Imaging of Neurotransmitter Deficits: New Potential Biomarkers for Alzheimer’s Disease?

There is growing agreement that early diagnosis of Alzheimer’s disease (AD) prior to onset of dementia is required for efficient clinical trials of neuroprotective interventions. In the past years, substantial progress has been made in that respect by refining clinical and neuropsychological assessment and quantitative evaluation of structural and functional brain imaging (mainly MRI and PET). It is also hoped that quantitative imaging will provide more efficient means to monitor disease progression than repeated neuropsychological testing. Alzheimer’s disease is likely to be a common clinical manifestation with diverse and multifactorial etiology, and it also needs to be distinguished from other dementias, such as fronto-temporal dementia (FTD), dementia with Lewy bodies (DLB), and vascular dementia (VD). Yet, currently available clinical tools do not yet allow identifying specific etiologies and distinguishing between different dementing diseases at the clinical stage of mild cognitive impairment.

To address these needs, we have formed a multicentre network to compare molecular and neurotransmitter imaging in mild cognitive impairment. Within this network we are including normal controls and patients with mild cognitive impairment using harmonized longitudinal study protocols that share common neuropsychological and clinical assessment (MMSE, DemTect, CDR, Rey auditory verbal learning and complex figure, digit span, verbal fluency, trail making, IADL, Geriatric depression scale, NPI). Participating laboratories have established positron emission tomography (PET) or single photon emission computed tomography (SPECT) procedures to assess in vivo key molecular events, specifically amyloid deposition (C-11-PIB) and microglial activiation (C-11-PK11195), and assessment of neurotransmitter deficits, specifically acetylcholine esterase (C-11-MP4A, C-11-MP4P), nicotinic receptors (I-123-A85380), serotonin and benzodiazepine receptors, and dopamine transporters.

Preliminary results and evidence from postmortem studies suggest that amyloid deposition and cholinergic deficits occur early in AD but not in FTD, serotonergic deficits may be present in AD and FTD, whereas a dopaminergic deficit is seen in DLB only. The ongoing studies in MCI patients should provide more information on whether early differential diagnosis is possible and could become available for testing of drugs that target specific molecular mechanisms and transmitter systems.