The term frontotemporal lobar degeneration (FTLD) designates a pathological concept that includes a group of molecular diseases that are classified according to the protein that accumulates in the central nervous system. In 2007, Cairns et al.1 established 4 main subtypes according to the protein deposits: tauopathies (FTLD-tau), ubiquitinopathies (FTLD-U), dementia without specific histopathological changes, and neuronal intermediate filament inclusion disease. Since then, following new breakthroughs in pathology and molecular biology, this classification system has been modified. FTLD cases are now classified into 3 main subtypes according to pathology: FTLD associated with tau protein (FTLD-tau), FTLD associated with the TAR DNA-binding protein 43 (FTLD-TDP), and FTLD associated with the fused-in sarcoma protein (FTLD-FUS). Only a very small percentage of cases will not fit any of these subtypes (FTLD-other).2 Each of these main pathological groups can be subdivided into different entities or variants according to the distribution and morphology of protein inclusions and the histological characteristics specific to the case (Table 1). These groups give rise to 6 well-defined syndromes: the 3 clinical variants of frontotemporal dementia or FTD (behavioural variant frontotemporal dementia [bv-FTD], progressive nonfluent aphasia [PNFA], semantic dementia [SD]); frontotemporal dementia associated with motor neuron disease (FTD-MND); progressive supranuclear palsy syndrome (PSPS); and corticobasal syndrome (CBS).

A small percentage of cases with clinical features suggesting FTD actually have Alzheimer disease (AD).3 This finding is more frequent in cases of logopenic primary progressive aphasia (PPA),4 but it has also been described in some cases of SD (10%)5 and bv-FTD (5%-7%).5–7 Cases of AD with an antemortem diagnosis of bv-FTD are referred to as frontal-variant AD.8

The purpose of this study is to revise the clinical-pathological and biomolecular correlations in FTD subtypes, especially bv-FTD, as well as the diagnostic accuracy of biomarkers used to hypothesise which disease was responsible for clinical symptoms.

FTLDs have classically been regarded as a heterogeneous group of neurodegenerative diseases and researchers have found it extraordinarily difficult to establish links between clinical presentation and the underlying pathological process. Doctors also believed it was not possible to deduce the type of clinical manifestation based on the pathological diagnosis. Advances in neuropathology, biochemistry, molecular biology, and genetics now let us establish clinical, histological, biomolecular, and genetic correlations, in addition to links between clinical and pathological findings.

In 2011, Josephs et al.9 published a review of several clinical-pathological studies10–17 performed in the preceding decade in 6 hospitals in the United States, Canada, the UK, and Australia, including a total of 544 cases of FTLD. They observed that bv-FTD showed similar percentages of underlying FTLD-tau and FTLD-TDP. Almost all cases of PSPS and CBS presented FTLD-tau, whereas 100% of the cases of FTD-MND displayed FTLD-TDP. FTLD-TDP was present in 83% of the patients with SD, whereas PNFA was fundamentally associated with FTLD-tau (70%). Examining by specific groups (FTLD-TDP and FTLD-tau), these researchers found significant associations between clinical phenotype and histopathological subtype, except for PNFA and the FTLD-tau subtype, for which associations were not statistically significant. Patients with bv-FTD and tauopathy were associated with Pick disease (PiD) in 70% of all cases. Those with TDP histopathology demonstrated an association with subtype 1 in the Mackenzie et al. classification.18 Nevertheless, the association between bv-FTD and the histopathological subtype was not robust (Fig. 1).

Figure 1.

Clinical, molecular, and genetic correlations in frontotemporal lobar degeneration. Arrows indicate the links between clinical syndromes and underlying disease, while continuous lines show the most robust associations. The most frequent histopathological subtype is listed for each syndrome. FTD: frontotemporal dementia; FTLD: frontotemporal lobar degeneration; PSPS: progressive supranuclear palsy syndrome; CBS: corticobasal syndrome; PNFA: progressive nonfluent aphasia; bv-FTD: behavioural variant frontotemporal dementia; SD: semantic dementia; FTD-MND: frontotemporal dementia associated with motor neuron disease; PSP: progressive supranuclear palsy; CBD: corticobasal degeneration; PiD: Pick disease; MAPT: microtubule associated protein tau; FUS: fused-in sarcoma protein; PGRN: progranulin; VCP: valosin containing protein; TARDBP: TAR DNA-binding protein 43; CHMP2B: charged multivesicular body protein 2B. FTLD-TDP subtypes 1-3 are designated according to Mackenzie's classification.

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In some cases of bv-FTD, doctors may find clinical features that point towards a specific histopathological subtype.19 One clinical subtype is characterised by changes in behaviour and personality, especially hypersexuality, hyperphagia, and stereotyped or obsessive behaviour. This subtype is strongly associated with atypical FTLD with immunoreactivity to ubiquitin only (aFTLD-U).20,21 These cases also show very early onset (mean age of about 40 years), and they are typified by pronounced striatal atrophy.22,23 On the other hand, the coexistence of psychotic symptoms or signs of motor neuron disease (MND) points to FTLD-TDP type 3 pathology,24 whereas apathy as the dominant trait is indicative of FTLD-TDP type 1 associated with PGRN mutations.25,26 The coexistence of marked disinhibition and alteration of the semantic axis of language suggests tau pathology associated with mutation of the microtubule-associated protein tau (MAPT) gene.14,26,27 The presence of vertical supranuclear gaze palsy is associated with tau pathology, and specifically with corticobasal degeneration; to a lesser extent, it is associated with progressive supranuclear palsy (PSP).28

Although the clinical-pathological correlations for the FTLD-FUS subtype have undergone less study,29–36 it seems there is also an association between clinical phenotype and FTLD-FUS. Neuronal intermediate filament inclusion disease has been linked to 3 syndromes; the most frequent is bv-FTD, followed by FTD-MND and CBS/primary lateral sclerosis. Basophilic inclusion body disease is associated with bv-FTD, FTD-MND, motor neuron diseases, and juvenile amyotrophic lateral sclerosis (JALS). There is a strong association between aFTLD-U and bv-FTD. There are no clinical-pathological studies on FTLD without inclusions, or on FTLD with cytoplasmic inclusions that are immunoreactive to proteins in the ubiquitin-proteasome pathway and negative for TDP-43 (FTLD-UPS).

Although one specific syndrome tends to be dominant in the first 4 years, it is common for different clinical syndromes in FTD to overlap as the disease progresses.37 Kertesz et al.38 prospectively studied 262 patients with clinical criteria of FTD. During follow-up, they documented the appearance of second and sometimes even third clinical syndromes. Patients with bv-FTD developed PNFA in 50% of the cases, CBS/PSPS in 22.5% of the cases, and SD in about 16% of the cases. Slightly more than 50% of the PNFA cases developed bv-FTD and a third developed CBS/PSPS. The rest of the PNFA cases did not exhibit any other syndromes. Three-quarters of the patients with SD developed bv-FTD and the rest did not progress to exhibit other clinical syndromes. Cases with CBS/PSPS were likely to develop bv-FTD (50%) or PNFA (50%).

Since the same patient may manifest different clinical syndromes as the disease progresses, it is possible to state that the same histopathological subtype may elicit different types of clinical disease due to unknown aetiological or neuropathological mechanisms.

Although most FTLD cases are sporadic, a small percentage of them are associated with specific genetic mutations. Seven genes are currently known to be involved in cases of familial FTLD: MAPT, the progranulin gene (PGRN), C9ORF72, valosin containing protein-1 (VCP-1), charged multivesicular body protein 2B (CHMP2B), TAR DNA-binding protein 43 (TARDBP) and fused-in sarcoma (FUS). Mutations in the MAPT, PGRN, and C9ORF72 are responsible for most FTD cases with an autosomal dominant inheritance pattern.

MAPT mutations39 are typically associated with FTLD-tau pathology and do not display a specific histological pattern;40 histological presentations may include PiD, PSP, and corticobasal degeneration (CBD).41 Patients with MAPT gene mutations usually present a bv-FTD phenotype, which is occasionally associated with extrapyramidal symptoms.27 This group characteristically presents pronounced symmetrical atrophy of the anterior medial temporal and orbitofrontal regions,42,43 and it is therefore quite common for the disease to manifest as SD with signs of bv-FTD (or bv-FTD with changes in the semantic processing of language). Disinhibition is a particularly common feature among these patients.23,26,27

Familial cases associated with PGRN mutations present a typical neuropathology pattern with marked atrophy at the level of the frontal lobe, caudate nucleus, substantia nigra, and medial area of the thalamus. Unlike MAPT mutations, which are associated with tauopathy, PGRN mutations are associated with deposits of TDP-43, especially in type 1 FTLD-TDP according to Mackenzie's classification.18 Neuronal intranuclear inclusions with a ‘cat's eye’ or ‘lentiform’ appearance are the most striking histological finding.44–46

Clinically, expression of PGRN mutations varies considerably, even within the same family in addition to between different families. Age at onset is also quite variable, once again, even among members of the same family.47 These mutations may present as CBS,48–51 PNFA,23,51,52 and bv-FTD,48 with apathy as the dominant trait.25 Cases of associated MND are exceptional.53 In patients with PGRN mutations, even when asymptomatic, plasma levels of PGRN are very low.47,54–56

Hexanucleotide repeat expansion of the nucleotide string GGGGCC in the first intron of the C9ORF72 gene is not only the known mutation most frequently associated with ALS and FTD-MND, but also the second-most frequent in FTLD after PGRN mutations. According to DeJesus-Hernandez et al.,57 12% of the familial cases of FTD and 22.5% of ALS cases are associated with that mutation. Slightly higher prevalences have been found in Nordic populations: the mutation was present in 46% of the population with familial ALS, 21.1% in sporadic ALS, and 29.3% in FTD in Finland.58

Mutations in the C9ORF72 gene, associated with FTLD-TDP pathology, may manifest clinically as bv-FTD, ALS, or FTD-MND. Presentations vary considerably, even between members of the same family. In the study by DeJesus-Hernandez et al.,57 26.9% of the patients with FTLD also presented ALS, and more than 30% had family members with ALS.

Mutations in the VCP-1 gene are associated with a rare autosomal dominant disorder that presents with myopathy (90%), Paget's disease of bone, and less frequently, FTD (30%). FTD usually appears years after the onset of muscular symptoms.59 According to Sampathu's and Mackenzie's histopathological classification systems for types of FTLD-TDP, the above entity is known as subtype 4.60 Biopsy typically reveals myopathic inclusion bodies.

Mutations in the CHMP2B gene, which until now have only been detected in 5 families, are typically associated with bv-FTD, with or without associated pyramidal or extrapyramidal signs.61,62 Myoclonia may also appear in later stages.61 There are only 2 published cases of associated MND.63 From a neuropathology viewpoint, they are associated with FTLD-UPS.

Mutations in the TARDBP and FUS genes are fundamentally associated with cases of familial ALS and only rarely do they cause FTD.64–67

The relationship between different clinical phenotypes and underlying disease in genetic cases differs from that found in sporadic cases. For example, PNFA and CBS in sporadic cases are more commonly associated with FTLD-tau, whereas in familial cases, the same symptoms would be more frequently found in FTLD-TDP (especially type 1). Either sporadic or familial bv-FTD may be associated with FTLD-tau or FTLD-TDP indiscriminately. Cases of SD and PSPS are almost always sporadic.

Recent years have seen increasing use of functional neuroimaging techniques, including single-photon emission computed tomography (SPECT) using Tc99m-hexamethylpropyleneamine oxime, or 18F-FDG-PET, in the diagnosis of bv-FTD. Hypoperfusion/hypometabolism is observed in frontal regions in bv-FTD, whereas AD displays hypoperfusion in the temporoparietal and posterior cingulate areas.108,109 Both SPECT and FDG-PET are more sensitive than brain MRI for detecting the early changes occurring in bv-FTD.110 FDG-PET is also very important for detecting phenocopies, since these cases will show preserved metabolism in the frontal regions. However, using FDG-PET in patients whose MRI shows clear cerebral atrophy is unlikely to provide any additional benefit.

Some PET techniques employ new radioisotopes. One uses a compound called carbon 11-labelled Pittsburgh compound B, which binds to β-amyloid and has shown promising results for differential diagnosis of AD and FDT,111,112 especially in cases displaying language alteration.113,114 Other techniques are currently being developed, including PET imaging of tau, PGRN, or FUS. These promising diagnostic tools may be ready for use in the near future.

Low CSF levels of the 42 amino acid beta-amyloid peptide (A β42), and high levels of tau protein, are biomarkers that are both sensitive and specific for diagnosis of AD.115,116 Tau/beta amyloid ratio: A β42 is a useful parameter for distinguishing FTLD from AD since it is lower in FTLD.117 Researchers have reported high levels of TDP-43 in cerebrospinal fluid from patients whose diagnosis of FTD-MND had not been confirmed by a histopathological study.118

Various studies have shown that patients with mutations in the PGRN gene display very low plasma levels of PGRN.54,55,119 Measuring plasma PGRN levels has been proposed as a sensitive and specific screening method for use in these patients.120

Other research indicates that plasma levels of TDP-43 may be related to cerebral impairment in patients with FTLD.121

Picturing FTLD on the molecular level is a way of gaining a more precise understanding of the disease in terms of its causal mechanisms. This also opens the doors to new treatment options. Ligand-specific drugs are currently being developed to search out defined molecular targets.

Of all of the clinical variants, bv-FTD is the most heterogeneous variety, which makes it difficult to predict the underlying disease type. It is possible that this syndrome describes a concept that is too broad and actually includes a number of very different entities. As a result, identifying differential clinical features and defining clinical subtypes may provide better clinical-pathological correlations. In any case, as a complement to clinical evaluation techniques, doctors must develop tools that will deliver in vivo histopathological and molecular diagnoses of these processes.

Structural and functional neuroimaging, biomarkers in laboratory analyses, and genetic studies are being transformed into useful tools for diagnosis or differential diagnosis and for predicting the underlying pathological process. Of all of the biomarkers that have been listed, we should stress the importance of functional neuroimaging. It is more sensitive than structural neuroimaging in early stages of the disease, and it can be used in novel techniques with specific radiotracers (11C-labelled Pittsburgh compound B and tracers for tau, PGRN, and FUS). This technique is emerging as an instrument that promises good results in the near future.

The authors have no conflicts of interest to declare.