Synaptic Function

1: Dopamine

Targets for dopaminergic ligands Dopamine synthesis

Glial cell

MAO-B COMT

Tyrosine L-DOPA DA Vesicles Post-synaptic cell Pre-synaptic terminal

Dopamine Transporters D2 Receptors

Targets for dopaminergic ligands I123 IBZM or epidepride F18-Dopa

Vesicles Tyrosine L-DOPA DA Pre-synaptic terminal Glial cell

MAO-B COMT I123 FPCIT or ß-CIT

*** Post-synaptic cell

Dopamine transporter imaging

Normal Dopamine Transporter (DATSCAN) images

Head of Caudate Body of Caudate

MRI

Putamen

DATSCAN SPECT

A PD image with DaTSCAN

Medial part of SN projects to caudate Lateral part of SN projects to putamen In PD the lateral part of SN always degenerates first preferential loss in putamen relative to caudate

Diagnosis and staging of Parkinson’s Disease

Clinical diagnosis Imaging diagnosis Accuracy of Diagnosis in Presumed PD Meara J et al Age and Ageing 1999;28:99-102 .

•26% of patients receiving inappropriate treatment Post-mortem data suggests figure may even be higher Even on first presentation SPECT shows loss of 50% of neurones Objective measurement of progression in assessment of therapy Normal PD: H&Y1 PD: H&Y2 PD: H&Y3

Can we show progression in an individual patient?

51 year old lady, first Presentation 18 months 36 months ––––––––––––––––––––––––––––––––––––––––––––––––– Caudate R L R L R L 4.29 3.84

4.14 3.14

3.31 2.40

--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- Putamen 2.05 1.32

1.56 1.17

1.17 1.07

–––––––––––––––––––––––––––––––––––––––––––––––––

Specific/Non-specific ratios

2: Serotonin Serotonin Transporter [SERT] imaging

Clinical depression Major Depression • • prevalence as high as 10% key symptoms low mood diminished interest in pleasure hopelessness, guilt, suicidality cognitive impairment changes in sleep, appetite, libido • World Bank report - global burden second only to IHD by 2020

Treatment of depression • • • The Monoamine Hypothesis 1950s - drugs used to treat TB and schizophrenia were found to elevate mood and stimulate activity First tricyclic antidepressant - found to increase the activity of the monoamine neurotransmitters by inhibiting their reuptake • Thus, antidepressants appeared to work by normalising a deficit in monoamines, especially serotonin Drugs highly selective for the serotonin system were developed

Action of SSRI antidepressants Pre-synaptic terminal Synapse Serotonin Serotonin transporters (SERT) Serotonin reuptake inhibitor (SSRI) 123 I-beta-CIT Post-synaptic cell Image available binding sites

Analysis of 123 I-beta-CIT scans for SERT availability SPECT scans at 3 hours reflect SERT binding in midbrain regions These are sagittal views through the midline in 2 patients High drug effect on transporters Lower drug effect on transporters Availability is a measure of the number of transporters available to transport neurotransmitter [serotonin] from the synapse back into the pre-synaptic terminal.

SERT availability = (MB - OCC)/ OCC where MB and O CC are tracer count rates in the mid-brain and in the occipital reference region.

Analysis of 123 I-beta-CIT scans for DAT availability SPECT scans at 24 hours reflect DAT binding in the striatum This is an axial view through the basal ganglia.

DAT availability = (ST - OCC)/ OCC where ST and O CC are tracer count rates in the striatum and in the occipital reference region.

SERT availability for patients on SSRIs or venlafaxine

1.00

0.80

SERT Availability 0.60

0.40

0.20

0.00

Non-responders Responders

The normal availability index is around 2.7

•9 out of 11 patients in the SSRI or SNRI groups with binding indices between 0.2 and 0.6 were responders and all 7 outside this range were non-responders •This suggests that response could be improved by better regulation of the degree of transporter downregulation See also( Meyer et al, Amer J Psych 2004)

DAT binding indices for patients on antidepressants as a function of age

12.00

10.00

8.00

DAT Availability 6.00

4.00

2.00

0.00

0 10 20 30 Age 40 50 60 70

•This is consistent with the literature and indicates a decline of 7.3% per decade.

Dementia: the diagnostic dilemma

• Alzheimer's disease • Dementia with Lewy bodies • Frontal lobe dementia, including Pick's disease • Alcohol related dementia • Vascular dementia [email protected]

The acetylcholine neurotransmitter system is selectively affected in AD

Therapy for AD

Cholinergic projections Therapies aim to improve cholinergic neurotransmission Septum Basal nucleus

MR in psychiatry

• Alzheimer’s disease - progression Normal ageing difference at 12m Early onset AD difference at 12m

Alzheimer’s disease - progression

A typical SPECT perfusion scan

The AD perfusion pattern • The probability that patients with memory loss and normal perfusion had Alzheimer's disease was 19 %.

• The probability of Alzheimer's disease with bilateral temporo parietal defects was 82%

Alzheimer's disease progression • 57 year old man presenting with gradually deteriorating memory Initial 99mTc HMPAO SPECT Follow-up at 4.5 years

Frontal lobe dementia • Frontal hypo-perfusion sometimes including temporal lobes Alzheimer’s disease Frontal lobe dementia Bi-lateral temporo-parietal deficits Bi-lateral frontal lobe deficits

Vascular dementia • Multiple regions of focally reduced perfusion

Early diagnosis?

Ann Neurol 2004;55:306-319