Study protocol on Alzheimer\u2019s disease and related disorders: focus on clinical and imaging predictive markers in co-existing lesions

Nawele Boublay,Frédéric Blanc,Marc Verny,Romain Bouet,Solveig Relland,Marc Paccalin,Thomas Desmidt,Estelle Bravant,Alain Pesce,Denis Fédérico,Olivier Moreaud,Pierre Krolak-Salmon,Pierre Grosmaître

doi:10.1186/s12877-018-0949-2

Abstract

BackgroundOne of the crucial challenges for the future of therapeutic approaches to Alzheimer’s disease (AD) is to target the main pathological processes responsible for disability and dependency. However, a progressive cognitive impairment occurring after the age of 70, the main population affected by dementia, is often related to mixed lesions of neurodegenerative and vascular origins. Whereas young patients are mostly affected by pure lesions, ageing favours the occurrence of co-lesions of AD, cerebrovascular disease (CVD) and Lewy body dementia (LBD). Most of clinical studies report on functional and clinical disabilities in patients with presumed pure pathologies. But, the weight of co-morbid processes involved in the transition from an independent functional status to disability in the elderly with co-lesions still remains to be elucidated. Neuropathological examination often performed at late stages cannot answer this question at mild or moderate stages of cognitive disorders. Brain MRI, Single Photon Emission Computed Tomography (SPECT) with DaTscan®, amyloid Positron Emission Tomography (PET) and CerebroSpinal Fluid (CSF) AD biomarkers routinely help in performing the diagnosis of underlying lesions. The combination of these measures seems to be of incremental value for the diagnosis of mixed profiles of AD, CVD and LBD. The aim is to determine the clinical, neuropsychological, neuroradiological and biological features the most predictive of cognitive, behavioral and functional impairment at 2 years in patients with co-existing lesions.MethodsA multicentre and prospective cohort study with clinical, neuro-imaging and biological markers assessment will recruit 214 patients over 70 years old with a cognitive disorder of AD, cerebrovascular and Lewy body type or with coexisting lesions of two or three of these pathologies and fulfilling the diagnostic criteria for dementia at a mild to moderate stage. Patients will be followed every 6 months (clinical, neuropsychological and imaging examination and collection of cognitive, behavioural and functional impairment) for 24 months.DiscussionThis study aims at identifying the best combination of markers (clinical, neuropsychological, MRI, SPECT-DaTscan®, PET and CSF) to predict disability progression in elderly patients presenting coexisting patterns.Trial registrationNCT02052947.

Highlights

One of the crucial challenges for the future of therapeutic approaches to Alzheimer’s disease (AD) is to target the main pathological processes responsible for disability and dependency
Whereas young patients presenting a neurocognitive disorder are mostly affected by pure lesions related to Alzheimer’s Disease (AD), Vascular Dementia (VaD) that may be induced by CerebroVascular Disease (CVD) or Lewy Body Dementia (LBD), ageing favours the occurrence of co-lesions of these pathologies (Fig. 1)
The aim of this study is to identify the markers, as assessed by Magnetic Resonance Imaging (MRI), Single Photon Emission Computed Tomography (SPECT-DaTs can®), Positron Emission Tomography (PET) and Cerebro Spinal Fluid (CSF), combined with clinical information, that are the most predictive of functional disability progression in the elderly presenting a progressive cognitive decline related to AD, Lewy body dementia (LBD), cerebrovascular disease (CVD) and all mixed patterns

Summary

Introduction

One of the crucial challenges for the future of therapeutic approaches to Alzheimer’s disease (AD) is to target the main pathological processes responsible for disability and dependency. The combination of these measures seems to be of incremental value for the diagnosis of mixed profiles of AD, CVD and LBD. Whereas young patients presenting a neurocognitive disorder are mostly affected by pure lesions related to Alzheimer’s Disease (AD), Vascular Dementia (VaD) that may be induced by CerebroVascular Disease (CVD) or Lewy Body Dementia (LBD), ageing favours the occurrence of co-lesions of these pathologies (Fig. 1). AD, the most frequent neurodegenerative aetiology of neurocognitive disorders, is marked pathologically by plaques composed of ß amyloid deposits (Aß) surrounded by dystrophic neuritis, neurofibrillary tangles composed of hyperphosphorylated tau, with activated microglia and reactive astrocytes, neuronal and synaptic loss These lesions lead to neural loss and brain atrophy [2]. Amnestic presentation including impairment of learning and recall of recently learned information is the most common syndromic presentation of AD at the mild cognitive stage [3], latterly combined with aphasia, agnosia, apraxia and executive function impairment, some functional decline and behavioural disorders at the dementia stage [4]

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