Dr Margaret PiggottDr Margaret Piggott
Neurochemistry of the DementiasNeurochemistry of the Dementias
and transmitter-based therapiesand transmitter-based therapies
Examining neurotransmitter mechanisms is important because
• Different dementias have different neurochemical profiles with implications for treatment
• Neurochemical changes underlie symptoms
• Antipsychotic, anxiolytic, pro-cognitive and antidepressant drugs all
Modulate Transmitter Systems
You will have varying familiarity with neuroscience
Apologies for fact-laden stuff
How much you know already?
Covering things that may be in MCQ
NEUROCHEMISTRY OF THE DEMENTIASNEUROCHEMISTRY OF THE DEMENTIAStransmitter therapiestransmitter therapies
THE OXFORD TEXTBOOK OF OLD AGE PSYCHIATRY(Psychiatry in the Elderly 4th edition)
Chapter 6Neurochemical pathology of neurodegenerative disorders of old age Piggott MA and Court JA (2008) (in revision)
Parkinson’s Disease Dementia, edited by Professor Murat Emre Chapter 13 - Neurochemistry of Parkinson’s disease dementia
Piggott MA and Perry EK (2010)
Early-Onset Dementia, edited by Professor John R Hodges Chapter 9 – Neurochemical pathology in degenerative dementias
Elaine Perry, Rose Goodchild and Margaret Piggott (2001)
Neurotransmitter types
Amino acids glutamate, aspartate, D-serine, glycine, amino butyric acid (GABA),
Biogenic amines dopamine, serotonin, norepinephrine, epinephrine, histamine
Others acetylcholine, adenosine, anandamide, nitric oxide
Peptides over 50 peptide neurotransmitters, somatostatin, substance P, endorphin
Neurotransmitters activate one or more types of receptors. The effect on the postsynaptic cell depends on the properties of those receptors
Cholinergic cell nuclei
• The nucleus basalis of Meynert projects to neocortex
• Cholinergic cells in the medial septum/diagonal band project to hippocampus and entorhinal cortex
• Cholinergic interneurons intrinsic to the striatum
• Brainstem pedunculopontine (PPN) neurons project to thalamus
Cholinergic systemCholinergic system
Cholinergic nuclei numbers - http://www.acnp.org/g4/gn401000012/ch012.html
Cholinergic terminal
Synthesising enzyme choline acetyltransferase (ChAT)
Acetylcholine released from synaptic vesicles in response to depolarisation
Acetylcholine interacts with receptors (muscarinic and nicotinic) on the pre and postsynaptic membrane
Acetylcholine in the synaptic cleft is removed by degrading enzyme acetylcholinesterase (AChE)
Muscarinic receptorsMuscarinic receptors
Five subtypes M1 - M5All metabotropic (G-protein coupled receptors)
M1 postsynaptic –cortex, hippocampus, striatum,low in thalamus, none in cerebellum
M2 - cortex, hippocampus, thalamus, striatum, cerebellum and brainstem,
M4 - mainly in striatum, also in cortex
M3 & M5 – substantia nigra, thalamus and hippocampus
M1, M3, M5 stimulate, M2 & M4 inhibit- overlapping distribution
M1 M1
M1M2
M4/M2 M2
Autoradiographs from frozen post mortem tissue
a4ß2 ß a3
a5
a7
42 a3ß2ß4a5 7
2 ACh Binding Sites
2 ACh Binding Sites
5 ACh Binding Sites
Neuronal Nicotinic Receptors (nAChR)Ligand-gated ion channels (ionotropic)
11 different subunits 2- 9, and ß2-ß4• (Ca2+, Na+) • rapid signalling• local changes
presynaptic activation of nicotinic receptors leads to transmitter release from several different neuronal types – heteroreceptor
(Metabotropic receptors slower, longer lasting changes)
Neuronal nicotinic receptor (42)
distribution
striatum
temporal cortex
occipital cortex
cerebellum
thalamus
midbrain
DOPAMINERGIC SYSTEM
Thalamus
nigrostriatal mesolimbic
mesocortical dopamine pathways
Dopamine receptors (all GPCR)Dopamine receptors (all GPCR)
D2, D3, D4 inhibitory, D1 & D5 stimulatory
D2 and D1 in striatum > thalamus > cortex
D3 is limbic, in nucleus accumbens, ventral pallidum, limbic thalamus (not cortex)
D4 - despite high affinity for clozapine, & links to ADHD, receptor protein has very low density in human
- many polymorphisms, and 48bp repeat (2x 4x or 7x) in third intracytoplasmic loop
- D4 variants not linked to disease (except ADHD, 7x repeats) - D4 variants not associated with clinical response -defective gene ~2% population → low sensitivity to dopamine and clozapine
D5 low density – cholinergic neurons, sub-thalamic nucleus antipsychotic drug potencies correlate with their ability to block D2
Major transmittersMajor transmitters – glutamate (excitatory) and GABA (inhibitory)
• Glutamate and GABA (-amino butyric acid) form basis of neurotransmission
• GABA neurons are interneurons in cortex, can be interneurons or projection neurons in subcortical areas (e.g. striatal projection neurons)
• Glutamate neurons are projection neurons – corticocortical, thalamocortical, cortical-subcortical (corticofugal)
Na+/ Ca2+
2+
PCPMg2+
AspGlu
H+
NMDAGlu
Na+
Glu
AMPA
(Ca 2+ )
Ca2+
IP3
DAG
PIP2
PI-PLC G
Group I
Glu
ATP
cAMPAC
G
Group II Glu
Mg2+
Glutamate receptorsGlutamate receptors
NMDA receptors Mg2+ block – long term potentiation (LTP), learning and memory
Multiple glutamate receptor subtypes, subunits and splice variants
Mg2+
• Glutamate has role in cognition at normal concentrations (LTP)
• Reduced glutamate affects learning and memory
• Excess glutamate leads to excitotoxic cell death (Ca++)
• Alzheimer’s disease - both too much and too little glutamate at different
times
• Glutamatergic pyramidal neurones in entorhinal cortex and hippocampus are particularly vulnerable to tangle formation and cell loss
Glutamate neurotransmissionGlutamate neurotransmission
GABA receptorsGABA receptors
GABAA chloride ion channel, post-synaptic
Different combinations of subunits have different pharmacology and cellular and regional distributions
diverse pharmacological properties of GABAA drugs
GABAB metabotropic G-protein coupled receptor (GPCR)
Many drug development programmes target GABA and glutamate
Benzodiazepines positively modulate GABAA and increase chloride conductance
Negative GABA modulators could enhance cognition
Modafinil –decreased GABA transmission and increased glutamate
SEROTONERGIC SYSTEM (5-HT)SEROTONERGIC SYSTEM (5-HT)
SEROTONIN ReceptorsSEROTONIN Receptors
7 classes of serotonin receptors, 5HT1 - 7
All GPCR (except 5HT3 - ligand-gated ion channel)
5HT4 - presynaptic, stimulate release of transmitters
This array of receptor subtypes provides huge signalling possibilities
• alternate splicing increases the number of proteins
• oligomerisation increases the number of complexes
• multiple G-proteins allow crosstalk between receptor families
NORADRENERGIC SYSTEMNORADRENERGIC SYSTEM
multiple - and -adrenergic receptors all metabotropic GPCR
.HISTAMINE SYSTEMHISTAMINE SYSTEM4 Histamine Receptor types
all GPCR
Any more neurotransmitters?Adenosine, Cannabinoid
Neuropeptide Transmitters (Substance P, Orexin, Neurotensin, Somatostatin, Substance Y, Opioids etc)
human genome shows more than 300 potential GPCR
About half remain ‘orphan receptors’, endogenous ligands unknown
Receptor heteromers and oligomers
A2A, D2, mGluR5 and M1 receptors form ‘raft’ of receptors
GPCR e.g. histamine H3, can have constitutive spontaneous activity where G-protein coupled in absence of agonist
If it causes a response, it's an If it causes a response, it's an agonistagonist
If it causes a response that is relatively smaller than If it causes a response that is relatively smaller than the response to another agonist, it's a the response to another agonist, it's a partial agonistpartial agonist
If it inhibits the response caused by an agonist, it's an If it inhibits the response caused by an agonist, it's an antagonistantagonist
If there is some baseline level of activity in the If there is some baseline level of activity in the absence of agonist and the drug inhibits that, it's an absence of agonist and the drug inhibits that, it's an inverse agonistinverse agonist
Agonist or Antagonist?
AD, DLB
Alzheimer’s Global cognitive impairmentMemory impairment plus
impaired language (aphasia) impaired movement (apraxia) impaired recognition (agnosia) or disturbed executive functioning
Gradual declineNo disturbance of consciousness
Additional featuresanxiety, wandering, anxiety, wandering,
depression, psychosisdepression, psychosis
DLB Progressive cognitive declineplus two out of three Core Features• Cognitive fluctuation of with variation in attention and alertness• Recurrent visual hallucinations• Spontaneous features of parkinsonism
REM sleep behaviour disorder, neuroleptic sensitivity, low DaTSCAN, falls and syncope, transient loss of consciousness, severe autonomic dysfunction, hallucinations in other modalities, delusions, depression
Dementia with Lewy bodies and Dementia with Lewy bodies and Parkinson’s disease dementiaParkinson’s disease dementia
• spectrum
• very similar clinically
• pathologically probably indistinguishable
• movement disorder before dementia by >one year PDD
• movement disorder within one year of dementia, or later, or not at all DLB
• 20% of DLB no EPS, while PDD begins with levodopa responsive Parkinsonism
• Some dopaminergic and cholinergic receptor differences (compensatory changes in PD esp. D2 up-regulation in PD)
Post-mortem % loss
ChAT activity 35-50 Choline uptake 60 AChE activity 40-60 Nicotinic binding 30-70
Cortical cholinergic markers in AD
In vivo imaging – loss of AChE, vesicular ACh transporter, M1 and nicotinic receptor
Biopsy – 3.5 yrs disease, ACh markers reduced up to 50%
Muscarinic M1 receptor reduced efficiency of coupling to G-protein as disease progresses, reduced receptor density late in disease
Cholinergic Changes in DLBpost-mortem neurochemistry
More extensive cholinergic loss than AD (cortex and brainstem rather than hippocampus)In vivo PET – loss of cortical acetylcholinesterase (AChE) in
DLB exceeds AD
Cortical ChAT loss greater than in AD
Striatal ChAT loss
Retained cortical M1 receptors and G-protein coupling
Reduced striatal M1 receptors
Cortical 42 nicotinic receptors reduced as in AD, but much more reduced in striatum
Clinical consequences of cholinergic lossesClinical consequences of cholinergic losses
Memory – hippocampus
Learning – hippocampus, cortex
Attention – cortex, thalamus
Consciousness, sleep, and dreaming -
brainstem, thalamus, cortex
Movement, balance and motor regulation –
striatum, brainstem, thalamus
Visual function – cortex, thalamus
Cholinergic transmission target frontal cortex
Basal Ganglia intrinsic
cholinergic neurons
Cholinergic transmission target - Thalamus, MD nucleus
Basal forebrain cholinergic nuclei - nbM Brain stem cholinergic
nuclei - PPN and LDTg
Cholinergic loss correlates with Cognitive DeclineReduced choline acetyltransferase (ChAT) in temporal and frontal cortex correlates with cognitive impairment
0
1
2
3
4
5
6
7
8
0 1 2 3 4 5 6 7 8 9Dementia rating
p<0.001
control value
AC
h s
ynth
esis
(d
pm
/mg
pro
t/m
in)
in AD
and in DLB and PDD
Prevalence of recurrent complex VH in different disorders relates to the extent of cortical ChAT loss
20 30 40 50 60
PD
ADPDD
0
10
20
30
40
50
60
70
80
90
100
0 10
PSP
DLB
Controls
VaD
Rate of hallucinations
Lev
el o
f ch
olin
ergi
c ac
tivi
ty
Inferior temporal cortex
Visual Hallucinations
picture of hallucinationby artist with PD
ChAT activity in temporal cortex
DLB with and without visual hallucinations
In DLB, more reduced ChAT is associated with visual hallucinations
+VH -VH
Ch
AT
nm
ol/h
r/m
g p
rote
in
0
1
2
3
4
12 5
p=0.02 Presence of VH is good predictor of response to ChEI
Hallucinations related to nicotinic receptors in DLB
Imaging –
• reduced 5IA85480 binding to 42 nicotinic receptors in DLB in striatum and frontal, temporal and cingulate cortex
• Increased 42 in occipital cortex associated with hallucinations
Fluctuations related to nicotinic receptors in DLBFluctuations related to nicotinic receptors in DLB
+FC -FC
0
1
2
3
4
3H
ep
iba
tid
ine
fm
ol/
mg
16 6
Temporal cortex
• Temporal cortex nicotinic receptor 42 reduced in DLB/PDD
• Greater reduction in cortex and thalamus in cases without fluctuations
Fluctuations impair ADL and are over seconds, minutes, hours, and days
In an environment of reduced cholinergic activity, a higher density of nicotinic receptors could amplify small transmitter changes leading to variations in consciousness and attention
Dopamine concentration and dopamine transporters are reduced in DLB, almost to the same extent as in
Parkinson’s disease
Dopamine in DLBDopamine in DLB
Control Alzheimer DLB no EPS DLB + EPS
Autoradiographs of dopamine transporter
posterior caudate
0.0
0.2
0.4
0.6
0.8
1.0
12
5I
PE
2I
bin
din
g f
mo
l/m
g
posterior putamen
0.0
0.2
0.4
0.6
0.8
1.0
Control
PD no dementia
PDD
DLB+EPS
DLB no EPS
AD
Dopamine transporters in PD, PDD, DLB±EPS, and AD
Significant loss even in DLB with no EPS – support for FP-CIT SPECT (DaTSCAN) in AD/DLB discrimination
Striatal D2 receptors in PD, DLB and AD
Control PD DLB
controls PD DLB AD
controls PD DLB AD 0
10
20
30
40
50
14
8
17
26
[3H
] ra
clo
pri
de
fm
ol/m
g
0
10
20
30
40
50
12
8
15
27
caudate putamen
nsb
20/21
2036
36
20
21
22Ent cx
36
20
21
22
Ent cx
36
20
21
22Ent cx
36
20
21
22
Ent cx
36
20
21
22
Cortical D2 receptors reduced in DLB and PDD
40% reduction in DLB (30% in PDD) in D2 receptors in temporal cortex; no change in AD
normal
DLB/PDD
Temporal cortex D2 decline with MMSE
DLB and PDD, Ba 20 N=20, r=0.58, p=0.008
Consistent with
• Neuroleptics impair cognition
• D2 PET in hippocampus correlates with memory
0 5 10 15 20 25 30
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
DLBPDD
MMSE
125I
ep
idep
rid
e b
ind
ing
fm
ol/m
g
Thalamic D2 receptors elevated in PD (~50%) compared to controls and other disease groups
centromedian
0
1
2
3
4
5
6
7
10 3 9 9 5
laterodorsal nucleus
0
1
2
3
4
5
12 5 12 10 6
MD
0
1
2
3
4
5
6
7
12 5 9 10 5
parafascicular
0
2
4
6
8
7 3 8 8 4
reticular nucleus
0.0
0.5
1.0
1.5
2.0
12 6 11 11 5
ventral area centromedian
0
2
4
6
8
7 3 8 8 4
paraventricular nucleus
0
2
4
6
8
10
12
11 6 8 9 4
ventroposterior
0
2
4
6
8
7 5 6 7 3
control
PD no dementia
DLB - EPS
PDD
DLB + EPS
reticular nucleus
0.0
0.5
1.0
1.5
12 5
centromedian
with DOC without DOC
0
1
2
3
4
5
6
10 6125
I ep
idep
rid
e f
mo
l/m
g
parafascicular
0
2
4
6
8
9 6
mediodorsal
0
1
2
3
4
10 5
with DOC
without DOC
Raised D2 in DLB/PDD with fluctuations in cortex and in thalamic nuclei with a role in maintenance of consciousness
reticular
MD
CM/pf
D2 cingulate cortex
0.00
0.25
0.50
0.75
1.00
6 5
D2 receptors are on GABA interneurons i.e. inhibiting inhibitory neurons - a higher density of D2 receptors will amplify small transmitter changes
Dopamine mechanisms
• Elevated D2 receptors in PD - compensates for low dopamine
• Reduced D2 receptors in DLB and PDD may correlate with poor levodopa response and neuroleptic sensitivity
D2 receptors decline as PD progresses faster in cortex than striatum and thalamus
Cortical pyramidal neurone loss leads to reduced glutamate activity and cognitive impairment in AD
Glutamate markers in AD – inconsistent reports
Reduced NMDA binding and NMDAR1 mRNA expression in AD
With reduced NMDA receptors in AD, odd that NMDA antagonist memantine effective
- it blocks NMDA receptor better than Mg2+
But reduced membrane potential(due to pathology, reduced energy metabolism) leads to release voltage dependent Mg2+ block of NMDA → and excessive, neurotoxic entry of Ca2+
So Memantine efficacy in moderate-severe AD with heavier pathology• acting as uncompetitive, low-affinity, open-channel blocker• limiting excessive glutamate• reducing signal to noise
Memantine is also a D2 agonist, 5HT3 antagonist
• neurone loss & tangles in raphe, reduced 5HT
• relatively retained 5-HT function linked to more psychosis (AD and DLB)
• 5-HT2A receptors more reduced with severe dementia
• 5HT receptor polymorphisms linked to
Aggression, Psychosis, Depression, Anxiety
Serotonergic abnormalities
Noradrenergic Abnormalities
• Extensive neuron loss locus coeruleus, reductions in noradrenaline, increased turnover in surviving neurons linked to upregulation of the noradrenaline transporter
• In PD noradrenaline loss linked to → PDD
• Noradrenaline changes may be related to
Aggression, Psychosis, Depression
Fronto-Temporal Dementia
Younger onset (45 – 60 years)
Pathology most apparent in the II and deep cortical layers, coinciding with location of D2 and 5HT1 receptors
Neurotransmitter lossesSerotonin – concentration and transporters reduced, 5HT1A and 5HT2A receptors reduced
Compulsive behaviours, sweet and carbohydrate consumption
Dopamine – concentration and transporters reduced, D2 receptors elevated in striatum
Rigidity, flat facies, depression
Norepinephrine and some neuropeptide transmitters – slight reduction
Anxiety, suspiciousness, restlessness
Acetylcholine – little or no reduction greater imbalance DA/ACh in striatum may exacerbate EPS
GABA, glutamate - unchanged
Cholinesterase inhibitors delusions, hallucinations, agitation, aggression, anxiety, apathy, as well as cognition (implying cholinergic mechanisms)
Galantamine (Reminyl, or Razadyne) AChEI and nicotinic receptor allosteric modulator Donepezil (Aricept) AChEIRivastigmine (Exelon) AChEI and BuCHEI
Cholinergic Therapy - Residual receptor availability
Why might DLB Patients respondto Cholinergic Treatment?
• Cortical muscarinic receptors up-regulated
• M1 receptors remain coupled to G-proteins (unlike AD)
• ACh very reduced
• Less neuron loss or cortical atrophy
• Little or no tangle burden
• Symptoms fluctuate potential for higher function to be restored
• Low M1 receptors in striatum avoids worsening parkinsonism
• AChEI only inhibit 30% AChE activity
0 10 20 30 40 50 600
50
100
150
Striatal D2
M1
DLB
PDD PD
ADControl
Smoking (and coffee drinking) inversely associated with PD, not
with AD (most studies)
Neuronal survival Alzheimer pathologyCognitive impairment
Cholinergic and dopaminergic influence and consequences
See table of anticholinergic medications – many regularly used by the elderly.
Implications – Anticholinergic Medication Use and Cognitive Impairment in the Older Population: The MRC Cognitive Function in Ageing Study. Fox et al JAGS 2011
Normal elderly (female) smokers and non-smokersNormal elderly (female) smokers and non-smokers
Nicotine use (tobacco) associated with lower plaque densities in normal elderly
• Muscarinic M1 Agonists reduce A levels in CSF in AD• In triple-Tg-AD mouse, M1 agonist AF267B rescued cognitive deficits
and reduced A and tau pathology
(dicyclomine M1 antagonist)
• Cholinesterase inhibitors may reduce amyloid
CHOLINERGIC TRANSMISSIONReduces Alzheimer-type pathology
Reviews
Fisher A., Neurotherapeutics: 5 2008, 433-442
Caccamo A., Current Alzheimer Research. 6 2009:112-7
Alzheimer pathology increased in PD in relation to antimuscarinic drugs
acute <2y, chronic 2-18y Anticholinergics: benztropine, orphenadrine, trihexyphenidyl, oxybutyninGroups matched for age and PD duration
0
0.2
0.4
0.6
0.8
1
1.2
1.4
1.6
1.8
21 15 18 21 15 18
SENILE PLAQUES
p=0.005compared to no drug
NEUROFIBRILLARY TANGLES
P=0.02 compared to no drug
0.5
1
1.5
2
2.5
3
3.5
4
4.5
0NO DRUG
ACUTE
CHRONIC
NO DRUG ACUTE CHRONIC
0
0.2
0.4
0.6
0.8
1
1.2
1.4
0
0.5
1
1.5
2
2.5
3
3.5
4
4.5
5
NEUROLEPTIC MEDICATION IS ASSOCIATED WITHINCREASED TANGLE DENSITY IN DLB/PDD
DLB/PDD matched for age, duration of PD, duration of dementia, MMSE, prevalence of delusions and visual hallucinations
anterior cingulate cortex frontal cortex
- NL(23)
+ NL(17)
- NL(23)
+ NL(17)
*p=0.04
Tan
gle
den
sity
Cognitive and Neuropsychiatric Symptoms in dementiaCognitive and Neuropsychiatric Symptoms in dementia
Can Cholinergic and Dopaminergic Mechanisms Explain All?Can Cholinergic and Dopaminergic Mechanisms Explain All?
Not quite – glutamate, serotonin and noradrenaline also important
other influences need elucidation
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