Transcript Managing Dementia - Interface with Primary Care

Does the association with diabetes
say more about schizophrenia?
- the GLUT theory
prasanna de silva
sugar – some history
• initially from sugar cane (150 factories, 1750)
• new technology - sugar from beet (1799)
causes ‘sugar mountain’
• tax on sugar removed (Gladstone, 1875)
• widespread reporting of adolescent decline
‘dementia praecox’ (Kreapelin, 1894)
dementia praecox
(later schizophrenia)
• cognitive deficits seen as the core feature
• hallucinations, delusions, thought disorder
• self neglect due to inattention and apathy
• evidence of continuing deterioration and
severe disability in ~20% (‘cure’ in 15 – 20%)
• needed an asylum network
epidemiology
• perinatal deficits
(low birth weight, obstetric complications)
• teachers pick up ‘odd’ traits aged 7 – 11
• young (late adolescent / early adult) onset
• predominantly urban / inner city
• family history of psychosis, OCD and diabetes
• acute episodes associated with life events
findings in untreated patients
• undirected / purposeless speech and
movements (stereotypies)
• apathy, inattention, poor planning can be
seen also at an early stage
• higher rates (5%) of hyperglycaemia in
drug naive subjects (1914, 2009)
• low dose Insulin / diet effective (1957)
as are neuroleptics (1954 onwards)
• reducing stress beneficial (1977)
1
2
3
structural brain findings
• reduced cortical volume
with ventricular enlargement ~ 40%
• decreased size and poor connectivity of
neurones in pre frontal cortex and hippocampus
( with reduced synaptic / dendritic markers)
• reduced cortical (mainly frontal) receptor load
involving Dopamine1, Glutamate (non NMDA)
and 5HT2A
• progressive gray matter loss
on serial scanning of individuals
• in childhood schizophrenia x4 loss of frontal
gray matter compared to control adolescents.
functional imaging
• ‘hypofrontality’- with reduced DA input
• ‘hot spots’ of increased blood flow and
metabolism in Broca’s area (motor speech
producer) – sp. when hallucinating
• reduced activity in association areas
• increased DA supply to striatum
and mesolimbic areas compared to
frontal / pre frontal areas
• reduced frontal Glutamate supply to striatum
(?causing increased DA input)
genetic findings
• vast majority of cases unexplained
• however, 60% ‘familial’
(Schizophrenia, BPAD, OCD)
• no clear explanation for higher 1st degree
relatives with DM (both type 1 and 2)
• recent interest in ‘single nucleotide
polymorphisms’ (SNIPs)
• matching phenotypic features to genome
(including common genetic loci between
psychosis and diabetes @ 1q 21-25)
blue sky thinking
pathogenesis of
schizophrenia
• prior to imaging findings, pharmacology
based (Dopamine and Glutamate blockers)
• post mortem brain findings led to
‘neuro developmental’ theories
(abnormal migration and maturation)
• imaging findings have modified above
– how do you explain ‘hypofrontality’ and
progressive cortical thinning?
• developmental versus degenerative debate
• or, both ( e.g. the GLUT theory)
what we know about GLUT
• Glucose transporter proteins, sited
across membranes (500 amino acids, 7
sub types, funnel shaped)
- think of a coin collecting funnel
• GLUT 4 (vast majority of GLUTs) present
peripherally sp. muscle and fat
– sensitive to Insulin and IGF
• GLUT 1 and 3, mainly in brain
(also in placenta) – Insulin insensitive
more about GLUT!
• GLUT 3 neurones (mainly frontal / pre
frontal brain), GLUT 1 endothelial cells
• GLUT 1 and 3 crucial to brain
–fixed availability, Glucose being the
only nutritional substrate
• GLUT 2 glucose sensors to detect
hypoglycaemia present in
hypothalamus, portal vain, kidneys
• in starvation, increased GLUT 1 and 3
production, and reduced GLUT 4
– brain needs to look for food (planning)
the GLUT hypothesis
(McDermott and de Silva, 2005)
• schizophrenia due to deficits in GLUT 1
and 3 (numbers or structural deficits)
• malnutrition of neurones
(neuronal maturational problems
and gradual loss of gray matter)
• particularly frontal lobe (contains most
GLUT 3) and thalamus (GLUT 1)
• excess sugar intake may further
down regulate GLUT 1 and 3
(GLUT 2 working in reverse)
evidence
Zhao et al., Molecular Psychiatry, 2009
• GLUT 3 deficient (heterozygous) mice
show perturbed social behaviour with
reduced vocalisations (and evidence of
stereotypies)
• abnormal spatial learning and working
memory
• abnormal cognitive flexibility
• GLUT 1 deficient mice show much more
neurological malformations and seizures
implications of neuronal
glucose malnutrition
• frontal lobe under activity causing ‘negative
symptoms’ (apathy, poor planning / executive
function) Also liable to get disinhibition
• Dopamine diverted to anterior cingulate,
mesolimbic and basal ganglia areas producing
‘positive symptoms’ (delusions / hallucinations)
and movement disorders (stereotypies)
• hyperactivity of Broca’s area (hallucinations)
could also be a ‘distress’ phenomena
• excess / inappropriate use of memory stores and
jumping to conclusions other distress signs
(thought disorder and delusions)
also explains….
• perinatal findings
(placenta only uses GLUT 1 and 3)
• adolescent onset
(increased demand for Glucose
followed by pruning)
• higher hyperglycaemia rates in drug
free subjects (brain uses 20%-50%
glucose, backlog producing insulin
resistance)
• higher DM in 1st* relatives
(GLUT gene deletions)
on pruning of the brain
• think of gardening (flowering shrubs)
• mid winter, major prune (Feb)
• then, pruning newly grown shoots (May)
• finally, pruning first flowering buds (June)
• think of the difficulties after bitter winter
• liable to prune excessively causing
reduced flowering, or, not prune at all.
GLUT deficit based neuronal pruning
– stages 1 to 3
• Stage 1 (perinatal), GLUT 1 and 3 deficiency in
placenta, causes low birth weight, prematurity
and low fat stores in childhood (at risk children)
• Stage 2 (adolescence), GLUT 1 and 3 deficits
with excessive pruning of gray matter,
causes cognitive deficits, social anxiety and
persecutory ideation, as seen in school children
prior to schizophrenia (the ‘prodrome’)
• Stage 3 (early adulthood) GLUT deficits,
excessive frontal pruning and Dopamine
diversion to meso limbic / striatal areas,
causes acute psychosis with
hallucinations and delusions
how do anti psychotics
really work?
Relevance of anti psychotics
(Dwyer and Donohoe, 2003)
• all effective anti psychotics block GLUT
• strongest GLUT blocker is Clozepine
• followed by Olanzepine, Quetiapine,
Risperidone
• Haloperidol weakest GLUT blocker
• most atypicals competitive (reversible)
blockers, Risperidone not.
consequences of GLUT blockade
in brain
• essentially, acts like a chemical pruner
(equivalent to a pair of shears)
• useful if there has been limited or
no pruning
• reduces metabolic activity in hot spots
(Broca’s area, reducing hallucinations;
hippocampus, reducing thought disorder)
• If already undergoing heavy pruning will
make functioning worse (negative
symptoms, psychomotor slowing)
consequences of GLUT blockade
peripherally
• can cause / worsen hyperglycaemia
(rat and human studies)
• excess appetite (GLUT 2 blockade
will increase GLUT 4)
• Hyperlipidaemia (Glucose converted to
lipids including Triglycerides)
• raised Leptin secondarily, then ‘Leptin
resistance’ (fat stores saturated)
• eventually, metabolic syndrome
on anti psychotic selection
• is it better to use moderate dose long
term treatment with additional means to
deal with acute exacerbations?
(BZ, CBT and supportive counselling)
• or, selection on toxicity, tolerability and
convenience? (Marie Stopes modal)
• how do we operationally define the
threshold of relevant patient / carer
information?
• how do we approach treatment of first
episode illness? (information, depots)
clinical relevance
of all this
• might need to learn from oncologists and
their treatment models used in managing
cancer
• need to clearly explain risks of the disease,
risks / benefits of treatment and associated
prognostic estimates to patients / carers
• need to be aware of potential problems with
high sugar intake and metabolic syndrome,
and consider preventative strategies
final thoughts
• we need to think ‘outside the box’ on
schizophrenia
• theories such as GLUT offers a solution to the
neuro developmental vs. neuro degenerative
split , which can hinder further progress
• we need to look at the neuronal pruning
process in more detail, including gene drivers
• we might need to think a bit more carefully
about nutritional and metabolic problems in
managing schizophrenia
selected references
• the history of sugarhttp://www.britishsugar.co.uk/isolated
storage/94175874-67b5-4c33-gf383802...25/08/2005
• Impaired glucose tolerance in drug naïve
schizophrenics - Kirkpatric,B et al.,
Schizophrenia Research 2009; 107 (2-3): 122127
• Anti psychotics and glucose intolerance –
Smith et al., (meta analysis) BJPsych 2008,
192, 406-417
selected references
• Progressive grey matter loss (MRI over 5 years)- Di Lisi,
L.E., 2008 Schizophrenia Bulletin 34, 312-321
• Childhood schizophrenia – Rapoport, J.L., Giedd, J.N. et
al, 1999 Progressive cortical change in childhood
schizophrenia Archives of General Psychiatry. 56(7),
649-654
• GLUT hypothesis – McDermott, E., de Silva, P., 2005,
Medical Hypothesis 65, 1076 – 1081
• GLUT 3 deficient mice – Zhao, Y et al., 2009,Molecular
Psychiatry, 1-14
• GLUT blockade by atypicals – Dwyer, D.S., Donohoe, D.
2003 Pharmacology, Biochemistry and Behaviour 75,
255-260
thank you