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Dementia
Ageing
Ageing
The world's population is ageing
...
For the first time in history, persons aged over 65 outnumber
children under five years of age, globally
...

The UN cutoff is 60+ years to refer to the older population
...
Lifespan is the
maximum time a person can live
...
In 2019 the average life expectancy at birth
worldwide is 70 years for males and 75 years for females
...
The aim is to increase average years of healthy life
...
Functional ability is about having the capabilities that
enable all people to be and do what they have reason to value, and is made up of the
intrinsic capacity, comprises all mental and physical capacities, of the individual, and
relevant environmental characteristics
...
WHO
also reported that the top ten causes of death in high income countries are all age related
...

The Gompertz-Makeham law of mortality states that the human death rate is the sum of an
age-dependent component which increases exponentially with age and an age-independent
component
...
Across species, broad
population conformity to the Gompert function is used as a test of whether a population or
species shows ageing
...
The imbalance of pro-oxidants and
antioxidants leads to an age related accumulation of oxidative damage in
macromolecules, resulting in progressive loss of function and ageing
...
dietary restriction in rodents and genetic

manipulations in invertebrates and in rodents
...
However, such a
correlation does not prove causation, all the experimental manipulations that
increase lifespan also alter processes other than oxidative stress, therefore the
increase in longevity in these animals could arise through another mechanism
...
, Bokov
...
, 2009, provide evidence
against the free radical theory
...
The study found only one genetic manipulation, the deletion of ​sod-1
genes, had an effect on lifespan
...

-

Disposable soma theory of ageing
An organism's lifetime budget is divided between population sustainment,
reproduction, and individual sustainment, individual body maintenance
...
Ageing is caused by the progressive accumulation
of unrepaired faults and damage
...


-

Mitochondrial theory of ageing
As mitochondrial DNA is far more abundant than nuclear DNA and is further exposed
to reactive oxygen species (ROS) action in the mitochondrial respiratory chain,
damage to mitochondrial DNA is frequent
...
Mitochondrial dysfunction features; reduced mitochondrial
content, altered mitochondrial morphology, reduced avity of the complexes of the
electron transport chain, opening of the mitochondrial permeability transition pore,
decreased ATP generation, and increased ROS formation
...
The expression of a variety of cardiac mitochondrial
proteins is affected by ageing, most of these proteins are involved in metabolism,
respiratory chain function, or stress resistance, pointing to the central role of
mitochondria in cardiac injury
...
Interventions, such as physical activity, that reduce oxidative
damage and improve mitochondrial function cannot totally prevent but attenuate the
age-associated rate of muscle loss
...
Mitochondrial dysfunction in
adipose tissue triggers systemic insulin resistance and cardiac dysfunction
...
The rationale behind this is
that high extrinsic mortality (hazardous environment) limits life expectancy and acts
against selection of somatic maintenance genes
...

-

Telomere length theory of ageing
Telomeres are nucleoprotein complexes that cap the ends of the linear chromosomes
of eukaryotes, they comprise a repetitive non-coding DNA sequence (TTAGGG)
bound up in a multi protein complex
...
Telomeres are dynamic in length, as a result of telomere attrition
(the shortening of telomeres over time via the loss of terminal repeats) and
elongation (the enzyme telomerase can extend telomeres via the addition of
telomeric terminal repeats)
...
Telomere
shortening has also been reported to happen independently of telomerase activity,
through ROS-induced telomere damage
...
Hence, there is a trade off between lifetime
replicative capacity through preservation of telomere length and cancer suppression
...
The costly maintenance hypothesis states that
telomere attrition is adaptive because telomere maintenance entails costs, such as
the utilization of resources that could be invested in other traits
...
The life-history regulation
hypothesis states that the signaling function of telomere attrition acts as a biological
clock for regulating the pace of an individual's life history in according to somatic
integrity
...
The progressive loss of telomere
repeats gradually undermined the shielding of the chromosomal end from the cells
DNA damage recognition machinery, ultimately triggering a DNA damage response,
leading to apoptosis or senescence
...
However, the
non-causal biomarker hypothesis suggests that telomere lengths utility as a predictor
of health and fitness could instead reflect it acting as a non-causal biomarker of
accumulated damage to other biological structures that themselves have causal
deleterious effects on future performance
...
A study conducted by Miller
...
, 2011 found the drug
Rapamycin to extend the lifespan of mice
...
Rapamycin is an inhibitor of the kinase enzyme, target of
rapamycin (TOR)
...
TOR is the
first protein that has been shown to modulate lifespan in each of the four model
organisms most commonly used to study ageing; yeast, worms, files, and mice
...
TOR
signalling mediates dietary restriction, a reduction in nutrient availability without
malnutrition
...
TOR activity is reduced by dietary restriction, and
genetic studies in invertebrate models have linked the inhibition of TOR to increased
longevity by dietary restriction
...
Autopahgy nust be induced for lifespan to be extended by dietary
restriction in c
...
Rapamycin may by functioning as a dietary mimetic, a small
molecule that provides the benefits of dietary restriction without requiring a reduction
in food intake
...
Rapamycin analogues
are used clinically to treat certain forms of cancer
...
The
hayflick limit is the limit on cell replication imposed by the shortening of telomeres
with each division
...

Senescence is controlled by two pathways; telomere p53 and p16 pRB axis
...
Many features associated

with senescent fibroblasts promote conversion to an immunogenic phenotype that
facilitates self- elimination by the immune system
...

Transition to a senescent state, rather than an apoptotic one, may be optimal in
certain physiological conditions since this can preserve tissue integrity that might
otherwise be compromised through cell loss
...
The appearance of senescent cells can
accumulate as a result of impaired immune clearing by an ageing immune system
...
Progressive telomere attrition as a result of
cell cycle traverse (replicative senescence), oncogene activation (oncogene induced
senescence), elevated reactive oxygen species (stress induced premature
senescence), and cell fusion, all trigger entry into a senescent state
...
Upon
sensing DNA damage, the ataxia telangiectasia mutated (ATM) and ataxia
telangiectasia and RAD3-related (ATR) gene products inhibit cell cycle progression
by promoting p53 accumulation, which subsequently regulates a number of target
genes, including the cyclin-dependent kinase and p21
...
The senescence secretome secretes proteins capable
of attracting and activating immune cells such as neutrophils, monocytes,
macrophages, T-cells, and natural killer cells
...
Since the senescence
secretome is part of the DNA damage response, it is doubtful that it is specific to
senescent cells and likely occurs in other cell contexts associated with DNA damage
...
This
response is likely not exclusive to senescent cells and the same mechanism
sanctions in immune surveillance of tumour cells
...
Immunosurveillance is the gradual deterioration of the immune system with
age, which leads to impaired elimination of senescent cells, and is due to many
factors; induction of cell senescence in immune cells, altered expression of surface
receptors on immune cells that impairs recognition and interaction with target
senescent cells, inability to efficiently respond to chemoattractants secreted by
senescent cells
...
Autophagy promotes cell survival

by the degradation of damaged cellular components as a result of elevated ROS
...
PGE can be observed in microarray analysis by comparing the gene
expression profiles of different cell types and lines
...
, et al
...
PGE may be generated by;
oxidative stress, methylation changes, epigenetic alterations, DNA damage which
alters binding capacity to transcription factors
...

Aerobic glycolysis generates reactive acyclic alpha-oxo aldehydes, such as
methylglyoxal and glyoxal, spontaneously from triose phosphates, these compounds
are highly reactive and damage proteins through non-enzymatic modification
producing a wide variety of covalent adducts known as advanced glycation end
products which are toxic and have been implicated in the pathologies of numerous
age related disorders
...
ER stress can promote a
senescent like response
...
Faragher, R
...
, et al
...
These included genes
with roles in inflammation (IL-1beta, IL-8, ICAM1, TNFAIP3, ESM1 and CCL2), tissue
remodelling (VEGF, VEGFbeta, ADM and MMPI4), and vascular calcification (MGP,
BMP2, SPP1, OPG and DCN)
...

Wang
...
, 2001, used the enhanced green fluorescent protein reporter system to
scan regulatory elements in the upstream region of p16ink4a
...
A 24kDa protein that is highly expressed in
young cells may inhibit p16ink4a by interacting with ITSE, this protein is absent in
older cells
...
This results in an acceleration
of telomere shortening, signalling a DNA damage response, eliciting p53 pathways involved
in the cell cycle, causing cells to arrest in G1
...
Features of
premature ageing are observed in the 20s and can include; loss of and graying if hair,
hoarseness, and scleroderma- like skin changes, followed by bilateral ocular cataracts, type
2 diabetes mellitus hypogonadism, skin ulcers, and osteoporosis in the 30s
...
The LMNA gene encodes the
signal protein needed for nucleus structure, dysregulation results in dysregulation of the
nuclear envelope leading to dysregulation of cell repair
...

Senescence associated secretory phenotype
- Lopes-Pacienia
...
, 2019
The senescence associated secretory phenotype (SASP) reinforces the senescent
cell cycle arrest, stimulates the immune-mediated clearance of potentially
tumorigenic cells, limits fibrosis and promotes wound healing and tissue
regeneration
...
The CCAAT/enhancer binding protein family
comprises transcription factors that are part of the basic leucine zipper superfamily
...
C/EBP-beta has been shown to regulate many cytokines and factors known to
constitute the SASP such as IL-1beta, IL-8, IL-16, GRO-alpha, and NAP2
...
C/EBP- beta is
upregulated during oncogene-induced senescence, it binds to the IL-6 promoter in
this context
...
However, non-canonical NF-KB activation can
bypass senescence in melanoma, indicating a context dependent function of this
transcription factor
...
P38 increases DNA binding and activity of
NF-KB while GATA4 induces the expression and secretion of ILIA, an activator of
NF-KB
...
ILIA is also regulated by mTOR and by the inflammasome
...
The adaptor protein STING activates NF-KB,
STING itself is activated via a non-canonical pathway triggered by DNA damage
which involves p53 and the ubiquitin E3 ligase TRAF6
...
CD36 is induced in senescence context playing a role in SASP
response to senescence inducing ligands such as beta-amyloid
...
Metformin inhibits the
expression of proinflammatory cytokines in cells that experienced oncogene-induced
senescence
...
The SASP
suppresses or promotes tumorigenicity depending on the status of p53
...
P53 promotes
upregulation of some secreted factors
...
P53 suppresses p38 MAPK signalling to NF-KB
...
The tumour suppressor
SOCSI is a modulator of SASP
...
DNA damage
may trigger the chromatin changes required to prime SASP genes for activation
...
Senescent cells secrete
these proteases, decreasing their immune clearance and contributing to a
deleterious/ protumorigenic features of the SASP due to their subsequent reduced
immune surveillance
...
Consequently, DAMPs can
stimulate immune cell recruitment, wound healing and tissue repair
...
secretion of DAMPs has
been linked to chronic inflammation and age-related disorders such as
atherosclerosis and arthritis
...
The production of
eicosanoids is mediated by the enzymes cyclooxygenase (COX) and arachidonate
5-lipoxygenase (ALOX5)
...

COX2 is overexpressed in replicative and stress-induced senescence, and a
selective COX2 inhibitor prevents senescence
...
Cancer
chemotherapy induces DNA damage both in tumour cells and in the surrounding
stromal cells, which subsequently enter senescent
...
The SASP
can stimulate tumorigenesis and drug resistance by inducing a proinflammatory
microenvironment
...
Cellular senescence is
triggered by defects in nuclear lamina assembly, such as in HGP
...
Agents which modulate SASP may be targets for
further research
...
Not all human cell types
immortalize in the presence of ectopic telomerase, eg
...
Non-telomere senescence is induced

by stress, leading to cellular damage, p16 blocks cyclin D/cdk4 which in turn affects cyclin E/
cdk2, consequently cells arrest in G1, and cellular senescence results
...
Other laboratory investigations include; looking for markers of senescence, and
monitoring proliferative capacity on cell cultures
...
Telomere-dysfunction induced foci (TIF) analysis is
a new method for identifying senescent cells in tissue pr culture
...
Cells
are only TIFF positive of more than 50% of its 53BP foci co-localised with telomere PNA
...
, Sheerin, A
...
, 2017
Treatment with resveralogues was associated with altered splicing factor expression
and rescue of multiple features of senescence
...
Under
growth permissive conditions, cells demonstrating restored splicing factor expression
also demonstrated increased telomere, re-entered the cell cycle and resumed
proliferation
...
Small molecules such as resveratrol have been reported to
influence splicing regulatory factor expression in transformed cell lines, unfortunately
resveratrol has multiple adverse biological effects
...
Treatment of
senescent human fibroblasts from different developmental lineages with
resveralogues shifts expression patterns of multiple splicing factors to those
characteristic of much earlier passage cells
...
Elevated splicing factor association is also associated with elongation of
telomeres
...
, et al
...
In the study by Zhu
...
,
transcript analysis revealed increased expression of pro-survival networks in
senescent cells, consistent with their established resistance to apoptosis
...
Drugs targeting
these same factors selectively killed senescent cells
...
The combination of dasatinib and
quercetin was effective in eliminating senescent mouse epithelial fibroblasts
...
In old mice, cardiac function and carotid
vascular reactivity were improved 5 days after a single dose
...

These results demonstrate the feasibility of selectively ablating senescent cells and
the efficacy of senolytics for alleviating symptoms of frailty and extending healthspan
...
, et al
...
Dasatinib (D) and Quercetin (Q) have the ability to
transiently disable SASO networks
...
Q is a
natural flavonoid which targets BCL-2 family members, HIF-1alpha, and particular
nodes in PI3-kinase and p21-related anti-apoptotic pathways
...
Q is senolytic in the case of human endothelial cells, but does not
target senescent human adipocyte progenitors
...
In the open label phase I pilot study
conducted by Justice
...
, 3 days of oral D 100mg and Q 100mg was administered
to subjects with diabetic kidney disease (N=9; 68
...
1 years old; 2 female; BMI:
33
...
3 kg/m^2; eGFR: 27
...
1 ml/min/1
...
Adipose tissue, skin
biopsies and blood were collected before and two days after completing senolytic
treatment
...
Diabetic kidney disease is characterized by increased
senescent cell burden
...
Adipose tissue macrophages, which are attracted,
anchored, and activated by senescent cells, and crown like structures were
decreased
...
“Hit and run”
treatment with senolytics significantly decreases senescent cell burden in humans
...
Neurons
possess axons, cell bodies and dendrites
...
To aid in their function, neurons possess ion
channels, receptors for neurotransmitters, ion pumps and amino acid transporters
...


-

Astrocytes
Astrocytes comprise a highly abundant population of glial cells, the function of which
is critical for the support of neuronal homeostasis
...
Astrocytes undergo a functional
decline with age
...

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Bhat
...
, 2012
The Abeta peptide has deleterious effects on synaptic cleft plasticity
...
Senescent astrocytes display
characteristics of senescence associated with secretory phenotype, such as
increased secretion of proinflammatory cytokines, such as IL-6
...
The study
also found an increase in p16ink4a- positive astrocytes from fetal to non-AD adults
and from non-AD adults to AD adults
...
p38MAPK
is a mediator of the senescnce arrest in response to diverse stimuli and regulates the
SASP
...
p38 MAPK is activated in senescent astrocytes
...
Oligodendrocytes function in the myelination of axons and thus
increase nerve impulse conduction
...
White matter if found in the deeper tissues of the brain
(subcortical)
...
When severe brain injury occurs,
microglia cells change their morphology, migrate to the lesion sites and proliferate
...
However, when over
activated in severe injury or neurodegenerative diseases microglia have neurotoxic
roles
...
Microglia can differentiate into
a proinflammatory or neuroprotective form
...


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Xiao-Guang Luo
...
, 2010
Microglial alterations play crucial roles in increased inflammation in the CNS during
ageing due to increased production of proinflammatory cytokines
...
The inflammatory state of microglia in the
aged brain primes them to be over responsive to small stimuli, eventually activation
of microglia in the aged brain becomes uncontrolled
...
The destructive roles of the activated
microglia in the aged neurodegenerative brain may result from age-associated
microglial senescence
...

The main feature of microglial senescence in the morphological alteration dystrophy
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Microglia in the aged brain is distinct from that in the
young brain both in morphology and in telomere length, which indicate senescence,
microglia dysfunction in the aged brain is more related to extrinsic events than
intrinsic events
...
Extrinsic factors include; neurotransmitter, oxidative
stress, neuroendocrine factors, hormones, and pathological factors
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Tau and senescence
Bussan, J
...

Various markers of senescence have been observed in patients with
neurodegenerative diseases
...
, et al
...
Clearance of
these cells, using INK-ATTAC transgenic mice prevents gliosis
...
Pharmacological intervention with senolytics modulates tau aggregation
...
Neurofibrillary tangles (NFTs) are characteristic of AD, and
are composed of hyperphosphorylated tau
...
, et al
...

Ultrastructural studies have shown decreased mitochondrial area and density in the
cerebral capillary endothelium, increased pinocytic vesicles, greater number of
interendothelial junctions per unit of vessel length, increased number of pericyte
profiles for vessel profile, and increased cleft index, suggesting a leakiness of the
BBB in AD patients
...
Deposition of amyloid in the vessel walls may both result from and
contribute to BBB dysfunction via direct interaction of toxic Abeta with the

neurovascular unit, impaired transvascular clearance across the BBB, and
perivascular drainage of Abeta
...
This suggests that
neuroinflammation and reactive oxygen species contribute to the endothelial toxicity
of Abeta and disruption of the BBB in capillary CAA
...
The replacement of the vessel wall with Abeta instead of increased
collagen may underlie the increased risk of vessel rupture and haemorrhage in CAA
...
BBB
permeability increases with age and is increased even further in vascular dementia
and AD
...
White matter
abnormalities are commonly seen in dementia and result from atherosclerosis and
ischemia, with associated BBB dysfunction and leakage of plasma proteins
...
The vascular basement membrane plays an important
role in the formation and maintenance of the BBB, and ISF formation is dependent on
active soluble transport across the BBB
...
In CAA, Abeta deposition and
BBB dysfunction may lead to further decreased clearance of Abeta, exacerbating
Abeta accumulation, increased propensity for haemorrhage, and leakage of blood
derived proteins into brain parenchyma occurs, resulting in neuronal dysfunction
...
, et al
...
Loss of smooth muscle cells occurs with
replacement of the vascular media by amyloid
...

Research using animal models suggests that vascular amyloid decreases adhesion
of vascular smooth muscle cells to the basement membrane and that capillary
amyloid deposition may be associated with capillary occlusion
...
The concept that CAN alter blood flow is further supported by
pathologic studies showing an increased prevalence of ischemic lesions in brains
with CAA and clinical studies showing that CAA is associated with cognitive
impairment independent of the presence of brain haemorrhage attributable to
ischemia
...
, et al
...
, et al
...
The
deposited material is composed of the breakdown product of amyloid precursor
protein, which is cleaved by beta- and gamma- secretases into amyloid-beta
fragments of different amino acid lengths (Abeta40 and Abeta42)
...

Unlike parenchymal amyloid deposition in AD, which is initially deposited in the tunica
media and adventitia
...
This is followed by disruption of the blood vessel
wall leading to microaneurysms formation and fibrinoid necrosis
...
CAA is prevalent in the elerly
...
Moderate and severe CAA
predisposes to intracerebral haemorrhage (ICH) and is also associated with cognitive
impairment and an increased risk of death
...
A set of clinical and radiological
criteria have been developed for diagnosis of possibble CAA
...
The most common clinical presentation of
CAA is a lobar ICH
...
CAA is the most common
cause of cASH in the elderly
...
cSAH is associated with higher risk of future lobar ICH
...
Lobar CMBs are associated with
CAA
...
cSS refers to hemosiderin deposits in
the subpial layers of the brain
...
cSS in
CAA is a risk factor for ICH
...

The white matter hypersensitivity pattern in CAA patients has a posterior predilection
consistent with pathologic data demonstrating the occipital lobe as having the
greatest CAA burden
...
Measuring the concentration of Abeta proteins in the cerebrospinal fluid may be
a biomarker for CAA, Abeta40/42 are deposited in the cerebral vasculature thus there
are reduced concentrations of Abeta 40/42 in the CSF
...
The direct oral anticoagulants dabigatran,
rivaroxaban, apixaban, and edoxaban have been shown to lower risk of ICH
compared to warfarin
...
CAA is associated with high risk
for progressive cognitive decline
...
Atrophy and
cognitive impairment in CAA could result from either of three pathways, or a
combination; the direct effects of tissue destruction by ICHs, the effects of

concomitant AD pathology, or pathomechanisms other than ICH or AD
...
CAA accounts for 2% of
all strokes
...
In CAA, the apolipoprotein E and
the allele epsilon 2 and 4 confer risk for CAA
...
In CAA the Abeta 40:42 ratio is higher than in AD
...
AD and
CAA share important aspects of their pathogenesis
...
However, neurodegeneration in CAA cannot be entirely accounted for by AD
pathology, and must involve other mechanisms
...
These pathways converge to cause grey and white matter atrophy,
disconnecting brain networks
...
CAA can cause hemorrhagic strokes
...
Ischemic strokes do not necessarily lead to dementia, however, multiple
ischemic strokes can lead to the development of dementia
...
Following a
hemorrhagic stroke brain damage is more widespread
...
IL-1 can then cause a stroke
...

Post stroke, IL-1 may function in repair, increasing angiogenesis
...
IL_1 may aid in glial scar formation
...

Vascular dementia
Vascular dementia is a rapid-onset, step-wise, decline in cognitive function caused by a lack
of oxygen, primarily as a result of hemorrhagic stroke
...
Abeta may the; be deposited as myeloid
in vascular and parenchymal structures, undergo proteolytic cleavage, undergo perivascular
drainage, or efflux across the blood-brain barrier
...
, et al
...
These
protein aggregation disorders are also known as amyloid disorders
...
Oligomeric
intermediates formed during fibrillation may be toxic
...
Intermediary oligomeric species can act as potential diagnostic
biomarkers
...

Dementia and urinary tract infection
Urinary tract infections
-

Goering, R
...
, Zuckerman, M
...
, 2019
...
6th ed
...

The urinary tract is one of the most common sites of bacterial infection
...
Catheterization is a
major predisposing factor to UTI development
...
Dementia patients have a much higher incidence of recurrent
UTIs in comparison to the general population
...
Other gram negative bacteria, such as citrobacter, klebsiella,
enterobacter, proteus, and pseudomonas aeruginosa, are frequently the cause of
nosocomial UTIs
...
UTIs may exacerbate the progression of UTIs
...
Recurrent UTIs may be due to inefficient antibiotic treatment
...
Dementia patients may
result in hospitalization, which can be distressing to the patient
...
Ammonia is produced in the small
intestine due to presence of bacteria and the enzyme glutaminase
...
In the kidneys
glutaminase facilitates acid-base regulation
...

Glutamate-glutamine cycle
Glutamate is released from presynaptic vesicles into the synaptic cleft
...
Astrocytes convert glutamate to glutamine in an
ATP dependent reaction
...
The glutamate-glutamine cycle has

several functions; it promotes rapid removal of glutamate from the synapse, it promotes
conversion of glutamate to glutamine which acts as a carrier of glutamate to neurons, it
promotes regeneration of glutamate, it enables provision of glutamine an essential neuronal
fuel, and it provides a mechanism for buffering ammonia which is toxic
...

Ammonia and alpha-ketoglutarate generate glutamate in an NADPH dependent reaction
...
high
concentrations of ammonia can cause neurological dysfunction, as ammonia is able to easily
diffuse or be transported to the BBB
...

High levels of ammonia promote the ATP-dependent glutamine synthase reaction
...
As ammonium ions have a similar structure to potassium ons, high levels
of ammonium ions leads to competition between ammonium and potassium ions for
potassium ion channels in the presynaptic neuron, resulting in an increase in extracellular
potassium which affects chloride ion concentration, leading depolarisation, and dysregulated
calcium metabolism, and ultimately cell death pathways are activated
...
, et al
...
The onset of hyperammonemia caused by UTI may occur as a
result of elevated intravesical pressure due to dysuria caused by neurogenic bladder
or prostatic hypertrophy
...
In addition,
urease-producing bacteria in the bladder likely promote hyperammonemia
...
As ammonium ions become
lipophilic ammonia in the alkaline urine, it is easily transferred to the vesical venous
plexus
...
A limitation of this
study is its small sample size of five patients
...

Ammonia and dementia
-

Adlimoghaddam
...
, 2016 and Jin
...
, 2018
Glucose is the main source of energy within the brain
...
The
dysregulation of glucose metabolism has been demonstrated by comparing the

enzymatic activity of glucose transporters in dementia versus control individuals
...
As a result of impaired MAS, the pyruvate:lactate
ratio decreases in astrocytes
...

Evidence indicates that energy metabolism is compromised in dementia and
ammonia is involved in the disruption of energy metabolism (ie
...
Abnormal ammonia metabolism in dementia brains
correlates with decreases of astrocyte glutamine synthetase activity
...
The lower
activity of glutamine synthase is related with the density of extracellular deposits of
Abeta in dementia brains, this suggests a link between impaired ammonia
detoxification (due to altered glutamine synthase activity) and Abeta plaque formation
in dementia brains
...
GABA mediated inhibitory neurotransmission
...

Neurotransmission imbalances caused by ammonia may be responsible for cognitive
deficits in dementia
...
Hyperammonemia induces apoptosis, which is
associated with neuronal degeneration, via signalling molecules such as NF-KB
...

Immunohistochemical analysis has shown that ammonia-treated astrocyte cultures
are able to increase NF_KB activity and astrocyte swelling
...
Memory disruption is a hallmark of dementia
...
Chronic ammonia exposure affects
cognitive function through neurosteroid metabolism
...

UTI, hyperammonemia, and dementia
-

Wood
...
, 2013
The urinary bladder is a common site of bacterial infection with a majority of cases
attributed to uropathogenic E
...
Sequels of UTIs include the loss of urothelial
barrier functions and subsequent clinical morbidity secondary to the formation of
urine potassium, urea, and ammonia into the subepithelium
...
This study models acute uropathogenic E
...
The ussing chamber sustains tissue viability while
physically separating submucosal and lumen influences, so this model is ideal for
quantitative measurement of transepithelial electrical resistance (TER) to assess
alteration of epithelial barrier function
...
Changes in both tissue

ultrastructure and TER indicated that uropathogenic E
...
In addition, bacterial interaction with
the urothelium promoted secretion of cytokines from the urinary bladder with
bioactivity capable of modulating epithelial barrier function including TNF-alpha, IL-6
and IL15
...

-

Smith
...
, 2015
Tight junctions are multicomponent structures, with claudin proteins defining
paracellular permeability
...

In this study normal human urothelial cells maintained as non-immortalized cell lines
were retrovirally-transduced to over-express or silence claudin 3 expression
...
expression
of claudin 3, ZO-1, and 2OHalpha were examined in native urothelium in
immunohistochemistry
...
Knockdown of claudin 3 inhibited
formation of a tight barrier in three independent cell lines, however, overexpression of
claudin 3 was not sufficient to induce tight barrier development in the absence of
differentiation
...
Whereas claudin 3 overexpression did not
induce the switch to c-=expression of ZO-1alpha-/ZO-1alpha+, claudin 3 knockdowns
decreased localisation of ZO-1 to the tight junction and resulted in compromised
barrier function
...
A coordinated
switch to ZO-1alpha+ isotype was observed, indicating that ZO-1alpha+ is involved in
the structural assembly and function of the urothelial terminal tight junction
...
coli can decrease ZO-1 and claudin 3 overexpression, resulting in a
leaky urothelium, and release of ammonia into the systemic circulation, which can
then cross the BBB and cause neurological dysfunction
...
, et al
...
The intestinal bacteria play an
important role in human health, such as by supplying essential nutrients, synthesising
vitamin k, aiding in the digestion of cellulose, and promoting angiogenesis and
enteric nerve function
...
Probiotics are intended to affect the hosts health
beneficially
...
Probiotics reduce the
total amount of ammonia in the portal blood because probiotics inhibit bacterial
urease activity due to the production of lactic acid
...
Probiotics

decrease the pH in the intestine, thus reducing ammonia absorption
...

Early detection of infection in dementia patients
A diaper pad may be used for diaper-based urine collection and screening of urinary
biomarkers

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