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.

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.

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.

Clustering of cerebral cortical lesions in patients with corticobasal degeneration

Clustering of ballooned neurons (BN) and tau positive neurons with inclusion bodies (tau+ neurons) was studied in the upper and lower laminae of the frontal, parietal and temporal cortex in 12 patients with corticobasal degeneration (CBD). In a significant proportion of brain areas examined, BN and tau+ neurons exhibited clustering with a regular distribution of clusters parallel to the pia mater. A regular pattern of clustering of BN and tau+ neurons was observed equally frequently in all cortical areas examined and in the upper and lower laminae. No significant correlations were observed between the cluster sizes of BN or tau+ neurons in the upper compared with the lower cortex or between the cluster sizes of BN and tau+ neurons. The results suggest that BN and tau+ neurons in CBD exhibit the same type of spatial pattern as lesions in Alzheimer's disease, Lewy body dementia and Pick's disease. The regular periodicity of the cerebral cortical lesions is consistent with the degeneration of the cortico-cortical projections in CBD.

Laminar distribution of ballooned neurons and tau positive neurons with inclusions in patients with corticobasal degeneration

The laminar distribution of ballooned neurons (BN) and tau positive neurons with inclusions (tau+ neurons) was studied in the frontal and temporal cortex in twelve patients with corticobasal degeneration (CBD). In the majority of brain areas, the density of BN and tau+ neurons was maximal in the lower and upper cortical laminae respectively. The densities of tau+ neurons in the upper and lower cortex were positively correlated. In the majority of brain areas, however, no correlations were observed between the densities of BN and tau+ neurons. The laminar distribution of the BN may reflect the degeneration of the feedback cortico-cortical and/or the efferent cortical pathways. By contrast, the distribution of the tau+ neurons may reflect the degeneration of the feed-forward cortico-cortical pathways. In addition, BN and tau+ neurons may arise as a result of distinct pathological processes.

Density and spatial pattern of β-amyloid (Aβ) deposits in corticobasal degeneration

Corticobasal degeneration (CBD) is a rare, progressive movement disorder characterized neuropathologically by widespread neuronal and glial pathology including tau-immunoreactive neuronal cytoplasmic inclusions (NCI), oligodendroglial inclusions (GI), and astrocytic plaques (AP). However, ß -amyloid (A ß) deposits have been observed in the cerebral cortex and/or hippocampus in some cases of CBD. To clarify the role of Aß deposition in CBD, the densities and spatial patterns of the Aß deposits were studied in three cases. In two cases, expressing apolipoprotein E (APOE) genotypes 2/3 or 3/3, the densities of the Aß deposits were similar to those in normal elderly brain. In the remaining case, expressing APOE genotype 3/4, Aß deposition was observed throughout the cerebral cortex, sectors CA1 and CA2 of the hippocampus, and the molecular layer of the dentate gyrus. The densities of the Aß deposits in this case were typical of those observed in Alzheimer's disease (AD). In the three cases, clustering of Aß deposits, with clusters ranging in size from 200 to >6400 µm in diameter, was evident in 25/27 (93%) of analyses. In addition, the clusters of Aß deposits were regularly distributed parallel to the tissue boundary in 52% of analyses, a spatial pattern similar to that observed in AD. These results suggest: (1) in some CBD cases, Aß pathology is age-related, (2) more extensive Aß deposition is observed in some cases, the density and spatial patterns of the Aß deposits being similar to AD, and (3) extensive deposition of Aß in CBD may be associated with APOE allele e4.

Spatial patterns of TDP-43 neuronal cytoplasmic inclusions (NCI) in fifteen cases of frontotemporal lobar degeneration with TDP-43 proteinopathy (FTLD-TDP)

Neuronal cytoplasmic inclusions (NCI) immunoreactive for transactive response DNA-binding protein (TDP-43) are the pathological hallmark of frontotemporal lobar degeneration with TDP-43 proteinopathy (FTLD-TDP). We studied the spatial patterns of the TDP-43 immunoreactive NCI in the frontal and temporal cortex of 15 cases of FTLD-TDP. The NCI were distributed parallel to the tissue boundary predominantly in regular clusters 50-400 µm in diameter. In five cortical areas, the size of the clusters approximated to the cells of the cortico-cortical pathways. In most regions, cluster size was smaller than 400 µm. There were no significant differences in spatial patterns between familial and sporadic cases. Cluster size of the NCI was not correlated with disease duration, brain weight, Braak stage, or disease subtype. The spatial pattern of the NCI was similar to that of neuronal inclusions in other neurodegenerative diseases and may reflect a common pattern of degeneration involving the cortico-cortical projections.

TDP-43-Immunoreactive pathology in frontotemporal lobar degeneration with TDP proteinopathy (FTLD-TDP) with and without associated motor neuron disease

A proportion of patients with motor neuron disease (MND) exhibit frontotemporal dementia (FTD) and some patients with FTD develop the clinical features of MND. Frontotemporal lobar degeneration (FTLD) is the pathological substrate of FTD and some forms of this disease (referred to as FTLD-U) share with MND the common feature of ubiquitin-immunoreactive, tau-negative cellular inclusions in the cerebral cortex and hippocampus. Recently, the transactive response (TAR) DNA-binding protein of 43 kDa (TDP-43) has been found to be a major protein of the inclusions of FTLD-U with or without MND and these cases are referred to as FTLD with TDP-43 proteinopathy (FTLD-TDP). To clarify the relationship between MND and FTLD-TDP, TDP-43 pathology was studied in nine cases of FTLD-MND and compared with cases of familial and sporadic FTLD–TDP without associated MND. A principal components analysis (PCA) of the nine FTLD-MND cases suggested that variations in the density of surviving neurons in the frontal cortex and neuronal cytoplasmic inclusions (NCI) in the dentate gyrus (DG) were the major histological differences between cases. The density of surviving neurons in FTLD-MND was significantly less than in FTLD-TDP cases without MND, and there were greater densities of NCI but fewer neuronal intranuclear inclusions (NII) in some brain regions in FTLD-MND. A PCA of all FTLD-TDP cases, based on TDP-43 pathology alone, suggested that neuropathological heterogeneity was essentially continuously distributed. The FTLD-MND cases exhibited consistently high loadings on PC2 and overlapped with subtypes 2 and 3 of FTLD-TDP. The data suggest: (1) FTLD-MND cases have a consistent pathology, variations in the density of NCI in the DG being the major TDP-43-immunoreactive difference between cases, (2) there are considerable similarities in the neuropathology of FTLD-TDP with and without MND, but with greater neuronal loss in FTLD-MND, and (3) FTLD-MND cases are part of the FTLD-TDP ‘continuum’ overlapping with FTLD-TDP disease subtypes 2 and 3.

A quantitative study of abnormally enlarged neurons in cognitively normal brain and neurodegenerative disease

Abnormally enlarged neurons (AEN) occur in many neurodegenerative diseases. To define AEN more objectively, the frequency distribution of the ratio of greatest cell diameter(CD) to greatest nuclear diameter (ND) was studied in populations of cortical neurons in tissue sections of seven cognitively normal brains. The frequency distribution of CD/ND deviated from a normal distribution in 15 out of 18 populations of neurons studied and hence, the 95th percentile (95P) was used to define a limit of the CD/ND ratio excluding the5% most extreme observations. The 95P of the CD/ ND ratio varied from 2.0 to 3.0 in different cases and regions and a value of 95P = 3.0 was chosen to define the limit for normalneurons under non-pathological conditions. Based on the 95P = 3.0 criterion, the proportion of AEN with a CD/ND ≥ 3 varied from 2.6% in Alzheimer's disease (AD) to 20.3% in Pick's disease (PiD). The data suggest: (1) that a CL/ND ≥ 3.0 may be a useful morphological criterion for defining AEN, and (2) AEN were most numerous in PiD and corticobasal degeneration (CBD) and least abundant in AD and in dementia with Lewy bodies (DLB). © 2013 Dustri-Verlag Dr. K. Feistle.

Spatial patterns of phosphorylation-dependent TDP-43-immunoreactive neuronal cytoplasmic inclusions (NCI) in frontotemporal lobar degeneration with TDP-43 proteinopathy (FTLD-TDP)

The transactive response (TAR) DNA-binding protein of 43kDa (TDP-43) is an RNA binding protein encoded by the TARDPB gene. Abnormal aggregations of TDP-43 in neurons in the form of neuronal cytoplasmic inclusions (NCI) are the pathological hallmark of frontotemporal lobar degeneration with TDP-43 proteinopathy (FTLD-TDP). To investigate the role of TDP-43 in FTLD-TDP, the spatial patterns of the NCI were studied in frontal and temporal cortex of FTLD-TDP cases using a phosphorylation dependent anti-TDP-43 antibody (pTDP-43). In many regions, the NCI formed clusters and the clusters were distributed regularly parallel to the tissue boundary. In about 35% of cortical regions, cluster size of the NCI was within the size range of the modular columns of the cortex. The spatial patterns of the pTDP-immunoreactive inclusions were similar to those revealed by a phosphorylation-independent anti-TDP-43 antibody and also similar to inclusions characterized by other molecular pathologies such as tau, ?-synuclein and ‘fused in sarcoma’ (FUS). In conclusion, the data suggest degeneration of cortical and hippocampal anatomical pathways associated with accumulation of cellular pTDP-43 is characteristic of FTLD-TDP. In addition, the data are consistent with the hypothesis of cell to cell transfer of pTDP-43 within the brain.

A comparison of spatial patterns of TDP-43 cellular inclusions in familial and sporadic frontotemporal lobar degeneration with TDP-43 proteinopathy

Abnormal protein aggregates of transactive response (TAR) DNA-binding protein (TDP-43) in the form of neuronal cytoplasmic inclusions (NCI), oligodendroglial inclusions (GI), neuronal internuclear inclusions (NII), and dystrophic neurites (DN) are the pathological hallmark of frontotemporal lobar degeneration with TDP-43 proteinopathy (FTLD-TDP). To investigate the role of phosphorylated TDP-43 (pTDP-43) in neurodegeneration in FTLD-TDP, the spatial patterns of the pTDP-43-immunoreactive NCI, GI, NII, and DN were studied in frontal and temporal cortex in three groups of cases: (1) familial FTLD-TDP caused by progranulin (GRN) mutation, (2) a miscellaneous group of familial cases containing cases caused by valosin-containing protein (VCP) mutation, ubiquitin associated protein 1 (UBAP1) mutation, and cases not associated with currently known genes, and (3) sporadic FTLD-TDP. In a significant number of brain regions, the pTDP-43-immunoreactive inclusions developed in clusters and the clusters were distributed regularly parallel to the tissue boundary. The spatial patterns of the inclusions were similar to those revealed by a phosphorylation-independent anti-TDP-43 antibody. The spatial patterns and cluster sizes of the pTDP-43-immunoreactive inclusions were similar in GRN mutation cases, remaining familial cases, and in sporadic FTLD-TDP. Hence, pathological changes initiated by different genetic factors in familial cases and by unknown causes in sporadic FTLD-TDP appear to follow a parallel course resulting in very similar patterns of degeneration of frontal and temporal lobes.

TDP-43-immunoreactive pathology in frontotemporal lobar degeneration with TDP proteinopathy (FTLD-TDP) with and without associated motor neuron disease (MND)

A proportion of patients with motor neuron disease (MND) exhibit frontotemporal dementia (FTD) and some patients with FTD develop the clinical features of MND. Frontotemporal lobar degeneration (FTLD) is the pathological substrate of FTD and some forms of this disease (referred to as FTLD-U) share with MND the common feature of ubiquitin-immunoreactive, tau-negative cellular inclusions in the cerebral cortex and hippocampus. Recently, the transactive response (TAR) DNA-binding protein of 43 kDa (TDP-43) has been found to be a major protein of the inclusions of FTLD-U with or without MND and these cases are referred to as FTLD with TDP-43 proteinopathy (FTLD-TDP). To clarify the relationship between MND and FTLD-TDP, TDP-43 pathology was studied in nine cases of FTLD-MND and compared with cases of familial and sporadic FTLD-TDP without associated MND. A principal components analysis (PCA) of the nine FTLD-MND cases suggested that variations in the density of surviving neurons in the frontal cortex and neuronal cytoplasmic inclusions (NCI) in the dentate gyrus (DG) were the major histological differences between cases. The density of surviving neurons in FTLD-MND was significantly less than in FTLD-TDP cases without MND, and there were greater densities of NCI but fewer neuronal intranuclear inclusions (NII) in some brain regions in FTLD-MND. A PCA of all FTLD-TDP cases, based on TDP-43 pathology alone, suggested that neuropathological heterogeneity was essentially continuously distributed. The FTLD-MND cases exhibited consistently high loadings on PC2 and overlapped with subtypes 2 and 3 of FTLD-TDP. The data suggest: (1) FTLD-MND cases have a consistent pathology, variations in the density of NCI in the DG being the major TDP-43-immunoreactive difference between cases, (2) there are considerable similarities in the neuropathology of FTLD-TDP with and without MND, but with greater neuronal loss in FTLD-MND, and (3) FTLD-MND cases are part of the FTLD-TDP 'continuum' overlapping with FTLD-TDP disease subtypes 2 and 3. © 2012 Nova Science Publishers, Inc. All rights reserved.

Survival in the pre-senile dementia frontotemporal lobar degeneration with TDP-43 proteinopathy:effects of genetic, demographic and neuropathological variables

Factors associated with survival were studied in 84 neuropathologically documented cases of the pre-senile dementia frontotemporal dementia lobar degeneration (FTLD) with transactive response (TAR) DNA-binding protein of 43 kDa (TDP-43) proteinopathy (FTLD-TDP). Kaplan-Meier survival analysis estimated mean survival as 7.9 years (range: 1-19 years, SD = 4.64). Familial and sporadic cases exhibited similar survival, including progranulin (GRN) gene mutation cases. No significant differences in survival were associated with sex, disease onset, Braak disease stage, or disease subtype, but higher survival was associated with lower post-mortem brain weight. Survival was significantly reduced in cases with associated motor neuron disease (FTLD-MND) but increased with Alzheimer's disease (AD) or hippocampal sclerosis (HS) co-morbidity. Cox regression analysis suggested that reduced survival was associated with increased densities of neuronal cytoplasmic inclusions (NCI) while increased survival was associated with greater densities of enlarged neurons (EN) in the frontal and temporal lobes. The data suggest that: (1) survival in FTLD-TDP is more prolonged than typical in pre-senile dementia but shorter than some clinical subtypes such as the semantic variant of primary progressive aphasia (svPPA), (2) MND co-morbidity predicts poor survival, and (3) NCI may develop early and EN later in the disease. The data have implications for both neuropathological characterization and subtyping of FTLD-TDP.