Claire E. Shepherd

Staging disease severity in pathologically confirmed cases of frontotemporal dementia

Objective: To devise a staging scheme for addressing the severity of atrophy in patients with pathologically proven frontotemporal dementia (FTD) and determine any relationship with clinical indices. Methods: Twenty-four cases with clinical and pathologic features of FTD were selected using standard inclusion and exclusion criteria from 125 dementia cases collected in Sydney, Australia, over an 8.5-year period. Patterns of gross atrophy were determined in two coronal brain slices. Reproducibility of a four-stage severity scheme was tested. Nonparametric statistics were used to determine relationships between the stage of atrophy and clinical indices (age at death, duration from diagnosis, and clinical severity at death). Results: The FTD cases studied could be reliably grouped (κ = 0.97) into four progressively severe stages of global atrophy. Initial mild atrophy occurred in the orbital and superior medial frontal cortices and hippocampus (stage 1), progressed to involve the other anterior frontal regions, temporal cortices, and basal ganglia (stage 2), then involved all remaining tissue in these coronal slices (stage 3), until very marked atrophy was observed in all areas (stage 4). These stages correlated with disease duration and clinical dementia severity, lending validity to the progressive nature of the staging scheme. Conclusions: The authors have identified a reproducible staging system for the severity of gross atrophy in cases of FTD. This staging scheme provides the required framework to compare different research indices and determine correlates relating to time and disease progression in FTD—information necessary to determine core disease processes and etiologic factors.

Alzheimer’s Disease And Inflammation: A Review Of Cellular And Therapeutic Mechanisms

1. Of the neurodegenerative diseases that cause dementia, Alzheimer’s disease (AD) is the most common. Three major pathologies characterize the disease: senile plaques, neurofibrillary tangles and inflammation. We review the literature on events contributing to the inflammation and the treatments thought to target this pathology.

Monocyte Chemoattractant Protein‐1 Plays a Dominant Role in the Chronic Inflammation Observed in Alzheimer's Disease

Chronic neuroinflammation correlates with cognitive decline and brain atrophy in Alzheimers disease (AD), and cytokines and chemokines mediate the inflammatory response. However, quantitation of cytokines and chemokines in AD brain tissue has only been carried out for a small number of mediators with variable results. We simultaneously quantified 17 cytokines and chemokines in brain tissue extracts from controls (n = 10) and from patients with and without genetic forms of AD (n = 12). Group comparisons accounting for multiple testing revealed that monocyte chemoattractant protein‐1 (MCP‐1), interleukin‐6 (IL‐6) and interleukin‐8 (IL‐8) were consistently upregulated in AD brain tissue. Immunohistochemistry for MCP‐1, IL‐6 and IL‐8 confirmed this increase and determined localization of these factors in neurons (MCP‐1, IL‐6, IL‐8), astrocytes (MCP‐1, IL‐6) and plaque pathology (MCP‐1, IL‐8). Logistic linear regression modeling determined that MCP‐1 was the most reliable predictor of disease. Our data support previous work on significant increases in IL‐6 and IL‐8 in AD but indicate that MCP‐1 may play a more dominant role in chronic inflammation in AD.

Variations in the neuropathology of familial Alzheimer’s disease

Mutations in the amyloid precursor protein (APP), presenilin 1 (PSEN1) and presenilin 2 (PSEN2) genes cause autosomal dominant familial Alzheimer’s disease (AD). PSEN1 and PSEN2 are essential components of the γ-secretase complex, which cleaves APP to affect Aβ processing. Disruptions in Aβ processing have been hypothesised to be the major cause of AD (the amyloid cascade hypothesis). These genetic cases exhibit all the classic hallmark pathologies of AD including neuritic plaques, neurofibrillary tangles (NFT), tissue atrophy, neuronal loss and inflammation, often in significantly enhanced quantities. In particular, these cases have average greater hippocampal atrophy and NFT, more significant cortical Aβ42 plaque deposition and more substantial inflammation. Enhanced cerebral Aβ40 angiopathy is a feature of many cases, but particularly those with APP mutations where it can be the dominant pathology. Additional frontotemporal neuronal loss in association with increased tau pathology appears unique to PSEN mutations, with mutations in exons 8 and 9 having enlarged cotton wool plaques throughout their cortex. The mechanisms driving these pathological differences in AD are discussed.

Inflammatory S100A9 and S100A12 proteins in Alzheimer's disease

Inflammation, insoluble protein deposition and neuronal cell loss are important features of the Alzheimers disease (AD) brain. S100B is associated with the neuropathological hallmarks of AD where it is thought to play a role in neuritic pathology. S100A8, S100A9 and S100A12 comprise a new group of inflammation-associated proteins that are constitutively expressed by neutrophils and inducible in numerous inflammatory cells. We investigated expression of S100B, S100A8, S100A9 and S100A12 in brain samples from sporadic and familial (PS-1) AD cases and controls using immunohistochemistry and Western blot analysis. S100B, S100A9 and S100A12, but not S100A8, were consistently associated with the neuropathological hallmarks of AD. Western blot analysis confirmed significant increases in soluble S100A9 in PS-1 AD compared to controls. S100A9 complexes that were resistant to reduction were also evident in brain extracts. A reactive component of a size consistent with hexameric S100A12 was seen in all cases. This study indicates a potential role for pro-inflammatory S100A9 and S100A12 in pathogenesis caused by inflammation and protein complex formation in AD.

C9ORF72 repeat expansion in clinical and neuropathologic frontotemporal dementia cohorts

Objective: To determine the frequency of a hexanucleotide repeat expansion in C9ORF72, a gene of unknown function implicated in frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), in Australian FTD patient cohorts and to examine the clinical and neuropathologic phenotypes associated with this expansion. Methods: We examined a clinically ascertained FTD cohort (n = 89) and a neuropathologically ascertained cohort of frontotemporal lobar degeneration cases with TDP-43 pathology (FTLD-TDP) (n = 22) for the C9ORF72 hexanucleotide repeat expansion using a repeat primed PCR assay. All expansion-positive patients were genotyped for rs3849942, a surrogate marker for the chromosome 9p21 risk haplotype previously associated with FTD and ALS. Results: The C9ORF72 repeat expansion was detected in 10% of patients in the clinically diagnosed cohort, rising to 29% in those with a positive family history of early-onset dementia or ALS. The prevalence of psychotic features was significantly higher in expansion-positive cases (56% vs 14%). In the pathology cohort, 41% of TDP-43-positive cases harbored the repeat expansion, and all exhibited type B pathology. One of the 17 expansion-positive probands was homozygous for the “nonrisk” G allele of rs3849942. Conclusions: The C9ORF72 repeat expansion is a relatively common cause of FTD in Australian populations, and is especially common in those with FTD-ALS, psychotic features, and a strong family history. Detection of a repeat expansion on the 9p21 putative “nonrisk” haplotype suggests that not all mutation carriers are necessarily descended from a common founder and indicates that the expansion may have occurred on multiple haplotype backgrounds.

Focal demyelination in Alzheimer's disease and transgenic mouse models

We have investigated alterations in myelin associated with Aβ plaques, a major pathological hallmark of Alzheimer’s disease (AD), in human tissue and relevant transgenic mice models. Using quantitative morphological techniques, we determined that fibrillar Aβ pathology in the grey matter of the neocortex was associated with focal demyelination in human presenilin-1 familial, sporadic and preclinical AD cases, as well as in two mouse transgenic models of AD, compared with age-matched control tissue. This demyelination was most pronounced at the core of Aβ plaques. Furthermore, we found a focal loss of oligodendrocytes in sporadic and preclinical AD cases associated with Aβ plaque cores. In human and transgenic mice alike, plaque-free neocortical regions showed no significant demyelination or oligodendrocyte loss compared with controls. Dystrophic neurites associated with the plaques were also demyelinated. We suggest that such plaque-associated focal demyelination of the cortical grey matter might impair cortical processing, and may also be associated with aberrant axonal sprouting that underlies dystrophic neurite formation.

Loss of the neuroprotective factor Sphingosine 1-phosphate early in Alzheimer's disease pathogenesis.

BackgroundThe greatest genetic risk factor for late-onset Alzheimers disease (AD) is the ϵ4 allele of Apolipoprotein E (ApoE). ApoE regulates secretion of the potent neuroprotective signaling lipid Sphingosine 1-phosphate (S1P). S1P is derived by phosphorylation of sphingosine, catalysed by sphingosine kinases 1 and 2 (SphK1 and 2), and SphK1 positively regulates glutamate secretion and synaptic strength in hippocampal neurons. S1P and its receptor family have been subject to intense pharmacological interest in recent years, following approval of the immunomodulatory drug Fingolimod, an S1P mimetic, for relapsing multiple sclerosis.ResultsWe quantified S1P levels in six brain regions that are differentially affected by AD pathology, in a cohort of 34 post-mortem brains, divided into four groups based on Braak neurofibrillary tangle staging. S1P declined with increasing Braak stage, and this was most pronounced in brain regions most heavily affected by AD pathology. The S1P/sphingosine ratio was 66% and 64% lower in Braak stage III/IV hippocampus (p = 0.010) and inferior temporal cortex (p = 0.014), respectively, compared to controls. In accordance with this change, both SphK1 and SphK2 activity declined with increasing Braak pathology in the hippocampus (p = 0.032 and 0.047, respectively). S1P/sphingosine ratio was 2.5-fold higher in hippocampus of ApoE2 carriers compared to ApoE4 carriers, and multivariate regression showed a significant association between APOE genotype and hippocampal S1P/sphingosine (p = 0.0495), suggesting a new link between APOE genotype and pre-disposition to AD.ConclusionsThis study demonstrates loss of S1P and sphingosine kinase activity early in AD pathogenesis, and prior to AD diagnosis. Our findings establish a rationale for further exploring S1P receptor pharmacology in the context of AD therapy.

Relationship between DNA fragmentation, morphological changes and neuronal loss in Alzheimer's disease and dementia with Lewy bodies

Abstract. This aim of the present study was to identify whether apoptotic features relate to the degree of cortical neuronal loss in cases with variable cortical degeneration. Neuronal apoptosis was assessed using histochemical and morphological criteria in cases with Alzheimers disease (AD, n=7) or Lewy bodies (n=11) compared with controls (n=11). AD cases had both significant plaque and tangle formation but no Lewy bodies, while cases with Lewy bodies had significant plaque formation but no tangles. Cortical sections were stained using (TdT)-mediated UTP nick end labelling (TUNEL), propidium iodide, and cell and pathology-specific labels. Cells identified as non-neuronal were excluded. Large cortical nuclei were classified as abnormal if they were TUNEL-positive with DNA condensation across the nucleus and no visible nucleolus, and further subdivided according to the presence or absence of visible neuronal cytoplasm. Nuclei were considered morphologically normal regardless of TUNEL staining if they possessed a clear nucleolus. Cortical fields containing the greatest density of TUNEL-positive nuclei were regionally sampled and the proportion of all classified nuclei calculated. Analysis of variance was used to identify any significant relationships. Only AD cases had significant numbers of abnormal nuclei (23±6%, P=0.002) and a corresponding decrease in normal neurons (28±7% loss, P=0.004). Absolute neuronal density was also decreased in AD (AD density 64±11% of other cases, P=0.02). Abnormal nuclei were not associated with plaque or tangle pathology. Our results suggest that nuclear abnormalities appear restricted to AD cases with substantial tau deposition and are related to the degree of neuronal degeneration.

Pick Bodies in a Family with Presenilin-1 Alzheimer's Disease

Presenilin‐1 (PS‐1) mutations can cause Picks disease without evidence of Alzheimers disease (AD). We describe a family with a PS‐1 M146L mutation and both Pick bodies and AD. Sarkosyl‐insoluble hyperphosphorylated tau showed three bands consistent with AD, although dephosphorylation showed primarily three‐repeat isoforms. M146L mutant PS‐1 may predispose to both Picks disease and AD by affecting multiple intracellular pathways involving tau phosphorylation and amyloid metabolism. Ann Neurol 2005;57:139–143