Final pathologies, first syndrome, and subsequent evolution through second and third syndromes in patients from our center presenting initially with bvFTD. Aphasia developing secondarily is indicated as progressive aphasia (PA). Second and third syndromes were CBS, PA, semantic dementia (SD), and MND. The size of the arrows is in proportion to the number of patients at each stage, and the average interval in years (standard deviation) between the syndromes is indicated. Pathologies as follows: MNDI = FTD with motor neuron disease-type inclusions, DLDH = dementia lacking distinctive histology, AD = Alzheimer’s disease, VaD = vascular dementia, LBD = Lewy body disease, CBD = corticobasal degeneration, GSS = Gerstmann Straussler Scheinker, Pick’s = Pick’s disease.
Neuropsychological deficits have been variable because of the types and methods of patient selection at different stages of illness and the tests used [16–18]. The Mini-Mental State Examination (MMSE) may be normal in early cases. Orientation and episodic memory are relatively preserved. Frontal lobe functions are often impaired, yet up to 25% of patients with behavioral presentation perform well on “frontal” tests especially if they are seen early. Although FTD can present as a “dysexecutive syndrome,” frontal lobe or executive deficits are often involved in AD as well. Although FTD is not a memory dominant disorder, the preservation of memory is not universal by any means even in pathologically confirmed cases [19]. The memory complaint in bvFTD could result from inattention, lack of motivation, and/or language impairment. Although drawings in bvFTD patients may be impoverished because of amotivational performance, visuospatial function is generally intact and in advanced cases with mutism, the copying of the intersecting pentagons in the MMSE may be the only element correct. Some patients may be perseverative in drawing. At times copying can be compulsively faithful to detail, even though the patient may not recognize the object drawn in SD. Visuospatial tasks that tap executive function, such as trail-making, are impaired at an early stage, but block design and Raven’s Coloured Progressive Matrices may be preserved. At times, impulsivity, disinhibition, perseveration, echopraxia, and utilization behavior are observed during neuropsychological testing. In later stages the patient may be too restless or language impaired to test.
The caregiver’s history and responses to a behavioral questionnaire, such as the Frontal Behavioral Inventory (FBI) [20], at the initial interview are the most useful diagnostic tools. The inventory was designed as a series of structured questions scripted so that both the normal and abnormal aspects of the behaviors were included. Each item was scored on a scale of 4, where 0 = none, 1 = mild or occasional, 2 = moderate, 3 = severe or most of the time. The first group of items were negative behaviors such as apathy, aspontaneity, indifference, inflexibility, concreteness, personal neglect, distractibility, inattention, loss of insight, logopenia, verbal apraxia, and alien hand. These last three items were included to capture specific motor and speech behaviors, which may be associated with FTD. The second group of items contained disinhibited behaviors such as perseveration, irritability, jocularity, irresponsibility, inappropriateness, impulsivity, restlessness, aggression, and hyperorality. A cutoff score above 27 was indicative of bvFTD. In our experience reliance on cognitive testing correctly classifies only 75% of cases, increasing to 100% with the addition of the FBI. Discriminant analysis found indifference, impulsivity, and socially inappropriate behavior to be the most diagnostic. Other studies have found roaming, food fads, and stereotypic behavior distinctive. Not all of these behaviors, however, appear in an individual patient and an overall score above the cutoff point on the FBI is probably the most useful confirmatory tool. Longitudinal FBI assessments showed worsening over time. Some behaviors disappear as the patients lose speech or mobility, while others, such as utilization behavior or incontinence, emerge in later stages of the disease.
Primary progressive aphasia (PPA)
Although aphasia with circumscribed frontotemporal atrophy was described by Pick almost a century before, it was redescribed as PPA by Mesulam [8]. Variations of this terminology – particularly progressive non-fluent aphasia (PNFA, nfvPPA) [21] and pure progressive aphemia [22] – have also been used. The condition was considered a separate entity for a while, but evidence emerged to consider it part of FTD/Pick complex [12]. A relatively isolated language disturbance in the first two years of the illness had been suggested by Mesulam as intrinsic to the operational definition of PPA. However, many cases have behavioral or extrapyramidal features, which can appear before the two years are up with FTLD pathology at autopsy (Figure 2.2). Conversely, isolated language disturbance for up to 14 years has been described [23] in some cases. As the initial presentation of PPA is often with word-finding difficulty or anomia, PPA cases may not appear much different to Alzheimer’s disease (AD) patients, except for relatively preserved memory and non-verbal cognition [24, 25]. In general though, by the time they show aphasic difficulty, AD patients usually have significant memory loss, disorientation, visuospatial and other cognitive impairments allowing their distinction.
Final pathologies, first syndrome, and subsequent evolution through second and third syndromes in patients from our center presenting initially with PPA. The average interval in years (standard deviation) between the syndromes is indicated. Pathologies as follows: AD = Alzheimer’s disease, AD+GT = Alzheimer’s disease and glial tau, CBD = corticobasal degeneration, LBD = Lewy body disease, GSS = Gerstmann Straussler Scheinker, MNDI = FTD with motor neuron disease-type inclusions, Pick’s = Pick’s disease.
Spontaneous speech in PPA is slowed with prominent anomia but relatively preserved word knowledge (in contrast to SD), combined with agrammatism (both in production and comprehension) as well as phonemic paraphasias. Some patients present with stuttering or slow, segmented speech and verbal apraxia, which includes articulatory difficulty and phonologic paraphasias which may herald the CBS or PSPS. Recent classification includes apraxia of speech (AOS) within PNFA [26] but a case has been made for this to be considered distinct, when it is a presenting feature [27]. Progressive limb and oro-buccal apraxia can also be a prominent feature [28], further indicating a clinical overlap between PPA and the apraxic-extrapyramidal syndrome of CBD.
MRI is less reliable for diagnosis than in bvFTD or SD but generally there will be asymmetric left hemisphere atrophy centered on the sylvian fissure, inferior frontal regions, anterior insula, and basal ganglia. The course of PPA is variable and may be considerably prolonged, despite a later age of onset [29], but sometimes patients who develop MND or pathology in the basal ganglia progress quickly with difficulty swallowing and choking. The preservation of appropriate social behavior tends to be the rule early on, but in our experience around half of cases develop significant behavioral disturbance as the illness progresses, with features of bvFTD as a secondary or third syndrome (Figure 2.2). Mutism has been considered characteristic of PiD, and it tends to be the end stage of all forms of FTD/Pick complex, even those starting with behavioral abnormalities rather than language disturbance. End-stage mutism also occurs in AD, but usually in a patient who already has global dementia with loss of comprehension and basic functions of daily living [30]. In bvFTD and PPA mutism occurs with relative preservation of comprehension, unlike in a global aphasia or severe AD. Detailed language testing with batteries such as the Western Aphasia Battery (WAB) can be helpful to quantitate fluency, comprehension, repetition, and naming, to determine the type of aphasia and map progression over time.
Semantic dementia (svPPA, semantic aphasia)
A distinct variety of PPA was described as “semantic dementia” by Snowden et al. [3]. These patients progressively lose the meaning of words, but retain fluency and are able to carry out a conversation. Subsequent descriptions adopted this term [4], which has recently become the semantic variety of PPA (svPPA). Early descriptions conceptualized the phenomenon as deficit in semantic memory as it involves non-verbal modalities as well [31]. MRI shows asymmetric atrophy of the anterior temporal lobes, usually left more than right but eventually bilateral and generally accompanied by some frontal atrophy also. Patients with left-predominant atrophy resemble cases of “transcortical sensory aphasia,” in which articulation, phonology, and syntax remain intact but the patient does not comprehend well and has word-finding difficulty. Initially such patients produce semantic substitutions and later fluent semantic jargon, often totally irrelevant to the questions asked or the topics discussed. Category-specific anomia is characteristic, often for living things before man-made objects or tools. Superordinate categories are used in place of specific items, so for example an “eagle” will be called a “bird” then a “creature” before all naming ability is lost. Patients with SD tend to differ significantly from the fluent aphasics of AD because of relatively preserved episodic and autobiographical memory, and visuospatial tasks tend to be well performed. They or their caregivers may complain of memory loss but closer questioning generally reveals this to be a form of word-finding and comprehension difficulty. Irregularly pronounced words will be read incorrectly as they can not be processed by meaning (surface dyslexia). SD is distinct from AD not by virtue of retained fluency, but by an early prominent deficit in noun comprehension followed by a visual agnosia and also by its frequent association with bvFTD, especially if the right temporal lobe is involved. Conversely, patients who present with the behavioral symptoms of bvFTD often have elements of SD at initial assessment or they emerge with time as a second or third syndrome of the Pick complex.
The behavior in SD can be so dissociative and bizarre that some of these patients are considered hysterical or schizophrenic. Compulsive behaviors are the norm but may be delayed, with the pattern determined by the side affected. The left-sided cases tend to focus on visually attractive items such as coins and card playing while right-sided cases tend towards word puzzles and writing. As the right side becomes affected, problems recognizing emotions in others emerge along with inability to recognize familiar faces (prosopagnosia) and buildings. Eventually a multimodality agnosia emerges and in our cohort a third of SD patients had a loss of the meaning of objects in the visual and tactile domains in addition to the usual auditory deficit.
Logopenic variant of PPA (lvPPA)
Subsequently a new variety of PPA was proposed [32]. Logopenia is defined as prominent word-finding difficulty, a phrase length still longer than four words, and preserved syntax while repetition is disproportionately impaired reflecting deficits in verbal working memory [33]. It is argued that logopenic PPA (LPA) tends to involve more posterior perisylvian structures on MRI such as angular and supramarginal gyri, which is consistent with the overrepresentation of underlying AD pathology in this form of PPA [34], but the predictive value of LPA may be limited compared with other variants [35].
Corticobasal degeneration (CBD) and progressive supranuclear palsy PSP)
There have been several case descriptions of PiD where the patients had prominent extrapyramidal features [36]. Sometimes unilateral rigidity and parkinsonism were the first symptoms to attract attention and it was recognized that subcortical changes occur in PiD, even without overt extrapyramidal symptomatology [37]. When Rebeiz et al. [38] described corticodentatonigral degeneration, they recognized the similarity of the pathology to PiD. The clinical syndrome of unilateral rigidity, prominent apraxia, gaze palsy, reflex myoclonus, and the alien hand syndrome was relabeled CBD [10]. Some case reports have described patients with clinical features of CBS as defined by unilateral rigidity, apraxia, and alien hand syndrome but who had the pathologic findings of PiD with Pick bodies [39]. Other cases pathologically typical of CBD have had bvFTD or PPA without the extrapyramidal features [40]. We suggested that the clinical syndrome of prominent apraxia, unilateral extrapyramidal syndrome, and alien hand phenomenon should be designated as corticobasal degeneration syndrome (CBDS), and CBD should be used for the pathologic picture [41] (CBS is the other abbreviation for the clinical syndrome most used currently, but it is less easily recognizable and it does not parallel the frequently used PSPS). CBS has shown significant overlap with the syndromes of FTD/Pick complex [42] and in recognition of that, recently proposed criteria [43] recognize four CBD phenotypes, namely the corticobasal syndrome (CBS), a frontal behavioral-spatial syndrome (FBS), the non-fluent/agrammatic variant of primary progressive aphasia (naPPA), and progressive supranuclear palsy syndrome (PSPS).
The syndrome of axial dystonia, bradykinesia, falls, dysphagia, and vertical gaze palsy was described as PSP by the Toronto group of Steele et al. [9], but the overlap with CBD/CBS has been increasingly recognized. Many CBD/CBS patients also have vertical gaze palsy; some have falls and symmetrical extrapyramidal syndrome. Some studies comparing the neuropsychological features of PSPS and CBS found no significant difference between them [44]. The pathologic, biochemical, and genetic features of PSP/CBD also overlap to a great extent [45, 46]. They are both considered to be predominantly 4 repeat tauopathies and have common tau haplotypes. There is continuing controversy to what extent PSP/PSPS and CBD/CBS can be differentiated, although pathologic criteria for each have been validated [47] and the evidence therefore very much favors that both are part of the FTD/Pick complex.
Motor neuron disease and FTD (FTD-MND)
In the 1980s and 1990s reports emerged integrating an association between dementia and MND/ALS (amyotrophic lateral sclerosis) [48, 49] into the concept of FTD but as with most phenomenology in FTD/Pick complex, precedence lies much earlier [50]. Cognitive and behavioral impairment has been observed in ALS and some estimate it to be as high as 50% [51, 52]; conversely features of MND occur in 15% of those with FTD/Pick complex. A characteristic finding in FTD-MND cases is the presence of psychotic features such as delusions and hallucinations which are relatively rare in most other FTD/Pick complex syndromes, certainly when compared with Alzheimer’s disease or dementia with Lewy bodies (DLB). Combined with prominent apathy, lack of motivation, and irritability it meant such cases were often erroneously diagnosed as depression before the motor features emerged, which they usually do within a year. Dysphagia and dysarthria are common with a severe progressive non-fluent aphasia ending in mutism for a significant number of cases of FTD-MND [49]. The illness course is rapid with a very poor prognosis and median survival of two years in florid cases [53].
Beyond shared clinical features, overlap on a molecular level was demonstrated by cases of dementia and MND with ubiquitin-positive, tau-negative inclusions in the cortex, which had been previously described in the motor neurons of ALS cases [54]. Subsequently these cases were named motor neuron disease inclusion dementia (MNDID) [55] and in the majority it has become apparent that these ubiquitinated inclusions contain transactive response DNA-binding protein 43 (TDP-43) as the main pathologic protein. A shared genetic overlap was shown in 2006 with linkage to chromosome 9p in FTD-MND families. Some family members developed MND alone, others pure FTD, and others again a mixture of both FTD and MND [56, 57]. A hexanucleotide repeat expansion in the non-coding region of C9orf72 gene was found to be causative [58, 59], generally resulting in TDP-43-positive pathology, thalamic atrophy, and a high prevalence of psychosis. C9orf72 is now known to be the commonest genetic cause of MND and FTD in those of European descent accounting for up to 14% of all sporadic and familial MND [60]. It is estimated that C9orf72 mutations account for 5–6% of sporadic FTD and up to 25% of familial cases, and preliminary evidence suggests a positive relation between repeat size in frontal cortex and age of onset but an inverse relation between repeat size (in the cerebellum only) and survival [61].
Neuropathology and molecular genetics
Pathology
Even more so than the clinical syndromes, pathology in FTLD is diverse, but has a great deal of morphologic and biologic overlap. Differences in the topographic distribution of the pathology determine the individual clinical syndromes within the Pick complex. Common to all, the gross macroscopic pathology consists of variable atrophy of the frontal and anterior temporal lobes with a shared histology of large neuronal cell loss, microvacuolation, and varying degrees of gliosis. Immunohistochemistry in the last decade has allowed the subcategorization of these disorders into various proteinopathies based on the major constituent of the inclusions and these are summarized in Table 2.2. Additional details on the neuropathology of FTLD are provided in Chapter 13.
| Molecular pathologies in FTLD | Associated genes | |
|---|---|---|
| FTLD-TAU (TAU-POSITIVE) | ||
| FTLD-tau (40%) | MAPT | |
| Argyrophilic grain disease (AGD) | ||
| Corticobasal degeneration (CBD) | ||
| FTLD with microtubule- associated tau mutations (FTLD-MAPT) | ||
| Neurofibrillary tangle dementia (NFTD) | ||
| Pick’s disease (PiD) Progressive supranuclear palsy (PSP) | ||
| Sporadic multiple system tauopathy with dementia (MSTD) | ||
| White matter tauopathy with globular glial inclusions (WMT-GGI) | ||
| FTLD-U (TAU-NEGATIVE, UBIQUITIN-POSITIVE) | ||
| FTLD-TDP types A to D [64] (50%) | TARDBP | |
| Type A | GRN | |
| Type B | C9orf72 | |
| Type C | ||
| Type D | VCP | |
| FTLD-fused in sarcoma (FUS) (5%) | FUS | |
| Atypical FTLD with ubiquitin inclusions (aFTLD-U) | ||
| Basophilic inclusion body disease (BIBD) | ||
| Neuronal intermediate filament inclusion disease (NIFID) | ||
| FTLD with immunochemistry against ubiquitin proteosome system (FTLD-UPS) (5%) | CHMP2B | |
| FTLD WITH NO INCLUSIONS Dementia lacking distinctive histology (DLDH) | ||
Historically speaking most neuropathologists required Pick bodies (intracytoplasmic argyrophilic inclusions) for the diagnosis of Pick’s disease as seen by light microscopy with the Bielschowsky silver stain. Constantinidis et al. [11] labeled Pick-body-positive cases as Pick type A. Those with absent Pick bodies but swollen achromatic neurons called “Pick cells,” which also contain tau protein, are Pick type B (these cases are now labeled CBD). Pick cells may occur in patients with typical Pick bodies as well and they are typical of CBD. These cases and PSP have a predominantly tau abnormality and are now labeled together as FTLD-T (for tau). Pick type C consists of neuronal loss, vacuolation in upper cortical layers, and extensive astrogliosis of the neocortex, and these changes are common to all histologic subtypes.
In the last decade it became apparent that the most common pathology of FTD/Pick complex had the ubiquitin-positive, tau-negative inclusions previously described in MND [54]. These inclusions (often abbreviated to FTD-MND type or MNDI or FTLD-U) were found in more than half of the FTD cases at autopsy [29, 62]. They appeared similar in location and morphology to Pick bodies, but differed in their histochemical characteristics. The more recent discovery of TDP-43 immunohistochemistry as the underlying protein in FTLD-U changed the concept of a ubiquinopathy as the most common pathologic and biologic variety of FTD/Pick complex to a “TDP43-pathy” instead [63]. As demonstrated in the initial reports and rapidly confirmed by numerous subsequent studies, antibodies against TDP-43 have proven to be the most sensitive and specific tool to detect most of the different types of ubiquitin-positive pathology found in most cases of FTLD-U, including the neuronal cytopasmic inclusions (NCIs) and neuronal intranuclear inclusions (NIIs). Different classification systems for FTLD-TDP exist but most recently a harmonized system defining four subtypes (types A–D) has been proposed [64].
Not all FTLD-U cases have the TDP-43 proteinopathy. The TDP-43-negative cases (also known as atypical FTLD-U [aFTLD-U], basophilic inclusion body disease [BIBD] and neuronal intermediate filament inclusion disease [NIFID]) have been shown to have antibodies to the fused in sarcoma (FUS) protein [65, 66]. Together they comprise a new biochemical category of neurodegenerative disease the “FUS proteinopathies.” Atypical FTLD-U is characterized by a very early onset of severe behavioral abnormality without motor deficits or aphasia. The consistent involvement of motor neurons in BIBD indicates that the association of FTLD and MND/ALS can occur on a FUS or TDP-43 pathologic substrate.
There is substantial overlap between all pathologic varieties, although their distinctiveness is also argued [45, 67]. Various purportedly distinctive features, such as Pick bodies in PiD, astrocytic plaques in CBD, tufted astrocytes in PSP, and ubiquitin-positive, tau-negative inclusions in MND-type dementia, are described, but they can occur with each of the other clinical varieties. The TDP-43 protein abnormality is present in ALS but also in about 20% of AD, so the specificity of that too remains to be determined. Equally, for genetic cases correlations with pathology are not absolute and cases of tau-positive CBD pathology presenting with FTD and parkinsonism but without MND have been found in some C9orf72 families [68].
A basic dichotomy lies between tau-positive (FTLD-tau) and FTLD-U. FTLD-tau accounts for approximately 40% of FTLD and includes classical Pick’s disease, CBD, PSP, FTLD associated with tau mutations (FTLD-T), argyrophilic grain disease, neurofibrillary tangle dementia (NFTD), and multiple system tauopathy with dementia (MSTD). FTLD-U accounts for approximately 50% of FTLD and is subclassified as FTLD-TDP (TDP-43), FTLD-FUS (fused in sarcoma), and FTLD-UPS (ubiquitin proteasome system (i.e., ubiquitinated inclusions negative for tau, TDP-43, and FUS). FTLD-TDP accounts for 85–90% of all FTLD-U and is subdivided into four subtypes A–D [64]. FTLD-FUS includes aFTLD-U, NIFID, and BIBD. Cases without signature protein histochemistry, the so-called dementia lacking distinctive histology (DLDH), were previously a prominent substrate in pathology cohorts but now comprise an ever-dwindling designation.
Genetic relationships
A family history of degenerative dementia, often autosomal dominant, is detected in 25–50% of cases. In 1998 the first identified causative gene for FTD/Pick complex was the microtubule-associated protein tau (MAPT) gene on chromosome 17. Since then multiple new genes have been identified, including progranulin (GRN), valosin-containing protein, (VCP), FUS, TARDBP, charged multivesicular protein (CHMP2B), and most recently C9orf72. GRN and C9orf72 account for the largest proportion of FTD/Pick complex families, followed by MAPT; VCP causes the rare combination of FTD, inclusion body myopathy, and Paget’s disease of bone, highlighting yet another overlap with heterogeneous neurodegenerative disease. TARDBP mutations account for 5% of familial ALS but only a handful of FTD kindreds. Each gene is associated with a particular pathology: MAPT with FTLD-tau; GRN, C9orf72, TARDBP, and VCP with FTLD-TDP; FUS mutations cause FTLD-FUS; and CHMP2B causes FTLD-UPS [69]. Additional details on the genetics of FTLD are reviewed in Chapter 14.
Clinicopathologic correlations in FTD/Pick complex
Our autopsy experience in FTD/Pick complex is summarized in Figures 2.1–2.3. Among the 58 autopsied patients with probable FTD/Pick complex, the diagnosis was confirmed pathologically in 50, whereas in 8 cases, 6 of them in the bvFTD group, the pathologic diagnosis was different: 2 AD + DLB, and 1 each of AD, vascular dementia, prion disease, and normal histology, as were 2 in the PPA group (AD and AD + DLB). All the possible PPA cases (they were also given an alternative diagnosis of AD in vivo) coming to autopsy received a pathologic diagnosis outside the FTD/Pick complex: AD in eight cases and DLB in one. Some of these cases turned out to have argyrophilic tau astrocyte clusters (ATAC), suggesting a double pathology of coexisting AD and a Pick complex tauopathy [70]. The diagnosis of probable FTD in our clinic has a positive predictive value (accuracy) of 87%. A chi square comparison showed that multiple syndromes predicted FTD/Pick complex pathology to a much greater extent than did a single syndrome (p < 0.001). In our experience the clinical varieties of Pick complex do not predict the overall pathologic spectrum, but some generalizations can be made. There is a prominence of tau-positive CBD or Pick body pathology (FTLD-tau) in the extrapyramidal and aphasic presentations, and the FTLD-U-type with the behavioral presentation and SD [29]. Further insights can be derived from histochemical profiles [71, 72]. The behavioral variant of FTD is associated with all histochemical and genetic subtypes but more than half will be caused by FTLD-TDP. The movement disorder of PSP/CBD predominantly aggregates with the expected tau-positive pathology but is also seen with FTLD-TDP and rarely with FTLD-FUS (NIFID) [73]. Two thirds of PNFA will be due to tau-positive pathology of CBD, PSP, and PiD particularly if associated with apraxia of speech, but PNFA is also seen with FTLD-TDP type A and B though probably not FTLD-FUS. SD is the most unitary of FTD/Pick complex syndromes and is associated most consistently with FTLD-TDP type C and to a lesser extent type B and PiD. Most logopenic PPA cases have AD pathology [34] as do cases with both output and comprehension difficulty (mixed aphasia). FTD-MND can be seen with tau mutations but overwhelmingly is associated with FTLD-TDP, typically type C, and infrequently FTLD-FUS. FTLD-FUS is associated with very young-onset bvFTD, psychosis, thought and mood disorders, with prominent caudate atrophy on imaging [74]. Increasing evidence of phenotypic heterogeneity of C9orf72 – including prominent psychotic symptoms, aphasia, and parkinsonism [75] – poses challenges in the future.
Final pathologies, first syndrome, and subsequent evolution through second and third syndromes in patients from our center presenting initially with CBD and PSP. Pathologies as follows: CBD = corticobasal degeneration, PSP = progressive supranuclear palsy, CBD/PSP = transitional features of both.
Differential diagnosis
Alzheimer’s disease
The typical presentation of AD in an elderly patient with a progressive amnestic syndrome combined with some degree of visuospatial and executive dysfunction rarely presents diagnostic difficulty. Similarly for bvFTD the reports of inappropriate behaviors, a lack of empathy, stereotypies, and changes in eating preference help differentiate it from AD [76]. However, focal variants of AD frequently enter the differential for all the FTD/Pick complex clinical syndromes, with 10–20% of cases in autopsy series meeting criteria for bvFTD but turn out to have Alzheimer’s pathology. Recently revised criteria for bvFTD relax the exclusion criteria somewhat to accommodate the phenotypic variability of FTLD but it has been suggested this may increase the false-positive rate [77]. In general, though, AD mimics show additional features of memory impairment and/or mild visuospatial impairment within the first one to three years which help distinguish them [78]. There are of course exceptions and severe amnesia has been described in cases with proven FTLD pathology, resulting in diagnoses of AD in life [19] even in specialist centers. In our experience the failure to develop a second or third Pick complex syndrome reliably identified the non-FTLD cases and AD in particular (Figures 2.1–2.3) but that feature may not be evident until several years into their illness.
Progressive aphasia is probably the Pick complex syndrome most likely to contain AD mimics which comprise the majority of cases with logopenic PPA and a substantial minority of PNFA but relatively few SD. Differentiation can be particularly difficult after the early stages of PPA when more widespread cognitive domains are involved. Logopenic aphasia, prominent phonologic errors, mixed aphasia, later age of onset, and memory complaints evident with follow-up point to underlying AD pathology [78].
AD can also mimic the movement disorder/parietal syndrome of CBS. AD can be the underlying pathology even in apparently prototypical cases of CBS with severe apraxia and extrapyramidal signs including alien limb phenomena. To add to the difficulty, dopamine transporter scanning can be normal in pathologically proven cases of CBD and so cannot always be relied upon to differentiate pathologies [79]. It has been suggested that a number of clinical features, such as early memory complaints and memory/orientation deficits on cognitive batteries versus frontal behaviors, non-fluent language, and oro-buccal apraxia, differentiate AD from CBD pathology in vivo [80], but this finding has not been replicated [81].
In addition to Alzheimer’s mimicking FTD/Pick complex on a clinical level, mutations in presenilin 1 (PS1), the main genetic cause of familial AD, have been described in several families with apparently typical bvFTD [82]. In some cases this has been with typical AD pathology, reflecting a focal variant of the disease. In others the PS1 mutations have been associated with mixed AD and Pick pathology [83] or even classical Pick’s disease in the absence of amyloid accumulation [84], suggesting PS1 mutations may predispose to both diseases by affecting amyloid precursor protein (APP) and/or tau processing. Differentiation of AD and FTLD may be aided by the increasing use of cerebrospinal fluid (CSF) biomarkers of neurodegeneration in diagnosis, perhaps to be complemented by molecular imaging techniques such as amyloid or tau PET. Lower CSF total tau to amyloid Aβ1–42 ratios have been demonstrated in FTLD compared with AD, differentiating the two with sensitivities and specificities over 90% [85], though for now such techniques are largely confined to research centers.
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