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Magnetic resonance imaging (MRI) has opened up the way to diagnose dementia in vivo. It provides clear evidence for hippocampal atrophy in Alzheimer's disease (AD), lobar atrophy in frontotemporal lobar degeneration (FTLD), vascular changes in VaD, and specific findings in some rare forms of dementia. In addition, the traditional role of excluding space-occupying lesions has been kept and the combination of both aspects has rendered MRI indispensable in the diagnostic work-up.

This chapter focuses on the “discovery” of Alzheimer disease (AD) and a somewhat condensed genealogy of its history to the present time. Emphasis is given to the virtual disappearance of AD for over four decades after its initial identification, followed by its rediscovery in the late 1960s in association with government and medical recognition of aging populations and their impending burden on society. The chapter also discusses the consolidation of what has been the dominant research paradigm in AD research for the past four decades-the amyloid cascade hypothesis, grounded in localization theory. Throughout the study, difficulties in attempting to unravel the entanglement of “normal” aging from dementia, evident from Alois Alzheimer's time, are pointed out.

This concluding chapter presents emerging knowledge in both epigenetics and epidemiology, suggesting that forms of prevention that take a public health approach, including lifestyle changes, reduced exposure to toxins, reductions in poverty, increased community support, and other variables, is likely to reduce the prevalence of dementia worldwide to a much greater extent than would an approach confined to expensive molecular micro-medical management of segments of those populations deemed to be at risk that happen to be located in wealthier countries. Furthermore, a molecular approach to Alzheimer disease prevention requires healthy individuals, some as young as 18 years of age, to become research subjects on whom repeated tests will be carried out.

P300 potentials are slow waves that depend on stimuli containing information that the subject must process. The types of stimuli are independent of the sensory modality of the stimuli, and have included auditory, visual, and tactile, among others. The function of these potentials is controversial, but it best correlates with evaluation time when unpredictable events have to be discriminated. At present, these studies can be helpful in distinguishing organic dementia (such as in Alzheimer's disease) from the pseudodementia associated with depression. P300 potentials can be used to evaluate drugs. In addition, abnormalities have been found in schizophrenics, alcoholics and their families, and patients with chronic renal failure. A pre-recorded sequence of intermixed tones is presented in two manners. At first, the subject is instructed to ignore the tone (“ignore” condition). Secondly, the subject is instructed to distinguish the tones (“attend” condition). The desired response occurs only in the latter condition.

The focus of this chapter is predicting cognitive decline or dementia in normal older people using structural imaging. Key questions addressed include the following: What are the major methods, both clinical and imaging, that may help us to predict decline? What underlying pathologies do structural changes preceding decline suggest are developing in the brain? What is the evidence from structural studies that anatomical changes are present before behavioral ones or precede the diagnosis of mild cognitive impairment or dementia? Does imaging provide information about the pace of future decline? What are the limitations of these studies? Finally, what are the implications of structural imaging outcomes for application to the conduct of treatment studies and future research?

Functional neuroimaging in neurodegenerative dementias provides 3D representations of brain activity that are relatively characteristic of the underlying phenotypic distribution of cerebral lesions. They are not specific for a given brain pathology and the heterogeneity of brain diseases must always be considered. However, when methodologies are optimized, the values for sensitivity, specificity, and early diagnostic accuracy approach 80%. A lot of studies have shown that Alzheimer's disease can be distinguished from depression, vascular dementia or frontotemporal dementia, and Lewy body dementia when two techniques are used. General recommendations are to rely on multiple key regions and to combine different neuroimaging techniques to make a differential diagnosis among dementias.

Although the Seattle Longitudinal Study was designed to focus on cognitive changes in normal community-dwelling populations, it is inevitable that a prospective study of aging will eventually include in its successive follow-up cycles individuals who are beginning to show cognitive impairment and eventually may develop full-blown symptoms of dementia. This chapter reports some initial findings on the apolipoprotein E genetic marker of dementia as it relates to cognitive decline. Studies involving the neuropsychological assessment of a community-dwelling sample of older adults who have not previously been identified as suffering from cognitive impairment are described, along with the extension analyses that link the clinical measures with the psychometric battery for the study of normal aging. The chapter ends by analyzing studies that obtain postdicted estimates of earlier performance on the neuropsychological measures and speak to the possibility of early detection of risk for cognitive impairment.

This chapter summarizes the large body of data on the initial organization of the conceptual system. The initial, and perhaps most important, conclusion that can be drawn from the data is that because the first concepts about objects are global in nature, the acquisition process tends to emphasize differentiation. The breakdown of the conceptual system in semantic dementia is discussed.

There is a clear need for biomarkers in neuro-degenerative and psychiatric disorders for both early and differential diagnosis, personalized prediction of treatment response, and in drug discovery. Non-invasive neuroimaging is a key area for biomarker development because it connects behavioural outcomes with structural, functional, and molecular mechanisms. This chapter discusses neuroimaging biomarkers in relation to dementia, schizophrenia, and mood disorders (bipolar and major depressive disorders). The current candidate biomarkers for each disorder are reviewed, across the full range of imaging modalities, followed by an evaluation of their future prospects. The chapter concludes that there has been substantial progress towards personalized neuroimaging-based biomarkers but much remains to be done. Such biomarkers must be validated for specific disorders and may include neuroimaging and non-neuroimaging components.

This chapter reviews the neuropsychological assessment of orbitofrontal functions. It starts by describing the major categories of neurological disorders that result in lesions of the orbitofrontal cortex (OFC). Traditional neuropsychological test batteries are generally insensitive to OFC dysfunction. A number of experimental tasks have been proposed as tests of OFC functions. These include objection alternation and object reversal learning tasks, gambling tasks, go/nogo tasks, olfactory recognition, theory of mind and social processing measures, and self- or family-rating scales of the patient's behavior. The sensitivity and specificity of these measures are discussed, with a particular emphasis on issues of functional localization. The chapter concludes with a description of rehabilitation programs aimed at addressing problems associated with OFC dysfunction.

Patients with frontotemporal dementia (FTD) manifest severe behavioral and personality alterations associated with orbitofrontal cortex (OFC) dysfunction. This chapter provides a review of the clinical features, neuropathology, neuroimaging, genetics, and neuropsychology of FTD as well as presenting two prototypical cases that provide a clinical picture of the disorder. Neuropathological and neuroimaging studies have identified the OFC as the brain region most prominently involved in the frontal-variant of FTD. The neuroanatomy, circuitry, and functions of the OFC are summarized, emphasizing its role in emotional and social cognition. Theories involving deficits in recognition of emotional expression, decision-making, and theory of mind have been proposed to explain the mechanism underlying the clinical expression of FTD, and the OFC is intimately involved in studies examining the neural basis underlying these deficits.

This chapter focuses on cognitive functioning in late adulthood. It discusses three related topics: dementia, the preclinical phase of dementia, and the risk factors for cognitive decline and dementia. Dementia, and Alzheimer's disease in particular, is characterized by severe impairment in cognitive functioning. It is a particularly devastating disease because it destroys one's sense of self, and there are currently no effective treatments to prevent or even delay the disease. Research has revealed differences in cognitive performance between individuals who will and will not develop the disease several years prior to the eventual diagnosis. However, what is responsible for these relations and whether it is meaningful to refer to a distinct diagnostic category are still controversial issues.

In depression, a fluoxetine treatment and a placebo treatment affect similar brain regions. In addition, covert (unexpected) administration of anti-anxiety drugs is less effective than overt (expected) administration, which indicates the key role of expectation in anti-anxiety therapy. In dementia, the disruption of prefrontal executive control in Alzheimer's disease may decrease the magnitude of placebo responses, and expectations appear to be particularly important when associated to the effects of drugs of abuse. In general, placebo effects appear to be powerful in psychotherapy and, interestingly, the brain areas involved in the psychotherapeutic outcome are different from those involved in the placebo effect, which suggests different underlying mechanisms.

This chapter presents a case study that illustrates the interplay between ethical conceptual analysis and neuroscientific findings in the resolution of moral dilemmas that arise in Alzheimer's disease. It defends the philosophical view that the immediate interests of an individual cannot be overridden as long as the individual possesses the capacity to value. In the context of each particular neurodegenerative disease, this recommendation must be guided by a scientifically informed assessment of when in the course of the disease the capacity to value could possibly be lost, and when it is likely to be retained. In the case of Alzheimer's disease, neuroscientific evidence indicates that the capacity to value is slowly and gradually weakened, and in some cases may not be completely lost until relatively far along in the disease's progression. Similar neuroethical analyses must be carried out for other diseases and disorders, and will probably yield different results.