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Neuropathology of Post-Stroke Depression:
Possible Role of Inflammatory Molecules and Indoleamine 2,3-dioxygenase
by
Amy Wong
A thesis submitted in conformity with the requirements for
the degree of Master of Science (MSc.)
Graduate Department of Pharmacology and Toxicology, University of Toronto
1.4.2 Inflammatory Processes and Stroke ............................................................. 18
1.4.3 Inflammatory Processes and Depression ...................................................... 21
1.4.4 Current Hypotheses on the Etiology of Post-Stroke Depression .................. 25
1.4.5 Neurological Consequences of Reduced Serotonin Synthesis and the Formation of Neurotoxic Metabolites ...................................................................... 29
1.4.6 Rationale for This Study ................................................................................ 38
Appendix A: Post-stroke Depression Study Patient Consent Form ......................... 122
Appendix B: Sunnybrook REB Approval Letter ....................................................... 126
Appendix C: York Central REB Approval Letter ...................................................... 129
Appendix D: Baycrese REB Approval Letter ........................................................... 130
Appendix E: St. John's REB Approval Letter ........................................................... 131
Appendix F: Toronto Research Institute Approval Letter ......................................... 132
Appendix G: Study Roles ........................................................................................ 133
Appendix H: Presentations and Publications ........................................................... 134
vi
LIST OF TABLES
Table 1: Mean KYN/TRP Levels in Various Depression, Neurodegenerative Diseases, and Inflammatory Illnesses ............................................................................................ 40
Table 4: Participant Demographics and Assessment Scores by Depression Group ..... 62
Table 5: Stroke Lesion Characteristics by Depression Group ....................................... 63
Table 6: Cerebrovascular Risk Factors and Concomitant Medication Use by Depression Group.......................................................................................................... 64
Table 7: Distribution of Hypertensive Patients on Anti-Hypertensive Medication ........... 69
Table 8: Measured and Imputed Cytokine Plasma Levels by Depression Group .......... 70
Table 9: Cytokine Detectability by Depression Group.................................................... 70
LIST OF FIGURES
Figure 1. The KYN Pathway: TRP Metabolism and its Products .................................. 35
Figure 3. Mean KYN/TRP ratios in stroke patients with and without depressive symptoms ..................................................................................................................... 65
Figure 4. Box-plot of unadjusted KYN/TRP ratios in stroke patients with and without depression ..................................................................................................................... 66
Figure 5. Correlation between CES-D total scores and KYN/TRP ratio ......................... 66
Figure 6. Correlation between LNAA concentrations and KYN/TRP ratio ...................... 67
Figure 7. Mean CES-D Scores by Hypertension Group ................................................. 68
Figure 8. Correlation between unadjusted IL-6 concentrations and KYN/TRP ratio ...... 71
1
1. INTRODUCTION
1.1 Statement of the Problem
Stroke is the third leading cause of death in Canada, with more than 50,000 strokes
occurring annually1. This figure amounts to approximately one stroke for every 10 minutes of
time that has elapsed. About 30% of stroke victims do not survive the acute attack1. For the
survivors, rehabilitation involves addressing the physical, cognitive, psychological and
psychosocial impairments that are common post-stroke sequelae. One of the major
psychological changes observed in post-stroke patients is depression.
Depression is a significant health problem among the elderly population leading to
diminished quality of life2, impaired daily functioning
3-6, greater health service use
7, poorer
perceived health7 and increased mortality risk
8. With regards to stroke, depression occurs in
approximately one-third of all reported cases9-14
and is the strongest predictor of quality of life
(QoL)15-18
. Consequentially, post-stroke depression (PSD) patients have increased functional
disabilities19-23
, increased health service utilization24, 25
, increased cognitive impairment26
,
higher mortality rates27-31
even after controlling for other factors such as associated illnesses and
prior stroke27, 28
and poorer rehabilitation outcomes32-34
compared to non-PSD patients.
Moreover, stroke survivors are at elevated risk for clinically significant depressive symptoms
even two years after stroke onset35
.
Although antidepressant medications can be prescribed, the drugs are not efficacious in
all depressed survivors despite the availability of different formulas acting upon distinct
neurological pathways. Even when effective for depressive symptoms, post-stroke cognitive
impairments frequently persist36
. Additionally, response rates to antidepressant treatments are
inconsistent between studies partly due to variable definitions of response. The high prevalence
of depression post-stroke (about three times greater than the general population) combined with
2
the impact of these symptoms on antidepressant response highlights the urgency to discover
possible pharmacological targets for disease management. The generation of reliable data
regarding the neurological, physical and social correlates impacting PSD is a crucial factor in
the field of stroke recovery. Ultimately, a sound understanding of PSD etiology may lead to
novel therapeutic approaches that can propagate into successful management of this stroke
outcome.
1.2 Purpose of the Study and Objectives
PSD remains profoundly problematic due to its high prevalence, negative impact, and
lack of effective treatments. Several hypotheses regarding the etiology of PSD have circulated
since the early 1980s, beginning with Robinson’s lesion location theory37
. It was published that
stroke victims suffering from left anterior lesions were more prone to PSD than those of right or
posterior lesions. His hypothesis not only stimulated several debates, but also generated the
formation of subsequent hypotheses by other groups exploring other biological and psychosocial
components relevant to the disease. Despite such increasing interest in PSD research, no
conclusive data have been collected to date. The primary objective of this study was to assess
novel biological components that may contribute to the etiology PSD. In particular,
concentration changes of specific inflammatory markers and their ability to modulate tryptophan
(TRP) metabolism post-stroke was investigated as a possible cause of PSD. Tryptophan was of
special interest since it acts as a precursor to both the mood modulatory neurotransmitter
serotonin and neurotoxic kynurenine (KYN) metabolites.
KYN is formed by metabolism of TRP by indoleamine 2,3-dioxygenase (IDO);
therefore, an increase in IDO activity as stimulated by increases in pro-inflammatory cytokines
post-stroke is thought to initiate the development of PSD. Here, it is hypothesized that a
decrease in serotonin synthesis accompanied by an accumulation of neurotoxic KYN
3
metabolites act as a possible mechanism of the disease. This study measured the KYN/TRP ratio
as a marker of IDO activity in order to elucidate the hypothesis. Additionally, measurements of
pro- and anti-inflammatory cytokines were taken and analyzed to examine the relationship
between cytokines, IDO, and PSD. Finally, demographic and clinical factors were characterized
between depressed and non-depressed stroke patients in order to elucidate any markers that may
contribute to post-stroke inflammatory response mechanisms.
1.3 Statement of Research Hypotheses and Rationale for Hypotheses
1.3.1 Primary Hypothesis
Hypothesis 1: Increased IDO enzyme activity will be found in stroke patients experiencing
depressive symptoms compared to non-depressed stroke patients as evidenced by an increased
kynurenine/tryptophan (KYN/TRP) ratio.
Rationale: Initially, an increased KYN/TRP ratio was documented among depressed
immunotherapy patients38
, in post-partum depression39
, and in major depression40
. Most
recently, our group demonstrated that an elevated KYN/TRP ratio was associated with
depression among coronary artery disease patients, a group similar with respect to age and a
high prevalence of cerebrovascular risk factors41
. It is hypothesized that post-stroke stimulation
of IDO activity increases the production of KYN from its TRP precursor. Since TRP also acts
as a precursor to serotonin synthesis42
, decreased levels of serotonin are left available for
synapses between mood regulatory neurons. In addition, KYN can be metabolized into
neurotoxic metabolites43-45
that may cause further damages to areas of the brain responsible for
processing emotions. The effect of decreased serotonin synthesis accompanied by an escalation
of neuronal injuries is hypothesized to play a major role in the etiology of PSD. Thus, it is of
interest to measure IDO activity as a potential marker of disease progression. Since IDO has an
extremely short half life, an indirect measurement of enzyme activity (KYN/TRP ratio) will be
4
utilized instead. The KYN/TRP ratio has been used as a sensitive estimate of IDO activity and
cellular immunity both in vivo and in vitro since the late 1980s
46, 47.
1.3.2 Secondary Hypothesis
Hypothesis 2: Increased levels of pro-inflammatory cytokines (IL-1, IL-6, TNF-, IFN-) and
decreased levels of anti-inflammatory cytokines (IL-10) will be found in stroke patients
experiencing depressive symptoms compared to non-depressed stroke patients.
Rationale: Early pre-clinical studies have documented several cases of behavioural disturbances
in animals administered a variety of pro-inflammatory cytokines48, 49
. These behavioural
changes were collectively termed ―sickness behaviors‖ and are thought to mimic those of
depressive symptoms observed in humans50, 51
. More recent experimental and epidemiological
studies have reported higher levels of inflammatory markers within the nervous and circulatory
systems of depressed people52-58
. Marked increases in peripheral pro-inflammatory cytokines
have been documented in several post-stroke cases59-64
. By linking the two findings together,
the development of depression in immunocompromised patients is thought to be cytokine-
mediated. This theory has been supported by reported cases of depression after cytokine
immunotherapy65-68
where pro- and anti-inflammatory cytokines are thought to have opposite
effects. Although data regarding the role of pro- and anti-inflammatory cytokines remain
controversial, it has been hypothesized that a balance between both inflammatory markers is
crucial for maintaining mental fitness69-71
. According to the mechanism proposed for the
primary hypothesis, elevations in pro-inflammatory cytokines and reductions in anti-
inflammatory cytokines contribute to IDO activation and may contribute to PSD.
5
1.4 Review of the Literature
1.4.1 Post-stroke Depression
1.4.1.1 Prevalence
One systemic review of observational studies reported a 33% prevalence of PSD at any
time after stroke10
. Although this number concurs with most PSD studies, it is difficult to define
the true prevalence of PSD due to methodological (evaluation time, study setting,
inclusion/exclusion criteria) and diagnostic (different cut-off scores in rating scales, non-
consistent use of structured-clinical interviews, clinical findings only) variability present
amongst studies. PSD may also be over-diagnosed due to similar somatic symptoms produced
by other medical illnesses, or under-diagnosed particularly in patients with co-morbid cognitive
impairment. The correct attribution of somatic symptoms is important since it is relevant to
accurate scoring of depression severity scales, namely the Hamilton Depression Scale (HAM-
avenues for alternative treatments to depression, since pro-inflammatory cytokine inhibitors and
anti-inflammatory drugs may be able to prevent or attenuate depressive symptoms in humans.
In cases of immune challenges, one study found that mild stimulation of the primary host
defense in humans (using a safe and well-tolerated dose of endotoxin) produces negative effects
on both emotional and cognitive function229
. Elevations in both anxiety and depression levels
23
have been reported in other human cases of immune challenges186, 230
with those of lower
socioeconomic status most affected231
. All together, these findings suggest that pro-
inflammatory cytokines may play a crucial role in the pathogenesis of mood disorders in
humans, with implications for novel cytokine targeting therapies in neuropsychopharmalogical
research.
1.4.3.4 Cytokines in Clinical Depression and Cognitive Decline
The involvement of cytokines in the etiology of psychiatric disorders has been
extensively reviewed in the past by various authors174, 175, 184, 232, 233
. Under physiological
conditions, cytokine concentrations remain low in the body but are up-regulated during various
disease states, particularly those involving inflammation. With regards to depression, both
experimental and epidemiological research has found that depressed people have higher levels
of inflammatory markers52-58, 234
. For example, one study examined the levels of inflammatory
cytokines in a community-based sample of already depressed elderly subjects and found that
persons with depressed mood had higher median plasma levels of IL-6 and TNF-α57
. These
results became more significant after adjustments for health and demographic variables,
suggesting that depressed mood is either causing or caused by systemic inflammation.
Clinical studies have associated depression with increased levels of systemic cytokines
and acute phase proteins52, 58, 235-238
although such results were not always reproducible239, 240
.
Note, however, that the complex balance between pro- and anti-inflammatory cytokines may
play a crucial role in the development of mood disturbances, highlighted by reports of elevated
IFN- to IL-470, 241
and IL-6 to IL-1069
ratios in major depression. This may explain why a few
studies did not find a positive correlation between pro-inflammatory cytokines and depression
since none of them explored the significance of this balance. In addition, one of the authors
based their concentrations on lipopolysaccharide (LPS) induced peripheral blood mononuclear
24
cell (PBMC) cytokine production, which may be drastically different from the natural biological
concentrations of interest.
Cytokines are believed to affect cognitive function via active transport into the CNS
through afferent neurons that centrally activate cognitive responses, or upon local release by
activated microglia causing neurodegeneration242
. As previously mentioned, the
neuropsychiatric effects of cytokine therapy on cancer and HIV patients encompasses cognitive
changes that may involve a decline in verbal memory, cognitive speed and executive function216,
243, 244. Other forms of neurological disease associated with cognitive impairment have been
well documented in the past. Most notably, the severity of dementia in Alzheimer’s disease
patients is often accompanied with higher levels of circulating cytokines than controls, including
IL-1245-248
, IL-6247, 249, 250
, IL-18251
, and TNF-248
, although conflicting reports exist251, 252
. This
is not a disease related phenomenon since healthy aging individuals who experience cognitive
decline also exhibit higher levels of inflammatory markers253-257
independent of demographic
status and social status, and may also be at higher risk for mortality258
. Although the mechanism
of cytokine-induced cognitive changes has yet to be elucidated, it has been suggested to involve
damages to the fronto-subcortical circuitry. For example, one study found that stroke lesions of
the frontal lobe were associated with amusia (the absence of music perception), and that the
disorder also entailed general cognitive deficits in working memory, learning, semantic fluency,
executive functioning, and visuospatial coordination259
. Therefore, post-stroke elevations in
cytokines may contribute to post-stroke cognitive deterioration alongside depression.
The precise mechanisms behind cytokines and their ability to induce radical changes in mood
states remain unanswered. Generally, it is believed that increased peripheral cytokine levels
enter the brain and alter neurotransmitter metabolism, neuroendorcrine function, and neural
plasticity mechanisms responsible for mood regulation184
. Additionally, cytokine-mediated
25
interactions between neurons and glial cells may contribute to cognitive impairment (especially
in cases of memory and learning) via alterations in cholinergic and dopaminergic pathways242,
260. The next step would be to determine the cytokine concentrations and their time of activation
post-stroke to create a more detailed definition of their pathological outcome. Nevertheless,
elevations in cytokine levels may be useful prognostic markers for PSD despite their detrimental
effect to neuronal functioning.
_____________________________________
1.4.4 Current Hypotheses on the Etiology of Post-Stroke Depression
The etiology of PSD is thought to be multifactorial involving both psychosocial
vulnerability and biological mechanisms. In addition, several scientists believe that location of
the infarct plays a crucial role in understanding the mechanisms behind the disease. Thus, three
major hypotheses currently exist in the etiology of PSD: lesion location, psychosocial factors,
and biological factors261
.
1.4.4.1 Lesion Location Hypothesis
Those who support the lesion location hypothesis believe that PSD is directly caused by
focal damage to brain regions involved in the mood regulatory system. An early pioneer of the
lesion location hypothesis is Robinson and his team who were the first to report that left-
hemisphere lesions located to the vicinity of the frontal pole were more frequently associated
with PSD than lesions elsewhere in the brain82
. Since then a couple of other studies have
reported the same phenomenon74, 159, 262, 263
. These findings were encouraging to the lesion
location hypothesis since they support theories regarding: 1) frontal structures in the regulation
of emotional behavior and 2) lateralized differentiation in the organization of emotion, where
the left side of the brain is more often activated than the right side during emotional
processing264, 265
. In support of this, a MRI study found that left lesions of the frontal-subcortical
26
circuits (i.e. pallidum and caudate) predisposed stroke patients to depression with size of infarcts
being larger in depressed patients12
. Furthermore, the severity of depression has been associated
with left frontal lobe damage, with the exception of the basal ganglia266
. However, two more
recent systematic reviews267, 268
and several other studies76, 89, 269-273
failed to confirm the
association between left-sided strokes and depression, while one review stated such an
association varied depending on whether patients were sampled as inpatients or from the
community97
. Post-stroke cognitive impairment may also be related to lesion location as
comorbid MDD and cognitive impairment has been associated with left-sided lesions274
.
To counter the unsuccessful replication of their findings, Robinson and colleagues
carried out a meta-analysis275
and claimed to have found an interaction between lesion location
and time of PSD onset. Here, left-hemisphere lesions would increase the risk of PSD especially
in the first couple of months after stroke, whereas in the subacute to chronic course,
psychosocial factors would play a more important role. In addition, it was suggested that the
proximity of the left hemispheric lesion to the frontal pole was correlated with depression
severity, but not in cases of right-hemisphere stroke276
. However, prior to such claims, Gainotti
and his team had tested this same assumption and found that symptom profiles and the
anatomical and clinical correlates of major PSD were no different in the acute and chronic
stages of stroke270
. Currently, confirmation or rejection of Robinson and colleagues’ findings
has yet to be elucidated. However, many researchers agree that the etiology of PSD does not
and cannot rely on the lesion location theory alone.
1.4.4.2 Psychosocial Factors Hypothesis
The psychosocial hypothesis states that PSD is a psychological reaction to the physical
devastation caused by stroke whereby disability is the major predictor to disease development.
Several studies have supported this hypothesis22, 270, 277, 278
even after controlling for other stroke
27
characteristics including size and location of infarct85, 89, 279
. Lack of social companionship272, 273,
280 and absence of family support
74 have also been associated with the development of PSD and
are predictive of depression severity at six months post-stroke272
. Additionally, the development
of functional disabilities as a result of the stroke may lead to greater depressive symptoms which
would further complicate functional outcome20, 33, 281
. In support of this, improvement of
depressive symptoms post-stroke has been also associated with better functional recovery88
.
Although the severity of functional disability has been shown to be a strong predictor of
depression at 3 months post-stroke74, 85
the association disappears after around 12 to 24 months
post-stroke74, 85, 279
. Instead, few social contacts outside the immediate family and diagnosis of
the disorder at an in-hospital setting contributes most to depression at those times. Thus,
disability may only be a risk factor for depression in the acute and subacute post-stroke period,
where it does not determine the onset of depression per se, but interacts with it to limit the
results of long-term rehabilitation280
. These suggestive findings have led to the hypothesis that
PSD is at least, in part, a consequence of the direct biological consequence (e.g. immune
response) of the stroke.
1.4.4.3 Other Biological Factors
It has been hypothesized that during acute brain infarction, there is decreased
monoamine synthesis leading to decreased serotonin levels in the brain. In blood, serotonin is
present in high concentrations in platelets and released into the plasma when platelets aggregate
at the site of tissue damage. It is then subsequently catabolized by monoamine oxidase enzyme
activity in the liver and lungs. In the CNS, serotonin is present in high concentrations in
localized regions of the midbrain, serving as a neurotransmitter. The level of CSF or brain
serotonin remains controversial—some studies associate MDD with reduced levels of CSF
serotonin and increased levels of serotonin turnover282, 283
whereas other studies find no
28
differences in CSF concentrations of serotonin metabolite (5-hydroxyindoleacetic acid) between
depressed and healthy subjects284, 285
.
It has been proposed that PSD is caused by ischemic brain lesions that directly disrupt
neural circuits involved in mood regulation286
. In particular, it has been postulated that stroke
lesion interrupts the biogenic amine containing axons ascending from the brainstem to the
cerebral cortex, thereby leading to a decreased production of serotonin and norepinephrine in
uninjured limbic structures of frontal and temporal lobes as well as basal ganglia287
. Thus,
deficits in important mood regulatory neurotransmitters or failure of the body to up-regulate
their respective receptors after stroke may trigger PSD. This hypothesis has been supported by
studies demonstrating significantly lower CSF and plasma concentrations of serotonin288
and
CSF concentrations of its metabolite, 5-hydroxy-indoleacetic acid289
, in PSD patients compared
to non-depressed stroke survivors. Moreover, one study reported an inverse correlation between
serotonin receptor binding in the left temporal cortex and HAM-D scores of depressed
patients290
.
In further support of the biological hypothesis, one study found that the most commonly
reported symptoms in a group of post-stroke patients were discouragement/hopelessness, self-
criticalness, tiredness and feelings of being punished159
, all of which describe non-physical
symptoms. Furthermore, a community-based post-stroke cohort was found to have an elevated
risk for clinically significant depressive symptoms that was not mediated by functional
disability35
. Lastly, one study reported an association between the presence of small silent
strokes and late-onset depression, suggesting that patients who are unaware of their existing
cerebral lesions develop depression independently of psychological mechanisms related to
functional debilitation291
.
_____________________________________
29
1.4.5 Neurological Consequences of Reduced Serotonin Synthesis and the Formation of Neurotoxic Metabolites 1.4.5.1 Serotonergic Hypothesis of Depression
The serotonergic hypothesis of depression has been in existence for over 40 years292
and
proposes that diminished activity of 5-HT pathways is responsible for the pathopysiology of
depression. The hypothesis was evidenced by countless observations of patient response to
treatment with tricyclic antidepressants in which inhibition of 5-HT and noradrenaline reuptake
was presumed to enhance 5-HT-mediated neuroendrocrine responses. Moreover, the
development of the more efficacious SSRIs suggested that depressive symptoms can sufficiently
be attenuated as a result of increased synaptic 5-HT concentration293
. Today, 5-HT is
recognized to influence many symptoms of depression, including mood, appetite and sleep
patterns, physical activity, sexual interest and cognitive dysfunction.
Imaging investigations of the 5-HT receptors via ligand detection in conjunction with
positron emission tomography (PET) or single photon emission computed tomography (SPECT)
have provided consistent and convincing evidence that the binding density of 5-HT1A294, 295
and
5-HT2296
receptors is significantly decreased in MDD patients. The reduction in receptor
binding density was particularly prominent in areas of the brain involving the amygdala297
,
midbrain297, 298
, and brainstem299
. Age-related effects may also be of significant importance in
which reduced receptor binding density occurs with increasing age298, 300, 301
. Similar results
have been reported for the serotonin transporter (SERT), where drug-free unipolar depressed
patients exhibited reduced SERT availability in the brain stem299
. However, these findings are
not necessarily reproducible as no difference in SERT availability between depressed and
healthy volunteers has also been documented302
. Similarly, no significant difference in 5-HT
binding potential was found between recovered depressed patients and healthy controls in one
study303
while another study documented widespread persistent reductions in 5-HT receptor
30
binding among patients who have already recovered from the disease. Taken together, these
results suggest that reduced binding density may represent a genetic abnormality that confers
vulnerability to recurrent major depression rather than an observation made only during the
course of the disease303
.
In relation to post-stroke cases, the presence of an acute infarct is hypothesized to reduce
monoamine synthesis (e.g. 5-HT) within the brain. In the past, PSD patients have been
consistently documented to have lower CSF concentrations of the serotonin metabolite 5-
concentrations of serotonin. It was reported that serotonin concentrations in the CSF and
plasma of PSD patients were considerably lower than non-depressed patients and that a greater
number of PSD patients had lower than normal serotonin concentrations than the control group.
Furthermore, a sound correlation was found between the plasma and CSF serotonin
concentrations in both PSD and control patients, suggesting that plasma concentrations of
serotonin may be useful in predicting the central concentrations in patients with stroke or
depression.
1.4.5.2 Tryptophan and Central Serotonin Synthesis
Tryptophan is an essential amino acid that can only be obtained through external
sources. Once absorbed by the body, tryptophan travels around the peripheral circulation in
equilibrium between its albumin-bound and free form, the former comprising of 90% of the
body’s tryptophan level42
. Tryptophan can only be transported across the BBB in its free form
by the L-type amino acid transporter304
and once in the CNS, tryptophan acts as a precursor in
various metabolic pathways. The end products of these pathways are comprised of various
proteins, kynurenine, and serotonin42
. Note that brain TRP levels can be considered a reflection
31
of its plasma levels since TRP transport across the BBB directly affects the amount of
metabolites synthesized.
Tryptophan hydroxylase (TPH) is located in the cytoplasm of neurons of the raphe
nuclei and acts as the rate limiting enzyme of 5-HT synthesis. Using molecular oxygen and the
cofactor tetrahydobiopterin, it catalyzes the hydroxylation of TRP into 5-hydryoxytryptophan
(5-HTP). A subsequent decarboxylase enzyme then rapidly converts 5-HTP into 5-HT using
pyridoxal-5’-phosphate as co-factor42
. Serotonin is then either: 1) bound by the carrier protein
serotonin-binding protein (SBP) and released into the extracellular fluid (synapse) via calcium-
dependent exocytosis; or 2) metabolized into 5-hydroxyindoleacetic acid (5-HIAA) by
monoamine oxidase enzymes and excreted from the cell via energy dependent mechanisms.
Following release into the synapse, 5-HT can be recycled back into the neuron through SERT
reuptake located on the pre-synaptic membrane or metabolized into 5-HIAA in the post-synaptic
neuron.
Several researchers have examined the role of TRP and 5-HT in depression and the
clinical and neuropsychological consequences of abnormal 5-HT activity in the brain. For
example, one of the most reliable pieces of evidences linking 5-HT abnormalities to depression
was first documented in the mid-1980s, where total plasma tryptophan was significantly lower
in depressed patients compared to controls305
. More recently, researchers have constructed a
technique to induce a brief tryptophan depleted state in healthy subjects in order to assess the
mood effects of reducing central 5-HT function. This is simply accomplished by administering
an amino acid mixture free of TRP; thus, lowering both plasma and brain TRP concentrations.
Because the rate limiting step of 5-HT synthesis is determined by TPH activity, and because
TPH is only 50% saturated with TRP under normal physiological conditions306
, tryptophan
depletion is predicted to produce a transient lowering of central 5-HT activity.
32
The return of depressive symptomatology as a result of TRP depletion has been
documented in recovered depressed patients withdrawn from medication307, 308
. However, TRP
depletion appears insufficient to cause clinically defined depressive symptoms in healthy
volunteers308
. Although the difference in response to tryptophan depletion between the two
populations has yet to be elucidated, it has been postulated that depression may be the result of
persistent neurobiological changes that produce clinically significant mood abnormalities when
affected individuals are exposed to low 5-HT activity309
. The types of neurobiological changes
remain undefined but are hypothesized to involve altered or impaired innervations in
neurocircuitry that consistently leads to negative biases in emotional perception. Whatever the
mechanism, it can be said that tryptophan depletion studies generally support a casual
relationship between decreased central 5-HT and depression, and that those with risk factors for
depression or a family history of depression are most affected.
1.4.5.3 Central Tryptophan Availability
Knowledge underlying the specificities of tryptophan uptake into the serotonergic
neurons remains scarce. In its most simple definition, it is generally agreed upon that a
dynamic, regulatory barrier exists between plasma and intraneuronal tryptophan concentrations.
Although it is known that the L-type amino acid transporter is responsible for tryptophan
transport into the brain, two important factors surrounding this transport system must be
considered in central tryptophan availability: 1) the ratio between free tryptophan to its albumin-
bound form since only the free fraction crosses the BBB; and 2) the competitive nature of other
large neutral amino acids (LNAA = tyrosine, valine, leucine, isoleucine and phenylalanine) for
entry into the brain via the same transporter.
Several studies have reported lower tryptophan and tryptophan to LNAA ratio
(TRP/LNAA) in MDD patients compared to healthy controls305, 310-312
or subjects with obsessive
33
compulsive disorder (OCD)311
. The ratio appears to be most correlated with depressed mood313
,
retardation313
, and melancholic features314
. While some studies demonstrated reduction by using
total tryptophan, others have found reductions in only free tryptophan. Depression severity has
also been related to lower TRP/LNAA ratio among the depressed population315
, though the
opposite finding has also been documented312
. TRP/LNAA analysis may also successfully
predict treatment response to antidepressants, with a lower baseline TRP/LNAA ratio indicative
of greater improvements in depressive symptoms316-318
. Additionally, one study reported that
good responders exhibited a steady increase in TRP/LNAA ratio as the length of treatment
proceeded for six weeks319
. All in all, there is substantial evidence to support the relationship
between reduced central tryptophan availability and the presence of depression. Indeed,
increased brain tryptophan availability can increase brain 5HT synthesis320
. However, these
findings have yet to be tested among the PSD population.
1.4.5.4 Kynurenine Biosynthesis and Metabolism
Tryptophan is a ubiquitous molecule that is not only essential for protein synthesis but
plays a crucial role in central 5-HT metabolism. Additionally, the amino acid is a precursor for
the kynurenine pathway of metabolism in astrocytes, infiltrating macrophages, microglia and
dendritic cells321, 322
. The end products include kynurenine and several of its metabolites, some
of which are neurotoxic and others which are neuroprotectant. Under this pathway, the indole
ring of tryptophan is first metabolized by the rate limiting enzymes tryptophan 2,3-dioxygenase
(TDO), found highly concentrated in hepatic cells323
, or by indoleamine 2,3-dioxygenase (IDO),
most prominently expressed by cells in the CNS and infiltrating macrophages321, 324
. It can then
be inferred that TDO regulates homeostatic plasma tryptophan concentration in non-
inflammatory conditions while the extra-hepatic IDO predominantly maintains brain tryptophan
levels and is thus, of special interest in to PSD.
34
IDO is up-regulated in response to infection and tissue inflammation by certain
cytokines325-330
and can be induced in vitro by other inflammatory molecules such as LPS331
and
amyloid peptides332
. Once IDO metabolizes tryptophan into kynurenine (KYN) it proceeds
along the pathway until nicotinamide adenosine dinuleotide (NAD) is achieved as the final
product. Several neuroactive intermediates are generated during this process and comprising of:
1) 3-hydroxykynurenine333, 334
and 3-hydroxyanthranilic acid45
, both free-radical generators; 2)
quinolinic acid335
, the excitotoxin and selective N-methyl-D-aspartic acid (NMDA) receptor
agonist; and 3) kynurenic acid (KA)336
, a neuroprotective NMDA antagonist. A detailed
diagram of TRP metabolism and its products are displayed in Figure 1. Since the kynurenine
pathway produces both neurotoxic and neuroprotective metabolites, the ratio between these
products are of great importance when correlating their concentrations to the pathological
consequences of PSD. For example, the KA/KYN ratio has been show to be decreased in
depressed hepatitis C patients undergoing IFN- therapy337
and MDD patients40
.
Several pro-inflammatory cytokines possess the ability to induce IDO activity, including
IFN-338
, IFN-339
, IFN-338, 340
, IL-2341
, IL-6342
, IL-18343
, and TNF-331
. Among this list, IFN-
has consistently been reported to be the most potent regulator of the enzyme. Conversely, the
anti-inflammatory cytokine IL-4, IL-10 and TGf- act to inhibit IDO activity344
. Interestingly,
one study found that IL-10 is able to suppress IFN- induced IDO expression in cells derived
from the hypothalamic-pituitary-adrenal axis (HPA)329
. It cannot be stressed enough that the
balance between pro- and anti-inflammatory cytokines is crucial for homeostatic maintenance of
the human body. Therefore, an excess of pro-versus anti-inflammatory cytokines have the
potential to cause mood dysfunction in several neurological diseases if IDO activity exceeds its
normal boundaries of TRP metabolism.
35
Figure 1. The KYN Pathway: TRP Metabolism and its Products345
36
1.4.5.6 Linking Cytokines and Tryptophan Metabolism to the KYN/TRP ratio
A newer hypothesis to the etiology of depression involving the metabolic pathways of
tryptophan was recently described336
. Increased cytokine levels (such as in the case of stroke)
upregulates IDO activity, an enzyme that is widely distributed in the intestinal tissues, lungs,
placenta and brain291, 343, 346-349
. Because it is in direct competition with TPH for the metabolism
of tryptophan into 5-HT, heightened IDO activity as a result of elevated in cytokine levels may
reduce tryptophan availability for 5-HT production. Consequently, central serotonin
concentrations become sparse, leading to mood complications and behavioural disturbances in
the affected individual. In support of this hypothesis, several studies have shown a significant
decrease in serum TRP concentrations in patients treated with cytokines350-352
. In addition, TRP
levels have been found to be decreased in depressed patients314
while the administration of TRP
produces an antidepressant effect340
. Based on such findings, one is inclined to postulate that
clinical conditions associated with increases in pro-inflammatory cytokines lead to activation of
the IDO enzyme, subsequently resulting in decreased 5-HT synthesis and thus, increased risk of
depression.
We postulate that the mechanism above may have a significant effect on the etiology of
PSD. To reiterate, elevations in post-stroke cytokine levels shunts tryptophan metabolism from
the serotonin pathway into the kynurenine pathway via upregulation of the IDO enzyme. Under
the kynurenine pathway, tryptophan is catabolized into kynurenine; thus reducing the
availability of tryptophan to be converted into the mood regulatory neurotransmitter 5-HT.
Kynurenine is subsequently broken down into several neuroactive intermediates, including three
potent neurotoxins; the hydrogen peroxide generators, 3-hydroxykynurenine and 3-
hydroxyanthranilic acid223
and the NMDA agonist, quinolinic acid (QUIN)335
. Indeed, one
study reported IFN-α immunotherapy treatment in hepatitis C patients significantly increased
37
peripheral blood KYN353
. This was accompanied by marked increases in CSF KYN and QUIN
and correlated with the severity of depressive symptoms.
Several studies have examined the effects of the neurotoxic kynurenine metabolites. 3-
hydroxykynurenine levels are elevated in Huntington’s disease patients354, 355
and has been
shown to induce neuronal cell death in cortical and striatal cell cultures44
. Intracerebral
injection of 3-hydroxyanthranilic acid can decrease choline acetyltransferase activity356
, thus,
decreasing acetylcholine synthesis. QUIN is produced by infiltrating macrophages, microglia
and dendritic cells under inflammatory conditions and acts as a potent agonist of the neuronal
NMDA subtype of glutamate receptors335
. Moreover, several neurodegenerative conditions
have been linked to QUIN-induced apoptosis, including Huntington’s disease357
and HIV-
associated dementia358
. Most recently, it was suggested that KYN preferentially metabolized
along the QUIN pathway at the subcortical level (amygdala/striatum) in mice models359
. This
has its importance since a reduction in 5-HT receptor binding density has been associated with
MDD and is most pronounced in the amygdala. Altogether, it is possible that these metabolites
inflict further damage to the post-stroke brain by destroying essential neuronal pathways
responsible for regulating mood and cognition.
Because measurement of IDO activity has not been thoroughly explored in stroke and is
difficult to measure, the kynurenine to tryptophan ratio (KYN/TRP) has been proposed as a
marker for its activity instead. The KYN/TRP is a reliable marker of IDO activity based on its
reproducibility in past studies examining depression and related neurologic diseases. For
example, enhanced TRP degradation and higher KYN/TRP ratios in Alzheimer's disease,
Parkinson's disease, Huntington's disease, cancer, malaria, and rheumatoid arthritis have been
associated with advanced stages of the diseases and more severe symptoms and fatal outcomes
360-367. Furthermore, it has been reported that the inflammatory marker neopterin, is correlated
38
with both KYN/TRP ratio and kynurenine concentrations and inversely correlated with
tryptophan in cases of immune activation368, 369
. Elevations in the KYN/TRP ratio has not only
been associated with the severity of well-known inflammatory diseases but has also been linked
to cases of depression. Individuals undergoing cytokine therapy for hepatitis C and cancer
developed depressive symptoms that were specifically linked to increases in plasma KYN and
KYN/TRP ratio38, 337
. Similar increases in the KYN/TRP ratio have also been found in women
with post-partum depression39, 370
. Most recently, our group demonstrated that a higher
KYN/TRP ratio was significantly associated with greater depression scores in coronary artery
disease (CAD) patients, a relatable population to the stroke population41
. Taken all together,
these findings support the possibility of a biological contribution to PSD (alongside the current
psychosocial models) through IDO activation, whereby upregulation of IDO activity stimulates
the KYN pathway; thus depleting the amount of TRP available for 5-HT synthesis and
increasing the levels of KYN neurotoxins. A summary of KYN/TRP levels in psychiatric,
neurodegenerative, and inflammatory illnesses is displayed in Table 1.
_____________________________________
1.4.6 Rationale for this Study
Currently, no definite relationship has been established between pro-inflammatory
cytokine levels and PSD in humans. This study attempts to determine the relationship between
such and expects to find a positive causal relationship between plasma pro-inflammatory
cytokine concentrations and depression after stroke. In addition, this study also aims to examine
the counterintuitive reports of elevated anti-inflammatory cytokine levels192, 191
in post-stroke
patients. Instead, it is proposed that anti-inflammatory cytokines are involved in an innate
protective mechanism initiated by the body to counterbalance the depressiogenic effects induced
by pro-inflammatory cytokines. .
39
Finally, the study will examine IDO activity as measured by the KYN/TRP ratio. Since
TRP can only be obtained through diet, and since KYN371
and TRP compete with LNAAs for
entry through the BBB, peripheral measurements of both molecules should reflect the
concentrations circulating within the CSF. As summarized in the literature review, an elevated
KYN/TRP ratio will act as a marker for both possible neurotoxicity and decreased central TRP
availability. The additive affects of the neurotoxic KYN metabolites and reduced 5-HT
synthesis is predicted to play a significant role in the development of PSD. Indeed, increased
KYN/TRP ratio has recently been associated with depressive symptoms of other diseases (e.g.
post-partum depression, CAD); however, this will be the first study to examine its relationship
to PSD.
40
Table 1: Mean KYN/TRP Levels in Various Depression, Neurodegenerative Diseases, and Inflammatory Illnesses
Author Condition KYN/TRP Controls*
KYN/TRP Patients*
p-value Comments
Depression
Kohl39
Post-partum depression
29.4 ± 44.7 (n=86)
35.1 ± 47.5 (n=9)
0.067
KYN/TRP measured 4 days after birth; Edinburgh Postnatal Depression Scale (EPDS) score ≥ 12 positive for depression
Myint40 Major depression disorder
25.0 ± 11.0 (n=58) 17.0 ± 14.0 (n=189) 0.036 DSM-IV used for diagnosis of MDD; fasting blood levels drawn
Neurodegenerative Diseases
Forrest367
Huntington's
disease
33.8 ± 8.3 (n=11)
45.0 ± 7.9 (n=40)
<0.05
KYN/TRP significantly higher in only patients with the severest form of the disease (≥37 CAG triplet expansions on the gene)
Widner365
Alzheimer's
disease
34.1 ± 9.91 (n=20)
46.1 ± 19.8 (n=21)
0.018
AD patients with cognitive score lower than the median (<6; as measured by the Mini Mental State Examination (MMSE)) had significantly higher KYN/TRP (p=0.02) than those with MMSE≥6
Widner366
Parkinson's
disease
36.1 ± 8.2 (n=11)
58.5 ± 34.2 (n=7)
<0.05
Means displayed only compare controls to patients with the severest form of PD. Mean difference between controls and mild-moderate PD patients was non-significant
Inflammatory Illnesses
Bonaccorso38
Hepatitis C virus (Before and after IFN-α therapy)
39.0 ± 14.0
61.0 ± 31.0
<0.001
Patient group with IFN-α therapy, control group without IFN-α therapy. Treatment resulted in significantly higher depression scores at 4-6 months (p=0.03) as measured by the Hamilton Depression Scale (HAM-D)
*Reported as mean ± SD unless otherwise indicated
41
Author Condition KYN/TRP Controls*
KYN/TRP Patients*
p-value Comments
Inflammatory Illnesses
Lögters372
Major trauma (with or without
sepsis)
5.6 ± 0.4 (n=42)
21.9 ± 1.1 (n=17)
<0.01
KYN/TRPx100 reported here. Plasma levels measured 6 days after trauma; patient group is with sepsis, control group without sepsis
Huengsberg373
HIV
34.9 (32.4, 36.9)ɸ (n=72)
50.5 (44.9, 54.5)ɸ (n=82)
<0.01
Most patients were on treatment during the course of the study (53 patients took zidovudine (AZT); 23 took didanosine or zalcitabine)
Pertovaara374
Sjögren's syndrome
Females (n=139): 24.3 (21.0–28.9)
---------------- Males (n=7):
27.0 (23.6–32.1)
Females (n=170): 34.0 (25.1–44.3)
--------------- Males (n=170):
34.5 (29.3–38.7)
<0.0001
-------- 0.014
Patients were not age-matched; mean years control = 45 ± 11 years vs. mean years patients = 60 ± 12 years
Schroecksnadel363
Rheumatoid
arthritis
26.9 ± 8.10 (n=49)
37.9 ± 42.4 (n=22)
N/A
KYN/TRP tended to be higher in men than women, strongly associated with age (p<0.01), and significantly correlated with neopterin (p<0.05)
Swardfager41
CAD
(depressed vs. non-depressed)
38.5 ± 15.7 (n=24)
45.6 ± 20.0 (n=71)
0.055
All patients had CAD; control group represents those who were non-depressed, patient group represents those who were depressed
Wirleitner375
Coronary heart
disease
28.1 ± 5.25 (n=35)
36.3 ± 13.0 (n=35)
<0.01
KYN/TRP positively correlated with neopterin levels. Neopterin concentrations also positively correlated with older age
Zangerle376
HIV
30.7 ± 8.7 (n=40)
79.2 ± 60.3 (n=45)
<0.001
KYN/TRP significantly decreased (p<0.001) in patient group during anti-retroviral therapy (ART)
*Reported as mean ± SD unless otherwise indicated
ɸReported as median (95% confidence intervals) Reported as median (interquartile ranges)
42
Author Condition KYN/TRP Controls*
KYN/TRP Patients*
p-value Comments
Cancer
Schroecksnadel369 Gynecological cancer
35.1(19.2-59.0) (n=19)
41.4 (not reported) (n=20)
N/A
Patients with ovarian cancer had higher KYN/TRP trending on significance compared to controls
Suzuki360
Lung cancer
32.9 ± 9.10 (n=45)
47.1 ± 21.3 (n=123)
<0.0001
Higher KYN/TRP ratio was associated with advanced stages of the disease
Weinlich377
Malignant melanoma
26.9 ± 8.10 (n=49)
46.3 ± 20.7 (n=87)
<0.001
KYN/TRP and neopterin levels were positively correlated. Patients with KYN/TRP above the median (=41.2μmol/mmol) had a significantly decreased survival time compared to those above the median (p=0.0025)
*Reported as mean ± SD unless otherwise indicated Reported as median (interquartile ranges)
43
2. METHODS
2.1 Study Design
This was a cross-sectional observational study examining the role of several
neurochemical factors in the etiology of PSD. Patients meeting the World Health Organization
Multinational Monitoring of Trends and Determinants in Cardiovascular Disease (WHO-
MONICA) Project378
and National Institute of Neurological Disorders and Stroke (WHO-
NINCDS)379
criteria for stroke with CT or MRI evidence of acute ischemic infarcts were invited
to participate into the study. Based on the WHO-NINCDS guidelines, stroke was defined as ―a
sudden, nonconvulsive, focal neurologic deficit persisting for greater than 24 hours‖ and
excluded cases of transient ischemic attacks (TIAs). Five different health and rehabilitation
centres were utilized for recruitment: (1) Sunnybrook Health Sciences Centre, (2) Baycrest
Rehabilitation Centre, (3) St. John’s Rehabilitation Centre, (4) York Central Hospital and (5)
Toronto Rehabilitation Centre. Only patients who had an ischemic stroke within 12 weeks of
the initial assessment who spoke and understood English were considered for enrolment into the
study. If the patient fully agreed to the voluntary terms outlined for the study, a written
informed consent was completed (Appendix A). The individual then remained an active
participant until all consent terms were met unless the patient chose to terminate participation
prematurely.
At baseline interview, patients were considered depressed if they met the Diagnostic and
Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria for depression, either
major or minor. Once screening tools and standardized mood questionnaires were completed, all
participants had blood samples drawn for cytokine, KYN, TRP, and LNAA analyses. In
addition, general cognitive function and stroke severity was examined in all consenting
participants.
44
2.2 Subjects
2.2.1 Inclusion and Exclusion Criteria
In all of the five listed recruitment sites, the study was approved by their respective
Research Ethics Boards (REBs) as shown by the most recent approval letters in Appendixes B
through F. The eligibility criteria for the study were carefully considered before approaching
patients and are described below:
Inclusion Criteria:
Age ≥18 years
Speaks and understands English
Clinical diagnosis of stroke according to WHO-MONICA378
and NINCDS379
criteria
Evidence of acute infarction on either CT or MRI
Maximum time since stroke onset <12 weeks
Written, informed consent
Exclusion Criteria:
Subarachnoid or intracranial hemorrhage
Severe aphasia or dysarthria that would interfere with the assessor’s ability to understand
patient response
Imminently suicidal or, in the opinion of the affiliated clinician, has inadequate family
monitoring for suicidality
Significant acute medical illness, including:
• Infection
Drug overdose
Alcohol abuse
Untreated hypothyroidism
Uncontrolled diabetes
Uncontrolled anemia
Severely disturbed liver,
kidney, or lung function
Significant acute neurologic illness, including:
Decreased Level of
Consciousness (LOC)
Active brain tumor
Parkinson’s disease
Huntington’s disease
Multiple sclerosis
Binswanger’s disease
Hydrocephalus
Subdural hematoma
Progressive supranuclear
paralysis
Severe aphasia
Presence of a premorbid Axis I psychiatric diagnosis, including:
Major depressive disorder
Schizophrenia
Bipolar disorder
Dementia
Concomitant use of psychotropics except for short acting benzodiazepines
47
2.2.2 Demographics and Medical History
Patient demographics including age, body mass index (BMI), level of education,
employment status, living status, marital status, history of depression, and number of vascular
risk factors (including hypertension, cigarette smoking, obesity, hyperlipidemia, and diabetes)
were either collected through patient interviews or medical histories stored on hospital
electronic databases. Current or past medical illnesses were determined through a review of
patient history, physical examinations, and/or routine laboratory test results by a licensed
practitioner as indicated in the patient charts. Finally, the time since stroke onset and
concomitant medications were recorded based on information gathered by the attending
physician upon admission.
_____________________________________
2.3 Clinical Assessments
2.3.1 Depression Scales
Centre of Epidemiological Studies Depression Scale (CES-D)
The Centre for Epidemiological Studies Depression Scale (CES-D)380
is a 20-item self-
rated questionnaire that was originally designed for use in community surveys as a means of
determining one’s depression quotient. Today, it is clinically employed as a screening tool for
depression and examines various aspects of the respondent’s perceived mood, anxiety and
physical functioning within the past seven days. However, because certain somatic symptoms
listed on the CES-D were originally intended to elicit symptoms of depression in otherwise
healthy individuals, the appropriateness of the scale requires validation among the stroke
population. Indeed, the scale has previously been validated in post-stroke patients using a
structured psychiatric interview as an established criterion. Here, a cut-off score of 16 was
found to be highly predictive of clinical depression, with a specificity of 90%, a sensitivity of
48
86%, and a positive predictive value of 80%381
. Thus, a score of 16 or greater was used as an
indicator of depressive symptoms in this study but may not have necessarily reflected definite
clinical depression. The CES-D has also been shown to exhibit high inter-observer reliability
and concurrent construct validity with several depression measures in the geriatric stroke
population (e.g. Geriatric Depression Scale (GSD), Zung Scale), as well as high discriminant
validity with measures of other factors including social functioning, cognition, and
disability382, 383
. As such, it has consistently been used as a screening instrument for
depression among the post-stroke population, including the NINCDS Stroke Data Bank384
and
other various PSD studies22, 385-387
.
Structured Clinical Interview for the DSM-IV: Depression Module (SCID)
In cases where patients scored 16 or greater on the CES-D, the attending psychiatrist
was called to further assess their depressive symptoms to ensure that they were not evoked by
the physical impairments suffered from stroke. The psychiatrist then confirmed a clinical
diagnosis of depression according to the DSM-IV criteria for a Major Depressive Episode
(MDE)388
, using the depression module of the Structured Clinical Interview for the DSM-IV
(SCID). The use of the SCID has previously been validated among the PSD population98, 99
.
Patients were considered to be suffering from major depression if at least five of the following
nine modules were met in the past two weeks: depressed mood, anhedonia, changes in weight
or appetite, insomnia or hypersomnia, psychomotor agitation or retardation, fatigue or loss of
energy, feelings of worthlessness or guilt, difficulties in concentration and decision-making, or
recurrent thoughts of death; with at least depressed mood or anhedonia present among their
symptoms. Patients were considered to be suffering from minor depression if they met three of
the nine modules, with at least depressed mood or anhedonia present among their symptoms.
Those who scored 16 or higher on the CES-D but failed to meet a formal diagnosis of
49
depression were placed in a "depressive symptoms only‖ group. However, the clinically
depressed group and the depressive symptoms only group were eventually combined for
analytical purposes due to the limitations of a small sample size. Thus, the patient population
used for analyses were not necessarily diagnosed with clinical depression. The CES-D has
consistently been used as a screening instrument for depression among the post-stroke
population, including the NINCDS Stroke Data Bank384
and other various PSD studies22, 385-
387. Even a briefer version of the CES-D that only included half of the original questions was
found to be a positive predictor of depression when compared to the DSM-IV criteria, with a
sensitivity of 97%, a specificity of 84%, and a positive predictive value of 85%
389.
2.3.2 Cognition Scales
Mini Mental State Examination (MMSE)
In addition to depression measurements, all patients were evaluated for general cognitive
function post-stroke. The Mini-Mental State Examination (MMSE)390
is the most is a popular
screening tool for this purpose and was administered to all recruited participants. It consists of
a brief, 30-point questionnaire for cognitive ability and evaluates various mental functions
including orientation, registration, short-term memory, attention, calculation, and visuo-spatial
skills. A patient who scored less than 24 was considered to be cognitively impaired and a
patient who scored 24 or more was considered non-cognitively impaired. Previously, the
MMSE has detected differences in concentration and memory function between depressed and
non-depressed stroke patients391
, as well as worse global cognitive function in PSD patients
with significant executive dysfunction392
. The MMSE has also been used to test the efficacy
of different antidepressants on reducing cognitive impairment in the PSD population128-130
.
50
2.3.3 Stroke Severity and Functional Disability
National Institutes of Health Stroke Scale (NIHSS)
Since the study was interested in examining the biological correlates related to PSD, it
was important to evaluate stroke severity and functional disability as possible confounding
factors to the results. To fulfill this task, The National Institute of Health Stroke Scale
(NIHSS)393
was administered to all stroke patients by the treating medical team or by a NIHSS
certified research associate. The NIHSS is a systematic assessment tool designed to
quantitatively evaluate the neurological deficits and degree of recovery of stroke patients. The
scale examines the following outcomes: level of consciousness, extraocular movements, visual
field defects, facial muscle function, extremity strength, sensory function, coordination
(ataxia), language (aphasia), speech (dysarthria), and hemi-inattention (neglect)394
. In this
study, the level of stroke severity was scored as follows: 0 = no stroke; 1-4 = minor stroke; 5-
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APPENDIX A: Post-stroke Depression Patient Consent Form
Stroke and Depression: The Role of Cytokine - Serotonin Interactions
Patient Information and Consent
Investigators: Dr. K.L. Lanctôt Sunnybrook Health Sciences Centre
Dr. N. Herrmann Sunnybrook Health Sciences Centre
Dr. S.E. Black Sunnybrook Health Sciences Centre
Dr. D. Gladstone Sunnybrook Health Sciences Centre
Dr. J. Ween Baycrest
Dr. W. Goldstein York Central Hospital
Dr. M. Waldman St. John’s Rehab
1. Information for subject:
You are being asked to participate in a study conducted at Sunnybrook Health Sciences Centre
under the supervision of the above investigators. Participation is voluntary and will involve
the following:
2. Description and purpose of the trial:
The purpose of this study is to evaluate determinants of the development of depressive and
cognitive (memory and thinking) symptoms after a stroke. Both symptoms are common post-
stroke, and may be related to levels of serotonin (an important brain chemical involved in
regulating mood and thinking). We are interested in assessing the relationship between
different types of cytokines (naturally produced inflammatory chemicals) and serotonin, and
the role they play in any depressive or cognitive symptoms that you may or may not have. In
addition, we are also interested in the impact of cytokines and other chemicals related to
Sunnybrook Health Sciences Centre
2075 Bayview Ave., Suite FG-05 Toronto, ON M4N 3M5
University of Toronto Faculty of Medicine 1 King’s College Circle, Toronto, ON M5S 1A8
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serotonin production on the size of the hippocampus (an important brain structure involved in
regulating mood and thinking).
3. Study Details:
If you agree to participate in this study, you will be asked to undergo an assessment with a
trained research assistant. The process of assessment will involve the following:
a) Assessments:
The study coordinator will first meet with you and review your medical chart in order to
assess your eligibility for the study. If you are eligible to participate, the study coordinator
will then interview you using standard questionnaires that assess your mood, cognition and
physical functioning. Certain details (e.g. medical history, demographic characteristics,
current medications and details of your stroke) will be copied from your medical chart.
Any CT and MRI scans conducted clinically during your hospital stay will also be
analyzed to determine the characteristics of your stroke. Lastly, if you report experiencing
significant depressive symptoms, the study physician will meet with you for further
assessment and treatment, if necessary. This study will not interfere with your selection of
treatment choice. However, information will be collected regarding your response to
treatment through the questionnaires described above.
b) Blood Draw:
A sample of blood will be drawn in order to measure levels of certain signaling molecules
related to the serotonin and inflammatory systems (called cytokines, kynurenines and
tryptophan). A total of 31 mL (2 tablespoons) of blood will be drawn.
c) Cheek Swab:
A sample of skin cells from the inside of your cheek will be taken using a sterile cotton-
tipped swab. The DNA inside these cells will be used for us to determine which forms of
certain genes (―polymorphisms‖) you have that are related to the cytokine, kynurenine and
serotonin pathways. Your sample will be identified only by a unique number and will be
destroyed once the genetic tests are complete.
4. Benefits:
You will not benefit directly from participation in this study.
5. Risks:
When your blood is drawn, there may be some discomfort and/or bruising, however these are
expected to be very mild. The mouth swab is simple and painless.
6. Alternative Treatments:
You are eligible to receive treatment for your stroke and any depressive symptoms you may
have even if you choose not to participate in this study. Participation in this study will not
affect your treatment in any way.
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7. Costs:
You will be given a $20.00 honorarium each time you visit Sunnybrook for the purposes of
this study. If you participate in the MRI substudy, you will be given a $40.00 honorarium for
your third visit. You will incur no costs as a result of participation in this study.
8. Participation/Termination:
Your participation in this study is voluntary. Thus, if you do not wish to take part in this study
or wish to withdraw at any time after commencing the study, your care will not be affected in
any way.
You may be withdrawn from the study, at any point, if the investigator of this study considers
it to be in your best interest. You may withdraw your consent at any point during the study.
9. Confidentiality:
Your identity in this study will be treated as confidential. Certain Sunnybrook research staff,
the Sunnybrook Research Ethics Board, and other agencies as required by law, may need to
review your medical chart. We will have access to your medical chart for information on:
blood pressure, heart rate, prescribed drugs, depressive symptoms and health status for 1 year.
On all data collected for this study, you will be identified only by a unique number. If you
disclose the intention to harm yourself or others, this information may not be kept confidential,
as required by law.
10. Contacts:
If you or your substitute decision maker have any questions about this study or for more
information, you may contact the Study Co-ordinators: Philip Francis or Amy Wong (416-
480-6100 x3185), Dr. Krista L. Lanctôt (416-480-6100 x2241) or Dr. Nathan Herrmann (416-
480-6100 x6133).
If you have any questions about your rights as a research subject, you may contact Dr. Philip
Hébert, the Chair of the Sunnybrook Research Ethics Board, at 416-480-4276.
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Stroke and Depression Study
Consent to Participate in this Study:
I, (patient’s name) _________________ _______ have read the above information and
fully understand the nature and the purpose of the study in which I have been asked to take
part. The explanation I have been given has mentioned both the possible risks and benefits of
the study. I understand that I will be free to withdraw from the study at any time without
affecting my subsequent treatment by my doctor in any way. I voluntarily consent to