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Studies suggest that neuronal density in left dorsolateral prefrontal
cortex is increased in schizophrenia.
To replicate these findings and extend them to both hemispheres.
Neuronal density, size and shape were estimated in the prefrontal cortex
(Brodmann area 9) of the left and right hemispheres of brains taken
postmortem from 10 people with schizophrenia and 10 without mental
illness (6 men, 4 women in both groups).
Overall neuronal density (individually corrected for shrinkage) did not
differ between the groups. In the control brains, density was generally
greater in the left than the right hemisphere, the reverse was seen in
the schizophrenia brains; this loss or reversal of asymmetry was most
significant in cortical layer 3. Pyramidal neurons in this cell layer
were significantly larger on the left and more spherical in shape than on
the right side in control brains, but size and shape did not differ
between the two sides in schizophrenia. Non-pyramidal and glial cell
densities were unchanged.
We failed to find an increase in neuronal density, but found evidence at
a cellular level of loss or reversal of asymmetry, consistent with the
hypothesis of a primary change in the relative development of areas of
heteromodal association cortex in the two hemispheres.
In this chapter we summarize the more important structures in the brain with which it is essential to be familiar when studying the pathological basis of dementia. As described in Chapter 3 many dementing conditions are impossible to distinguish on naked eye examination of the brain since they do not display gross regional pathology. In order to reach the correct diagnosis, it is necessary to select the appropriate areas for more detailed examination. To do that requires knowledge of the parts of the brain that are significant in the particular context of dementia. For more detailed information textbooks of neuroanatomy such as Paxinos (1990), Heimer (1995), Parent (1996), or Nolte (2001) should be consulted.
Chapter 1 has already emphasized the crucial importance of the cerebral cortex for the cognitive functions which deteriorate in dementia. The cerebral cortex can be divided anatomically into a phylogenetically older and simpler allocortex consisting of the hippocampus and closely related entorhinal cortex, subiculum and olfactory regions, and the remaining, much more voluminous and phylogenetically more recent, neocortex.
Hippocampus, subiculum and entorhinal cortex (archicortex allocortex)
These structures have already been mentioned in Chapter 1 but because of their importance it is worth providing a brief supplementary account here. Excellent reviews of the structure of the human hippocampus and related cortex can be found in Amaral and Insausti (1990) and Duvernoy (1988).
The entorhinal cortex lies in the uncus and anterior parahippocampal gyrus and forms an intermediate type of cortex between the complex six-layered neocortex of the temporal lobe and the simpler, basically three-layered, cortex of the hippocampus.
Completely rewritten and updated, this new edition is almost twice the size of its predecessor. Illustrated in colour throughout, and with contributions from the world's leading authorities, it is the definitive reference on the neuropathology of dementia. It gives practical guidance to pathologists, describes the contribution of neuroimaging to diagnosis, and surveys the clinical features of dementia. New material includes:Three entirely new chapters on neuroimaging, molecular diagnostics, and transgenic models.Two chapters on tauopathies under new authorship. A chapter under new authorship on synucleinopathies, which includes multiple system atrophy. From reviews of the first edition:'This up-to-date and authoritative account will be invaluable for practising neuropathologists and a treasured work of reference for psychiatrists and neuroscientists with an interest in dementia.' Nigel J. Cairns, International Journal of Geriatric Psychiatry' ... this publication is a 'must have' for every practising neuropathologist.' Journal of Neuropathology and Experimental Neurology
The first edition of this book was conceived with the intention of providing a practical guide to the neuropathological diagnosis of dementia. It was intended particularly for those who did not regard themselves as experts in this increasingly complex field. The relatively small number of authors was encouraged to share their diagnostic experience with others. This second edition still aims to provide practical assistance in this way, but it now goes further than that. The pace of scientific research advances in this field of dementia is such that it has become a formidable enough task for an expert to remain fully conversant with his or her own subfield, let alone with the field as a whole. Therefore we have aimed to widen the authorship greatly so that many chapters could be written by those specialists with research interests in the topic that is covered by each. We are delighted that those approached have responded so generously and enthusiastically since the outstanding contributions from the authors have made the second edition the most up-to-date and comprehensive monograph on the neuropathology of dementia. Because of the wider international authorship it has also been possible to extend the scope of the coverage of each topic to include more about research findings and the background science so that the book can now claim to provide comprehensive coverage of current understanding of the dementias rather than a more restricted practical guide. We hope, therefore, that a wider readership of neurobiologists and clinicians as well as pathologists will find much of interest here. Those familiar with the first edition will find that there are many new chapters and even more new authors contributing to the second edition.
In this chapter we consider a number of diverse pathological conditions that may occasionally give rise to a clinical picture in which dementia predominates (Table 23.1). Other neurological features are also likely to be present at some stage in the course of these diseases. In some, perhaps most, such cases these other clinical features may have led to the correct diagnosis being established before clinical dementia develops, but in a few the diagnosis may be impossible to achieve before death. Therefore, a pathologist can expect to encounter these diseases occasionally among cases of dementia presenting at autopsy. Full treatment of pathological aspects of these diseases and their illustration is beyond the scope of this chapter and for details a more general textbook of neuropathology should be consulted, e.g. Greenfield's Neuropathology (Graham & Lantos, 2002) or Davis and Robertson's Textbook of Neuropathology (1996).
Neuronal intranuclear hyaline inclusion disease (NIHID) is a rare neurodegenerative disorder characterized by the presence of large eosinophilic inclusions in neuronal nuclei in a wide distribution (Sung et al., 1980; Funata et al., 1990). Whilst most cases present clinically with predominantly motor or other non-cognitive problems, some cases have had dementia (Weidenheim & Dickson, 1995). The neuronal inclusions are present in peripheral ganglionic neurons as well as at all levels of the CNS from cerebral cortex to spinal cord. In addition to the presence of neuronal inclusions, there may be somewhat smaller inclusions in astrocytic nuclei. Neuronal inclusions consist ultrastructurally of haphazardly arranged 10 nm diameter straight filaments without any surrounding membrane.
The ancient term hydrocephalus refers to an excessive accumulation of fluid (water) inside the head. It is most readily detected in infants and children with congenital hydrocephalus since its existence before the skull sutures are closed causes the formation of an enlarged head. Such children have long been recognized commonly to have mental impairment, manifest as mental retardation, although the extent of this is very variable. Morgagni (1769) first described hydrocephalus due to enlarged cerebral ventricles in an adult without head enlargement. If this condition develops insidiously during adult life, dementia is an almost invariable accompaniment, though not the only one. More familiarly hydrocephalus in adults develops acutely or subacutely and presents with symptoms of raised intracranial pressure – headache, vomiting and drowsiness. However, in this chapter we are concerned with chronic hydrocephalus in adults, a condition in which symptoms and signs of raised intracranial pressure are commonly clinically absent and in which the cerebrospinal fluid (CSF) pressure is often normal when measured randomly – hence the commonly used term – normal pressure hydrocephalus (NPH). The recognition of this condition, and the realization that it is responsible for some cases of progressive dementia in adults are recent (Riddoch, 1936; Foltz & Ward 1956; McHugh, 1964; Hakim & Adams, 1965; Adams et al., 1965). Cases of NPH, some of which respond well to a shunting procedure, are to be distinguished from cases of dementia due to neurodegenerative diseases in which the ventricles dilate as a consequence of cerebral atrophy (hydrocephalus ex vacuo).
It has been said, with a good deal of truth, that the answer to every question in medicine is in three parts: first, take a history, second, make a physical examination, and third, perform the relevant special tests and investigations. For the pathologist, the first two parts of this rubric are fulfilled by reading the patient's chart. The third is the performance of what, in at least one sense, is the ultimate diagnostic test, the post-mortem examination.
History and examination
The clinical information available to the pathologist called upon to perform an autopsy examination on a case of dementia is extraordinarily variable. At one extreme is the patient who has been studied over an extended period where the quality and extent of cognitive failure has been documented and, often, a presumptive pathological diagnosis is made. This type of history is often supplemented by more or less objective tests of intellectual function and the results of numerous investigations. Patients submitted to this degree of investigative rigour are often in centres that have a particular interest or active research programme into dementia. In these circumstances it can (we hope) be assumed that there is good liaison between the clinical service and the pathology department and the cases will be dealt with according to protocol.
The opposite end of this particular spectrum is the patient coming to autopsy examination who is reported to have an unspecified degree of cognitive decline, variously described in imprecise terms. In such cases recourse to considerable ingenuity is required to form an idea of the nature and severity of the decline. Clues can sometimes be gleaned from the nursing notes or even from the patient's address.
Claims that schizophrenia is a disease of the limbic system have been strengthened by meta-analyses of magnetic resonance imaging (MRI) studies finding reduced hippocampus and amygdala volumes. Some post-mortem studies do not find these abnormalities.
To assess the volume of the amygdala in a series of brains post-mortem.
Amygdala volume was estimated using point-counting in both hemispheres of the brains of 10 male and 8 female patients with schizophrenia, and a comparison group of 9 males and 9 females.
No significant reduction of amygdala volume was found.
Significant volume reduction of the amygdala is not a consistent feature of schizophrenia; findings from early MRI studies using coarse delineation methods may introduce bias to subsequent meta-analyses.
It has been suggested that there is frontal lobe involvement in schizophrenia, and that it may be lateralised and gender-specific.
To clarify the structure of the frontal lobes in schizophrenia in a postmortem series.
The volume of white matter and cortical components of the frontal lobes was measured in brains of controls and patients with schizophrenia using planimetry and the Cavalieri principle. The components measured were: superior frontal gyrus, middle frontal gyrus, a composite of inferior frontal gyrus and orbito-frontal cortex, as well as total frontal lobe cortex and white matter. In addition, the anterior cingulate gyrus was measured.
No diagnosis, gender, diagnosis × side, diagnosis × gender or diagnosis × gender × side interactions were observed in the volume of any of the components, the grey matter as a whole or the white matter. No evidence for volumetric inter-group differences was found for the anterior cingulate gyrus.
Such structural abnormalities as are present in the frontal lobes are more subtle than straightforward alterations in tissue volume; they may include changes in shape and the pattern of gyral folding.
A previous report by Crow of a left-sided increase in temporal horn volume in schizophrenia implies a left-sided loss of tissue.
To elucidate the structural nature of schizophrenia.
The volume of grey matter in the temporal pole and inferior, middle and superior temporal gyri was measured, in addition to the total volume of grey and white matter, in the temporal lobes of the brains of 29 patients with schizophrenia and 27 controls.
We found a significant left-sided reduction in the superior temporal gyrus in both males and females with schizophrenia, which was related to increasing age of onset in the males. The total volume of temporal lobe grey and white matter was also significantly reduced. Although being more marked on the left than the right, the lateralisation for these total grey and white measures (by contrast with the superior temporal gyrus alone) did not attain formal statistical significance.
Confirmation of a lateralised reduction in the superior temporal gyrus, which is differentially related to age of onset according to gender, adds to evidence that the changes in schizophrenia are in systems that are lateralised. The findings implicate language as the relevant function.