The neurometabolic landscape of cognitive decline: in vivo studies with positron emission tomography in Alzheimer’s disease

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Abstract

Alzheimer’s disease, the most common form of dementia in the elderly, is characterized by the progressive, global and irreversible deterioration of cognitive abilities. The development of positron emission tomography (PET) methodologies has made it possible to study the in vivo brain metabolic correlates of human cognitive and behavioral functions. Moreover, as PET scan examinations can be repeated, the progression of the neuropathological process and its relation to cognitive dysfunction can be followed over time. In an effort to understand the changes in neural function that precede and accompany onset of dementia and their relation to clinical manifestations, in the last several years, we have conducted clinical, neuropsychological and brain metabolic studies in groups of Alzheimer’s disease patients at different stages of dementia severity or with distinct clinical pictures and in populations at risk for developing the disease. Here, we discuss the main findings and implications obtained from these studies.

Introduction

Alzheimer’s disease, which affects 5–10% of people over 65 years of age and up to 47% of those aged 85 years or older (Evans et al., 1989, Bachman et al., 1992), is the most common cause of primary progressive dementia, followed by cerebrovascular and other neurodegenerative diseases, including Pick’s dementia (Chui, 1989). Alzheimer’s disease is characterized by a progressive, global, and irreversible deterioration of cognitive functions, which usually begins with memory problems, followed by deficits in language, mathematical, and visuospatial skills, abstract thinking, and planning, as well as personality and behavioral changes. From a neuropathological point of view, the brains of patients with Alzheimer’s disease show heterogeneous regional accumulations of neuritic plaques and neurofibrillary tangles especially in the neocortical association areas of the temporal and parietal lobes, with relative sparing of primary motor and sensory cortical regions (Arnold et al., 1991). Macroscopically, there is evidence of progressive cortical atrophy, associated with increases in ventricular and cortical cerebrospinal fluid space (Rusinek et al., 1991).

In the last two decades, the development of positron emission tomography (PET) methodologies has made it possible to study the in vivo biochemical correlates of cognitive and behavioral functions in human beings (Mazziotta et al., 1981, Mazziotta et al., 1982, Holcomb et al., 1989, Pietrini et al., 1998b, Pietrini et al., 1999a, Kety, 1999, Rapoport, 1999; Pietrini and Rapoport, in press). Using different compounds labelled with positron-emitting nuclides, PET can provide measures of cerebral glucose metabolism, blood flow and neurotransmitter metabolism in a variety of physiological conditions and can be used to evaluate the effects of neurological or psychiatric disorders (Holcomb et al., 1989). In neurodegenerative disorders, such as Alzheimer’s disease, these methods that allow for in vivo brain metabolic measurements offer an unprecedented opportunity to determine the effects of the pathological process on brain function throughout the course of disease (including subtle changes in the preclinical stages of disease to aid in early diagnosis), to assess the relation between the regional distribution of the pathology and distinct symptomatological or cognitive manifestations in clinical subtypes, and to evaluate the response to potential therapeutic interventions Furey et al., 1997, Furey et al., 2000.

Over the last several years, we have studied brain metabolic functions in healthy individuals at different ages and in distinct clinical groups, including patients with Alzheimer’s disease or subjects at risk for developing Alzheimer’s disease, in an effort to determine the changes in neural activity that precede and accompany cognitive decline (Fig. 1). Recently, we also have begun to investigate brain metabolic functions in subjects with sleep apnea syndrome (SAS), a disorder characterized by repeated episodes of temporary cessation of breathing during sleep that lead to brain hypoxia and sleep fragmentation. Patients with SAS present some degree of cognitive impairment which resembles aspects of the decline that is observed in patients with early Alzheimer’s disease. However, while cognitive decline in patients with Alzheimer’s disease is inexorably progressive, it is possible to at least partially reverse neuropsychological dysfunction in subjects with SAS using available treatments, providing a unique clinical model to examine the metabolic changes that occur in the brain in relation to dysfunction and recovery of cognitive abilities (Pietrini et al., 1998a).

In this paper, we will provide a brief background on the metabolic bases of neural activity, followed by a presentation of results from our studies of cerebral metabolism with PET in patients with Alzheimer’s disease to demonstrate how in vivo assessments of neurometabolic functions can enhance our understanding of the neurobiological correlates of cognitive decline.

Section snippets

Relation of cerebral glucose metabolism to neural activity

Regional cerebral metabolic rates for glucose (rCMRglc), as determined using PET with 18F-fluoro-2-deoxy-d-glucose (18FDG), represents a reliable index of functional synaptic activity in the human nervous system (Sokoloff et al., 1977, Reivich et al., 1979, Sokoloff, 1981, Mazziotta et al., 1981, Mazziotta et al., 1982, Holcomb et al., 1989, Pietrini et al., 1999a, Pietrini and Rapoport, 2000).

Adenosine triphosphate (ATP), the main energy carrier in the cell, is produced in the brain almost

Cerebral glucose metabolism in Alzheimer’s disease

Beginning in the early 1980s, many studies have been conducted with PET to compare regional cerebral glucose metabolism in patients with Alzheimer’s disease at different stages of dementia severity and in healthy controls (Rapoport, 1998, for a review). In agreement with autopsy studies that demonstrated a variable distribution of neurofibrillary tangles in Alzheimer’s disease brains, studies using PET with 18FDG in the ‘resting-state’ (eyes covered/ears plugged, minimal sensory stimulation)

Distinct distribution of brain metabolic abnormalities in the clinical subtypes of Alzheimer’s disease: the visual variant

Assessments of cerebral metabolism also can help to identify distinct pathophysiological features in relation to different symptomatological and cognitive patterns observed in clinical subtypes of Alzheimer’s disease. A relatively rare clinical subtype of Alzheimer’s disease is characterized by early and prominent disturbances of visuospatial functions, in the absence of memory complaints. While visual functions also may become impaired in patients with typical Alzheimer’s disease, in this

Cerebral glucose metabolic abnormalities in the preclinical stages of Alzheimer’s disease: a tool for early diagnosis?

The abnormalities in brain metabolic functions discussed above are described in patients who had already received a diagnosis of possible or probable Alzheimer’s disease based on standardized research criteria (McKhann et al., 1984). That is, in these patients, dementia was already evident based on clinical observations. In the last few years, however, scientists working in this field have been trying to identify early changes in brain metabolic function that could lead to a diagnosis of

Brain metabolic response progressively declines with worsening dementia

The use of stimulation paradigms with PET can facilitate the investigation of changes in neuronal/synaptic efficiency in patients with Alzheimer’s disease as a function of dementia severity. The audiovisual stimulation paradigm described above offers the advantage of requiring no active performance from the patient and therefore can be used successfully to evaluate brain metabolic responses in severely demented subjects who have minimal compliance and would be otherwise completely unable to

Conclusions

The development of methodologies for the in vivo, non-invasive measurement of biochemical processes in the human brain has represented a major step forward for studying the neurophysiological basis of mental functions. Brain metabolic studies have begun to elucidate the neurobiological substrate of cognition in healthy subjects, and to determine the changes that occur in relation to neuropathological processes, such as in patients with Alzheimer’s disease.

In these individuals, subtle brain

Acknowledgements

The authors wish to thank Drs Stanley I. Rapoport, Mark B. Schapiro and Alessio Dani for their dedicated support to the research projects presented in this review; Dr Peter Herscovitch for the excellent organization of the PET facilities at the NIH; the PET Dept. technologists, headed by Paul Baldwin, for their precious assistance with PET scanning. Supported by the NIH Intramural Program. Dr Guazzelli was partially supported by the Italian Minister of University and Scientific and

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