Neurochemistry of Dementias

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Neurochemistry of the Dementias
and transmitter-based therapies
Dr Margaret Piggott
[email protected]
[email protected]
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 DEMENTIAS
transmitter therapies
THE OXFORD TEXTBOOK OF OLD AGE PSYCHIATRY
(Psychiatry in the Elderly 4th edition)
Chapter 6
Neurochemical 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 system
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 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 receptors
Five subtypes M1 - M5
M1
M1
All metabotropic (G-protein coupled receptors)
 M1 postsynaptic –
cortex, hippocampus, striatum,
low in thalamus, none in cerebellum
M4/M2
M2
 M2 - cortex, hippocampus, thalamus,
striatum, cerebellum and brainstem,
 M4 - mainly in striatum, also in cortex
M3 & M5 – substantia nigra, thalamus and
hippocampus

M2
M1
M1, M3, M5 stimulate, M2 & M4 inhibit
- overlapping distribution
Autoradiographs from
frozen post mortem tissue
Neuronal Nicotinic Receptors (nAChR)
Ligand-gated ion channels (ionotropic)
a4  2
a3ß2ß4a5
a7
a5
ß2
a4
2 ACh
Binding Sites
ß a3
2 ACh
Binding Sites
a7
5 ACh
Binding Sites
11 different subunits a2- a 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 (a42) distribution
temporal cortex
striatum
cerebellum
thalamus
occipital cortex
midbrain
DOPAMINERGIC SYSTEM
nigrostriatal
mesolimbic
mesocortical
dopamine
pathways
Thalamus
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 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)
Glutamate receptors
Multiple glutamate receptor
subtypes, subunits and
splice variants
NMDA receptors
Mg2+ block
– long term
potentiation (LTP),
learning and memory
Na+/ Ca2+
Asp 2+
Mg2+
Glu
(Ca2+)
Na+
H+
NMDA
PCP
Glu
2+
Mg2+
Mg
Glu
AMPA
Group II
G
Ca2+
cAMP
IP3
ATP
DAG
PI-PLC
PIP2
G
Group I
Glu
AC
Glu
Glutamate neurotransmission
• 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
GABA 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)
SEROTONIN 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 SYSTEM
multiple a- and -adrenergic receptors
all metabotropic GPCR
HISTAMINE SYSTEM
.
4 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
Agonist or Antagonist?




If it causes a response, it's an agonist
If it causes a response that is relatively smaller than
the response to another agonist, it's a partial agonist
If it inhibits the response caused by an agonist, it's an
antagonist
If there is some baseline level of activity in the
absence of agonist and the drug inhibits that, it's an
inverse agonist
AD, DLB
Alzheimer’s
DLB
Global cognitive impairment
Memory impairment plus
impaired language (aphasia)
impaired movement (apraxia)
impaired recognition (agnosia) or
disturbed executive functioning
Gradual decline
No disturbance of consciousness
Progressive cognitive decline
plus two out of three Core Features
• Cognitive fluctuation of with variation
in attention and alertness
• Recurrent visual hallucinations
• Spontaneous features of
parkinsonism
Additional features
anxiety, wandering,
depression, psychosis
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
Parkinson’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)
Cortical cholinergic markers in AD
Post-mortem
% loss
ChAT activity
Choline uptake
AChE activity
Nicotinic binding
35-50
60
40-60
30-70
Muscarinic M1 receptor reduced efficiency of coupling to G-protein
as disease progresses, reduced receptor density late in disease
In vivo imaging – loss of AChE, vesicular ACh transporter,
M1 and nicotinic receptor
Biopsy – 3.5 yrs disease, ACh markers reduced up to 50%
Cholinergic Changes in DLB
post-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 a42 nicotinic receptors reduced as in AD, but much
more reduced in striatum
Clinical consequences of cholinergic losses
Memory – hippocampus
Learning – hippocampus, cortex
Cholinergic
transmission target
frontal cortex
Basal Ganglia intrinsic
cholinergic neurons
Cholinergic
transmission target Thalamus, MD nucleus
Attention – cortex, thalamus
Consciousness, sleep, and dreaming brainstem, thalamus, cortex
Movement, balance and motor regulation –
striatum, brainstem, thalamus
Visual function – cortex, thalamus
Basal forebrain cholinergic
nuclei - nbM
Brain stem cholinergic
nuclei - PPN and LDTg
Cholinergic loss correlates with Cognitive Decline
(dpm/mg prot/min)
in AD
ACh synthesis
Reduced choline acetyltransferase (ChAT) in temporal
and frontal cortex correlates with cognitive impairment
8
control value
7
6
p<0.001
5
4
3
2
1
0
0
1
2
3
4
5
6
7
8
9
Dementia rating
and in DLB and PDD
Visual Hallucinations
Level of cholinergic activity
Prevalence of recurrent complex VH in different
disorders relates to the extent of cortical ChAT loss
Controls
PSP
100
90
PD
80
VaD
70
60
50
40
PDD
AD
DLB
30
20
10
0
0
10
20
30
40
50
Rate of hallucinations
Inferior temporal cortex
60
picture of hallucination
by artist with PD
In DLB, more reduced ChAT is associated with
visual hallucinations
ChAT activity in temporal cortex
ChAT nmol/hr/mg protein
4
3
Presence of VH is
good predictor of
response to ChEI
p=0.02
2
1
12
5
+VH
-VH
0
DLB with and without visual hallucinations
Hallucinations related to nicotinic receptors in DLB
Imaging –
• reduced 5IA85480 binding to a42 nicotinic receptors in
DLB in striatum and frontal, temporal and cingulate cortex
• Increased a42 in occipital cortex associated with
hallucinations
Fluctuations related to nicotinic receptors in DLB
• Temporal cortex nicotinic receptor a42 reduced in DLB/PDD
• Greater reduction in cortex and thalamus in cases without
fluctuations
Temporal
cortex
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
3H epibatidine fmol/mg
4
3

2
1
16
6
0
+FC
-FC
Fluctuations impair ADL and are over seconds, minutes, hours, and days
Dopamine in DLB
Dopamine concentration and dopamine transporters are
reduced in DLB, almost to the same extent as in
Parkinson’s disease
Control
Alzheimer
DLB no EPS
DLB + EPS
Autoradiographs of dopamine transporter
Dopamine transporters
in PD, PDD, DLB±EPS, and AD
125I PE2I binding fmol/mg
posterior caudate
posterior putamen
1.0
1.0
0.8
0.8
0.6
0.6
0.4
0.4
0.2
0.2
0.0
0.0
Control
Significant loss
even in DLB with no EPS –
support for FP-CIT SPECT
(DaTSCAN) in AD/DLB
discrimination
PD no dementia
PDD
DLB+EPS
DLB no EPS
AD
Striatal D2 receptors in PD, DLB and AD
Control
PD
DLB
[3H] raclopride fmol/mg
caudate
50
putamen

17
12
40
14
26
30
40
20
20
10
10
0
0
DLB
27
8
30
8
controls PD

15
50
AD
controls PD
DLB
AD
Cortical D2 receptors reduced in DLB and PDD
20/21
22
Ent cx
normal
36
20
36
36
22
21
nsb
20
20
21
DLB/PDD
22
22
22
Ent cx
Ent cx
Ent cx
21
21
36
21
20
36
36
20
20
40% reduction in DLB (30% in PDD) in D2 receptors in
temporal cortex; no change in AD
125I epidepride binding fmol/mg
Temporal cortex D2 decline with MMSE
0.7
DLB and PDD, Ba 20
N=20, r=0.58, p=0.008
0.6
0.5
0.4
Consistent with
0.3
• Neuroleptics impair
cognition
• D2 PET in hippocampus
0.2
correlates with memory
0.1
DLB
PDD
0.0
0
5
10
15
MMSE
20
25
30
Thalamic D2 receptors elevated in PD (~50%)
compared to controls and other disease groups
parafascicular
ventral area centromedian

8
7


8
centromedian
6
6
4
4
6
5
reticular nucleus
u
4
2.0
2
2
2
0
0
1.0
0.5
1
0

1.5
3
10
3
9
9
5
7
3
8
8
4
7
3
8
8
0.0
4
12
6
11
11
5
ventroposterior
8
laterodorsal nucleus
5
paraventricular nucleus
6

4

12

4
u
3
u
control
2
2
10
PD no dementia
1
0
8
0
12
12
10
6
MD
7
6
5
4
3
2
1
0
0
11
6
8
9
4
6
7
3
PDD
DLB - EPS
5
2
5
DLB + EPS

6
4
7
12
5
9
10
5
Raised D2 in DLB/PDD with fluctuations in cortex and in
thalamic nuclei with a role in maintenance of consciousness
8
with DOC
parafascicular
125I epidepride fmol/mg
without DOC
6
centromedian
6
5
reticular nucleus

4
1.5
4

3
1.0

0.5
2
2
0.0
12
1
5
0
0
10
6
with DOC
without DOC
mediodorsal
9
6
D2
1.00
cingulate cortex
MD
4
0.75
3

2

0.50
1
0.25
0
10
5
reticular
CM/pf
0.00
6
5
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
D2 receptors are on GABA
interneurons i.e. inhibiting
inhibitory neurons
- a higher density of D2
receptors will amplify small
transmitter changes
Glutamate markers in AD – inconsistent reports
Reduced NMDA binding and NMDAR1 mRNA expression in AD
Cortical pyramidal neurone loss leads to reduced glutamate
activity and cognitive impairment 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
Serotonergic abnormalities
• 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
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 losses
Serotonin – 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
Cholinergic Therapy - Residual receptor availability
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)
AChEI
Rivastigmine (Exelon)
AChEI and BuCHEI
Why might DLB Patients respond
to 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
150
100
M1
potential for higher function
to be restored
50
• Low M1 receptors in striatum
0
0
10
avoids worsening parkinsonism
• AChEI only inhibit 30% AChE activity
20
30
40
50
Striatal D2
DLB
PDD
Control
AD
PD
60
Cholinergic and dopaminergic influence and consequences
Neuronal survival
Alzheimer pathology
Cognitive impairment
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
Smoking (and coffee drinking)
inversely associated with PD, not
with AD (most studies)
Nicotine use (tobacco) associated with lower plaque densities in
normal elderly
Normal elderly (female) smokers and non-smokers
CHOLINERGIC TRANSMISSION
Reduces Alzheimer-type pathology
• 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
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
SENILE PLAQUES
NEUROFIBRILLARY TANGLES
p=0.005
compared to no drug
P=0.02
compared to no drug

4.5
4
1.6
3.5
1.4
3
1.2
2.5
1
2
0.8
1.5
0.6
1
0.4
0.5
0
21
15
NO DRUG
ACUTE
18
CHRONIC

1.8
0.2
0
21
NO DRUG
15
ACUTE
18
CHRONIC
acute <2y, chronic 2-18y
Anticholinergics: benztropine, orphenadrine, trihexyphenidyl, oxybutynin
Groups matched for age and PD duration
NEUROLEPTIC MEDICATION IS ASSOCIATED WITH
INCREASED TANGLE DENSITY IN DLB/PDD
anterior cingulate cortex
5
1.4
4.5
Tangle density
frontal cortex
1.2
4
3.5
1
3
0.8
*p=0.04
2.5
2
0.6
1.5
0.4
1
0.2
0.5
0
0
- NL
(23)
+ NL
(17)
- NL
(23)
+ NL
(17)
DLB/PDD matched for age, duration of PD, duration of dementia,
MMSE, prevalence of delusions and visual hallucinations
Cognitive and Neuropsychiatric Symptoms in dementia
Can Cholinergic and Dopaminergic Mechanisms Explain All?
Not quite – glutamate, serotonin and noradrenaline
also important
other influences need elucidation
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