Pathologic issues and new methodologies in the evaluation of non-Alzheimer dementias
Introduction
This chapter will highlight a variety of neuropathologic considerations in studies of non-AD dementias, including disorders commonly encountered in centers with an academic interest in dementia (diffuse Lewy body disease (dLBD), fronto-temporal dementias (FTDs)) and those seen much less often (e.g. progressive supranuclear palsy (PSP), corticobasal ganglionic degeneration (CBGD)). Our ability to diagnose these disorders has evolved as their nosology has become more clearly defined in recent years; however, among some non-AD dementias there remains much confusion as to their precise morphologic substrates and clinical manifestations, how these are most accurately ascertained by the neuropathologist, and precisely what features distinguish one entity from another. Indeed, the question often arises as to whether they are simply subtle variants of a single group of diseases. The tools of quantitative morphometry and immunohistochemistry (the latter especially incorporating primary antibodies to newly discovered cytoskeletal and synaptic components) have proven remarkably illuminating in the descriptive neuropathologic approach to their characterization [1], [2], [3].
The rate-limiting factor in providing detailed characterizations of the rarest non-AD dementias is often this ‘rarity’ itself, i.e. with few exceptions any given center lacks the numbers of well characterized cases to allow for meaningful ‘between case’ comparisons. In theory, this problem could be easily overcome by sharing of case material among centers in a way analogous to this ongoing process in the NIA-funded network of Alzheimer Disease Centers (ADCs) within the USA. As well, brain banks with a focus on rare dementias accumulate meaningful numbers of such cases. Successful ‘consensus conferences’ have already been convened to discuss clinical and neruropathologic diagnostic criteria for several of these diseases, while detailed investigations have illuminated the unique clinicopathologic features of many of them [4], [5], [6], [7], [8], [9], [10].
This review will not seek to be either encyclopedic or fully inclusive of the rapidly growing world literature in this area. Results of investigations on non-AD dementias will be presented, as will examples of new techniques that have been ‘piloted’ effectively on AD brain tissue, but in theory could easily provide data on non-AD dementias in the near future—including crucial comparisons between AD and non-AD neurodegenerative disorders. Indeed, some of the techniques (e.g. tissue microarrays (TMA)) to be described are ideally suited to making such quantitative comparative analyses.
Section snippets
Morphometry
Many factors have driven the need to re-evaluate both gross and microscopic abnormalities in the brains of individuals with dementia, using quantitative, often computer-assisted, methods. The first is a practical one: simple inspection of the brain externally, in cut slices, or paraffin sections, while valuable for confirming severe focal or regional atrophy/cell loss, is inadequate for documenting more subtle tissue or cell loss. Secondly, neuropathologists are increasingly being asked to
Characteristics of inclusions in specific disorders
Just as in AD the research agenda has been determined over the past 20+years by neuropathologic observations—i.e. there has been a focus on explaining the origin of brain parenchymal amyloid (SPs) and intra-neuronal NFTs—so various neuronal/glial inclusions discovered within the CNS of individuals having non-AD dementias have piqued the curiosity of neuropathologists. Relevant questions about them include: How do they form? Do they have any pathophysiologic consequences for cell function or are
Conclusion
The 21st century is an exciting time in which to undertake neuropathologic analysis of human tissues—especially from patients with degenerative diseases that have, until recent years, been understood only as distinctive clinicopathologic entities. Routine and empirical staining techniques, though still valuable in the work-up of these cases, are supplemented by sophisticated immunohistochemical, molecular and morphometric methods that will revolutionize our understanding of the pathogenesis of
Acknowledgements
Work in the senior author's (HVV) laboratory supported by PHS Grants P50 AG16570 and P01 AG12435, and by a grant from the National Alzheimer Coordinating Center (NACC). Dr Paul Thompson provided helpful discussion and key articles on neuroimaging. ESF supported by in part by PHS Training Grant T32 AG 00093-21 (University of Southern California).
References (99)
- et al.
Mapping histology to metabolism: coregistration of stained whole-brain sections to pre-mortem PET in Alzheimer's disease
NeuroImage
(1997) - et al.
Regional pattern of hippocampus and corpus callosum atrophy in Alzheimer's disease in relation to dementia severity: evidence for early neocortical degeneration
Neurobiol Aging
(2003) - et al.
A reliable MR measurement of medial temporal lobe width from the Sunnybrook Dementia Study
Neurobiol Aging
(2003) - et al.
Accurate, robust, and automated longitudinal and cross-sectional brain change analysis
NeuroImage
(2002) New stereological methods for counting neurons
Neurobiol Aging
(1993)- et al.
Two-dimensional versus three-dimensional cell counting: a practical perspective
Trends Neurosci
(2001) - et al.
Stereological estimation of total microglia number in mouse hippocampus
J Neurosci Methods
(1998) - et al.
Immunohistochemical quantification of the synapse-related protein synaptophysin in Alzheimer disease
Neurosci Lett
(1989) - et al.
Expression of the Alzheimer amyloid precursor gene transcripts in the human brain
Neuron
(1988) - et al.
Amplification of tissue by construction of tissue microarrays
Exp Mol Pathol
(2001)
Software tools for high-throughput analysis and archiving of immunohistochemistry staining data obtained with tissue microarrays
Am J Pathol
Automated acquisition of stained tissue microarrays for high-throughput evaluation of molecular targets
J Mol Diagn
Lewy bodies contain altered alpha-synuclein in brains of many familial Alzheimer's disease patients with mutations in presenilin and amyloid precursor protein genes
Am J Pathol
Diagnostic neuropathology
Neuropathology. Reference text of CNS pathology (2/e)
Corticobasal degeneration: neuropathologic and clinical heterogeneity
Neurology
Accuracy of the clinical diagnosis of corticobasal degeneration: a clinicopathologic study
Neurology
Diffuse lewy body disease in Japan
J Neurol
Dementia of frontal type and dementias with subcortical gliosis
Brain Pathol
Frontotemporal lobar degeneration. A consensus on clinical diagnostic criteria
Neurology
Update on the neuropathological diagnosis of frontotemporal dementias
J Neuropathol Exp Neurol
Dementia with lewy bodies: reliability and validity of clinical and pathologic criteria
Neurology
Aging-associated changes in human brain
J Neuropathol Exp Neurol
Neuropathological and neuropsychological changes in normal aging: evidence for preclinical Alzheimer disease in cognitively normal individuals
J Neuropathol Exp Neurol
Patterns of cerebral atrophy in HIV-1-infected individuals. Results of a quantitative MRI analysis
Neurology
The relation-ship of quantitative brain magnetic resonance imaging measures to neuropathologic indexes of human immunodeficiency virus infection
Arch Neurol
Progressive cerebral volume loss in human immuno-deficiency virus infection. A longitudinal volumetric magnetic resonance imaging study
Arch Neurol
Assessment of Alzheimer's disease progression by neuroimaging
NeuroSci. News
Imaging the progression of Alzheimer pathology through the brain
Proc Natl Acad Sci USA
Progressive brain atrophy on serial MRI in dementia with Lewy bodies, AD, and vascular dementia
Neurology
MRI of entorhinal cortex and hippocampus in Alzheimer's disease, subcortical ischemic vascular dementia and mixed dementia
Quantitation of cerebral atrophy in preclinical and end-stage Alzheimer's disease
Ann Neurol
The assessment of postmortem brain volume: a comparison of stereological and planimeteric methodologies
Neuroradiology
Estimation of nuclear population from microtome sections
Anatomic Record
Stereology: a practical primer for neuropathology
J Neuropathol Exp Neurol
Methods for determining numbers of cells and synapses: a case for more uniform standards of review
J Comp Neurol
Some new, simple and efficient stereological methods and their use in pathological research and diagnosis
Acta Pathol Microbiol Immunol Scand
Comparison of two quantitative methods for the evaluation of neuronal number in the frontal cortex in Alzheimer disease
J Neuropathol Exp Neurol
Neuronal pattern correlates with the severity of human immunodeficiency virus-associated dementia complex. Usefulness of spatial pattern analysis in clinicopathological studies
Am J Pathol
Neuropathologic substrates of ischemic vascular dementia
J Neuropathol Exp Neurol
Morphometric comparison of hippocampal microvasculature in ageing and demented people: diameters and densities
Acta Neuropathol (Berl)
Dementia in hereditary cerebral hemorrhage with amyloidosis-Dutch type is associated with cerebral amyloid angiopathy but is independent of plaques and neurofibrillary tangles
Ann Neurol
Immunocytochemistry (3/e)
Techniques in immunocytochemistry. Application to diagnostic pathology
Arch Pathol Lab Med
Review of selected lineage-directed antibodies useful in routinely processed tissues
Arch Pathol Lab Med
Cytochemistry of brain amyloid in adult dementia
Acta Neuropathol (Berl)
An immunohistochemical study on cerebral vascular and senile plaque amyloid in Alzheimer's disease
Virchows Arch [Cell Pathol]
An immunoperoxidase study of senile cerebral amyloidosis with pathogenetic considerations
J Neuropathol Exp Neurol
Cited by (1)
PET of brain amyloid and tau in mild cognitive impairment
2006, New England Journal of Medicine