive
human chorial villi and amniotic fluid derived cells. These cells also release significant amounts of brain-
derived neurotrophic factors, as well as vascularendothelial growth factor
8/10/2019 Neuroregeneration Journal Reading
37/61
Neurotrophic factors
Among others:
the neurotrophin nerve growth factor (NGF),
glial cell-derived neurotrophic factor (GDNF)and
brain-derived neurotrophic factor (BDNF)
Some degree of success has been obtainedregarding survival, existence and regenerationof specific neuronal populations in the adultbrain suffering from Parkinson's or Alzheimer's
disease
8/10/2019 Neuroregeneration Journal Reading
38/61
Natural Substances
Cerebrolysin
A peptide preparation mimicking the
action of neurotrophic factors
In vitro and in vivo studies showed that it
enhances neurogenesis in dentate gyrusand subventricular zone
Other effect:
Promotes neuralprogenitor cellmigration
Increases synaptic
density rebuildingneuronal
cytoarchitecture
Inducesrestorativeprocesses
Decreases theinfarct volume andedema formation
And promotesfunctional recovery
8/10/2019 Neuroregeneration Journal Reading
39/61
Natural Substances
Quercetin, a natural flavonoid could be protectiveof neuronal precursors of adult brain It neutralizes the oxidative stress by reducing peroxynitrite
formation, protein nitration and M2 isoform of pyruvatekinase depletion
Isoquercitrin (other flavonoid) also promotesneuronal differentiation through multiple Rho GTPasemediated mechanisms Inactivation of RhoA/Rho kinase: isoquercitrin reduces
47% of the RhoA activity and induces neurite growth (atconcentrations 40 M).
Another mechanism is the affection of RhoA localizationthat underwent translocation to the cytoplasm
8/10/2019 Neuroregeneration Journal Reading
40/61
Pathways in olygodendrocyte.
Bhat P, Chakrabarty M, Thawani V, Saxena A. Signalled roads to Memory and ItsDegeneration. Annals of Neurosciences. 2012; 19(2)
8/10/2019 Neuroregeneration Journal Reading
41/61
Hormonal Substances
Neurosteroid allopregnanolone (AP, 3-
hydroxy-5-pregnan-20-one), a metabolite of
progesterone that is normally generated in the
nervous system
It promoted
neurogenesis,
improved the
cognitive function,
reversed theneurogenic deficits in
the hippocampal
dentate gyrus andthe cerebralsubventricular zone
8/10/2019 Neuroregeneration Journal Reading
42/61
Mechanism of allopregnanolone-induced neural stem cell and oligodendrocyte
precursor progenitor mitosis.
Brinton RD. Neurosteroids as regenerative agents in the brain: therapeutic implications.
Nature Reviews Endocrinology. 2013; 9: 241-50
8/10/2019 Neuroregeneration Journal Reading
43/61
Hormonal Substances
Melatoninhas good antioxidant properties
In clinical trials using treatments with
melatonin has been effective in slowing the
progression of Alzheimer's disease, but not ofParkinson's disease.
Melatonin has multiple ways of preserving
mitochondrial homeostasis.It reduces free radicalgeneration by
enhancingmitochondrial
glutathione levels and
it safeguards protonpotential and ATP
synthesis by stimulatingcomplex I and IV
activities
8/10/2019 Neuroregeneration Journal Reading
44/61
Conclusion
Elucidating the cellular and molecular basis forinvolved in neurodegeneration and neuroregenerationin the aging brain could reveal new therapeuticapproaches to dementia in the elderly.
Development of novel and effective therapies tosustain the brain's self-repair will hopefully lead to animproved management of dementia in olderpopulation.
Multiple strategies should be targeted to prevent thedevelopment and the progression of the disease.Further investigation to update these strategiesare required for an efficient therapeutic response in
dementia.
8/10/2019 Neuroregeneration Journal Reading
45/61
Critical Appraisal
8/10/2019 Neuroregeneration Journal Reading
46/61
The critical appraisal instrument we used are the
DISCERN instrument which has been designed to
judge the quality of written information about
treatment options.
8/10/2019 Neuroregeneration Journal Reading
47/61
Are the aims clear?
Yes, the publication has clear aims.
8/10/2019 Neuroregeneration Journal Reading
48/61
Does it achieve its aims ? ?
Yes, it is achieved its first aim which is to summarize
up to date findings describes and evaluates by a
number of different authors
For example:
8/10/2019 Neuroregeneration Journal Reading
49/61
Does it achieve its aims ? Contd
But, the publication did not achieved its second
aim. This article does not discussing
contradictory results of different research group
Is it clear what source of information were
8/10/2019 Neuroregeneration Journal Reading
50/61
Is it clear what source of information were
used to compile the publication ??
Yes, it is clear. The
article provided
both in the textand in the
bibliography.
Is it clear when the information used/reported in the
8/10/2019 Neuroregeneration Journal Reading
51/61
Is it clear when the information used/reported in the
publication was produced ?
No. It is partially
clear when the
information
used/reported inthe publication
was produced
?
?
?
8/10/2019 Neuroregeneration Journal Reading
52/61
Is it balanced and unbiased ??
Yes the information is completely balanced and
unbiased.
Does it provide details of additional sources
8/10/2019 Neuroregeneration Journal Reading
53/61
Does it provide details of additional sources
of support & information ?
Yes, the publication provides full details of anyadditional source in bibliography
For example...
8/10/2019 Neuroregeneration Journal Reading
54/61
Does it refer to areas of uncertainty ?
No uncertainty about treatment choices is
mentioned
The author does not includes a clear reference to
any uncertainty regarding treatment choice
8/10/2019 Neuroregeneration Journal Reading
55/61
Does it describe how each treatment works?
No, the details provided are unclear or incomplete
There are no details of how the treatment is
given or administered
Nor the details of how the treatment works
Does it describe the benefits of each
8/10/2019 Neuroregeneration Journal Reading
56/61
Does it describe the benefits of each
treatment ?
Yes, the benefit is described for each treatment
8/10/2019 Neuroregeneration Journal Reading
57/61
Does it describe the risk for each treatment?
No risks are described for any of these treatment
Does it describe what would happen if no
8/10/2019 Neuroregeneration Journal Reading
58/61
Does it describe what would happen if no
treatment is used?
No, the publication does not include any reference to
the risks or benefits of no treatment option
Does it describe how the treatmentchoices affect overall quality of life ?
No, there is no reference to overall quality of
life in relation to treatment choices
Is it clear that there may be more than one
8/10/2019 Neuroregeneration Journal Reading
59/61
Is it clear that there may be more than one
possible treatment choice ?
It is partially clear. The publication indicate that there
may be more than one possible choice but the
information is unclear on incomplete
Does it provide support for shared-decision making?
No, the publication does not provide anysupport for shared decision making.
8/10/2019 Neuroregeneration Journal Reading
60/61
Conclusion
Based on the question above, the overall quality of
the publication are moderate.
The publication is a useful source of information
about treatment options but has some limitations.
Additional information or support would definitely be
needed.
8/10/2019 Neuroregeneration Journal Reading
61/61