Imaging of amyloid plaques and cerebral glucose metabolism in semantic dementia and Alzheimer’s disease
Introduction
Semantic dementia (SD) is a rare clinical syndrome which has been assigned to the frontotemporal lobar degenerative disorders (FTLD), which include other subtypes such as progressive non-fluent aphasia or frontotemporal dementia (Neary et al., 1998). The main symptoms of SD include selective impairment of semantic memory, impaired naming and word comprehension and impaired knowledge about persons and objects. Speech is usually fluent, with normal articulation. These symptoms can be somewhat similar to the typical symptoms in dementia of the Alzheimer type (AD), however, in contrast to AD, in SD working-memory functions, visuospatial functions and the autobiographical (episodic) memory are often relatively spared (Garrard and Hodges, 2000, Grossman, 2002, Neary et al., 1998, Snowden, 1999, Tolnay and Probst, 2001).
In general, the incidence of FTLD is lower than that of AD. Approximately, 15% of all early-onset dementias have been classified as FTLD in epidemiologic studies, with SD ranging between 11% and 36% of all FTLD cases. However, it has been discussed that all FTLD syndromes may be occasionally underdiagnosed due to diagnostic difficulties (Ikeda et al., 2004, Johnson et al., 2005, Snowden, 1999). The average age of onset of the FTLD-types of dementia is younger (between 45 and 65 years) compared to AD which usually starts in patients older than 65 years. In published cases of SD, the mean age has been reported to be ∼ 58–59 years (Garrard and Hodges, 2000, Johnson et al., 2005). Due to its rapid progression, the prognosis of FTLD is considered worse than that of AD, although a recent study showed comparable progression rates of SD and AD (Roberson et al., 2005).
In the small number of SD cases that underwent postmortem histopathological analysis, ubiquitin pathology has been most commonly described. Only recently, mutations leading to a loss of function of the progranulin glycoprotein have been identified in ubiquitin-positive FTLD (Goedert and Spillantini, 2006). Amyloid plaques – one of the major pathological hallmarks in AD – have rarely have been described in FTLD in general and particularly in SD (Davies et al., 2005, Garrard and Hodges, 2000, Johnson et al., 2005, Shi et al., 2005). However, in principle, atypical forms of AD may clinically present as SD, and vice versa. Generally, SD is a clinical syndrome and no single characteristic underlying pathology is necessarily associated with the SD-type symptom complex (Garrard and Hodges, 2000, Neary et al., 2000). Diagnosis based on neuropsychological criteria alone will not be able to assess underlying pathology and to reliably differentiate SD based on non-amyloid pathology from atypical AD clinically presenting with SD-like symptoms (Neary et al., 1998). Postmortem studies demonstrate that clinical diagnosis alone leads to confusion of FTLD and AD in some cases (Godbolt et al., 2005).
In functional imaging studies, abnormalities of cerebral glucose metabolism and perfusion have been well established with F-18 Fluorodeoxyglucose (FDG) PET and perfusion SPECT in AD. Characteristic bilateral temporoparietal and frontal cortical abnormalities have been shown and the value of functional imaging, particularly of FDG PET, for early and differential diagnosis of dementia has often been confirmed (Drzezga et al., 2005, Herholz, 1995, Minoshima, 2003, Mosconi, 2005, Silverman et al., 2001). SPECT and FDG PET studies also have been performed in SD. The predominant finding in SD was temporal cortical hypometabolism/hypoperfusion (with the left temporal lobe often being more severely affected), but frontal cortical abnormalities also were present in some cases (Diehl et al., 2004, Garrard and Hodges, 2000, Grossman, 2002, Nestor et al., 2006). This pattern of cerebral hypometabolism in SD can show some similarities to AD, particularly the involvement of temporal lobes. In AD, however, more extensive extratemporal abnormalities have been consistently described (Nestor et al., 2006). In morphological MRI studies temporal and frontal atrophy has been demonstrated in SD. Recent comparative volumetric MRI studies showed atrophic changes of the medial temporal lobes in both AD and SD, with more asymmetry and greater left-sided and anterior involvement in SD (Chan et al., 2002, Davies et al., 2005, Galton et al., 2001, Garrard and Hodges, 2000, Nestor et al., 2006). In summary, symptoms and imaging findings in SD may resemble AD to some extent, but specific differences can be found.
Recently, in vivo PET tracers for amyloid plaque imaging have been introduced, such as the naphthylethylidene-derivative [18F]FDDNP or the thioflavine-T-derivative [11C]6-0H-BTA-1 termed Pittsburgh Compound-B (PIB) (Klunk et al., 2004, Villemagne et al., 2005). First studies using these tracers were able to demonstrate amyloid plaque deposition in vivo in patients with AD in several cortical areas such as temporoparietal and frontal cortex (Klunk et al., 2004, Shoghi-Jadid et al., 2002). Postmortem studies indicate that the binding of [11C]PIB is dominated by the amyloid component and not by other abnormalities, such as Tau-pathology (Bacskai et al., 2003). Based on postmortem histopathological data, we hypothesized that no comparable cerebral amyloid plaque deposition would be found using amyloid imaging in the majority of patients with clinical SD. If true, this would support the role of amyloid plaque imaging for assessment of underlying pathology and for differential diagnosis of dementing disorders. To our knowledge, no specific findings using amyloid plaque imaging in SD as a clearly defined clinical subgroup of FTLD have been reported.
Thus, the aim of the current study was to evaluate if AD and SD can be differentiated with [11C]PIB amyloid plaque imaging in vivo. SD was chosen as a clearly defined example of the frontotemporal lobar degenerative disorders. Furthermore, we planned to compare findings of amyloid plaque imaging with differences in cerebral metabolism determined with [18F]FDG-imaging between the two groups and to correct our findings for potential effects of atrophy.
Section snippets
Inclusion and exclusion criteria
Patients were recruited from the research unit for cognitive disorders at the department of psychiatry, Technical University of Munich (TUM), Germany. They had been referred for the diagnostic evaluation of cognitive impairment by general practitioners, neurologists, or psychiatrists, or from other institutions and underwent a standardized diagnostic protocol. All examinations were part of their routine check-up in the course of the evaluation of the patient’s neurodegenerative disorders.
Patient characteristics at baseline
Based on the above inclusion and exclusion criteria, 8 patients with SD and 8 individuals with AD were included in the study (see Table 1). Both groups were comparable according to gender distribution and cognitive performance (MMSE, CDR). On average, AD patients were slightly older than the SD group (as expected due to the typically later onset of dementia in AD), the difference, however, did not reach statistical significance. Distribution of APOE-genotype varied between the groups, with
Discussion
In the current study, characteristic hypometabolic patterns were observed using [18F]FDG PET in AD and SD by visual analysis and statistical comparison with a healthy control group. The abnormalities included typical temporoparietal, posterior cingulate and frontal hypometabolism in AD, sparing sensorimotor and occipital cortex. In SD, bilateral temporal (left > right, including polar portions) and frontal mesial hypometabolism was found. In accordance with previous studies, some asymmetry of the
Conclusion
In matched groups of clinically defined patients with Alzheimer’s disease and patients with semantic dementia, cerebral glucose metabolism was examined using [18F]FDG PET and amyloid plaque load was assessed using [11C]PIB PET. Using voxel-based comparison, typical cerebral hypometabolic abnormalities were observed in both patient groups compared to healthy controls. Between AD and SD some regional overlap of the hypometabolic patterns was observed as well as subtle differences, which may
Acknowledgments
We thank the team of the medical technicians for their assistance and the radiochemistry group for their reliable supply of radiopharmaceuticals. We also wish to thank all participants of the study and their families for their commitment to this work. This work has been supported in part by a DFG-grant (Deutsche Forschungsgemeinschaft) Project Number: HE 4560/1-2 (A. Drzezga, G. Henriksen, H.J. Wester) and by a KKF-grant for clinical research of the Technische Universität München (A. Drzezga).
References (49)
- et al.
Cerebral metabolic patterns at early stages of frontotemporal dementia and semantic dementia. A PET study
Neurobiol. Aging
(2004) - et al.
Thresholding of statistical maps in functional neuroimaging using the false discovery rate
NeuroImage
(2002) - et al.
IC-103-05 Pittsburgh Compound-B four years later: what have we learned, what lies ahead?
Alzheimer’s and Dementia: J. Alzheimer’s Assoc.
(2006) Imaging Alzheimer’s disease: clinical applications
Neuroimaging Clin. N. Am.
(2003)- et al.
Declarative memory impairments in Alzheimer’s disease and semantic dementia
NeuroImage
(2006) - et al.
Localization of neurofibrillary tangles and beta-amyloid plaques in the brains of living patients with Alzheimer disease
Am. J. Geriatr. Psychiatry
(2002) - et al.
Automated anatomical labeling of activations in SPM using a macroscopic anatomical parcellation of the MNI MRI single-subject brain
NeuroImage
(2002) - et al.
Imaginem oblivionis: the prospects of neuroimaging for early detection of Alzheimer’s disease
J. Clin. Neurosci.
(2005) - et al.
Evaluation of voxel-based methods for the statistical analysis of PIB PET amyloid imaging studies in Alzheimer’s disease
NeuroImage
(2006) - et al.
Four-dimensional multiphoton imaging of brain entry, amyloid binding, and clearance of an amyloid-beta ligand in transgenic mice
Proc. Natl. Acad. Sci. U. S. A.
(2003)
Normal ranges of neuropsychological tests for the diagnosis of Alzheimer’s disease
Stud. Health Technol. Inform.
Patterns of temporal lobe atrophy in semantic dementia and Alzheimer’s disease
Ann. Neurol.
Differing patterns of temporal atrophy in Alzheimer’s disease and semantic dementia
Neurology
The pathological basis of semantic dementia
Brain
Prediction of individual clinical outcome in MCI by means of genetic assessment and (18)F-FDG PET
J. Nucl. Med.
Two-year follow-up of amyloid deposition in patients with Alzheimer’s disease
Brain
Inverse relation between in vivo amyloid imaging load and cerebrospinal fluid Abeta42 in humans
Ann. Neurol.
The relationship between global and local changes in PET scans
J. Cereb. Blood Flow Metab.
Statistical parametric mapping in functional imaging: a general linear approach
Hum. Brain Mapp.
Differing patterns of temporal atrophy in Alzheimer’s disease and semantic dementia
Neurology
Semantic dementia: clinical, radiological and pathological perspectives
J. Neurol.
Sporadic and familial dementia with ubiquitin-positive tau-negative inclusions: clinical features of one histopathological abnormality underlying frontotemporal lobar degeneration
Arch. Neurol.
Frontotemporal lobar degeneration through loss of progranulin function
Brain
Frontotemporal dementia: a review
J. Int. Neuropsychol. Soc.
Cited by (0)
- 1
Both authors contributed equally.