Can neurodegenerative disease be defined by four 'primary determinants':anatomy, cells, molecules, and morphology?

Traditional methods of describing and classifying neurodegenerative disease are based on the clinico-pathological concept supported by molecular pathological studies and defined by 'consensus criteria'. Disease heterogeneity, overlap between disorders, and the presence of multiple co-pathologies, however, have questioned the validity and status of many traditional disorders. If cases of neurodegenerative disease are not easily classifiable into distinct entities, but more continuously distributed, then a new descriptive framework may be required. This review proposes that there are four key neuropathological features of neurodegenerative disease (the 'primary determinants') that could be used to provide such a framework, viz., the anatomical pathways affected by the disease ('anatomy'), the cell populations affected ('cells'), the molecular pathology of 'signature' pathological lesions ('molecules'), and the morphological types of neurodegeneration ('morphology'). This review first discusses the limitations of existing classificatory systems and second provides evidence that the four primary determinants could be used as axes to define all cases of neurodegenerative disease. To illustrate the methodology, the primary determinants were applied to the study of a group of closely related tauopathy cases and to heterogeneity within frontotemporal lobar degeneration with TDP-43 proteinopathy (FTLD-TDP).

Relationship between the microcirculation and the pathological changes in the spradic and variant forms of Creutzfeldt-Jakob Disease (CJD)

This chapter is concerned with the influence of the brain microcirculation on the development of the pathological changes in Creutzfeldt-Jakob disease (CJD). Hence, the spatial correlations between the vacuolation, prion protein (PrP) deposits, and the blood vessel profiles were studied in immunolabelled sections of the cerebral cortex, hippocampus, and cerebellum in two subtypes of CJD, viz., sporadic Creutzfeldt-Jakob disease (sCJD) and variant CJD (vCJD). In sCJD, both the vacuolation and the ‘synaptic-type’ PrP deposits were spatially correlated with the blood vessels; the PrP deposits being the more strongly correlated than the vacuoles. In vCJD, there were no significant spatial correlations between either the vacuolation or the diffuse-type of PrP deposit and the microvessels. By contrast, a consistent pattern of spatial correlation was observed in gyri of the cerebral cortex between the florid PrP deposits and blood vessels. In both sCJD and vCJD, the frequency of positive spatial correlations was similar in the different gyri of the cerebral cortex and in the upper compared with the lower laminae. In conclusion, the microcirculation appears to be more significantly involved in determining the pathological changes in sCJD than in vCJD. The spatial correlations of the florid PrP deposits in vCJD and the synaptic deposits in sCJD and the blood vessels may be attributable to factors associated with the microcirculation which enhance the aggregation of PrP molecules rather than representing a possible haematogenous spread of the disease.

Pathological changes in the primary visual cortex (Area V1) in Creutzfeldt-Jakob syndrome

About 10% of patients with Creutzfeldt-Jakob syndrome (disease) (CJD) exhibit visual symptoms at presentation and approximately 50% during the course of the disease. The objectives of the present study were to determine, in two subtypes of CJD, viz., sporadic CJD (sCJD) and variant CJD (vCJD), the degree of pathological change in the primary visual cortex (area V1) and the extent to which pathology in V1 may influence visual function. The vacuolation (‘spongiform change’), surviving neurons, glial cell nuclei, and deposits of prion protein (PrP) were quantified in V1 obtained post-mortem in nine cases of sCJD and eleven cases of vCJD. In sCJD, the vacuoles and PrP deposits were regularly distributed along the cortex parallel to the pia mater in clusters with a mean dimension from 450 to 1000 µm. Across the cortex, the vacuolation was most severe in laminae II/III and the glial cell reaction in laminae V/VI. Surviving neurons were most abundant in laminae II/III while PrP deposition either affected all laminae equally or was maximal in lamina II/III. In vCJD, the vacuoles and diffuse PrP deposits were distributed relatively uniformly parallel to the pia mater while the florid deposits were consistently distributed in regular clusters. Across V1, the vacuoles either exhibited a bimodal distribution or were uniformly distributed. The diffuse PrP deposits occurred most frequently in laminae II/III while the florid deposits were more generally distributed. The data suggest that in both sCJD and vCJD, pathological changes in area V1 may affect the processing of visual information in laminae II/III and its transmission from V1 to V2 and to subcortical visual areas. In addition, the data suggest an association in sCJD between the developing pathology and the functional domains of V1 while in vCJD the pathology is more uniformly distributed. These changes could be a factor in the development of poor visual acuity, visual field defects, cortical blindness, diplopia, and vertical gaze palsy that have been observed in Creutzfeldt-Jakob syndrome.

The identification of pathological subtypes of Alzheimer's disease using cluster analysis

A culster analysis was performed on 78 cases of Alzheimer's disease (AD) to identify possible pathological subtypes of the disease. Data on 47 neuropathological variables, inculding features of the gross brain and the density and distribution of senile plaques (SP) and neurofibrillary tangles (NFT) were used to describe each case. Cluster analysis is a multivariate statistical method which combines together in groups, AD cases with the most similar neuropathological characteristics. The majority of cases (83%) were clustered into five such groups. The analysis suggested that an initial division of the 78 cases could be made into two major groups: (1) a large group (68%) in which the distribution of SP and NFT was restricted to a relatively small number of brain regions, and (2) a smaller group (15%) in which the lesions were more widely disseminated throughout the neocortex. Each of these groups could be subdivided on the degree of capillary amyloid angiopathy (CAA) present. In addition, those cases with a restricted development of SP/NFT and CAA could be divided further into an early and a late onset form. Familial AD cases did not cluster as a separate group but were either distributed between four of the five groups or were cases with unique combinations of pathological features not closely related to any of the groups. It was concluded that multivariate statistical methods may be of value in the classification of AD into subtypes. © 1994 Springer-Verlag.

Structure and regulation of type 2 transglutaminase in relation to its physiological functions and pathological roles

This chapter contains sections titled: Introduction Structure and Regulation Physiologic Functions of TG2 Disruption of TG2 Functions in Pathologic Conditions Perspectives for Pharmacologic Interventions Concluding Comments Acknowledgements References

Laminar distribution of the pathological changes in frontal and temporal cortex in 8 patients with progressive supranuclear palsy

OBJECTIVE: To determine the laminar distribution of the pathological changes in the cerebral cortex in progressive supranuclear palsy (PSP). METHOD: The distribution of the abnormally enlarged neurons (EN), surviving neurons, neurofibrillary tangles (NFT), glial inclusions (GI), tufted astrocytes (TA), and neuritic plaques (NP) were studied across the cortex in tau immunolabeled sections of frontal and temporal cortex in 8 cases of PSP. RESULTS: The distribution of the NFT was highly variable with no consistent pattern of laminar distribution. The GI were distributed either in the lower laminae or uniformly across the cortex. Surviving neurons exhibited either a density peak in the upper laminae or a bimodal distribution was present with density peaks in the upper and lower laminae. The EN and glial cell nuclei were distributed primarily in the lower cortical laminae. There were positive correlations between the densities of the EN and glial cell nuclei and negative correlations between the surviving neurons and glial cells. No correlations were present between the densities of the NFT and GI. CONCLUSION: Cortical pathology in PSP predominantly affects the lower laminae but may spread to affect the upper laminae in some cases. The NFT and GI may have different laminar distributions and gliosis occurs concurrently with neuronal enlargement.

Measuring the spatial arrangement patterns of pathological lesions in histological sections of brain tissue

The development of abnormal protein aggregates in the form of extracellular plaques and intracellular inclusions is a characteristic feature of many neurodegenerative diseases such as Alzheimer's disease (AD), Creutzfeldt-Jakob disease (CJD) and the fronto-temporal dementias (FTD). An important aspect of a pathological protein aggregate is its spatial topography in the tissue. Lesions may not be randomly distributed within a histological section but exhibit spatial pattern, a departure from randomness either towards regularity or clustering. Information on the spatial pattern of a lesion may be useful in elucidating its pathogenesis and in studying the relationships between different lesions. This article reviews the methods that have been used to study the spatial topography of lesions. These include simple tests of whether the distribution of a lesion departs significantly from random using randomized points or sample fields, and more complex methods that employ grids or transects of contiguous fields and which can detect the intensity of aggregation and the sizes, distribution and spacing of the clusters. The usefulness of these methods in elucidating the pathogenesis of protein aggregates in neurodegenerative disease is discussed.

Multiple system atrophy: laminar distribution of the pathological changes in frontal and temporal neocortex--a study in ten patients

OBJECTIVE: To determine the distribution of the pathological changes in the neocortex in multiple-system atrophy (MSA). METHOD: The vertical distribution of the abnormal neurons (neurons with enlarged or atrophic perikarya), surviving neurons, glial cytoplasmic inclusions (GCI) and neuronal cytoplasmic inclusions (NI) were studied in alpha-synuclein-stained material of frontal and temporal cortex in ten cases of MSA. RESULTS: Abnormal neurons exhibited two common patterns of distribution, viz., density was either maximal in the upper cortex or a bimodal distribution was present with a density peak in the upper and lower cortex. The NI were either located in the lower cortex or were more uniformly distributed down the cortical profile. The distribution of the GCI varied considerably between gyri and cases. The density of the glial cell nuclei was maximal in the lower cortex in the majority of gyri. In a number of gyri, there was a positive correlation between the vertical densities of the abnormal neurons, the total number of surviving neurons, and the glial cell nuclei. The vertical densities of the GCI were not correlated with those of the surviving neurons or glial cells but the GCI and NI were positively correlated in a small number of gyri. CONCLUSION: The data suggest that there is significant degeneration of the frontal and temporal lobes in MSA, the lower laminae being affected more significantly than the upper laminae. Cortical degeneration in MSA is likely to be secondary to pathological changes occurring within subcortical areas.

Are pathological lesions in neurodegenerative disorders the cause or the effect of the degeneration?

Pathological lesions in the form of extracellular protein deposits, intracellular inclusions and changes in cell morphology occur in the brain in the majority of neurodegenerative disorders. Studies of the presence, distribution, and molecular determinants of these lesions are often used to define individual disorders and to establish the mechanisms of lesion pathogenesis. In most disorders, however, the relationship between the appearance of a lesion and the underlying disease process is unclear. Two hypotheses are proposed which could explain this relationship: (i) lesions are the direct cause of the observed neurodegeneration ('causal' hypothesis); and (ii) lesions are a reaction to neurodegeneration ('reaction' hypothesis). These hypotheses are considered in relation to studies of the morphology and molecular determinants of lesions, the effects of gene mutations, degeneration induced by head injury, the effects of experimentally induced brain lesions, transgenic studies and the degeneration of anatomical pathways. The balance of evidence suggests that in many disorders, the appearance of the pathological lesions is a reaction to degenerative processes rather than being their cause. Such a conclusion has implications both for the classification of neurodegenerative disorders and for studies of disease pathogenesis.

Quantification of the pathological changes with laminar depth in the cortex in sporadic Creutzfeldt-Jakob disease

The laminar distribution of the vacuolation ('spongiform change'), surviving neurons, glial cell nuclei, and prion protein (PrP) deposits was studied in the frontal, parietal and temporal cortex in 11 cases of sporadic Creutzfeldt-Jakob disease (CJD). The distribution of the vacuolation was mainly bimodal with peaks of density in the upper and lower cortical laminae. The density of surviving neurons was greatest in the upper cortex while glial cell nuclei were distributed largely in the lower cortex. PrP deposits exhibited either a bimodal distribution or reached a maximum density in the lower cortex. The vertical density of the vacuoles was positively correlated with the surviving neurons in 12/44 of cortical areas studied, with glial cell nuclei in 16/44 areas and with PrP deposition in 15/28 areas. PrP deposits were positively correlated with glial cell nuclei in 12/31 areas. These results suggest that in sporadic CJD: (1) the lower cortical laminae are the most affected by the pathological changes; (2) the development of the vacuolation may precede that of the extracellular PrP deposits and the glial cell reaction; and (3) the pathological changes may develop initially in the lower cortical laminae and spread to affect the upper cortical laminae. © 2001 Elsevier Science Ireland Ltd. All rights reserved.

A quantitative study of the pathological lesions in the neocortex and hippocampus of twelve patients with corticobasal degeneration

The density of ballooned neurons (BN), tau-positive neurons with inclusion bodies (tau+ neurons), and tau-positive plaques (tau+ plaques) was determined in sections of the frontal, parietal, and temporal lobe in 12 patients with corticobasal degeneration (CBD). No significant differences in the mean density of BN and tau+ neurons were observed between neocortical regions. In the hippocampus, the densities of BN were significantly lower than in the neocortex, and densities of tau+ neurons were greater in sectors CA1 and CA2, compared with CA3 and CA4. Tau+ plaques were present in one or more brain regions in six patients. Significantly more BN were recorded in the lower (laminae V/VI) compared with the upper cortex (laminae I/II/III) but tau+ neurons were equally frequent in the upper and lower cortex. No significant correlations were observed between the densities of BN and tau+ neurons, but the densities of BN in the superior temporal gyrus and tau+ plaques in the frontal cortex were positively correlated with age. A principal components analysis (PCA) suggested that differences in the density of tau+ neurons in the frontal and motor cortex were the most important sources of variation between patients. In addition, one patient with a particularly high density of tau+ neurons in the hippocampus appeared to be atypical of the patient group studied. The data support the hypothesis that, although clinically heterogeneous, CBD is a pathologically distinct disorder. (C) 2000 Academic Press.

What does the study of the spatial patterns of pathological lesions tell us about the pathogenesis of neurodegenerative disorders?

Discrete pathological lesions, which include extracellular protein deposits, intracellular inclusions and changes in cell morphology, occur in the brain in the majority of neurodegenerative disorders. These lesions are not randomly distributed in the brain but exhibit a spatial pattern, that is, a departure from randomness towards regularity or clustering. The spatial pattern of a lesion may reflect pathological processes affecting particular neuroanatomical structures and, therefore, studies of spatial pattern may help to elucidate the pathogenesis of a lesion and of the disorders themselves. The present article reviews first, the statistical methods used to detect spatial patterns and second, the types of spatial patterns exhibited by pathological lesions in a variety of disorders which include Alzheimer's disease, Down syndrome, dementia with Lewy bodies, Creutzfeldt-Jakob disease, Pick's disease and corticobasal degeneration. These studies suggest that despite the morphological and molecular diversity of brain lesions, they often exhibit a common type of spatial pattern (i.e. aggregation into clusters that are regularly distributed in the tissue). The pathogenic implications of spatial pattern analysis are discussed with reference to the individual disorders and to studies of neurodegeneration as a whole.

A quantitative study of the pathological changes in the cerebellum in 15 cases of variant Creutzfeldt–Jakob disease (vCJD)

Aims: To determine in the cerebellum in variant Creutzfeldt–Jakob disease (vCJD): (i) whether the pathology affected all laminae; (ii) the spatial topography of the pathology along the folia; (iii) spatial correlations between the pathological changes; and (iv) whether the pathology was similar to that of the common methionine/methionine Type 1 subtype of sporadic CJD. Methods: Sequential cerebellar sections of 15 cases of vCJD were stained with haematoxylin and eosin, or immunolabelled with monoclonal antibody 12F10 against prion protein (PrP) and studied using spatial pattern analysis. Results: Loss of Purkinje cells was evident compared with control cases. Densities of the vacuolation and the protease-resistant form of prion protein (PrPSc) (diffuse and florid plaques) were greater in the granule cell layer (GL) than the molecular layer (ML). In the ML, vacuoles and PrPSc plaques occurred in clusters regularly distributed along the folia with larger clusters of vacuoles and diffuse plaques in the GL. There was a negative spatial correlation between the vacuoles and the surviving Purkinje cells in the ML. There was a positive spatial correlation between the vacuoles and diffuse PrPSc plaques in the ML and GL. Conclusions: (i) all laminae were affected by the pathology, the GL more severely than the ML; (ii) the pathology was topographically distributed along the folia especially in the Purkinje cell layer and ML; (iii) pathological spread may occur in relation to the loop of anatomical connections involving the cerebellum, thalamus, cerebral cortex and pons; and (iv) there were pathological differences compared with methionine/methionine Type 1 sporadic CJD.

The spatial patterns of pathological brain lesions in 12 patients with corticobasal degeneration

Corticobasal degeneration (CBD) is a rare and progressive neurological disorder characterised by the presence of ballooned neurons (BN) and tau positive inclusions in neurons and glial cells. We studied the spatial patterns of the BN, tau positive neurons with inclusions (tau + neurons), and tau positive plaques in the neocortex and hippocampus in 12 cases of CBD. All lesions were aggregated into clusters and in many brain areas, the clusters were distributed in a regular pattern parallel to the tissue boundary. In the majority of cortical areas, the clusters of BN were larger in the lower compared with the upper laminae while the clusters of tau + neurons were larger in the upper laminae. Clusters of BN and tau + neurons were either negatively correlated or not significantly correlated in the upper and lower cortical laminae. Hence, BN and tau + lesions in CBD exhibit similar spatial patterns as lesions in Alzheimer's disease (AD), dementia with Lewy bodies (DLB) and Pick's disease (PD). The location, sizes and distribution of the clusters in the neocortex suggest that the tau + lesions may be associated with the degeneration of the feedforward and the BN the feedback cortico-cortical and/or the efferent cortical pathways. © 2001 Elsevier Science Ireland Ltd. All rights reserved.

Progressive supranuclear palsy (PSP):A quantitative study of the pathological changes in cortical and subcortical regions of eight cases

In eight cases of progressive supranuclear palsy (PSP), neurofibrillary tangles (NFT) were numerous in the substantia nigra (SN), red nucleus (RN), locus caeruleus (LC), pontine nuclei (PN), and inferior olivary nucleus (ION) and abnormally enlarged neurons (EN) in the ION, LC and PN. Loss of Purkinje cells was evident in the cerebellum. Tufted astrocytes (TA) were abundant in the striatum, SN and RN and glial inclusions ('coiled bodies') (GI) in the midbrain (SN, RN) and pons (LC). Neuritic plaques were frequent in one case. NFT, GI, and TA densities were uncorrelated in most areas. NFT and EN densities were positively correlated in the midbrain and surviving neurons and disease duration in several areas. These results suggest: 1) predominantly subcortical pathology in PSP with widespread NFT while TA and GI have a more localized distribution, 2) little correlation between neuronal and glial pathologies, and 3) shorter duration cases may be more likely to develop cortical pathology. © 2007 Springer-Verlag.