Neural correlates of Alzheimer's disease and mild cognitive impairment: A systematic and quantitative meta-analysis involving 1351 patients
Introduction
Alzheimer's disease (AD) is the most common form of dementia (Blennow et al., 2006, Cummings, 2004). Its prevalence is below 1% in individuals aged 60–64 years, but shows an almost exponential increase with age, so that in people aged 85 years or older the prevalence is between 24% and 33% in the Western world. In 2001, more than 24 million people had dementia, a number that is expected to double every 20 years up to 81 million in 2040. Accordingly, AD is a major public health problem. The majority of patients suffer from sporadic AD, whereas familial AD is a very rare autosomal dominant disease with early onset before 48 years of age and prevalence below 0.1% (Reisberg, 2006). AD is a slowly progressive disorder, with insidious onset and early impairment of episodic memory; other signs include impaired judgment, decision-making, orientation, aphasia, apraxia, and agnosia (Blennow et al., 2006, Caselli et al., 2006, Hodges, 2006). Histopathological changes consist of amyloid β aggregation and deposition in senile or neuritic plaques, and of tau hyperphosphorylation with formation of neurofibrillary tangles in medial temporal and other cortical regions, starting already 20–30 years before clinical onset and finally injuring neurons and synapses (Blennow et al., 2006).
The preclinical phase is designated amnestic mild cognitive impairment (MCI) (Gauthier et al., 2006, Petersen et al., 1999, Petersen et al., 2001a, Petersen et al., 2001b, Petersen, 2004, Schott et al., 2006). It is defined as memory complaints and deficits, which are greater than expected for an individual's age and education level but do not interfere notably with activities of daily life such as in dementia. Some people with MCI remain stable or return to normal over time, but more than half progress to dementia within 5 years. Because the identification of MCI as a risk state for AD might enable disease modifying treatment strategies in the future, one of the most important challenges for neuroimaging is discriminating MCI patients progressing later to AD from patients who will not (Chong and Sahadevan, 2005, Gauthier et al., 2006, Klafki et al., 2006, Schott et al., 2006).
Internationally accepted ante mortem diagnostic criteria for AD/MCI are based on clinical symptoms (American Psychiatric Association, 1987, American Psychiatric Association, 1994, McKhann et al., 1984, Petersen et al., 1999, Petersen et al., 2001a, Petersen et al., 2001b, Petersen, 2004, World Health Organization, 1993). These criteria have now fallen behind the unprecedented growth of scientific knowledge regarding biomarkers for AD/MCI, namely structural and functional neuroimaging. It was proposed to incorporate these biomarkers into revised diagnostic criteria in the future (Dubois et al., 2007, Hyman, 2007, Reisberg, 2006).
Accordingly, one aim of the present meta-analysis was to characterize the prototypical neural substrates of AD and its prodromal stage amnestic MCI. We applied the systematic and quantitative meta-analytic approach as suggested by Turkeltaub et al. (2002), which is considered the most sophisticated and best-validated of coordinate-based voxel-wise meta-analyses (Fox et al., 2005). This method can extract the prototypical neural networks for AD and MCI, because it considers only peak coordinates for each region, whether small or large. We included morphometric studies investigating brain atrophy with magnetic resonance imaging (MRI) and imaging studies measuring reduction in glucose utilization or in perfusion with positron emission tomography (PET) or single photon emission computed tomography (SPECT) during rest. Moreover, we wanted to isolate neural markers predicting conversion from amnestic MCI to AD. Because AD progressively impairs episodic memory (Blennow et al., 2006, Hodges, 2006), we hypothesized alterations in the medial temporal lobes, medial diencephalon, parietal cortex and prefrontal regions (Braak and Braak, 1991a, Braak and Braak, 1991b, Braak and Braak, 1995, Braak et al., 1996, Brand and Markowitsch, 2005, Cabeza and Nyberg, 2000, Cavanna and Trimble, 2006, Hyman et al., 1984, Petersen et al., 2006, Wagner et al., 2005). Furthermore, we postulated that alterations of these brain regions may predict conversion from amnestic MCI to AD.
Section snippets
Data sources and study selection
MedLine and Current Contents search engines were used to identify studies on morphometry, glucose utilization and perfusion in AD and MCI (search strategy: [Alzheimer or [mild and cognitive and impairment]] and [MRI or MRT or PET or SPECT]) published until February 2007. Primary authors were contacted to obtain additional information if necessary. Studies were examined to fulfill the following inclusion criteria: peer-reviewed, original studies, patients diagnosed according to internationally
Trial flow and study characteristics
Fig. 1 shows the meta-analysis flow. The initial search yielded for MCI/AD 311/1703 studies. Finally, 14/26 studies met inclusion and exclusion criteria and were included into the meta-analysis (Tables S1 to S3 in the supplementary information). Table 1 illustrates the number of studies, the number of subjects and clinical characteristics for the several groups. In sum, 1351 patients (826 with AD, 525 with amnestic MCI) and 1097 healthy control subjects were involved in the meta-analysis. We
Discussion
We applied a systematic and quantitative meta-analytic approach to characterize the prototypical neural substrates of AD/amnestic MCI and to isolate neural markers predicting the conversion from amnestic MCI to AD. It revealed specifically for each imaging method the impaired neural networks for AD and MCI. Results for AD agree with a previous comprehensive meta-analysis that calculated effect sizes for various predefined anatomical regions (Zakzanis et al., 2003). Because more relevant studies
Conclusion
The meta-analysis characterizes the prototypical neural substrates of Alzheimer's disease and its prodromal stage amnestic mild cognitive impairment with a systematic and quantitative meta-analysis. It places Alzheimer's disease in cognitive neuropsychiatry by explaining clinical characteristics in terms of deficits to normal cognitive mechanisms and linking them to affected neural structures. By isolating predictive markers it contributes to standardized imaging inclusion criteria for
Acknowledgments
Jane Neumann is supported by the NIH (Grant Number: R01 MH74457; PI: Peter Fox). The authors would like to thank Stefan Frisch for helpful suggestions during the preparation of the manuscript and Stefan Liebig for help in preparing the figures.
References (118)
- et al.
Alzheimer's disease
Lancet
(2006) - et al.
Self-projection and the brain
Trends Cogn. Sci.
(2007) - et al.
Functional imaging of autobiographical memory
Trends Cogn. Sci.
(2007) - et al.
The Talairach coordinate of a point in the MNI space: how to interpret it
NeuroImage
(2005) - et al.
Preclinical Alzheimer's disease: diagnosis and prediction of progression
Lancet Neurol.
(2005) - et al.
Rates of forgetting in Alzheimer dementia
Neuropsychologia
(1998) - et al.
Research criteria for the diagnosis of Alzheimer's disease: revising the NINCDS-ADRDA criteria
Lancet Neurol.
(2007) Parahippocampal and retrosplenial contributions to human spatial navigation
Trends Cogn. Sci.
(2008)- et al.
Functional imaging of theory of mind
Trends Cogn. Sci.
(2003) - et al.
Mild cognitive impairment
Lancet
(2006)
A quantitative meta-analysis of voxel-based morphometry studies in schizophrenia: application of anatomical likelihood estimation
Biol. Psychiatry
Deconstructing episodic memory with construction
Trends Cogn. Sci.
The distributed human neural system for face perception
Trends Cogn. Sci.
The prediction of rapid conversion to Alzheimer's disease in mild cognitive impairment using regional cerebral blood flow SPECT
NeuroImage
Tensor-based morphometry as a neuroimaging biomarker for Alzheimer's disease: an MRI study of 676 AD, MCI, and normal subjects
NeuroImage
Voxel- and VOI-based analysis of SPECT CBF in relation to clinical and psychological heterogeneity of mild cognitive impairment
NeuroImage
Semantic memory and the brain: structure and processes
Curr. Opin. Neurobiol.
Improving the quality of reports of meta-analyses of randomised controlled trials: the QUOROM statement
Lancet
The nature and staging of attention dysfunction in early (minimal and mild) Alzheimer's disease: relationship to episodic and semantic memory impairment
Neuropsychologia
Aging, sexual dimorphism, and hemispheric asymmetry of the cerebral cortex: replicability of regional differences in volume
Neurobiol. Aging
Pain processing in dementia and its relation to neuropathology
Lancet Neurol.
Age-dependency of the hemodynamic response as measured by functional near-infrared spectroscopy
NeuroImage
Perception of affect in patients with dementia of the Alzheimer type
Arch. Neurol.
Diagnostic and Statistical Manual of Mental Disorders.
Diagnostic and Statistical Manual of Mental Disorders.
Inhibitory functioning in Alzheimer's disease
Brain
Neurofibrillary tangles but not senile plaques parallel duration and severity of Alzheimer's disease
Neurology
Immunotherapy targeting pathological tau conformers in a tangle mouse model reduces brain pathology with associated functional improvements
J. Neurosci.
The decline of working memory in Alzheimer's disease: a longitudinal study
Brain
Attentional control in Alzheimer's disease
Brain
Stability of the preclinical episodic memory deficit in Alzheimer's disease
Brain
Multiple cognitive deficits during the transition to Alzheimer's disease
J. Intern. Med.
Cognitive impairment in preclinical Alzheimer's disease: a meta-analysis
Neuropsychology
Neocortical neurofibrillary tangles correlate with dementia severity in Alzheimer's disease
Arch. Neurol.
The hippocampus and memory: insights from spatial processing
Nat. Rev., Neurosci.
A longitudinal study of language decline in Alzheimer's disease and frontotemporal dementia
J. Int. Neuropsychol. Soc.
Evidence of subtypes of Alzheimer's disease and implications for etiology
Arch. Gen. Psychiatry
Alzheimer's disease affects limbic nuclei of the thalamus
Acta Neuropathol.
Neuropathological stageing of Alzheimer-related changes
Acta Neuropathol.
Staging of Alzheimer's disease-related neurofibrillary changes
Neurobiol. Aging
Pattern of brain destruction in Parkinson's and Alzheimer's diseases
J. Neural. Transm.
Amnesia I: clinical and anatomical issues
Molecular, structural, and functional characterization of Alzheimer's disease: evidence for a relationship between default activity, amyloid, and memory
J. Neurosci.
Imaging cognition II: an empirical review of 275 PET and fMRI studies
J. Cogn. Neurosci.
Heterogeneity of semantic and visuospatial deficits in early Alzheimer's disease
Neuropsychology
Anterior cingulate cortex, error detection, and the online monitoring of performance
Science
Alzheimer's disease a century later
J. Clin. Psychiatry
The precuneus: a review of its functional anatomy and behavioural correlates
Brain
Patterns of cognitive decline in presymptomatic Alzheimer disease: a prospective community study
Arch. Gen. Psychiatry
Direct voxel-based comparison between grey matter hypometabolism and atrophy in Alzheimer's disease
Brain
Cited by (278)
-
Relationship between neuroimaging and emotion recognition in mild cognitive impairment patients
2024, Behavioural Brain Research -
Multiclass prediction of different dementia syndromes based on multi-centric volumetric MRI imaging
2023, NeuroImage: Clinical -
The Association Between Neurocognitive Disorders and Gustatory Dysfunction: A Systematic Review and Meta-Analysis
2024, Neuropsychology Review