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Folia Neuropathologica
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Original paper

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

Richard A. Armstrong

Folia Neuropathol 2016; 54 (2): 137-148
Online publish date: 2016/06/07
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Introduction

Studies of the life expectancy of patients with dementia are important in calculating prevalence rates, while identifying factors that influence survival is useful both in counseling patients and their families and in public health planning [14,60]. However, there have been relatively few studies of survival especially in the pre-senile dementias [36] including frontotemporal dementia (FTD), the second most common form of cortical dementia of early-onset after Alzheimer’s disease (AD) [55,59]. Frontotemporal dementia is associated with a variety of clinical syndromes including FTD-motor neuron disease (FTD-MND), behavioral variant FTD (bvFTD), nonfluent variant of primary progressive aphasia (nfPPA), and the semantic variant of PPA (svPPA) [12].
Frontotemporal dementia is a clinical diagnosis, and pathological variants of the disease are termed frontotemporal lobar degeneration (FTLD). A specific pathological subtype of FTLD, viz., FTLD with transactive response (TAR) DNA-binding protein of 43 kDa (TDP-43) proteinopathy (FTLD-TDP), previously call­ed FTLD with ubiquitin-immunoreactive inclusions (FTLD-U) [38,64], is characterized by a variable neocortical and allocortical atrophy principally affecting the frontal and temporal lobes. In addition, there is neuronal loss, microvacuolation of superficial cortical laminae, and a reactive astrocytosis [10,19]. A variety of TDP-43-immunoreactive inclusions are present in these cases including neuronal cytoplasmic inclusions (NCI), neuronal intranuclear inclusions (NII), dystrophic neurites (DN), and glial inclusions (GI) [10].
FTLD-TDP exhibits considerable pathological heterogeneity which may affect survival [10]. First, various genetic defects have been identified, the majority being caused by mutation of the progranulin (GRN) gene (FTLD-TDP-GRN) [11,13,23,46,51,61]. A less prevalent disorder, FTLD with valosin-containing protein (VCP) gene mutation [28], also has TDP-43 immunoreactive inclusions, and familial cases have also been shown to be caused by the chromosome 9 open reading frame 72 (C90RF72) gene [39,52]. Second, FTLD is associated with various co-morbidities including MND (FTLD-MND), such cases being associated with a more localized pattern of frontal lobe atrophy [63] and with hippocampal sclerosis (HS) [1], in which significant neuronal loss occurs in the subiculum and sector CA1 of the hippocampus [35]. In addition, cases of later onset exhibit AD neuropathological change (ADNC), viz. senile plaques (SP) and neurofibrillary tangles (NFT) [10]. Third, various subtypes of FTLD-TDP have been proposed based on pathological criteria [20,40,53]. Using the system proposed by Cairns et al. [20]: type 1 cases are characterized by long DN in superficial cortical laminae with few or no NCI or NII, type 2 by numerous NCI in superficial and deep cortical laminae with infrequent DN and sparse or no NII, type 3 by pathology predominantly affecting the superficial cortical laminae with numerous NCI, DN and varying numbers of NII, and type 4 by numerous NII, and infrequent NCI and DN especially in neocortical areas [20].
Many published studies suggest that survival rates in the dementias vary considerably and may depend on numerous factors [17]. Hence, survival may depend on age at diagnosis, sex, disease subtype, and severity of progression [5]. The objective of the present study was to investigate the influence of genetics, demographic variables, co-morbidity, and neuropathology on survival, as measured by duration of dementia, in a sample of well-documented FTLD-TDP cases [10]. Kaplan-Meier survival analysis was used to determine whether survival was influenced by genetics, demographic factors, or co-morbidity, while Cox regression analysis was used to determine whether there were correlations between survival and predictor variables such as the densities of TDP-43-reactive inclusions in various brain regions [33,48,66].

Material and methods

Cases

Eighty-four cases of FTLD-TDP (see Table I) were obtained from dementia centers in the USA and Canada: (1) Washington University School of Medicine, St. Louis, MO, USA; (2) University of California, Davis, CA, USA; (3) University of Pittsburgh, Pittsburgh, PA, USA; (4) Vancouver General Hospital, Vancouver, Canada; (5) Harvard Brain Tissue Resource Center, Belmont, MA, Emory University, Atlanta, GA, USA; (6) University of Washington, Seattle, WA, USA; (7) Columbia University, New York, NY, USA; (8) University of California, Irvine, CA, USA and (9) University of Michigan, Ann Arbor, MI, USA. All cases exhibited FTD with neuronal loss, microvacuolation in the superficial cortical laminae, and reactive astrocytosis consistent with diagnostic criteria for FTLD-TDP [19,39]. A variety of TDP-43-immunoreactive inclusions were present in these cases including NCI, NII, DN, and GI. Of the 84 cases, 39 (46%) were familial (one or more first degree relatives affected) and of these, 16 cases (19%) had GRN mutations [11,13,23,46,51,61], one had a VCP gene mutation [28], and one case was associated with C90RF72 [39,52]. The genetic defects in the remaining familial cases have not been identified to date. Nine of the cases (11%) had coexisting MND (FTLD-MND) [34,37] and seven (8%) were identified as having associated HS (FTLD-HS). Twelve cases (14%) were identified as having ADNC greater than expected from normal aging [44]. Braak staging was based on the density and distribution of -amyloid (A) deposits and NFT [15,16] and cases were also assigned to the four pathological subtypes [20].

Case records

The following data were obtained from case and post-mortem records: (1) family history, (2) the presence of MND, HS, or AD co-morbidity, (3) age at death, (4) disease duration, measured from the onset of dementia symptoms, determined by clinical assessment, and defined as cognitive dysfunction sufficiently severe to impair activities of daily living, and (5) total brain weight.

Histological methods

After death, consent of the next-of-kin was obtained for brain removal, following local Ethical Committee procedures and the 1995 Declaration of Helsinki (as modified in Edinburgh, 2000). Tissue blocks were taken from the frontal lobe at the level of the genu of the corpus callosum to study the middle frontal gyrus (MFG) and temporal lobe at the level of the lateral geniculate body to study the inferior temporal gyrus (ITG), parahippocampal gyrus (PHG), CA1/2 sectors of the hippocampus, and dentate gyrus (DG). Tissue was fixed in 10% phosphate-buffered formal saline and embedded in paraffin wax. Immunohistochemistry (IHC) was performed on 4 to 10 µm sections with a rabbit polyclonal antibody that recognizes TDP-43 epitopes (dilution 1 : 1000; ProteinTech Inc., Chicago, IL). Sections were counterstained with hematoxylin.

Quantitative analysis of neuropathology

In the MFG, ITG, and PHG of each case, histological features were counted along strips of tissue (1600 to 3200 µm in length) located parallel to the pia mater, using 250 x 50 µm sample fields arranged contiguously [3]. The sample fields were located in both the upper and lower cortex, the short edge of the field being orientated parallel with the pia mater and aligned with guidelines marked on the slide. Between 32 and 64 fields were used to quantify each region. In the majority of cases, the upper and lower fields quantified lesions in lamina II and part of lamina III and in laminae V/VI respectively. In the hippocampus, the features were counted in the cornu ammonis (CA) in a region extending from the prosubiculum/CA boundary to the maximum point of curvature of the pyramidal layer before it extends to join the dentate fascia via CA3 and CA4. Hence, the region sampled encompassed approximately sectors CA1 and CA2, the short dimension of the contiguous field being aligned with the alveus. Little pathology was observed to extend into CA3/4 in these cases [10]. To quantify pathology in the dentate gyrus [38,41,64], the sample field was aligned with the upper edge of the granule cell layer. The NCI are rounded, spicular, or skein-like in shape [24,65], while the GI morphologically resemble the ‘coiled bodies’ reported in various tauopathies such as corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), and argyrophilic grain disease (AGD). The NII are lenticular or spindle-shaped [50] and the DN characteristically long and contorted [31]. Small spherical or asymmetrical nuclei without cytoplasm but with the presence of a thicker nuclear membrane and more heterogeneous chromatin were identified as glial cells [2]. Abnormally enlarged neurons (EN) had enlarged perikarya, lacked NCI, had a shrunken nucleus displaced to the periphery of the cell, and the maximum cell diameter was at least three times the nucleus diameter [2,4]. The number of discrete vacuoles greater than 5 µm in diameter was also recorded in each field [9].

Data analysis

First, the survival data as a whole were tested for normality using the Kolmogorov-Smirnov and chi-square (2) goodness of fit tests. The degree of skew in the data was also tested. Second, the Kaplan-Meier ‘product limit estimator’ was used to study the overall pattern of survival among the 84 cases and is the fraction of cases which survive for a certain pe­riod after disease onset. In typical applications, the cases can also be grouped according to a categorical predictor variable and the effect of the variable on survival tested. Where two groups were present, e.g., familial/sporadic, male/female, presence/absence of co-morbidity, survival was compared using the log-rank test which determines whether the hazard ratio (HR) is significantly different from unity [5]. An assumption of this analysis is that the HR is relatively constant across time intervals (‘proportionality assumption’). This assumption was tested by two methods: (1) by examining changes in the HR over time and (2) by fitting a model that includes, in addition to a fixed covariate group, a time-dependent variable. If the time-dependent covariate is not significant, then proportionality can be assumed and a model with the single fixed covariate is likely to be appropriate. Where more than two groups were present, survival was compared using the chi-square (2) test. In addition, a life table analysis was performed to predict the life expectancy of FTLD-TDP patients at each age. Third, Cox regression was used to study the relationship between survival and various predictor variables. Two such groups of variables were tested: (1) demographic variables such as age at death, and disease onset, and gross neuropathological assessments such as brain weight, Braak stage and disease subtype and (2) quantitative estimates of density of histological features. In each of these analyses, variables were modeled individually and were corrected for gender and age. Statistical significance in these tests was based on t and the Wald statistic [5].

Results

The distribution of the data as a whole did not deviate from normality (KS d = 0.13, p > 0.05; 2 = 9.52, DF = 5, p > 0.05; Skew = 0.45, SE = 0.26). Mean disease duration of the 84 FTLD-TDP cases was 7.9 years (median: 7.0, range: 1-19 years, SD = 4.64). The survival function for all cases is shown in Figure 1, suggesting that 25% of cases died within four years, 50% within 6.9 years, and 75% within 10 years after onset of dementia. In addition, the data are summarized as a ‘life table’ (Table II), suggesting that median life expectancy was 7.58 years immediately after diagnosis, 3.4 years 10 years after, and 0.75 years 18 years after diagnosis.
The effect of various categorical predictor variables on survival is shown in Table III. The data suggest no significant differences in survival between familial and sporadic cases (log rank = 0.03, p > 0.05) or among cases divided into sporadic, GRN mutation, and remaining familial cases (2 = 1.81, DF = 2, p > 0.05). In addition, there were no significant differences in survival in males and females (log rank = 0.68, p > 0.05). However, significant effects of comorbidity on survival were evident (2 = 22.70, DF = 3, p < 0.001), cases with associated MND exhibiting reduced survival compared with those without copathology (HR = 2.23, CI = 0.18) and those with associated AD (HR = 0.51, CI = 0.30) and HS (HR = 0.51, CI = 0.35) showing increased survival (2 = 6.83, DF = 2, p < 0.05). The HR for MND and HS were relatively constant across time intervals and the time-dependent covariates non-significant, suggesting that the proportionality assumption was valid. However, HR for AD varied between time intervals, and the time-dependent covariate was significant (t = 2.23, p < 0.05), thus violating the assumption of proportionality.
The results of the Cox regression analysis, corrected for gender, which included the demographic variables, brain weight, Braak staging, and pathological disease subtype, are shown in Table IV. The data suggest: (1) a relationship between patient age and survival (t = 8.81, p < 0.01), better survival being associated with a later age at death, (2) no significant association between survival and disease onset (t = 0.79, p > 0.05), (3) a significant relationship with brain weight (t = 3.07, p < 0.01), lower brain weight being associated with increased survival, and (3) no significant association between survival and Braak stages (A: t = 0.33, p > 0.05; NFT: t = 0.75, p > 0.05), or disease subtype (t = 0.82, p > 0.05).
The results of the Cox regression analysis, corrected for gender, applied to the quantitative neuropathological variables measured in each brain region, are shown in Table V. Some histological features were associated with increased survival, including GI in the MFG (t = 2.19, p < 0.05), DN in the ITG (t = 2.21, p < 0.05), EN in the PHG (t = 2.31, p < 0.05), neurons in the MFG (t = 2.54, p < 0.05) and ITG (t = 2.86, p < 0.001), and vacuoles in the PHG (t = 3.26, p < 0.001). By contrast, density of NCI was associated with poorer survival in the ITG (t = 3.56, p < 0.001) and HC (t = 2.67, p < 0.05). A similar pattern of relationships was seen when the analysis was corrected for patient age. Only correlations between NCI in the ITG and EN in the PHG remained significant in these analyses after Bonferroni correction.

Discussion

Mean survival of the 84 FTLD-TDP cases was 7.9 years, similar to the 7.1 years recorded in a recent study of 102 AD cases [5], but longer than the 5.2 years and 6.5 years in AD estimated by Doody et al. [26] and Feldman et al. [27] respectively. Mean survival was also greater than the 6.08 years reported for a large sample of pre-senile dementia cases in the north of England, UK, but which comprised largely AD and vascular dementia (VD) [36]. Survival was increased compared with that reported for a specific group of AD cases, which had vascular disease co-morbidity, in which mean survival was less than five years [27]. This difference probably reflects the relative ages of the cases, vascular disease co-morbidity being less of a factor in pre-senile dementia. Median survival of the group (7 years), however, was similar to that of 61 pathologically confirmed FTLD patients [32]. Survival was reduced compared with a specific clinical subtype of FTLD, viz. svPPA, in which 50% of patients survived more than 12.8 years [33].
Two distinct subtypes of dementia progression have been identified, especially in AD [47,54,58], cases having either a very short (median survival 10 months) or a significantly longer survival and which may reflect education level [18,21]. Short survival cases were also evident in the present sample of FTLD-TDP, nine cases surviving for two years or less. A multiple discriminant analysis (MDA) [6] which compared these cases with the remaining FTLD-TDP cases suggested that reduced survival was not associated with different ages at death, disease onset, brain weight at post-mortem, difference in quantitative neuropathology, or co-morbidity.
No significant difference in survival was observed between males and females with FTLD-TDP, contrasting with some studies which show poorer survival in males with dementia [21,26,29]. In addition, the data suggested that survival was similar in familial and sporadic FTLD-TDP. This result contrasts with AD in which familial cases in general and cases specifically linked to presenilin 1 (PSEN1) mutation exhibited increased survival [5].
The data suggest that the presence of co-morbidity had a significant effect on survival, associated MND significantly shortening the lifespan. This result is similar to that previously reported for FTD-MND, which exhibited substantially reduced survival (median survival 3 years) [33]. Similarly in AD, the presence of at least one co-morbidity decreased survival [5,67] and the presence of combined co-morbidity and functional disability was an important predictor of lower survival [66]. In FTLD-TDP, however, the presence of associated AD or HS increased survival, suggesting possible synergistic interactions between competing pathologies. Consistent with this suggestion, Hodges et al. [32] found that the presence of tau pathology in FTLD improved prognosis (median survival 9.07). However, caution is necessary in interpreting these results as, first, HR for AD varied between time intervals and the time-dependent covariate was significant (t = 2.23, p < 0.05), thus violating the assumption of proportionality, and, second, numbers of patients were small. Bowen et al. [14] also found a strong association between decreased survival in AD and cardiovascular disease (CVD), regarded as a significant determinant of progression to dementia. No effect of CVD or hypertension on survival, however, has been observed in other studies of AD [62] or in Down’s syndrome (DS) patients [22], who frequently develop AD-type pathology [42,43,45]. Accurate quantitative data on CVD load, e.g., lacunar infarcts, micro-infarcts, and atherosclerosis of large vessels, were not available for many of the FTLD-TDP cases studied, but available data from some cases suggested that CVD load was significantly lower than in AD [5].
Whether brain weight significantly changes over the course of dementia has been controversial [5]. There are limitations in studying this complex variable post-mortem as many factors can influence brain weight, including body height and weight and the presence of systemic disease such as osteoporosis [5]. In the present study, lower brain weights were associated with better survival consistent with a gradual loss of brain volume in FTLD-TDP with disease progression. By contrast, in one study of AD, poorer survival was associated with lower gray matter volume, and smaller volume reductions in brain predicted better survival [56].
Cox regression analysis incorporating Bonferroni correction suggested that the density of NCI was positively associated with decreased survival in the ITG, suggesting either that abundant NCI could shorten survival times or that NCI could be characteristic of the early stages of the disease, being lost as the disease progresses. By contrast, the density of EN in the PHG was negatively associated with decreased survival, suggesting either that EN developed later in the disease or they could represent the earliest affected regions exposed to accumulating pathology over time. Studies suggest that pathological proteins in various neurodegenerative disorders may spread through the brain via anatomical connections [7,30,57]. In AD, for example, this spread frequently occurs from an origin in the medial temporal lobe to the cortical association areas and hippocampus, and then to the primary sensory areas [8,25,49]. Pathogenic TDP-43 may also exhibit this property, and therefore changes in density with duration in specific areas could reflect this spread. That the density of a ‘signature’ pathological change, viz., NCI, may vary with degree of survival has implications for both the neuropathological characterization and subtyping of FTLD-TDP, which rely on the relative density and distribution of TDP-43-reactive inclusions [20].
In conclusion, factors associated with survival were studied in 84 cases of pre-senile dementia frontotemporal dementia lobar degeneration (FTLD) with transactive response (TAR) DNA-binding protein of 43 kDa (TDP-43) proteinopathy (FTLD-TDP). The data suggested that survival in FTLD-TDP was greater than typical for the pre-senile dementias but shorter than some clinical subtypes such as SD. In addition, MND co-morbidity is a predictor of shorter survival times. There are also changes in the density of some neuropathological changes with survival, and hence the data may have implications for both diagnosis and subtyping of FTLD-TDP.

Acknowledgements

I thank the following for making tissue sections available for this study: Knight Alzheimer’s Disease Research Center, Washington University School of Medicine, St. Louis, MO, USA, William Ellis (Department of Pathology, University of California, Davis, Sacramento, CA, USA), Ronald L. Hamilton (Department of Pathology, University of Pittsburgh, Pittsburgh, PA, USA), Ian R. A. Mackenzie (Department of Pathology, Vancouver General Hospital, Vancouver, Canada), E. Tessa Hedley-Whyte (Massachusetts General Hospital and Harvard Brain Tissue Resource Center, Belmont, MA, USA), Marla Gearing (Center for Neurodegenerative Disease, Emory University, Atlanta, GA, USA).

Disclosure

Author reports no conflict of interest.

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