Concept of functional imaging of memory decline in Alzheimer’s disease

Abstract

Functional imaging methods such as Positron Emission Tomography (PET) and functional Magnetic Resonance Imaging (fMRI) have contributed inestimably to the understanding of physiological cognitive processes in the brain in the recent decades. These techniques for the first time allowed the in vivo assessment of different features of brain function in the living human subject. It was therefore obvious to apply these methods to evaluate pathomechanisms of cognitive dysfunction in disorders such as Alzheimer’s disease (AD) as well. One of the most dominant symptoms of AD is the impairment of memory. In this context, the term “memory” represents a simplification and summarizes a set of complex cognitive functions associated with encoding and retrieval of different types of information. A number of imaging studies assessed the functional changes of neuronal activity in the brain at rest and also during performance of cognitive work, with regard to specific characteristics of memory decline in AD. In the current article, basic principles of common functional imaging procedures will be explained and it will be discussed how they can be reasonably applied for the assessment of memory decline in AD. Furthermore, it will be illustrated how these imaging procedures have been employed to improve early and specific diagnosis of the disease, to understand specific pathomechanisms of memory dysfunction and associated compensatory mechanisms, and to draw reverse conclusions on physiological function of memory.

Introduction

The neurodegenerative disorder Alzheimer’s disease (AD) represents the most frequent cause for the development of dementia, which is characterized by an insidious onset and a progressive impairment of cognitive functions, finally leading to an impairment in the capabilities of daily living [1], [2]. In the public perception, AD is strongly associated with memory impairment. Although the equation of AD with memory impairment is simplifying the complexity and diversity of cognitive problems conditioned by the disorder, memory problems do actually represent one of the earliest symptoms of AD and one of the most serious and subjectively affecting cognitive deficits for the individual. The term “memory” itself represents a simplified summarization of an entire set of different associated functions, such as short-term, long-term, procedural, declarative, semantic or episodic memory. Furthermore, memory can be subdivided in functions occupied with encoding and with retrieval of information. The hallmark symptom of AD is an impairment of the declarative memory. The term “declarative memory” describes the aspect of human memory that stores facts and experiences, which can be explicitly discussed, or declared by the individual. The declarative memory is subdivided in the semantic memory (non-context specific fact, word and object memory) and the episodic memory (memory of events, including time, place and associated emotions). In AD, the episodic memory is among the earliest affected functions [3]. Typically, AD results in a deficit in the establishment of new episodic memories, whereas events dating from more remote periods in the past are better preserved. In later stages of dementia of the Alzheimer type, most other memory domains are hampered as well. For this reason, memory impairment is also a fundamental criterion of the diagnosis of AD, which today is mostly based on neuropsychological evaluation [2]. A definite diagnosis of Alzheimer’s disease, however, is currently only possible by post mortem histopathological analysis of the brain. In contrast to other disease entities, the in vivo extraction of tissue for histopathology (e.g. by biopsy) can hardly be reasonably justified for diagnosis of dementia. Besides this limitation regarding the definite diagnosis of AD by neuropsychology, it is well accepted that the pathology of AD starts years to decades before onset of cognitive symptoms, which limits the value of clinical examination also for early detection of the disease [4]. Following a period free of symptoms, it is assumed that patients go through a stage of mild cognitive impairment (MCI) for 5–10 years (often particularly in the memory domain), before clinically manifest dementia can be diagnosed [5], [6], [7]. Thus, the MCI group is regarded a risk population for AD, important for scientific exploration of the disease in early stages. However, the diagnosis “MCI” can also be based on other factors (vascular pathology, depression, etc.) and not all MCI-patients will develop Alzheimer dementia. Clinical/neuropsychological examination does not permit a reliable identification of the patients with early Alzheimer’s disease in this group [5], [8].

In summary, the early and definite diagnosis of Alzheimer’s disease is hampered by the low sensitivity and specificity of clinical/neuropsychological evaluation and the limited accessibility of brain tissue for histopathological analysis. Furthermore, the specific brain pathology underlying selected cognitive deficits can not be uncovered in vivo without the help of suitable diagnostic tools. Consequently, the search for specific surrogate markers of the disease and for tools for the non-invasive assessment of regional brain pathology in vivo has been intense. Regarding the fact that imaging procedures have been successfully applied for the scientific evaluation of cognitive functions such as memory in vivo, it suggests itself to direct efforts towards the application of different neuroimaging modalities for the improvement of early and specific diagnosis of Alzheimer’s disease in the stage of MCI and for a better understanding of ongoing pathomechanisms of the disease. The general purpose of the assessment of cognitive deficits in AD with imaging tools has been manifold: (1) to improve early diagnosis of the disease in the stage of MCI or even before measurable cognitive symptoms arise, (2) to allow a specific differential diagnosis of the type of disorder, underlying cognitive symptoms, (3) to assess the association of particular symptoms such as memory impairment with type and localization of underlying pathology and in such, to improve understanding of specific pathomechanisms, (4) to learn about the physiologic role particular brain regions play in healthy cognitive function, using AD as a “lesion model”.

It has been shown that modern imaging technologies, such as Magnetic Resonance Imaging (MRI) and Positron Emission Tomography (PET), allow the detection of structural, functional and molecular pathological changes associated with the disease progression and are superior to neuropsychological testing regarding early diagnosis of Alzheimer’s disease [9], [10]. In addition to the improvement of diagnosis, functional imaging procedures have enabled a better correlation of cognitive functional deficits with particular affected brain regions.

Due to the sheer abundance of literature on this matter, the current article will exclusively focus on methods of imaging that allow the visualization of functional changes of neural activity associated with memory decline in AD. Other imaging procedures (MRI volumetry, voxel-based morphometry, etc.) directed to the detection of structural abnormalities (such as hippocampal atrophy), imaging studies of neuronal transmitter and receptor status and modern molecular imaging procedures, which allow detection of specific pathology (amyloid plaque imaging) appearing in the course of AD cannot be discussed here.