Frontotemporal lobar degeneration: recent progress in antemortem diagnosis

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1 Acta Neuropathol (2007) 114:23 29 DOI /s REVIEW Frontotemporal lobar degeneration: recent progress in antemortem diagnosis Hong Bian Murray Grossman Received: 19 March 2007 / Revised: 5 May 2007 / Accepted: 8 May 2007 / Published online: 2 June 2007 Springer-Verlag 2007 Abstract Frontotemporal lobar degeneration (FTLD) is a neurodegenerative disorder characterized by changes in behaviour and language dysfunction. Two broad pathological subdivisions of FTLD are recognized in a recent classiwcation scheme based on biochemical features: tau-positive pathology due to the accumulation of various forms of the microtubule-associated protein tau, such as FTLD with Pick bodies and corticobasal degeneration; and tau-negative pathology such as frontotemporal lobar degeneration with ubiquitin/tdp-43-immunoreactive inclusions. Etiologically based treatments aim to target the mechanisms underlying the accumulation of these abnormal proteins in these conditions. It is essential for us to develop biomarkers that support the accurate diagnosis of the speciwc diseases causing FTLD. These biomarkers also can be useful in assessing eycacy during treatment trials. This review summarizes the epidemiologic, clinical, neuropsychological, imaging and cerebrospinal Xuid (CSF) biomarker features that can help identify these pathologically dewned conditions during life. This work was supported in part by USPHS (AG17586, AG15116, and NS44266) and the Dana Foundation. H. Bian M. Grossman Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, PA, USA H. Bian Department of Neurology, Jinan Central Hospital, Shandong University School of Medicine, Jinan, Shandong Province, People s Republic of China M. Grossman (&) Department of Neurology, 2 Gibson, Hospital of the University of Pennsylvania, 3400 Spruce Street, Philadelphia, PA , USA mgrossma@mail.med.upenn.edu Keywords Frontotemporal lobar degeneration Biomarkers Neuropsychology Neuroimaging Cerebrospinal Xuid Introduction Frontotemporal lobar degeneration (FTLD) is an earlyonset progressive neurodegenerative condition. The most common presenting features include language dysfunction or a disorder of social comportment, executive functioning, and personality [17, 47]. Prevalence studies of FTLD are inconsistent, with values ranging between 3.6 and 15.0 per 100,000 [43]. FTLD is the second most common cause of dementia in individuals younger than 65 and is almost as common as Alzheimer s disease (AD) within this age group [22, 24, 25, 30, 43]. Age at onset is typically between 45 and 65 years [16, 40]. The distribution of FTLD is equal between male and female. FTLD has a high rate of familial occurrence, ranging between about 30 and 45% depending on the speciwc criteria used to identify a signiwcant family history [21, 25, 43, 45, 47, 50]. Known mutations involve MAPT and PGRN on chromosome 17 [2, 7, 10, 48], although rarer mutations of other chromosomes also are associated with FTLD [46]. The age of onset and the distribution of clinical phenotypes do not appear to diver across familial and sporadic cases [16, 40]. Multiple neuropathological abnormalities are associated with FTLD [32, 34]. Two broad pathological subdivisions are recognized, according to a recent classiwcation scheme from an FTLD work group. This scheme incorporated both immunohistochemical and biochemical data in the diagnostic algorithm [11]. Some of these FTLD patients are said to have tau-positive pathology. Conditions causing FTLD in these patients are associated with the accumulation of the

2 24 Acta Neuropathol (2007) 114:23 29 microtubule-associated protein tau, including FTLD with Pick bodies, corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), and argyrophilic grain disease (AGD). Other pathologic entities are said to be tau-negative since these conditions do not accumulate tau. For example, frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U) is associated with the accumulation of tau-negative but ubiquitin-immunoreactive inclusions. TDP-43 was recently described as the disease protein in this condition [39]. TDP-43 is now known to be the major disease protein in FTLD-U and amyotrophic lateral sclerosis (ALS), and pathological TDP-43 is ubiquitinated, phosphorylated and fragmented in these disorders [39]. Less common tau-negative conditions associated with the absence of both tau- and ubiquitinimmunoreactive inclusions are dementia lacking distinctive histopathology (DLDH) and neuronal intermediate Wlament inclusion disease (NIFID). Both tau-positive and tau-negative subtypes of FTLD diver from AD where pathological tau Wlaments accumulate as neurowbrillary tangles together with extracellular deposits of β-amyloid (Aβ) [31]. Clinical pathological studies are crucial to understanding brain behavior relations. FTLD clinical syndromes have been associated with speciwc neuropathological disorders by some researchers [23], although this association is controversial [34]. With the imminent development of therapies that target the underlying pathology and cell biology of speciwc diseases, the recognition of the speciwc pathological entity causing a patient s FTLD spectrum disorder during life will become increasingly important. Moreover, biomarkers useful for diagnosis also can be employed to monitor eycacy during treatment trials. In this review, we summarize recent progress in understanding the epidemiologic, clinical, neuropsychological, imaging and biological biomarker characteristics that correspond to a known underlying pathology causing FTLD. Epidemiology The clinical value of epidemiologic observations is immense. For example, prognostic information is very important in helping patients and their families develop a long-term plan of care. Moreover, epidemiologic studies can contribute to determining the pathological basis for a patient s clinical disorder. While survival studies emphasize the importance of the histopathologic abnormality in determining disease duration, a consensus has not yet been attained on the precise role of these disease proteins. Some reports thus suggest that tau-negative patients have an earlier age of onset and more rapid decline, while other work describes more rapid decline in tau-positive patients. Finally, several studies report no diverence between taupositive and tau-negative patient groups. Tau-negative patients are younger at onset than tau-positive patients, according to some work [23, 27]. However, other studies Wnd no diverence between tau-positive and tau-negative groups in age at onset [11, 19, 29, 50]. This discrepancy may be due in part to the variable inclusion of patients with clinical amyotrophic lateral sclerosis (ALS) in the tau-negative group. These patients have the same underlying pathology as FTLD-U, although ALS patients tend to be younger at onset and have a shorter disease duration than those with FTLD alone [11, 26]. In one clinical pathological analysis, for example, diverences between tau-positive and FTLD-U/DLDH groups in age at onset disappeared once clinical ALS was considered [11]. This has not been a universal Wnding, however, since another study of survival in FTLD revealed that FTLD/ALS may have a similar age of onset relative to patients with a behavioral variant of FTLD [24]. Two studies of FTLD report that tau-negative pathology results in more rapid disease progression [24, 50]. When clinical ALS is associated with FTLD, more rapid disease progression is seen than in FTLD without clinical ALS [24, 26, 44], despite the identical underlying neocortical histopathology in FTLD and FTLD/ALS [9, 49]. One analysis included patients with clinical ALS, but a second analysis excluding ALS still replicated their basic Wnding that tau-negative pathology is associated with more rapid disease progression [24, 50]. Some studies report equivalent survival in tau-positive and tau-negative patients [26, 42]. Yet other work examined the clinical and pathological characteristics contributing to survival in autopsy-proven FTLD by excluding cases with clinical features of ALS to minimize the interpretive confound associated with the known brief survival of this disorder and its associated pathology [55]. The median survival time from symptom onset in this cohort was 80 months, resembling other studies of autopsy-proven FTLD with median survival ranging from 72 to 104 months [24, 26, 42, 44]. These authors found that tau-positive pathology is associated with more rapid progression of FTLD. Education appears to have somewhat of a protective evect, while disease in the basal ganglia appears to worsen prognosis. Another study shows a trend toward briefer survival in tau-positive patients [27]. In addition to variations in survival that may depend in part on the inclusion of tau-negative cases with ALS, another potential reason for these discrepancies may be the various tau-positive pathologies contributing to the cohorts in each study. For example, studies including a large number of patients with CBD tend to associate tau-positive disease with a shorter disease duration [27, 55]. Moreover,

3 Acta Neuropathol (2007) 114: not all tau-negative patients have equal survival risk. Grossman et al investigated 23 patients with FTLD-U pathology who were subtyped depending on the conformation of TDP-43. Mean ( S.D., range) survival in the entire cohort was 87.3 ( 32.5, ) months. Survival was longer in patients with TDP-43 associated with more extensive pathology in neurites compared to patients with TDP-43 who have more extensive neuronal intracytoplasmic inclusions [20]. This is consistent with another study including 60 autopsy-proven FTLD-U cases from two UK centers. This report also revealed that TDP-43 patients with extensive neuronal intracytoplasmic inclusion pathology have a shorter survival than cases with more profound neuritic pathology [33]. Clinical features at presentation also may contribute to survival. For example, impaired letter Xuency may be associated with reduced survival [44]. Other investigators Wnd that anxiety and suicidal ideation are associated with a signiwcantly decreased mortality, while reduced speech, neurological dewcits such as incontinence, Parkinsonism and epileptic seizures, and dysphagia are associated with shorter survival [13]. This work has begun to suggest that the speciwc histopathologic abnormality causing FTLD has a signiwcant impact on important issues such as age at onset and survival. One unfortunate factor limiting the interpretability of these results is the small number of cases included in each of these studies. FTLD is not as common as AD, for example, and multi-center studies will be needed to answer questions such as these. Moreover, statistical techniques such as multivariate analysis may optimize the interpretability of the observations. Clinical manifestations To the extent that a medication regimen can be found to treat the tau-positive or tau-negative histopathologic abnormality, then it would be extraordinarily important to identify these speciwc conditions during life. Some reports appear to indicate that tau-positive patients and tau-negative patients have partially distinct clinical manifestations or present with a particular syndrome. For example, tau-positive patients frequently present with a non-xuent form of progressive aphasia or with corticobasal syndrome, while tau-negative patients tend to have a social disorder and/or semantic dementia. However, there are many exceptions to these observations, and indeed others argue that these syndromes are unstable and patients tend to develop diverent impairment prowles over time. Up to two-thirds of tau-positive patients appear to have an extrapyramidal disorder [15, 37]. This includes patients with CBD and PSP [11]. This may be due in part to signiwcant tau pathology in the basal ganglia. These patients do not necessarily present with a motor complaint [37]. Taupositive pathology also may be associated with the clinical syndrome of progressive non-xuent aphasia (PNFA) [23, 28]. This is a disorder of evortful speech with frequent speech errors. Many of these patients have FTLD with Pick bodies or CBD [23, 27], although this is not conwrmed in other series [36]. Patients with CBD also may have a visual-perceptual disorder and apraxia [37]. Tau-negative patients, by comparison, tend to have alterations in behavior and social comportment, often labeled the behavioral variant or social/dysexecutive subgroup of FTLD. Tau-negative patients also may have a Xuent form of language diyculty with impairments of naming and comprehension known as semantic dementia (SD) [8, 11, 19, 28]. In a direct comparison, Forman et al. found that the presence of a behavioral/social disorder and aphasia is more evident at onset in FTLD patients with tau-negative disease compared to tau-positive disease, while tau-positive patients appear more likely to have an extrapyramidal syndrome [11]. Tau-negative but ubiquitin-positive inclusions are also associated with a mutation of the progranulin (PGRN) gene on chromosome 17. Gass et al. reported that patients with a PGRN mutation often present with a language impairment [12], although this is not a universal observation [52]. There may be diverences within FTLD-U patients, moreover, depending on the associated form of TDP-43. TDP-43 is the ubiquinated protein in FTLD-U [39]. There appear to be three conformational subtypes of FTDP-43. Social complaints are present in all FTLD-U/TDP-43 patient subgroups. However, FTLD-U/TDP-43 patients with more extensive pathology in neurites also have language complaints and the syndrome of semantic dementia, while FTLD-U/TDP-43 patients with more extensive neuronal intracytoplasmic inclusion pathology have additional language and memory complaints, and FTLD-U/TDP-43 patients with neuronal intranuclear inclusions may have a PNFA syndrome [20, 33]. In sum, there appear to be important trends associating speciwc syndromes with a particular underlying pathology. These observations implicate tau-positive disease in PNFA and CBD, and tau-negative disease in SD and a social disorder. It is important to point out, however, that some investigators emphasize the changes that occur over time in the syndromic characterization of patients [27]. This work shows that the presenting syndrome of a patient often becomes associated with additional syndrome(s) over time, or may change syndromes from one to another as the disease progresses. From this prospective, further studies on syndromic diagnosis with large samples would be helpful.

4 26 Acta Neuropathol (2007) 114:23 29 Neuropsychology Neuropsychological tests also may be helpful at distinguishing FTLD histopathologic subtypes from each other. While an individual neuropsychological test does not provide as comprehensive a picture of a patient s clinical presentation as a syndromic diagnosis, a battery of test results can be very informative at conwrming a clinical phenotype. Moreover, in the context of etiologic treatments, neuropsychological tests have the distinct advantage that they are quantitative and thus can be used to establish whether an intervention is eycacious. Recent work reports distinctive prowles of performance on neuropsychological tests among pathological subgroups of FTLD patients. The most compelling evidence for the utility of neuropsychological tests comes from recently observed double dissociations. Tau-positive patients appear to be more impaired than tau-negative patients on measures assessing geometric Wgure copy and executive functioning, for example, while tau-negative patients are more impaired than taupositive patients on language-mediated measures such as confrontation naming and measures of category naming Xuency. Moreover, some of these double dissociations are maintained longitudinally. Tau-positive patients are signiwcantly more impaired than tau-negative patients in their performance on visualspatial measures that involve an executive component such as copying a geometric Wgure [19]. This resembles earlier studies of visual-perceptual diyculty in pathologically con- Wrmed patients with a tau-positive disorder [11, 37, 51]. Performance on this measure correlates signiwcantly with antemortem cortical atrophy on MRI in frontal and parietal regions in FTLD patients. Moreover, tau-positive patients have signiwcant disease burden in frontal and parietal regions that is correlated with performance on visual perceptual-spatial tasks [19]. Tau-negative FTLD patients, by comparison, are more impaired on language-mediated tasks, consistent with their frequent language complaints. The tau-negative group produces low scores on the animal Xuency test and on letterguided Xuency tests [11, 19]. On the Boston Naming test, tau-negative patients produce signiwcantly fewer correct responses than members of the tau-positive group. Recent longitudinal analyses in our lab indicate that key dissociating features preserve important distinctions between tau-positive patients and tau-negative patients throughout the course of disease. Visual-constructional impairments thus remain signiwcantly more diycult for tau-positive patients than tau-negative patients throughout the course of the disease. By comparison, confrontation naming diyculty is signiwcantly more impaired in tau-negative patients than tau-positive patients during the entire course of their disease. While neuropsychological studies are reasonably good at distinguishing between pathologically dewned FTLD subgroups and have distinct advantages because of their quantitative nature, there are diyculties associated with identifying a pathologic diagnosis based solely on neuropsychological measures. For example, FTLD-U/TDP-43 subgroups appear to diver in their neuropsychological pro- Wles, even though these subgroups appear similar histopathologically and MMSE scores do not diver across FTLD-U/ TDP-43 subtypes [20]. Only FTLD-U patients with neuronal intranuclear inclusions are signiwcantly impaired on measures of executive functioning like digit span, for example. By comparison, FTLD-U patients with prominent disease in neurites have the greatest dewcit for confrontation naming. Category naming Xuency, a language-mediated executive measure, is signiwcantly impaired in all three of the FTLD-U/TDP-43 subgroups. Another problem is related to the speciwc measures used to ascertain performance within a particular cognitive domain. While performance on the Boston Naming test consistently shows greater diyculty in tau-negative patients than tau-positive patients at onset, and while this diverence is maintained longitudinally throughout the disease, other investigators report that performance on a survey instrument of language functioning becomes less distinctive as these diseases progress [5]. Studies with additional instruments are needed in pathologically proven cases of taupositive and tau-negative disease. Imaging assessment High-resolution structural MRI imaging also may be useful as a way to evaluate patients and monitor response to disease-modifying therapies in FTLD [53]. Some studies suggest that tau-positive patients and tau-negative patients have distinct imaging characteristics. However, the value of MRI techniques in the diverential diagnosis in FTLD remains unclear because of the small groups of patients that have been assessed, and some authors argue that no speciwc brain imaging diverences are observed when comparing tau-positive and tau-negative groups. One study examined 17 cases of pathologically con- Wrmed FTLD, including 9 tau-positive and 8 tau-negative patients. The authors reported that tau-positive and tau-negative subgroups share extensive areas of regional brain atrophy, predominantly avecting the frontal and anterior temporal lobes [54]. Another study also Wnds no clear diverential pattern of amygdala and hippocampal atrophy across tau-positive and tau-negative patients [3]. A study of 21 cases of pathologically conwrmed FTLD (9 tau-negative patients with FTLD-U, 12 tau-positive cases including 7 patients with FTLD with Pick bodies and 5 patients with

5 Acta Neuropathol (2007) 114: FTDP-17) showed atrophy that involves the middle and inferior temporal gyri, medial temporal lobes, insula, orbitofrontal cortex, and subfornical regions in all three pathology groups. However, these investigators also observed predominantly left temporal lobe atrophy in taunegative cases, severe bifrontal atrophy in FTLD with Pick bodies, and relatively focal right medial temporal lobe atrophy in cases with an exon mutation of tau [53]. Grossman et al. examined 12 patients with autopsyproven FTLD imaged with high-resolution structural MRI during life, and correlated atrophy with performance on cognitive measures to verify the contribution of the observed atrophy to the patient s clinical phenotype [19]. Tau-positive patients show signiwcant atrophy in left inferior frontal, right frontal, and right parietal regions. Performance on a visual constructional task correlated with right frontal and parietal cortical atrophy on imaging studies, and correspondingly, the burden of disease in tau-positive patients was densest in parietal and frontal cortices. Taunegative patients demonstrated signiwcant atrophy in bilateral frontal and temporal distributions, and performance on category naming Xuency and naming tasks correlated with cortical atrophy in a frontal and temporal distribution. Quantitative imaging studies in pathologically dewned cases that have been well studied clinically are very diycult, and only a small number of such cases have been reported to date. Caution must be exercised when interpreting these Wndings. Nevertheless, multimodal studies during life such as these can provide powerfully converging evidence consistent with a speciwc histopathologic disease. CSF biomarkers Given the limitations of clinical and imaging studies, investigators have begun to develop other potential biomarkers. One obvious biomarker is blood, where a mutation of FTDP-17 or PGRN may be identiwed. Cerebrospinal Xuid (CSF) is also of interest because it is in direct contact with the extracellular spaces of the central nervous system. Many studies focus on CSF biomarkers in FTLD. Among the currently available CSF biochemical markers for neurodegenerative diseases, the protein tau appears most promising for diverentiating FTLD from AD. Some validation of this impression comes from imaging studies in patients with CSF tau levels [18]. The level of CSF tau thus correlates signiwcantly with cortical volume in left ventral temporal and right frontal cortical regions, areas implicated in FTLD pathologically. Nevertheless, results of CSF biomarkers have been inconsistent because of the relatively small autopsy samples that have been studied. Moreover, there is no good marker of tau-negative disease. Most studies of CSF tau levels are reported in patients clinically diagnosed with FTLD. Some studies show statistically increased CSF tau levels. However, others report normal CSF tau concentrations compared with AD and healthy senior controls [14, 18, 35, 41]. The reason for the inconsistent results across previous studies may be related in part to the clinical nature of the diagnosis, raising concern about the possibility of misdiagnosis. Moreover, it is unclear whether CSF tau levels can distinguish between tau-positive and tau-negative disease. Only very few cases with neuropathologically proven disease have been reported. Even when the autopsy-proven diagnosis is known, the results of studies examining CSF total tau levels have been inconsistent. One study reports signiwcantly increased CSF tau level in autopsy-proven FTLD patients compared with normal controls [1] while another study shows no signiwcant diverence between FTLD and controls [6]. Unfortunately, these studies involve very small numbers of patients. Moreover, inconsistent results may be due in part to the diversity of the pathology in these small FTD groups. One recent study of CSF biomarkers included 30 FTLD cases with known tau-positive or tau-negative disease (found at autopsy or due to a genetic mutation) and 19 AD subjects [4]. The premise of this study was that patients with FTLD must be distinguished from patients with frontal-variant AD or progressive aphasia due to AD for the purpose of clinical trial eligibility. We found that CSF total tau level and the ratio of CSF tau to Aβ 42 (tau/aβ 42 ) are signiwcantly lower in FTLD than in autopsy-proven AD, while Aβ 42 is signiwcantly higher in FTLD than in AD. Receiver operating characteristic (ROC) curve analysis revealed that tau/aβ 42 (92.7% area under the curve) is sensitive at 78.9% and speciwc (96.6%) at discriminating between AD and FTLD, and these values exceed the comparable values for CSF tau alone. No signiwcant group diverence is found in CSF tau, Aβ 42 and tau/aβ 42 in direct comparison of taupositive and tau-negative groups. Studies on CSF biomarkers in patients with pathologically conwrmed FTLD are rare. The small numbers of cases included in each of these studies, and the heterogeneity of the underlying pathologies, limits the interpretability of these results. Multi-center study with large autopsy-proven samples should provide much more reliable evidence in future. Conclusion Growing interest in FTLD in recent years rexects the rapid advances in our understanding of its pathological and molecular basis [38]. Better understanding, however, also has revealed increased complexity. Recent studies indicate

6 28 Acta Neuropathol (2007) 114:23 29 that antemortem clinical, neuropsychological, neuroimaging, and biomarker evaluations can potentially contribute to identifying the underlying pathology of FTLD cases during life. Tau-positive pathology may be associated with the emergence of extrapyramidal signs at some point during the disease, syndromes such as corticobasal degeneration and progressive non-xuent aphasia, diyculty on visual-constructional measures such as copying a geometric Wgure, and the presence of MRI atrophy in left frontal, right frontal, and right parietal regions. In contrast, tau-negative pathology may be associated with behavioral/social and language dysfunction, signiwcant naming diyculty, and the presence of signiwcant atrophy in frontal and temporal cortical regions. The Wndings of the above assessments, while promising, leave much room for improvement. Since we are interested in distinguishing between two relatively rare conditions, some of the discrepancies between studies assessing similar features may due in part to the small sizes of study groups, the diverse pathologies contributing to the FTLD subgroups, and the diverent statistic methods used across these studies. Future work may integrate clinical, neuropsychological and imaging measures during life to determine the optimal combination that can contribute to identifying patients with a speciwc histopathologic disease. The ability to distinguish between FTLD due to tau-positive disease or tau-negative disease is a crucial goal for clinical research, and is central to the development of strategies for the evective treatment of the etiologies underlying neurodegenerative diseases such as FTLD. References 1. 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