Primary progressive aphasia

The PPA syndrome is subdivided into three main clinical subtypes: the agrammatic (PPA-G), semantic (PPA-S) and logopenic (PPA-L) subtypes. PPA-L is most often caused by underlying AD neuropathology, and therefore will not be discussed further in this article. PPA-G and PPA-S are caused by FTLD neurodegeneration and will be discussed here briefly.

Each PPA subtype has well-defined diagnostic criteria based on clinical and radiographic features.9 In the earliest stages of disease, patients with PPA-G present with isolated difficulty maintaining grammatical constructs, often manifesting as improper use of verb tenses or adjectives. In other patients, non-fluent speech, decreased phrase length, effortful speech and dysprosody are evident. Brain imaging of these patients reveals predominant left posterior frontoinsular atrophy on MRI, and/or hypoperfusion/hypometabolism in this area on single-photon emission CT (SPECT)/positron emission tomography (PET). Patients with PPA-S experience an insidious loss of meaning of words, objects and other factual information about the world, while grammatical knowledge remains well preserved. These patients reveal predominant ATL atrophy on MRI and/or hypoperfusion/hypometabolism of this area on SPECT/PET imaging. Patients with PPA-S and PPA-G often have language-comprehension problems due to loss of word-meaning and impoverished grammar, respectively. Psychiatric manifestations occur in patients with PPA due to FTLD, particularly in PPA-S; however, psychiatric manifestations in PPA most often occur in the setting of a preceding or concurrent progressive language syndrome, which should alert clinicians to the presence of a neurological disease. This is not the case in bvFTD, which presents with isolated psychopathology.

Behavioural variant frontotemporal dementia

Patients with bvFTD experience dramatic changes in baseline personality and behavioural traits, which may initially occur in the absence of obvious cognitive impairment, as illustrated in the vignette below.3 These changes represent clinical manifestations of dysfunction in well-defined brain circuits that have reciprocal neural connections between the orbitofrontal, dorsolateral prefrontal and medial prefrontal cortices (see figures 1 and 2 for neuroanatomical orientation) and subcortical brain nuclei (basal ganglia and thalamic structures). These circuits are in turn influenced by cortical inputs from the temporal and parietal lobes.7 ,12 ,13 Normal function of these brain circuits correlates with normal social behaviours and emotional states in humans,12 ,13 and the gradual breakdown of these circuits due to FTLD leads to the bvFTD syndrome. Below, we briefly review the cardinal clinical signs and symptoms of bvFTD in light of relevant cortical functional neuroanatomy.

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Figure 1

Lateral (A and C) and medial (B and D) views of the right hemisphere of a male patient with behavioural variant frontotemporal dementia (bvFTD) due to frontotemporal lobar degeneration (FTLD) τ-Pick's disease (A and B) compared to an age-matched normal brain (C and D) (A and C were flipped for easier comparison). The dorsolateral prefrontal cortex (DLPFC) is seen on the lateral surface of the brain, anterior to the primary motor and premotor cortices (indicated by yellow stars above) in the frontal lobe. In a normal brain (C), the volume of cortical gyri (folds) and the width of sulci (grooves) of the DLPFC are roughly equal to those of gyri and sulci in more posterior brain regions. In the affected brain (A) there is prominent atrophy (volume loss) of gyri within the DLPFC, leading to widening of sulci compared to more posterior brain regions; this atrophy pattern is striking when compared to the DLPFC of the normal brain (C). A similar degree of atrophy can be seen on the medial/mesial surface of the frontal lobe of the affected brain (B) compared to the normal brain (D); the affected brain shows prominent atrophy of the anterior cingulate gyrus (blue stars) and superior frontal gyrus (red stars), as well as the orbitofrontal cortex (pink stars).

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Figure 2

Brain MRI T1 of the patient presented in figure 2 7 years before death due to frontotemporal lobar degeneration (FTLD) τ-Pick's disease (A–C) compared to an age-matched normal control (D–F). There is prominent atrophy of the orbitofrontal cortex seen on axial T1 images (A); note prominent widening of the olfactory sulcus (A, white arrow) compared to normal (D). There is also prominent atrophy of the mesial frontal lobes seen on axial T1 images (B), as indicated by space between yellow arrowheads, compared to normal (E). On sagittal views, there is significant atrophy of the superior frontal gyrus and anterior cingulate gyrus (C) compared to normal (F).

Normal activity in the medial prefrontal cortex, including the anterior cingulate cortex (ACC), is strongly associated with motor and emotional motivation.13 ,14 Lesions in this area lead to dramatic reductions in spontaneous motor behaviours including speech. They also impede goal-directed behaviours in general, and produce marked psychomotor slowing. The ACC is most often attacked by the neurodegenerative disease process in bvFTD, particularly on the right side,15 and manifests clinically as marked apathy or inertia.3 Patients with apathetic bvFTD may spend all waking hours watching television, without attending to personal hygiene or other personal and social responsibilities. Patients with apathetic bvFTD do not initiate conversation and speak only when prompted, if at all. Apathy in bvFTD is often an early feature,3 but when it presents late in the disease it may ‘mask’ the more obvious signs of frontal lobe dysfunction. Clinically, there is notable overlap with the apathy associated with schizophrenia.

Patients with bvFTD often lose the ability to interpret and/or process the emotional states of people and animals. Thus, they demonstrate a general lack of self-awareness, and lack of empathy and sympathy towards strangers, friends and family, as well as pets. Spouses of patients with bvFTD often comment on their lack of interpersonal warmth, and diminished response to social cues. Such lack of empathy/sympathy in bvFTD is also predominately a right-sided manifestation of the disease including the right ATL, as well as the right medial orbitofrontal cortex (OFC) and anterior insula.16–19

Disinhibition is perhaps the most striking feature of bvFTD. The OFC may be conceptualised as a ‘relay station’ between higher order frontal cortices that inhibit a more ‘primitive’ (ie, reward-driven) limbic cortex; therefore, the OFC plays a critical role in modifying behaviour according to perceived reward and punishment values.13 ,20 Dysfunction of the OFC, particularly on the right side, is associated with behavioural disinhibition (ie, poor reward/punishment processing) and emotional lability. Right OFC neurodegeneration in bvFTD manifests as marked behavioural disinhibition,21 such as cursing, hugging or kissing strangers, urinating in public, performing inappropriate sexual acts, or telling offensive jokes to inappropriate audiences. Behavioural disinhibition may also manifest as impulsivity, such as reckless driving, new-onset gambling or substance abuse, excessive buying of unnecessary items, or criminal behaviours. Criminal behaviours occur in up to 54% of patients with bvFTD.22 Impulsivity related to food consumption is especially common in bvFTD, and this is also a manifestation of right OFC neurodegeneration, as well as insular, ventral striatal and ventral hypothalamic dysfunction.23 Patients with bvFTD tend to prefer sweet foods although some manifest indiscriminate hyperphagia; this results in significant weight gain.

Patients with bvFTD may engage in simple repetitive movements or verbal utterances, such as clapping, tapping, rubbing, humming and throat clearing, among others. More complex repetitive movements and utterances (that acquire a ritualistic or compulsive character) occur, such as repetitive counting, complex organising and cleaning routines, repetitive trips to the bathroom, or repetitive verbalisation of phrases or stories that have no communicative value. The brain localisation of these phenomena has not been studied satisfactorily in bvFTD, but there is evidence to suggest that frontosubcortical dysfunction is also responsible for these phenomena.24 From a phenomenological perspective, at our centre we do think of these repetitive phenomena as motor manifestations of disinhibition/impulsivity.

Finally, deficits in executive function, which are commonly seen in bvFTD, although not always early in the disease course, occur due to involvement of the dorsolateral prefrontal cortex.12 ,13 This manifests as trouble in multitasking, poor recall of recently learned material (poor working memory), mental rigidity, and environmental dependency (utilisation and imitation behaviours).3 These changes are not invariably present during the first phases of the illness, and can be found with many other conditions ranging from AD, parkinsonian dementias, cerebrovascular disease and depression.

It is important to note that the signs and symptoms of bvFTD can all occur in a single patient at different time points in the disease course. This is presumably the result of the spatial and temporal spread of the neurodegenerative disease process although further staging clinicopathological studies are needed to substantiate this hypothesis.

bvFTD case vignette: The following vignette briefly summarises the most salient clinical features of a patient with autopsy-confirmed bvFTD who was diagnosed and followed in our centre.The patient was 55 years of age when she first came to our attention. She was right-handed. Her doctor referred her to our centre at the insistence of the patient's husband, who upon learning of bvFTD thought his wife may have the disease. The first serious ‘red flag’ occurred during a family trip abroad 4 years prior to presentation; she made several racial comments about a restaurant server despite clearly causing discomfort to everyone present, including the server. A few months later, she repeatedly interrupted her son's graduation ceremony by initiating conversation with guests during the ceremony. She also attempted to take a bouquet of flowers from another family to give it to her son. Her behaviour in social situations became increasingly erratic over the ensuing 2 years. She regularly initiated conversations with strangers about sex, and also made sexual jokes in front of children. She worked in an elementary school at the time, and her supervisor noted that she developed a tendency to play roughly with children, to the extent that she made some of them cry. She lost her job 3 years after onset of her illness. One year before seeing us, she developed a voracious appetite for sweets leading to a 25-pound weight gain within 12 months. By the time we first saw her in our centre, her behaviours had diminished in intensity. Her neurological examination was notable for stimulus-bound behaviours and lack of respect for social boundaries. She repeatedly tried to kiss and hug the examiner. There were no signs of MND. Neuropsychological testing was notable for a score of 26/30 on the mini-mental state examination. She was presented with 16 photographs of faces with a particular emotion, and was able to correctly identify the emotion of only 6 faces (normal=13.3±1.7). On the Interpersonal Reactivity Index—Perspective Taking (IRI-PS), she scored 8/35 (normal=24.5±5.5), suggestive of a profound inability to think of others’ emotions; likewise, she scored 15/35 (normal=28.6±4.5) on the IRI empathic concern (IRI-EC) scale, suggestive of a profound impairment in her ability to experience the emotional state of others. Her brain MRI revealed marked bilateral frontal and anterior temporal lobar atrophy. Genetic testing revealed a C9ORF72 gene expansion (interestingly, and pertinent to this review article, the patient's family history was only notable for a distant paternal uncle with suspected Parkinson's disease). Her syndrome evolved into a predominantly apathetic state. She died at age 59 years, approximately 8 years after onset. Brain autopsy confirmed FTLD.

Macroscopic and microscopic characteristics

Macroscopically, FTLD results in varying degrees of focal atrophy of all the cortical regions that form part of the cortical-subcortical brain circuits discussed above. These include limbic, paralimbic and association cortices of the frontal and temporal lobes, insular cortex, as well as atrophy of subcortical nuclei (basal ganglia and thalamic structures).34 Brain atrophy due to FTLD is observed on gross brain sections (see figure 1), and can also be appreciated on brain neuroimaging (see figure 2). Microscopically, all forms of FTLD demonstrate neuronal loss, manifesting as tissue vacuolation, and inflammatory changes, or gliosis, of the affected regions (see online supplementary figures A and B).34

Abnormal protein inclusions

At a molecular level, nearly all cases of FTLD are associated with the accumulation of one of four abnormal protein inclusions (or proteinopathies) in neurons and/or glial cells of the brain, which serve to divide FTLD into four main diagnostic categories (see online supplementary figures C–F):35 ,36 (1) τ protein (FTLD-τ), (2) transactive response DNA-binding protein 43 (FTLD-TDP), (3) fused-in sarcoma (FTLD-FUS) protein, and (4) dipeptide proteins generated from mutant forms of the C9ORF72 gene (see genetics section below).

FTLD is nearly evenly divided between FTLD-τ and FTLD-TDP, whereas about 10% of cases are associated with FUS and other substrates including C9ORF72 dipeptides.1 FTLD-τ and FTLD-TDP-43 are further subdivided into several subtypes, based on specific morphological features, biochemical properties, and distribution of protein aggregates within the brain. For example, the diagnostic subtypes of FTLD-τ include progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and PiD. Note that these designations are used independently of similar designations used to identify specific clinical syndromes. For example, although most cases of CBS are caused by CBD, CBS can also be caused by PSP and even AD pathology.

Causative genetic mutations

From 30% to 50% of FTD cases are familial, and up to 10–15% show an autosomal dominant pattern of inheritance. Presently, mutations in three genes have been linked to the majority of familial FTLD,37 ,38 with nearly 100% penetrance:28 microtubule-associated protein τ, granulin (GRN), and C9 open reading frame 72 (C9ORF72). To date, the largest proportion of familial FTD (12–25%) is caused by pathogenic expansions of C9ORF72.28

Five other genes have been linked to a few families affected with FTLD: valosin-containing protein, charged multivesicular body protein 2b, fused-in sarcoma (FUS), TAR DNA binding protein, and the UBQLN2 gene. These genes and their associated phenotypes will not be discussed further in this article.

Diagnostic criteria

The International behavioural Variant FTD Criteria Consortium (Frontotemporal Dementia Consortium, FTDC) published consensus criteria for bvFTD in 2011.3 These criteria are rooted on the clinical, neuroanatomical and neuropathological data described above, and they represent the diagnostic gold standard for bvFTD. These criteria stratify the bvFTD diagnosis hierarchically into three categories—possible, probable and definite—based on increasing levels of certainty attained according to clinical, neuroimaging, molecular and histopathological data, as shown in table 2. In short, whereas possible bvFTD is diagnosed based exclusively on clinical signs and symptoms, probable and definite bvFTD are supported by radiological findings and neuropathological data (brain tissue or genetics), respectively. These criteria were shown to be superior to previously published criteria for bvFTD.44

The fifth edition of the DSM-5 also contains diagnostic criteria for bvFTD (shown in table 2), within a new classification system for cognitive disorders. Briefly, in the DSM-5, all acquired primary cognitive disorders are referred to as NCDs. The DSM-5 recognises that many patients with chronic psychiatric disorders exhibit cognitive impairment; hence, all patients with NCD must exhibit cognitive impairment as a core feature of their respective syndrome. Accordingly, cognitive impairment is defined by the presence of subjective and objective signs/symptoms in at least one of six neurocognitive domains: complex attention, executive function, learning and memory, language, perceptual motor abilities and social cognition. NCDs are further subdivided into the syndromes of Mild and Major NCD, according to severity of cognitive and functional impairment. Specific diagnostic criteria are subsequently provided for 13 aetiological subtypes of Mild and Major NCD, including Mild and Major Frontotemporal NCD. Table 2 presents both the FTDC and DSM-5 bvFTD criterion sets next to each other for comparison. Important similarities and differences between these criteria will be discussed later in this article.

Previous editions of the DSM do not include social cognition among the more traditional brain-based cognitive domains (memory, language, etc). Hence, it is important to discuss this domain briefly, particularly given its involvement in bvFTD. Broadly, social cognition is defined as ‘the processes by which people understand themselves and other people’.45 The principal dimensions of social cognition include self-perception (ie, awareness of one's own emotional and mental processes in response to internal and/or external stimuli) and person-perception (ie, awareness of other people's feelings and emotions in specific contexts, also referred to as ‘theory of mind’), as well as knowledge of social norms and expectations (ie, ethical and moral behaviour).45 It has long been recognised that all dimensions of social cognition are entirely dependent on specific regions/structures of the frontal and temporal lobes of the brain (predominately on the right).45 Indeed, the seamless integration of these neural processes is necessary for normal social behaviour. As can be gathered from the previous neuroanatomical discussion of the signs and symptoms of bvFTD and the associated case vignette, the principal dimensions of social cognition are typically severely disrupted in patients with bvFTD owing to the fact that the neurodegenerative process in these patients is centred in the frontal and temporal lobes.

Differential diagnosis of early bvFTD

By the time patients with bvFTD are referred to a neurologist, patients are usually in the middle stages of the disease, when the differential diagnosis is relatively narrow, and accurate syndromic and neuropathological diagnosis is achieved with high sensitivity and specificity based on clinical, neuropsychological, radiographic, genetic and cerebrospinal fluid (CSF) biomarker data (CSF analysis is useful to rule in AD and to rule in/out degenerative/non-degenerative causes of rapidly progressive dementia).46

The differential diagnosis of early bvFTD is far more challenging largely due to the syndromic overlap that exists between early bvFTD and late-onset psychiatric disease. The psychopathological changes of early bvFTD (disinhibition, impulsivity, apathy, compulsive behaviours, etc) can occur in the absence of other neurological signs or symptoms, including common signs of cognitive impairment such as memory loss.3 The paucity of neurological and/or cognitive complaints, and the lack of insight observed in early bvFTD,47 leads caregivers and primary physicians to routinely seek psychiatric evaluation for such patients. Therefore, non-specific/atypical psychiatric presentations have long been recognised to occur in early bvFTD,48–50 dating back to the 1940s when bvFTD was referred to as PiD.51 Furthermore, in a significant proportion of patients, the psychopathology of early bvFTD may cluster into DSM-compatible psychiatric diagnoses. Indeed, in one large study, up to 50% of patients diagnosed with bvFTD received a previous psychiatric diagnosis per DSM criteria.52 A sample of these and other cases is presented below.