Week 9 RF-Early life adversity exposure and genetic risk for depression/dementia

Question 1

What is the link between Early life adversity and subsequent psychopathology? (Teicher et al., 2022)

Answer 1

■ Exposure to early life adversity alters presentation of psychopathology profiles
– earlier onset of psychiatric disorders
– greater symptom severity
– greater resistance to treatment
– more comorbidities
– clearer profiles of adaptation/compensation (brain and cognitive changes to adapt to the adversity but this can be detrimental in the long-term)

Question 2

What is the Stress Response Model? (Agorastos & Chrousos, 2022)

Answer 2

-The stressor and adaptive response play a role in the homeodynamic balance

Stressor-related:
-Timing
-Duration (longer stressors have a more negative effect)
-Type (physical, social etc.,)
-Magnitude (the intensity of the stressor)
-Novelty (1st time experiencing the stressor)

Experiencer-related:
-Genetic
-Sex
-Age
-Coping skills
-Genetics
-Epigenetics

-People tend to be in Hyperstasis (a good state) BUT a stressful experience can shift the balance and fall into Cacostasis (a bad state)

-It is good for people to dip intially (i.e., struggle emotionally and physically) rather than being resistant to this change in environment

-Some bounce back but others stay in the Cacostasis state

Question 3

How can Context shape the Impact of Stress Exposure? (Hodes & Epperson, 2019)

Answer 3

■ Timing
– Stress exposure in childhood/adolescence is linked to quicker cognitive ageing and dementia risk in older adulthood

■ Peripubertal exposure to social stress was linked to stronger fear responses in anxiety arousing environments, while exposure in late adolescence amplified exploration (receptivity) of novel environments (rodents, Schnider et al., 2022)

■ Life stage (same/different for exposure/effect)
– Immediate vs Distant effects

■ Distant effects: particularly relevant since the clinical onset of most neuropsychiatric disorders is preceded by symptom-silent stages lasting years/decades

■ The biological/behavioural phenotype examined

Question 4

What are the Consequences of Stress Exposure across the Life Course? prenatal stage (Hodes & Epperson, 2019)

Answer 4

Emerging illnesses:
* ASD
* Attention Deficit Disorder

Immediate:
-Male:
* risk of still birth
Female: more resilient than male babies
* risk of premature birth
* low fetal energy & growth

Distant:
Male: Social deficits

Question 5

What are the Consequences of Stress Exposure across the Life Course? From childhood (Hodes & Epperson, 2019)

Answer 5

Emerging illness:
* Attention Deficit Disorder
* ASD

Immediate:
Both sexes: Higher cortisol levels

Distant:
Males:
* Impulsivity
* Anhedonia (the inability to feel pleasure)
* Social deficits
Females:
* Depression/anxiety

Question 6

What are the Consequences of Stress Exposure across the Life Course? From adulthood (Hodes & Epperson, 2019)

Answer 6

Emerging Illnesses:
* Anxiety Disorders
* Schizophrenia
* Post-traumatic Stress Disorder
* Depression

Immediate:
Male:
* Intrusive thoughts/trauma re-
experience
Female:
* Internalisation of trauma
* Generalisation of fear cues

Question 7

What are the Consequences of Stress Exposure across the Life Course? From old age (Hodes & Epperson, 2019)

Answer 7

Emerging Illnesses:
* Dementia

Immediate:
Males:
*Stronger depression-dementia link
Females:
* Sleep problems
* Stronger stress reactivity (cortisol, memory deficits) also relates to menopause

Question 8

What is the Causal sequence between Early Life Adversity, Depression and Later Dementia Risk? HYPOTHESIS 1
EARLY LIFE MOOD PATHOLOGY CONTRIBUTES TO DEMENTIA RISK
IN OLDER ADULTHOOD

Answer 8

-Brain changes from depression sets in motion a trajectory of brain ageing conducive to dementia

Depression and Alzheimer’s Disease (AD) (Dafsari & Jessen, 2020; Hodes & Epperson, 2019):
* Positive relationship between length of depression diagnosis and AD risk
* Genetic evidence that depression may be a cause of subsequent AD (Harerimana et al., 2022)
* Depression may be a risk factor for AD among men only

Question 9

What is the Causal sequence between Early Life Adversity, Depression and Later Dementia Risk? HYPOTHESIS 2
SHARED MECHANISMS UNDERPIN EARLY LIFE MOOD PATHOLOGY AND DEMENTIA RISK IN OLDER ADULTHOOD

Answer 9

Depression and Alzheimer’s Disease (AD) (Dafsari & Jessen, 2020; Hodes & Epperson, 2019):
* Depressive symptoms in older adulthood, but not midlife predicted AD onset.
* The correlation between depression and AD is thus more likely to reflect a shared cause or the fact that depression is an early sign of AD.

Question 10

What is the 3rd hypothesis for the link between depression and AD? (Dafsari & Jessen, 2020)

Answer 10

• Depression may accelerate cognitive decline in AD
• Older adults with mild cognitive impairment and depression are at particularly high risk for dementia

Question 11

Depression-Related Mechanisms and Alzheimer’s Disease (AD) Pathologies: How do anti-depressant treatments help? (Dafsari & Jessen, 2020)

Answer 11

• Reduce risk of later AD
• Ameliorate (makes better) AD neuropathology
• Anti-inflammatory effects

Question 12

Depression-Related Mechanisms and Alzheimer’s Disease (AD) Pathologies: What is the impact of low responsiveness to glucocorticoids? (Dafsari & Jessen, 2020)

Answer 12

• Glucocorticoid-induced neurotoxicity, observed particularly in the hippocampus
  (reduced neurogenesis and neuroplasticity), leading to cognitive decline

Question 13

Depression-Related Mechanisms and Alzheimer’s Disease (AD) Pathologies: What is the impact of Chronic Inflammation and NTs? (Dafsari & Jessen, 2020)

Answer 13

• Chronic inflammation reduces serotonin and dopamine synthesis and synaptic
  availability
• Untreated depression is linked to chronic microglial activation, which, in turn,
  increases risk for dementias, including AD

Question 14

Depression-Related Mechanisms and Alzheimer’s Disease (AD) Pathologies: What is the impact of Chronic Inflammation and Nerve Growth Factors? (Dafsari & Jessen, 2020)

Answer 14

• Chronic inflammation has a negative effect on growth factors, such as the brain-derived neurotrophic factor (BDNF)
• Reduced neurogenesis and synaptic plasticity

Question 15

Early Life Adversity, Depression and Later Dementia Risk: What is The Role of HPA Axis Dysregulation?

Answer 15

-It leads to an imbalance of serotonergic and dopaminergic systems

-Leads to the impaired creation of new brain cells

-Sets the stage for neurodegeneration leading to AD

Question 16

Adverse Life Experiences and Epigenetic Risk Factors: What is the Relevance to Depression and Dementia Vulnerability?

Answer 16

-Measured the extent to which exposure to adversity during childhood adolescence, may be linked to epigenetic changes=may enhance the risk for mood pathology

-It also sets the stage for suboptimal brain ageing trajectories which enhances the risk of dementia in later life.

Question 17

Adverse Life Experiences and Epigenetic Risk Factors: How do Neurodevelopmental Alterations mediate the link between family conflict and psychopathology in late childhood/adolescence? SYSTEMS level (Petrican, Miles, Rudd, Wasikowska, Graham, & Lawrence, 2021)

Answer 17

-Adolescent Brain and Cognitive Development (ABCD) study (N = 1514)

-Tested regarding cognition and also looked at twins/non-twins and parents (wanted to look at the relationship between exposure to different types of adversities=changes in gene patterns=neurodegeneration)

Findings:
-Only family conflict was predictive of patterns of brain development at the levels of brain systems
-Evidence of greater network differentiation (i.e., faster maturation involved in cognitive control) BUT delayed maturation for sensory/perceptual systems=greater risk of depression/anxiety
-Children experiencing adversity tend to adapt and show faster brain development in areas involving cognitive control and coping with stress

Question 18

Adverse Life Experiences and Epigenetic Risk Factors: How do Neurodevelopmental Alterations mediate the link between family conflict and psychopathology in late childhood/adolescence? MOLECULAR level (Petrican, Miles, Rudd, Wasikowska, Graham, & Lawrence, 2021)

Answer 18

-The link between family conflict and psychopathology (i.e., depression and anxiety) was linked to altered gene expressions relevant to myelination and axonal structure (in the immediate now)

-Also associated with a different pattern of cellular metabolism (from the distant past) e.g., mitochondrial dysfunction

Question 19

How is the link between Adverse Life Experiences and Genetic Risk Factors
Relevant to Cognitive Functioning? (Paine, A. L., Perra, O., Anthony, R., & Shelton, K. H., 2021).

Answer 19

• Based on genetic data from saliva/blood
  samples
• Adoptees (N = 117) vs non-adoptees (N = 4382); adoptees tend to be exposed to significantly more adversity in early life (Paine et al., 2021; Turney & Wildeman, 2017)
• Fluid cognition because of its relevance to both depression and AD (Yan & Rein, 2022)

Question 20

Adverse Life Experiences and Genetic Risk Factors: What is the effect of Superior Fluid Cognition? (Paine, A. L., Perra, O., Anthony, R., & Shelton, K. H., 2021).

Answer 20

• Effects were significantly stronger
  among adoptees relative to non-adoptees.
• AD risk: Faster cortical thinning = faster structural neurodevelopment= better fluid cognition
• Depression risk: Higher Inhibitory control activity= greater fluid cognition

Question 21

What is the link of Bronfenbrenner’s Ecological Systems Theory to Early Life Adversity, Depression, Dementia and HPA Axis Dysregulation? (Lopez et al., 2021)

Answer 21

Important factors are:
1. Nutrition
2. Social relationships

Question 22

What is the link between Nutrition and the HPA Axis? (Shoubridge et al., 2022)

Answer 22

• The gut microbiome can regulate HPA axis activity following social stress (and nutrition is linked to this!)
• Specific gut bacteria can restrain HPA axis activation and modulate social responses to stress (Wu et al., 2021)

Question 23

What was the link found between Nutrition and Gut Microbiota in Rodents? (Nagpal & Cryan, 2021)

Answer 23

• Prenatal stress and maternal separation are linked to microbiota changes leading to
  exaggerated HPA axis responses
• Microbiota changes may play a
  causal role in depressive symptoms
• Microbiota changes (e.g., via
  antibiotic treatment) are linked to AD-predictive neuropathological alterations

Question 24

How can Social Relationships act as Buffers? (Stenton, Slatcher, & Reis, 2019)

Answer 24

• Maternal responsiveness in childhood shapes HPA axis responses to stressors (Hackman et al., 2013).
• Following a socially stressful task, supportive notes from a parent help normalise HPA axis responses in childhood, but not adolescence (Hostinar, Johnson, & Gunnar, 2015).
• Maternal warmth moderates the link between financial stress and HPA axis activity in adolescence (Jiang et al., 2021).

Question 25

Psychological resilience in adolescence: What is the link between genetic risk, lifestyle buffers and environmental adversity? (Petrican, Fornito, & Boyland, 2024)

Answer 25

-Adolescent Brain and Cognitive Development (ABCD) study (N = 834: non-siblings)

-Wanted to look at the interaction between protective factors, social factors, lifestyle factors and risk factors and the effect they have on brain development with the addition of adversity in how it would interact with the above

-Looked at the deviance from the typical working-memory relevant functional neurodevelopment

-Risk is from poor availability of lifestyle buffers and high genetic risk

-The relevance of the protective + risk related brain factors on psychopathology depended on adversity exposure

-High adversity exposure the protective brain profile linked to low genetic risk, high environmental support was linked to lower psychopathology

Question 26

How is Neuroinflammation linked to Psychological resilience in Adolescence? (Petrican, Fornito, & Boyland, 2024)

Answer 26

-Risk-related profile may be related to risks of neuroinflammation

Question 27

What are the Overall Conclusions of this Lecture?

Answer 27

• The neurocognitive consequences of adverse life events vary as a function of
  genetic sex and the life stage in which the events are experienced/consequences
  are assessed
• Dysregulation of HPA axis activity constitutes a candidate mechanism
  underpinning the inter-relationships among early life adversity exposure,
  depression in adolescence/young
  adulthood and dementia risk in older age
• In late childhood/adolescence, genetic risk for depression and/or dementia
  interacts with early life adversity to predict deviations in brain development and
  expression of genes relevant to lifespan brain development/ageing
• Nutrition (via the gut microbiome community structure) and social relationships (e.g., responsiveness) are two robust moderators of early life adversity effects on neurodevelopment, affective functioning and dementia risk.