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Imaginem oblivionis: the prospects of neuroimaging for early detection of Alzheimer's disease,☆☆

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Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterised by the gradual onset of dementia. The pathological hallmarks of the disease are amyloid plaques, neurofibrillary tangles, and reactive gliosis.

Current diagnosis of AD is made by clinical, neuropsychologic, and neuroimaging assessments. Routine structural neuroimaging evaluation is based on non-specific features such as atrophy, a late feature in the progression of the disease, hence the crucial importance of developing new approaches for early and specific recognition at the prodromal stages of AD.

Functional neuroimaging techniques such as positron emission tomography (PET) and single photon emission computed tomography (SPECT) could prove to be valuable in the differential diagnosis of AD, as well as in assessing prognosis. With the advent of new therapeutic strategies aimed at reducing the amyloid burden in the brain, there is increasing interest in the development of PET and SPECT radioligands that will permit the assessment of Aβ amyloid burden in vivo. From this, the prospect of specific preclinical diagnosis arises, possibly in conjuction with other related Aβ biomarkers in plasma and CSF.

Introduction

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterised by the gradual onset of dementia,1 leading invariably to death, usually between 7 and 10 years after diagnosis. Age is the major risk factor. AD is the leading cause of dementia in the elderly and affects about 5% of individuals at age 65, with its prevalence increasing exponentially with each successive decade, with 10–15% and 20–30% of 75- and 85-year olds affected, respectively.

Section snippets

Clinical features and diagnostic criteria

The clinical diagnosis of AD is currently based on progressive memory impairment and decline in at least one other cognitive domain, and by excluding other diseases such as frontotemporal dementia, dementia with Lewy-bodies (DLB), stroke, brain tumour, normal pressure hydrocephalus or depression, that might also present with dementia.[2], [3]

The clinical diagnostic accuracy for AD depends on the stage of disease and can exceed 90% in academic settings in mid or late stages.4 Diagnostic criteria

Genetic predisposing factors

While mutations of the PS-1, PS-2,11 and amyloid precursor protein (APP) genes – resulting in increased production and elevated plasma levels of amyloid-β protein – on chromosomes 1, 14, and 21, respectively, have been associated with the rare form of familial AD, the only consistent marker for the late-onset non-familial form of dementia is the apolipoprotein ε allele on chromosome 19.12 This refers specifically to the ε4 allele, though it is absent in approximately 30–40% of patients with AD

Neuropathologic features

By means of clinical, laboratory, and imaging evidence only a provisional diagnosis of either possible or probable AD can be made in living subjects. In the absence of biologic markers, direct pathologic examination of brain tissue derived from either biopsy or autopsy remains the only definitive method for establishing a diagnosis of AD.15

The typical macroscopic picture is gross cortical atrophy. Microscopically, there is widespread cellular degeneration and neuronal loss that affects

Structural neuroimaging

Structural neuroimaging techniques, such as computed tomography (CT) and magnetic resonance imaging (MRI), are routinely used in the clinical evaluation of AD patients.

Widespread cortical atrophy with a thinning of medial temporal lobe structures are the most consistent structural neuroimaging findings associated with AD,26 though not pathognomonic of the disease because there is overlap with “normal” aging.

CT is mainly used to exclude other treatable causes of dementia.27 Studies reporting

Amyloid imaging

Extracellular amyloid plaques are the hallmark brain lesions of sporadic Alzheimer's disease. These microscopic Aβ aggregates91 are well beyond the resolution of the usual neuroimaging techniques used for the evaluation of patients with AD. Furthermore, current techniques focus on non-specific features derived mainly from neuronal loss and atrophy, which are late features in the progression of the disease, and are secondary to the basic functional alteration. However, the distribution and

Novel therapeutic approaches

Neuronal degeneration with impairment in cholinergic transmission in hippocampal and cortical areas associated with memory and cognition are characteristic of AD. No current therapy has been shown to halt or reverse the underlying disease process. Though now approved for AD, the cholinesterase inhibitors tacrine, donepezil, rivastigmine, and galantamine only provide patients with modest relief to their symptoms.142 Recently, the non-competitive NMDA antagonist memantine has been proposed as a

Conclusions

While clinical criteria together with current structural neuroimaging techniques (CT or MRI) are sensitive and specific enough for the diagnosis of AD at the mid or late stages of the disease, the development of a reliable method of assessing Aβ amyloid burden in vivo may permit early diagnosis at presymptomatic stages, more accurate differential diagnosis, while also allowing treatment follow up.

The criteria for the diagnosis, management, and early detection of dementia[62], [167], [168]

Acknowledgements

This work is supported in part by grants from the National Health and Medical Research Council of Australia, Prana Biotechnology, and Schering AG.

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    Supported in part by grants from the National Health and Medical Research Council of Australia, Prana Biotechnology and Schering AG.

    ☆☆

    Quo pacto dicam imaginem oblivionis teneri memoria mea, non ipsam oblivionem, cum eam memini? (How can I assert that the image of oblivion is retained by my memory, and not oblivion itself, when I remember it?) St Augustine. Confessiones. Liber X, Caput 16.

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