Amyloid β protein deposition in patients with frontotemporal lobar degeneration: relationship to age and apolipoprotein E genotype

doi:10.1016/S0304-3940(01)01785-2

Neuroscience Letters

Volume 304, Issue 3, 25 May 2001, Pages 161-164

https://doi.org/10.1016/S0304-3940(01)01785-2 Get rights and content

Abstract

Amyloid β protein (Aβ) deposition was investigated in the frontal cortex of 54 autopsy cases of frontotemporal lobar degeneration (FTLD) using methenamine silver staining, and immunohistochemistry employing the monoclonal end-specific antibodies BC05 and BA27 to visualize deposits containing Aβ₄₂₍₄₃₎ and Aβ₄₀, respectively. Aβ was detected in 14 (26%) patients, nearly always in the form of diffuse Aβ₄₂₍₄₃₎ containing plaques though some cored, neuritic plaques with trace amounts of Aβ₄₀ were occasionally seen. The 14 patients showing Aβ deposits were significantly older at onset of illness than those 40 patients without Aβ. It was only possible to genotype 46/54 cases, 16 of whom bore at least one copy of the Apolipoprotein E (APOE) ε4 allele, giving an allele frequency of 20%. Possession of APOE ε4 allele was significantly associated with deposition of Aβ such that 10/16 ε4 allele bearers had Aβ deposits. Eight of these ten patients showed only mild to moderate amounts of Aβ, but in two patients, one homozygous and one heterozygous for ε4 allele, there was extensive neuritic plaque and neurofibrillary tangle formation. In contrast, only few non-ε4 allele bearers (4/30) showed minor Aβ deposits. When stratifying for APOE ε4 allele, both bearers and non-bearers of ε4 allele with Aβ deposits had a significantly later age at onset than their respective groups without Aβ deposits. We conclude that the likelihood of Aβ deposition, as a secondary and coincidental feature unrelated to the primary pathological process, within the brains of individuals with FTLD will be high if patients have a sufficiently late onset of illness or happen to be a bearer of the APOE ε4 allele. Indeed 9/14 patients with Aβ deposits studied here had an onset of illness after 55 years of age and bore APOE ε4 allele.

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Cited by (39)

Frontotemporal lobar degeneration: Study of a clinicopathological cohort
2018, Journal of Clinical Neuroscience
Citation Excerpt :
In polymorphism analysis of H1/H2 MAPT gene was carried out also in the 52 cases. The most frequent haplotype was H1/H1 (48.6%), which was more frequent in PSP and CBD cases, as reported in the literature [44]. H1/H2 was observed in 17% of the cases and it was related to TDP cases (42.9%) whilst H2/H2 was not found in any case.
Frontotemporal dementia results from different neurodegenerative diseases heterogeneous from a clinical, neuropathological and genetic point of view.
Our main objective was to analyze the sociodemographic, clinical, neuropathological and molecular characteristics of cases with frontotemporal lobar degeneration from different Neurological Tissue Banks.
FTD has been considered as a disease with onset below 65. However, diagnosis at higher ages is increasingly common. In our study, there was a correlation between symptoms and disease course with certain neuropathological diagnoses, with different distribution depending on age and sex. Combined pathology with Alzheimer’s and vascular pathology was observed and presence of argyrophilic grains, with a different distribution in the different subgroups and a particular clinical and progression phenotype. Low percentage of APOE4 was detected. H1/H1 haplotype of the MAPT gene was the most frequent and appeared in relationship with 4R tauopathies.
These results point to biologically significant differences between the different types of FTLD.
Cerebrospinal fluid Aβ40 is similarly reduced in patients with Frontotemporal Lobar Degeneration and Alzheimer's Disease
2015, Journal of the Neurological Sciences
Citation Excerpt :
In fact, in four of these patients, intracerebral Aβ deposits were seen in PIB-PET scans. This is in line with the results of Mann et al. [55], that found Aβ plaques in FTLD patients associated with older age and a higher ApoE- ε 4 allele frequency. It is known that older individuals are more likely to have a CSF-AD biomarkers profile [58] and that the association between the pathological features of Alzheimer's Disease and dementia is stronger in the younger old than in older old persons [78].
Cerebrospinal fluid (CSF) biomarkers have been increasingly studied for dementia diagnosis, however the accuracy to distinguish between different forms of dementia is still unsatisfactory. In this study, the added value of another CSF Aβ-peptide (Aβ40), along with the core CSF markers t-Tau, p-Tau, and Aβ42, in the discrimination between two large dementia groups of Frontotemporal Lobar Degeneration (FTLD; n = 107), Alzheimer's Disease (AD; n = 107) and non-demented subjects (n = 33) was evaluated.
In FTLD, t-Tau and p-Tau were significantly increased in relation to controls, but lower than in AD, while Aβ42 was similar in FTLD and controls, but higher than in AD. Equally reduced Aβ40 levels were seen in both dementia groups, and therefore the combination of Aβ40 with core CSF biomarkers optimally discriminated FTLD and AD patients from controls. Aβ42 and t-Tau were selected as the best biomarker subset to differentiate FTLD from AD, with no added value of Aβ40 to the model. Diagnostic accuracy between FTLD and AD was still sub-optimal, with a significant percentage (23%) of FTLD patients, in particularly women, carrying an ApoE-ε4 allele, showing a CSF-AD biomarkers profile.
Although CSF Aβ40 does not appear to have an additional value in the distinction between FTLD and AD, it increases the discrimination between subjects with dementia from controls. A CSF-AD biomarker profile can be seen in patients with a clinical phenotype of FTLD, reinforcing the need for autopsy confirmation.
The Many Faces of Tau
2011, Neuron
Citation Excerpt :
Interestingly, mutations in the tau gene cause FTLD disorders such as progressive supranuclear palsy, corticobasal degeneration, and frontotemporal dementia, but never AD. While the clinical spectrum associated with the many rare tau mutations varies, most FTLD disorders differ from AD both in the types of tau inclusions and in the brain regions affected (Mann et al., 2001), indicating a possible divergence in the roles of tau in these conditions. The trigger for increased phosphorylation and aggregation of tau is also likely different in AD and FTLD.
Intrafamilial clinical phenotypic heterogeneity with MAPT gene splice site IVS10+16C>T mutation
2009, Journal of the Neurological Sciences
Two families with frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) resulting from the microtubule associated protein tau (MAPT) gene IVS10+16C>T splice site mutation are reported, members of which showed variable clinical phenotypes at presentation. Possible explanations for the intra- and interfamilial clinical heterogeneity associated with this MAPT mutation are discussed.
Neuropathology of Hereditary Forms of Frontotemporal Dementia and Parkinsonism
2008, Handbook of Clinical Neurology
Citation Excerpt :
The brains of mutation‐carriers dying from other causes very early in the disease show that neuronal and glial tau deposition precedes spongiosis, gliosis, and neuronal loss, and thus alterations in the function and structure of tau are considered primary events. Deposits of β‐amyloid are present in one‐fourth of cases, usually in association with the APOE4 allele, late onset, or long duration of disease (Mann et al., 2001). The pathogenic mechanisms of the different mutations provide the key to logically organizing the myriad of pathological changes observed in MAPT mutations.
This chapter focuses on human neuropathology, excluding data on transgenic animal models. The chapter describes that the pathology associated with some of the mutations appears very similar to or indistinguishable from that seen in certain sporadic forms of frontotemporal dementia, including Pick's disease, corticobasal degeneration, progressive supranuclear palsy, and tangle-predominant dementia. The proposed term, frontotemporal dementia and Parkinsonism linked to chromosome 17 associated with tau gene mutations (FTD P-17T), may represent a better name for this group. The chapter emphasizes that the G183V presenilin 1 mutation has been associated with familial frontotemporal dementia and a taupathy with Pick bodies in the absence of β-amyloid deposits. There are additional reports of presenilin 1 mutations with clinical and imaging frontotemporal pattern, but without histological confirmation. Finally, α-synuclein deposits accompanying predominant tau pathology have been described in a familial frontotemporal dementia with progressive aphasia and Parkinsonism, for which no linkage information is yet available.
Frontotemporal dementia
2005, Lancet Neurology
Citation Excerpt :
However, there is evidence that the ɛ4 allele may selectively increase the risk of FTLD in men.129 Many patients with this allele have (sometimes prominent) deposition of amyloid β plaques when disease onset is after age 65 years, or duration of illness is long and stretches into later life.130 The clinical phenotype in familial cases of FTD is generally similar to that in sporadic cases.14,131
Frontotemporal dementia (FTD) is a focal clinical syndrome characterised by profound changes in personality and social conduct and associated with circumscribed degeneration of the prefrontal and anterior temporal cortex. Onset is typically in the middle years of life and survival is about 8 years. The presence of microtubule-associated-protein-tau-based pathological features in some patients and the discovery, in some familial cases, of mutations in the tau gene links FTD to other forms of tauopathy, such as progressive supranuclear palsy and corticobasal degeneration. However, more than half of all patients with FTD, including some with a strong family history, show no apparent abnormality in the tau gene or protein, indicating pathological and aetiological heterogeneity. FTD provides a challenge both for clinical management and for theoretical understanding of its neurobiological substrate.

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Amyloid β protein deposition in patients with frontotemporal lobar degeneration: relationship to age and apolipoprotein E genotype

Abstract

Neurosci. Lett.

Neuron

Neurosci. Lett.

Exp. Neurol.

A clinical pathological comparison of 3 families with frontotemporal dementia and identical mutations in the tau gene (P301L)

Brain

Neuropathological staging of Alzheimer-related changes

Acta Neuropathol.

Frontal lobe degeneration of non-Alzheimer type I

Neuropathology, Arch. Gerontol. Geriatr.

Clinical, neuropsychological and neuropathological criteria for fronto-temporal dementia

J. Neurol. Neurosurg. Psychiatry

Missense and silent tau gene mutations cause frontotemporal dementia with parkinsonism-chromosome 17 type, by affecting multiple alternative RNA splicing regulatory elements

Proc. Natl. Acad. Sci. USA

Frontotemporal dementia and parkinsonism linked to chromosome 17: a consensus conference

Ann. Neurol.