1. Neural

2. Key gaps Is this an unique syndrome? Is it more than one syndrome?
Epidemiology of this syndrome.
Is there one or few underlying biological causes or interactions?
Unexplained pathology.
Are comorbid diseases the cause or effect modifiers.
Need hypothetical models to address the causation of the co-occurrence of these three symptoms.
Is this syndrome due to a lack of adaptation or decreased reserve?
Is vascular disease or risk factors an initiator?
Directionality of triad and underlying risks
Do the biological effects of aging result in this triad. Eg. Accumulation of mitochondrial dysfunction, insulin resistance, inflammation.

3. Barriers and opportunities
Valid biomarkers: Are all interleukins equal?
What is the prevalence of this aggregation? Use national databases or large cohort studies.
Need to be inclusive. People with this syndrome get excluded from cohort studies or clinical trials.
Relationship to outcomes : function, falls, death.
Intervene on known causes and study effect on syndrome. Effect of treating one symptom on the other two.
What are protective mechanisms?

4. Methodological work Operational definitions of syndrome.
Clustering: is this an useful approach?
Poor instruments for measuring depression. Extend ‘feeling’ to more than depression: anxiety, apathy…
Contribution of medications, comorbid illnesses.
Inclusion of subjects with this syndrome in trials.
Biomarkers (imaging, neurotransmitters..)
Mechanisms of cerebral vascular pathology – leukoaraiosis - and how does this cause the syndrome.
Animal models.
Gender and ethnic differences
Early life exposure.
Cognitive: minimal data set.
Metabolic or genetic profiles of people with and without syndrome.
Lifespan studies
Study this syndrome also in isolated/ homogenous populations.

5. Research priorities
Define the syndrome and its epidemiology. Validate it in existing populations.
Identify and develop standard set of measures to apply to population studies or to add on to clinical trials.
Study candidate initiators of this syndrome such as genes, vascular risk, insulin resistance, inflammation, and mitochondrial dysfunction.