TDP-43 and Frontotemporal Dementia

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1 TDP-43 and Frontotemporal Dementia William T. Hu, MD, PhD, and Murray Grossman, MD Corresponding author William T. Hu, MD, PhD Department of Neurology, University of Pennsylvania School of Medicine, 3400 Spruce Street, Philadelphia, PA 19106, USA. Current Neurology and Neuroscience Reports 2009, 9: Current Medicine Group LLC ISSN Copyright 2009 by Current Medicine Group LLC TAR DNA-binding protein of about 43 kda (TDP- 43) is the main ubiquitinated peptide in tau-negative frontotemporal lobar degeneration (FTLD). TDP-43 is typically a nuclear protein, and its aggregation and cytoplasmic translocation are thought to represent major steps in the pathogenesis of FTLD due to TDP-43 proteinopathy (FTLD-TDP). Certain clinical syndromes of frontotemporal dementia are preferentially associated with pathologic findings of FTLD-TDP, and TDP-43 pathology represents the connection between FTLD-TDP and amyotrophic lateral sclerosis. Recent advances in clinical, genetic, and pathologic studies of FTLD-TDP and amyotrophic lateral sclerosis have shed light on the potentially pathogenic role of TDP-43 and identified TDP-43 itself as a candidate biomarker for antemortem diagnosis of FTLD-TDP. Introduction Frontotemporal lobar degeneration (FTLD) represents a family of neurodegenerative disorders that result in a clinical picture of pronounced behavioral or language abnormalities [1,2]. On autopsy, patients invariably have atrophy in the frontal and/or temporal lobar regions, neuronal loss in the superficial layer of the neocortex, and a mixture of neuronal and glial pathology. One group of patients with FTLD has cellular pathology containing hyperphosphorylated tau, including those with Pick s disease, corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), tau-predominant senile dementia (TPSD), and frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) [3]. These patients are collectively referred to as having FTLD-Tau [4]. The other major group of patients has intracellular pathology immunoreactive to TAR DNA-binding protein of about 43 kda (TDP-43) [5 ] and is said to have FTLD-TDP [4]. About half of the patients with FTLD have pathology associated with TDP-43, making FTLD-TDP the single most common cause of FTLD. Since its identification as the major ubiquitinated peptide in FTLD without tau pathology, TDP-43 has been the focus of intensive international investigation. Significant progress has been made toward understanding the clinical characterization, neuropathologic analysis, genetics, and molecular and cellular biology of TDP-43 associated disorders. TDP-43 is a nuclear protein thought to be involved in transcriptional and splicing regulation [6]. Importantly, TDP-43 is also the major ubiquitinated peptide in autopsyconfirmed amyotrophic lateral sclerosis (ALS) [5 ], making TDP-43 the common link between FTLD and ALS. This family of disorders, collectively referred to as TDP-43 proteinopathies, is believed to represent a continuum of neocortical and pyramidal system TDP-43 involvement. This review summarizes the recent advances in TDP-43 proteinopathies in the context of clinical and pathologic FTLD. Clinical Syndromes of FTLD-TDP Patients with FTLD pathology caused by FTLD-Tau or FTLD-TDP often present clinically with prominent behavioral or language features, although the absence of these features early in the disease course does not completely rule out the possibility of FTLD. Onset generally occurs before age 65, but Rosso et al. [7] reported that 20% of patients with autopsy-proven FTLD had onset after age 65. Cases are equally divided between males and females. Patients with altered personality and comportment are classified as having behavioral variant frontotemporal dementia (bv-ftd), and patients with progressive language difficulties have language variant frontotemporal dementia (lv-ftd). Patients with lv-ftd have also been referred to as having primary progressive aphasia (PPA), which can be classified further into three subtypes: semantic dementia (SD), progressive nonfluent aphasia (PNFA), or logopenic progressive aphasia (LPA). As we enter the era of etiologically specific treatments for neurodegenerative diseases, a special focus in the clinicopathologic analysis of FTLD-TDP and FTLD-Tau has been the noninvasive antemortem clinical prediction of underlying tau- or TDP-43 associated pathology. A number of clinical features have been correlated with a high likelihood of FTLD-TDP instead of FTLD-Tau pathology. One clue that the FTD patient has FTLD-TDP is the development of clinical ALS. One clinicopathologic series estimated that 5% of FTLD-TDP patients had ALS [8]. In 234 consecutively evaluated patients with FTD at the University of Pennsylvania, 12.5% of

2 354 I Dementia Figure 1. Relative frequency of frontotemporal dementia (FTD) syndromes and related disorders at the Department of Neurology, University of Pennsylvania, after excluding patients with Alzheimer s disease pathology by autopsy or cerebrospinal fluid. Patients with semantic dementia (SD), logopenic progressive aphasia (LPA), and FTD with amyotrophic lateral sclerosis (FTD-ALS) are likely to have frontotemporal lobar degeneration with TAR DNA-binding protein of about 43 kda (FTLD-TDP); those with corticobasal syndrome (CBS) and progressive nonfluent aphasia (PNFA) are likely to have FTLD-Tau; and those with behavioral variant FTD (bv-ftd) are equally likely to have FTLD-TDP or FTLD-Tau. patients developed ALS before, after, or at the same time as the onset of cognitive FTD symptoms. With rare exceptions of tau-positive cases of FTD motor neuron disease (MND) (such as ALS/Parkinson dementia complex of Guam) or concurrent Alzheimer s disease (AD) with ALS, the development of ALS in FTD (FTD-ALS) is nearly always associated with FTLD-TDP pathology involving the motor cortex, lower motor neurons, and extramotor neocortex. The relative ratio of patients with behavioral deficits to language deficits in those with both FTD and ALS is similar to the ratio seen in those with FTD but no ALS, and PNFA and PPA not otherwise specified are much more common variants of language syndromes associated with ALS than SD [9]. ALS patients can also develop subtle cognitive impairment typically resembling FTD (ALS-FTD) in the course of ALS. Clinically, ALS-FTD patients and most FTD-ALS patients have short survival (similar to ALS without dementia; 2 3 years after symptom onset), but some FTD-ALS patients survive much longer [9]. At the same time, the neuroanatomic distribution of TDP-43 pathology in patients with clinical FTD and ALS has been reported as much more similar to those with FTLD-TDP without motor neuron involvement than those with ALS alone [10]. Thus, patients with FTD-ALS or ALS-FTD represent a clinical and pathologic link between the two TDP-43 proteinopathies, FTLD-TDP and ALS, and multiple lines of evidence in clinical phenotypes, survival, and pathologic distribution suggest that FTD-ALS and ALS-FTD should be analyzed together as two variants of the same disease. Aside from the presence of ALS, the subclassification of patients with language impairment has been useful in the prediction of underlying pathology (Fig. 1): SD, the fluent form of PPA with pronounced loss of naming and object knowledge but preserved grammar, is much more often associated with FTLD-TDP than AD or FTLD- Tau [3,11,12], and only about 20% of cases of PNFA are associated with FTLD-TDP [8]. LPA, an intermediate form of PPA with some features of SD and PNFA, is hypothesized to reflect AD pathology [13], although some patients with clinical LPA have been found at autopsy to have FTLD-TDP pathology [14]. Their clinical and neuropsychological characteristics are indistinguishable from those with LPA and AD pathology, making FTLD-TDP a potential pathology for any of the three PPA subtypes. Similarly, bv-ftd can be equally caused by FTLD-TDP or FTLD-Tau [3,8,15]. Although some clinical features may be preferentially associated with FTLD-TDP, it remains difficult to predict the specific underlying FTLD pathology on clinical grounds alone [16]. Similarly, even though early evidence suggested that patterns of atrophy on MRI can help differentiate FTLD-TDP from FTLD-Tau, subsequent studies with detailed analysis of autopsy-confirmed cases of bv-ftd or FTD in general have found little difference in atrophy between FTLD-TDP and FTLD-Tau [17,18]. Lastly, patients with clinical corticobasal syndrome (CBS) or PSP almost invariably have FTLD-Tau pathology if AD is not the underlying cause [3,8]. Thus, the diagnosis of FTD-ALS remains the strongest predictor of FTLD-TDP pathology among patients with an FTD syndrome, and the diagnosis of CBS/PSP is rarely associated with FTLD-TDP. Each of the remaining FTD syndromes, including SD, PNFA, LPA, and bv-ftd, are associated with varying probability of FTLD-TDP pathology on the individual patient level. Genetic Causes of TDP-43 Proteinopathies Up to 50% of patients with clinical FTD have a positive family history of a neurodegenerative disorder. Mutations in the gene responsible for TDP-43 have been implicated recently in three ALS patients whose clinical course began with FTD. ALS is familial in up to 10% of cases, and the inheritance pattern is usually autosomal dominant. Until recently, the best characterized mutations in familial ALS (FALS) were found in the copper/zinc superoxide dismutase (SOD1), which accounted for about 20% of FALS cases [19]. In neuropathologic analysis, postmortem tissue with the SOD1 mutation invariably had pathology not immunoreactive to TDP-43, but tissue from patients with non-sod1 FALS often had TDP-immunoreactive pathology [20]. In 2008, four groups independently identified mutations in the TARDBP gene on chromosome 1 as causes of FALS [21,22 24 ]. Most of the mutations were found in exon 6, a region known to be involved in protein protein interaction, and one additional mutation was identified in the RNA recognition motif [24 ].

3 TDP-43 and Frontotemporal Dementia I Hu and Grossman I 355 More recently, analysis from large numbers of FTD-ALS patients suggested that TARDBP mutations can at least be implicated in cases of FTD involving ALS. Two variants of TARDBP gene (Ala90Val and Gly295Ser) may have conferred increased risk of or directly resulted in FTD-ALS in three patients [25,26]. The disease course in all of these individuals began with FTD, and these patients represent the first TARDBP variants/mutations directly associated with FTD. Although the available pathologic analysis of patients with TARDBP mutations showed cytoplasmic TDP-immunoreactive lesions to resemble pathology seen in sporadic cases of ALS [23 ], cellular expression of these mutations did not result in cytoplasmic translocation or nuclear aggregation of TDP-43 peptides [21,23 ]. Instead, there is only limited evidence of increased aggregation or cell death [24 ]. Although these mutations may be rare, accounting for about 5% to 10% of non-sod1 FALS cases [27] and up to 2% or 3% of all ALS cases in some areas [28], the discovery of these mutations provided early evidence that TDP-43 may itself be pathogenic. Nevertheless, more work is necessary to determine if TARDBP mutations can result in FTD in the absence of ALS and why expression of these presumed pathogenic mutations failed to induce any specific pathologic changes in vitro. The identification of progranulin as a major peptide involved in the pathogenesis of FTLD-TDP represented another major advancement in the understanding of FTD. In 2006, two groups reported that a mutation in PGRN, which encodes for progranulin, is a significant cause of tau-negative FTLD [29,30 ]. Progranulin is a precursor protein to granulin and is itself a growth factor [31] implicated in wound healing and inflammation [32]. PGRN mutations largely lead to premature stop codons, and the resulting mrna transcripts undergo nonsensemediated mrna decay [29,30 ]. Consequently, there is a PGRN haploinsufficiency, and this effect can be detected in the decreased level of granulin mrna in the peripheral blood [33], serum progranulin level [34], and brain progranulin level. Beyond mutations, a common genetic variant in the 3 -untranslated region of the PGRN gene is associated with a more than threefold increased risk of FTLD-TDP [35]. This region is a putative binding site for micro-rna mir-659 and may represent a mechanistic link between PGRN mutations and FTLD-TDP because TDP-43 is involved in micro-rna regulation. Exactly how PGRN haploinsufficiency leads to FTLD-TDP remains to be elucidated, although FTLD- TDP without PGRN mutations may differ pathogenically and clinically from FTLD-TDP with PGRN mutations. Microarray studies have shown striking differences in the number and type of dysregulated genes between FTLD- TDP with and without PGRN mutations [36]. Clinically, patients with PGRN mutations can present with any of the FTD syndromes, including bv-ftd, lv-ftd, and CBS [37]. When their clinical features are analyzed in detail, PGRN mutation carriers may be more likely to demonstrate features typically associated with FTLD-Tau than FTLD-TDP patients without PGRN mutations, including dysexecutive syndrome, apraxia, extrapyramidal features, and even parietal dysfunctions such as acalculia [16,38,39]. A number of less common mutations have also been associated with familial tau-negative FTLD. Mutations in valosin-containing protein (VCP) lead to a multisystem disorder involving FTD, inclusion body myopathy, and Paget s disease of the bone and are associated with ubiquitin- and TDP-43 immunoreactive lesions [40]. Mutations in chromatin modifying protein 2B (CHMP2B) were identified in a large Danish pedigree with autosomal dominant FTD linked to chromosome 3 and a Belgian patient with familial FTD, although CHMP2B mutations typically have cellular inclusions negative for FTLD-TDP [41,42]. Although these mutations are rare, VCP and CHMP2B may represent important links in the pathogenesis of sporadic and familial FTLD-TDP, and the unique neuropathologic features associated with each mutation (including PGRN) should shed light on the significance of FTLD-TDP pathologic subtypes in terms of genetic susceptibilities. Pathology of FTLD-TDP Histologically, TDP-43 is a diffusely distributed nuclear peptide in patients without FTLD [5 ]. A number of key features characterize FTLD-TDP, including loss of diffuse nuclear staining, aggregation and, in many cases, cytoplasmic translocation [5 ]. Abnormal TDP-immunoreactive pathology thus includes neuronal intranuclear inclusions (NIIs), neuronal cytoplasmic inclusions (NCIs), and dystrophic neurites (DNs) that are also immunoreactive to TDP-43. According to the presence of each of these pathologic changes, most FTLD-TDP cases can be further classified into three subtypes: type 1, mostly with DNs; type 2, with DNs and NCIs; and type 3, with DNs, NCIs, and NIIs [43]. In some series, this subtyping scheme has been correlated with certain clinical FTD phenotypes, including type 1 with SD, types 2 and 3 with FTD-ALS, and type 3 with PNFA [44 ]. The reason for this association is not clear. Because each clinical FTD syndrome may be preferentially associated with region-specific atrophy (temporal pole in SD, inferior and dorsolateral prefrontal cortex in bv-ftd), one explanation may be lobar-specific deposition of TDP-immunoreactive pathology. This has not been found to be the case. Alternatively, FTLD-TDP subtypes may reflect distinct TDP-43 response mechanisms according to genetic susceptibility, and limited support for this comes from the finding that all FTLD-TDP cases with PGRN mutations have type 3 FTLD-TDP and the rare FTLD-TDP cases with VCP mutations have DNs and NIIs without NCIs (type 4) [4]. Because there is little antemortem clue to the FTLD subtype without neuropathologic confirmation, further work on the association between genetic susceptibilities (such as PGRN variant associated with increased risk of FTLD [35]) and FTLD subtypes will be useful to determine what genetic factors predispose to the development of FTLD-TDP subtypes.

4 356 I Dementia Pathologic changes involving TDP-43 have also improved the understanding of TDP-43 pathogenesis. Key features of pathologic TDP-43 include hyperphosphorylation, ubiquitination, abnormal cleavage to form a truncated C-terminal insoluble fragment, cytoplasmic translocation, and aggregation [5 ]. Expression of truncated C-terminal fragments in vitro led to many of these features, including cytoplasmic localization, aggregation, ubiquitination, hyperphosphorylation, and, in turn, gain-of-toxic function effect in its pathologic cytoplasmic location [45 ]. Interestingly, simple overexpression of the full TDP-43 peptide may also have a neurotoxic effect [46]. Furthermore, because TDP-43 is a nuclear protein whose function may include transcriptional silencing and splicing regulation [6], its overexpression has been demonstrated to alter the splicing of pre-mrna for the survival motor neuron (SMN) gene in addition to the splicing of cystic fibrosis transmembrane conductance regulator premrna [47]. Because SMN is associated with the lower motor neuron form of MND, this dysregulation may be involved in the pathogenesis of ALS or FTD-ALS and raises the possibility of other loss-of-function effects associated with the cytoplasmic translocation of the normally nuclear TDP-43. Because experimental progranulin knockdown and VCP mutations both lead to similar cytoplasmic translocation of TDP-43, TDP-43 proteinopathies may potentially result from transcriptional dysregulation, altered pre-mrna splicing, toxicity associated with cytoplasmic aggregation, or a combination of these changes. Atypical TDP-43 and Tau-Negative FTLD No discussion on the role of TDP-43 in tau-negative FTLD is complete without reviewing cases of FTLD without tau- or TDP-43 immunoreactive lesions. With modern immunohistopathologic techniques, it is now well established that there exist at least two other small subgroups of FTLD beyond FTLD-Tau and FTLD- TDP. A few patients have dementia lacking distinctive histopathology (DLDH), a term that described tau- and alpha-synuclein negative FTLD before the discovery of ubiquitin and TDP-43 pathology in FTLD. Perhaps slightly more common but still rare are ubiquitin-positive but TDP-43-negative inclusions. Both of these subtypes are now referred to as FTLD-U, a term that previously was used to describe all cases of tau-negative FTLD when ubiquitin immunoreactivity is detected [4]. However, these two groups are now recognized as representing an entity that is pathologically and clinically distinct from FTLD-TDP. In clinical studies, nearly all of the patients with TDP-43-negative FTLD-U presented with bv-ftd, and most of them experienced onset before the age of 50 [48 50]. Motor symptoms are uncommon, and only one patient (age 63) had a clinical diagnosis of CBS [49]. Unlike other FTD patients, a family history of neurodegenerative conditions is rare. Pathologically, NCIs and sometimes DNs or NIIs are most consistently found in the frontal cortex, and hippocampal sclerosis is a frequent finding. Some patients only have limited involvement of ubiquitin-positive inclusions in brain regions usually affected by FTLD-TDP, and such patients therefore were previously diagnosed as having DLDH [50]. Importantly, no pathologically truncated form of TDP-43 was found in brain homogenates from these patients [50]. Therefore, these atypical cases of FTLD-U likely represent a FTLD group distinct from FTLD-TDP and FTLD-Tau, although it remains to be determined if they form a clinicopathologic continuum with DLDH and perhaps even FTLD-TDP with mild TDP-immunoreactive pathology. Biomarkers for TDP-43 Proteinopathy Because abnormal TDP-43 biology is found in many cases of FTLD without tau pathology, TDP-43 is an important candidate for biomarker development for diagnosis of TDP-43 proteinopathies and possibly monitoring of disease progression or response to future therapeutic trials. As total tau, phosphorylated tau at threonine 181, and amyloid β were commonly measured peptides in the cerebrospinal fluid (CSF) of patients with AD and other neurodegenerative diseases including tauopathies, we hypothesized that CSF levels of tau and hyperphosphorylated tau may differ between those with TDP-43 proteinopathies and tauopathies. In a small series of autopsy-confirmed patients with antemortem CSF analysis, we showed that patients with tauopathies have a trend toward lower levels of total and hyperphosphorylated tau than patients with TDP-43 proteinopathies, although this finding did not achieve significance [51]. To further test this hypothesis, we extended the analysis to patients with clinically diagnosed FTD syndromes. Patients with a CSF profile inconsistent with AD were divided into those with likely tauopathies (including those clinically diagnosed with CBS and PNFA) and those with likely TDP-43 proteinopathies (including those clinically diagnosed with SD and FTD-MND). Patients with likely tauopathies had significantly lower phosphorylated tau levels in the CSF than those with likely TDP-43 proteinopathies on the group level, although a significant number of patients had intermediate levels of phosphorylated tau. Therefore, although extremely high or extremely low levels of phosphorylated tau may be useful in the prediction of underlying TDP-43 proteinopathy, additional biomarkers beyond those used in the diagnosis of AD are necessary. The first report of potentially detectable levels of TDP- 43 in plasma came from a clinical cohort of patients with FTD without autopsy confirmation [52]. Plasma samples from these clinically characterized patients were analyzed in an enzyme-linked immunosorbent assay (ELISA) using a monoclonal capturing antibody and a polyclonal detection antibody. Compared with cognitively healthy subjects and patients with clinically probable AD (early and late onset), FTD patients had higher absolute levels of TDP-43 in the plasma (0.26 ± 0.52 vs 0.02 ± 0.32 optical density

5 TDP-43 and Frontotemporal Dementia I Hu and Grossman I 357 units in controls and 0.13 ± 0.33 in AD). Using a cutoff value corresponding to 99th percentile of control values, more FTD patients had elevated plasma TDP-43 levels (43% in FTD vs 22% in AD and 9% in controls). In a separate study, TDP-43 levels were measured in CSF samples from ALS patients using a similar ELISA method [53]. Compared with cognitively healthy controls and controls with nondegenerative neurologic disease, ALS patients (none with dementia) had mildly elevated levels of TDP-43 in the CSF (6.92 ± 3.71 ng/ml in ALS vs 5.31 ± 0.94 in controls), with only 20% of ALS patients having CSF TDP-43 levels above control values. Although promising, this difference between patients with highly probable TDP-43 proteinopathy and control subjects is likely insufficient for clinical diagnostic purposes. However, future investigation is warranted given the difference in TDP-43 lesion burden between FTLD-TDP and ALS without dementia and the unclear source of plasma and CSF TDP-43. Another viable alternative is the use of multiplex assays. In a multiplex assay incorporating 30 analytes, one study was successful in identifying (with 87.5% sensitivity and 91.2% specificity) five proteins in the CSF that segregated ALS patients from controls with neurologic disease [54]. When applied to CSF or plasma from patients with autopsy-confirmed FTLD-TDP/ALS or clinical syndromes highly suggestive of FTLD-TDP such as SD, such an approach could identify useful biomarkers for diagnosis and dysregulated peptides associated with FTLD-TDP pathogenesis. Conclusions TDP-43 was identified as the major ubiquitinated peptide in tau-negative FTLD shortly after the discovery of PGRN as a major genetic cause of tau-negative FTLD. These two major discoveries in 2006 led to significant advances in understanding FTLD-TDP from clinical, genetic, neuropathologic, and pathophysiologic perspectives. FTLD-TDP represents a major cause of clinical FTD syndromes with and without ALS, and cellular changes associated with TDP-43 translocation and dysfunction are the likely causes of FTLD-TDP and ALS. A better understanding of genes and pathways regulated by TDP-43 during normal circumstances will be essential to formulate therapeutic strategies against TDP-43 proteinopathies, and antemortem diagnosis with clinical and biofluid biomarkers that distinguish FTLD-TDP from FTLD-Tau and FTLD-U is necessary for future therapeutic trials targeting TDPimmunoreactive pathology. Disclosure Dr. Grossman is a consultant for Allon Therapeutics. No other potential conflicts of interest relevant to this article were reported. 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