Differentiation of Alzheimer's disease from dementia with Lewy bodies utilizing positron emission tomography with [18F]fluorodeoxyglucose and neuropsychological testing
Introduction
We are pleased to contribute to this special edition of Experimental Neurology honoring the 15-year tenure of Dr. John Sladek as Editor-in-Chief of the journal. Dr. Sladek had a profound influence on the journal, improving its quality and focusing its content upon the newly emerging fields of neuronal transplantation, plasticity, and regeneration while continuing to encourage publication of articles in the broad field of experimental neurology. He also improved the size and appearance of the journal, bringing it distinctively into the modern era. In appreciation of his accomplishments, we present in this communication a new study involving experimental approaches to two common neurological disorders affecting principally the elderly.
Alzheimer's disease (AD) accounts for 50–60% of cases of dementia in the elderly, and dementia with Lewy bodies (DLB) appears to be the second most frequent cause, occurring in 15–25% of cases (Heidebrink, 2002). The neuropathological features of AD include widespread neuronal loss, neurofibrillary tangles affecting many surviving neurons, and deposition of beta-amyloid plaques (Trojanowski et al., 1997). DLB involves widespread neuronal degeneration with deposition of Lewy bodies and Lewy neurites, which contain alpha-synuclein as a major filamentous component (Galvin et al., 1999). Substantial neuronal loss occurs in the substantia nigra with consequent marked decrease in the density of nigrostriatal projections. Despite the distinctive pathology in these two common forms of dementia, many cases of dementia in the elderly show the neuropathological changes of both AD and DLB (Gearing et al., 1999).
Recent progress in neuroscience and particularly in neurotherapeutics makes it possible that disease-modifying therapy may become available for AD within the next decade. Consequently, early diagnosis of this disorder has become important, particularly to differentiate patients with early pure AD from those with early DLB or early AD plus DLB. To this end, surrogate markers for these diseases have been sought intensively. Positron emission tomography (PET) with [18F]fluorodeoxyglucose ([18F]FDG) shows a distinctive profile of cerebral hypometabolism in AD, involving initially the posterior cingulate cortex (Minoshima et al., 1997), then posterior parietotemporal regions (Foster et al., 1983), and later prefrontal regions (Minoshima et al., 1995). The metabolic profile of DLB similarly displays widespread cerebral hypometabolism with marked decreases in association cortices and relative sparing of subcortical structures and primary somatomotor cortex, but unlike AD, hypometabolism also affects the primary visual cortex and occipital association cortex Albin et al., 1996, Imamura et al., 1997, Minoshima et al., 2001, Vander Borght et al., 1997. Similar results are reported with single photon emission computed tomography (SPECT) with 99m Tc-HMPAO or 99m Tc-ECD to compare regional cerebral blood flow in AD and DLB Donnemiller et al., 1997, Lobotesis et al., 2001.
Neuropsychological studies have demonstrated differences between AD and DLB patients in a variety of cognitive domains, including visual spatial skills, language, attention, and memory Calderon et al., 2001, Galasko et al., 1996, Hansen et al., 1990, Noe et al., 2004. Although there is some variability across reports, AD patients generally show more impairments in memory and naming skills in comparison to DLB, whereas DLB patients show relatively greater abnormalities of visual–spatial functioning, attention, verbal fluency, and fine motor/psychomotor speed.
We report here a study of DLB and AD comparing the utility of PET with [18F]FDG to examine cerebral metabolic profiles with neuropsychological testing and with evaluation of motor function by a family member. The study was designed to determine whether studies of cerebral metabolism would verify previously described differences between groups and whether neuropsychological profiles provide equally useful means of differentiating between groups. This study is unique in comparing evaluation of cerebral metabolism with neuropsychological patterns in distinguishing these groups. We selected patients with well-established disorders across a range of dementia with the intention of examining patients with early dementia in a later study.
Section snippets
Subject selection
The study was approved by the Institutional Review Board of the University of Michigan Medical School, and informed consent was obtained from all participants or their caregivers. Sixty-four subjects were studied, including 25 with AD aged 69.3 ± 9.1 years (mean ± SD, range 52–85 years, 7 males and 18 females); 20 with DLB aged 72.8 ± 7.2 years, (range 54–81 years, 15 males and 5 females); and 19 normal elderly controls aged 69.1 ± 7.6 years, (range 55–86 years, 10 males and 9 females).
Subject group comparisons
The three groups did not differ in mean age (P = 0.15), but the AD group contained a higher ratio of females to males than the DLB group (P = 0.003). There was no difference in duration of symptoms between the two patient groups (5.4 ± 2.8 years in DLB and 5.3 ± 2.8 years in AD, P = 0.89).
Neuropsychological results
No significant differences between the two patient groups were found for MMSE, confrontational naming, or verbal learning (Table 1). The DLB group was significantly more impaired than the AD group in verbal
Discussion
This comparison of the relative utility of neuropsychological testing and PET scanning with [18F]FDG in the diagnosis of well-established cases of AD and DLB shows a clear difference between the two approaches. Although neither global lCMRglc values nor values in the regions typically affected in AD (posterior cingulate cortex, lateral temporal, and superior parietal) showed differences between groups, the occipital cortex, particularly Brodmann areas 17 and 18, was markedly different between
Acknowledgements
This study was supported in part by NIH grants P50 AG08671 from the National Institute of Aging and P01 NS15655 from the National Institute of Neurological Disorders and Stroke.
We thank Drs. Roger Albin, Nancy Barbas, Norman L. Foster, Douglas Gelb, Judith Heidebrink, Kirk Frey, and R. Scott Turner for thoroughly evaluating and referring these patients to this study.
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