- Email: [email protected]
Early stage of behavioral variant frontotemporal dementia: clinical and neuroimaging correlates
Accepted Manuscript Early stage of behavioral variant Frontotemporal Dementia: clinical and neuroimaging correlates B. Borroni, M. Cosseddu, A. Pilotto, E. Premi, S. Archetti, R. Gasparotti, S.F. Cappa, A. Padovani PII:
S0197-4580(15)00379-6
DOI:
10.1016/j.neurobiolaging.2015.07.019
Reference:
NBA 9339
To appear in:
Neurobiology of Aging
Received Date: 20 January 2015 Revised Date:
11 July 2015
Accepted Date: 12 July 2015
Please cite this article as: Borroni, B., Cosseddu, M., Pilotto, A., Premi, E., Archetti, S., Gasparotti, R., Cappa, S., Padovani, A., Early stage of behavioral variant Frontotemporal Dementia: clinical and neuroimaging correlates, Neurobiology of Aging (2015), doi: 10.1016/j.neurobiolaging.2015.07.019. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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ACCEPTED MANUSCRIPT Early stage of behavioral variant Frontotemporal Dementia: clinical and neuroimaging correlates
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B. Borronia, M. Cosseddua, A. Pilottoa, E. Premia, S. Archettib, R. Gasparottic, SF. Cappad, A. Padovania
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Corresponding Author: Barbara Borroni, MD
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Centre for Ageing Brain and Neurodegenerative Disorders, Neurology Unit, University of Brescia, Italy b III Laboratory of Analyses, Brescia Hospital, Brescia, Italy c Neuroradiology Unit, University of Brescia, Brescia, Italy d Institute for Advanced Study IUSS Pavia, Pavia, Italy
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Neurology Unit, University of Brescia
Piazza Spedali Civili 1, Brescia 25125, Italy
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Email: [email protected]
Word counts: Abstract: 189 words; Text: 4149 words Tables/Figures: 5; Supplementary Material: 0; References: 40
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ACCEPTED MANUSCRIPT ABSTRACT
The early stages of behavioural variant Frontotemporal Dementia (bvFTD) are still not
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completely characterised. In a consecutive series of patients with probable bvFTD diagnosis confirmed by follow-up, we retrospectively evaluated the features at onset. Patients were reclassified according to presenting features and current diagnostic criteria into probable and
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possible bvFTD. The term “pre-bvFTD” was adopted for patients with cognitive and/or
behavioural impairment not fulfilling bvFTD criteria and no deficits in activities of daily
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living. One-hundred ninety four subjects were included; at first visit, 70% (n=136) patients were already classified as probable bvFTD. Of the remaining 30% (n=58), 60% fulfilled criteria for possible bvFTD, while 40% did not, and were classified as pre-FTD. The neuropsychological pattern in possible bvFTD and pre-bvFTD was similar, though possible
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bvFTD showed more behavioural abnormalities. Pre-bvFTD subjects had frontotemporal grey matter atrophy, even though less extensive than possible bvFTD. Conclusively, most bvFTD patients fulfil current diagnostic criteria at first admission, whereas a relatively small group is
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characterized by mild behavioural and/or cognitive abnormalities in spite of frontotemporal grey matter atrophy. Our preliminary findings will require a validation in prospective studies
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involving larger samples of patients.
Keywords: Frontotemporal Dementia; prodromal; behavioural variant Frontotemporal Dementia (bvFTD); MRI; Mild Cognitive Impairment (MCI); behavioural impairment, prebvFTD.
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ADL, activities of daily living APOE, Apolipoprotein E BADLs, Basic Activities of Daily Living
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bvFTD, behavioural variant Frontotemporal Dementia CSF, cerebrospinal fluid
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FBI, Frontal Behavioral Inventory FTD frontotemporal dementia
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Abbreviations:
FTD-modified CDR, Frontotemporal Dementia-modified Clinical Dementia Rating scale FTDC, Frontotemporal Dementia Consortium
GM, gray matter GRN, granulin HC, healthy controls
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FWE, family-wise error
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IADLs, Instrumental Activities of Daily Living MAPT, microtubule associated protein tau
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MCI, Mild Cognitive Impairment
MMSE, Mini-Mental State Examination MRI, magnetic resonance imaging
TARDBP, TDP-43 transactive response DNA-binding protein UPDRS, Unified Parkinson’s Disease Rating Scale VBM, Voxel-based Morphometry
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ACCEPTED MANUSCRIPT INTRODUCTION Frontotemporal dementia (FTD) is the second most frequent form of neurodegenerative earlyonset dementia and is the clinical manifestation of progressive nerve cell loss in the frontal and anterior temporal lobes (Seelaar et al., 2011; Warren et al., 2013). Histopathological
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changes are characterised by protein misfoldings, in most cases either Tau or transactive
response DNA-binding protein (TDP-43) (Rademakers et al., 2012). It is generally considered that there is a phase of frontotemporal disease when individuals experience a gradually
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progressive cognitive decline and behavioural change resulting from the accumulation of pathological protein in the brain. When the cognitive impairment and the behavioural
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abnormalities are sufficiently severe, such that there is interference with activities of daily living (ADL) functions, the patient is diagnosed with FTD.
It is important to note that, as FTD is a progressive disorder with no clear-cut fixed events that indicates its onset, on clinical grounds it is particularly challenging to identify transition
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points for the individual patient. In the realm of dementia, prodromal stages have been largely investigated in order to identify markers of early diagnosis and promptly introduce therapeutic interventions when functional disabilities are not yet present. Thus, Mild Cognitive
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Impairment (MCI) has been proposed as a nosological entity useful to identify subjects at higher risk of developing dementia, thus with likely prodromal disease, suffering from
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cognitive complains but with preserved ADLs (American Psychiatric Association Committee on Nomenclature, 2013, 2000; Petersen et al., 1999). Initially developed to detect prodromal stages of Alzheimer’s disease, MCI term has been extended to subjects progressing to different dementing illnesses. Indeed, different MCI subtypes have been described. Whereas amnestic MCI subjects have higher risk of having prodromal AD, non amnestic MCI or multidomain MCI subjects have higher risk of developing other neurodegenerative dementias, i.e. Dementia with Lewy Bodies or FTD (Ferman et al., 2013; Gauthier et al., 2006; Huey et al., 2013; Petersen and Bennett, 2005). If a large body of literature exists on MCI related to
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ACCEPTED MANUSCRIPT Alzheimer disease pathology, no particular attention has been paid to MCI subjects who have pre-FTD and will develop disease over years. Behavioural variant Frontotemporal Dementia (bvFTD) is characterized by executive dysfunction, behavioral disturbances and personality changes (Kertesz et al., 2005; Seelaar et
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al., 2011).
Applying the definition of dementia status, namely the presence of cognitive deficits that impact on ADLs (American Psychiatric Association Committee on Nomenclature, 2013,
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2000) is still challenging in frontotemporal disease. At early FTD disease stages, patients may present preserved ADLs (Gauthier et al., 2006; Huey et al., 2013; Kertesz et al., 2005), thus
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not satisfying diagnosis of dementia, despite significant behavioural disturbances and executive deficits.
Recently, new revised criteria have been developed by Rascovsky and colleagues (Rascovsky et al., 2011) to increase diagnostic accuracy and to capture the early disease stages of FTD.
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The authors required 3 out of 6 clustered key symptoms to reach possible bvFTD diagnosis, and additional impairment of ADLs and compatible features on neuroimaging to reach probable bvFTD diagnosis. Pathologically confirmed series showed the usefulness of these
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criteria in ameliorating diagnostic sensitivity (Harris et al., 2013; Rascovsky et al., 2011). Notwithstanding this, it is still not clear whether these criteria are effective to detect patients
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in the early stages. This would be mandatory for anticipating diagnosis, avoiding medicolegal problems and ensuring early work retirement. Theoretically, the criteria for possible bvFTD might represent a pre-dementia stage giving the requirement of the absence of functional impairments. However, the requirement of 3 out of 6 core symptoms may exclude very early or atypical cases, thus reducing the possibility of identifying patients with early stages of disease. These premises prompted the present work, aimed at identifying the clinical and neuroimaging features associated with early bvFTD. To this end, we considered a large cohort
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ACCEPTED MANUSCRIPT of patients diagnosed as having probable bvFTD diagnosis at follow-up, on the basis of current clinical criteria, neuroimaging and cerebrospinal fluid analysis (Irwin et al., 2013; Rohrer et al., 2011). In this selected cohort, we retrospectively considered features at disease onset, with the aim to i) assess the clinical and behavioural profile of early stage bvFTD, and
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ii) evaluate the neuroimaging correlates, iii) assess the sensitivity of current diagnostic criteria for bvFTD.
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METHODS
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Patient selection. In the present work, we considered a consecutive series of patients with diagnosis of probable bvFTD at follow-up evaluation (range 2-9 years) recruited from January 2001 to April 2014 at the Centre for Ageing Brain and Neurodegenerative Disorders, University of Brescia, Italy.
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At enrollment and at each year follow-up, patients underwent a general medical and neurological evaluation, and neuropsychological assessment. Moreover, at enrollment, each patient underwent a routine laboratory analysis and brain structural imaging study (magnetic
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resonance imaging, MRI).
The comprehensive neuropsychological and behavioral assessment (Borroni et al., 2007)
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included Basic Activities of Daily Living (BADL) and Instrumental Activities of Daily Living (IADL) (Katz et al., 1970; Lawton and Brody, 1969) to test functional abilities. The neuropsychological testing was performed by a standardized neuropsychological battery including Mini-Mental State Examination (MMSE), Raven Colored Progressive Matrices, Controlled Oral Word Association Test and Category Fluency, Clock Drawing Test, Rey Complex Figure Copy and Recall, Story Recall Test, Digit Span, Trail Making Test A and B, Token Test, and De Renzi Imitation Test (Lezak et al., 2012). Frontotemporal Dementiamodified Clinical Dementia Rating scale (FTD-modified CDR) was not available for all the
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ACCEPTED MANUSCRIPT subjects as introduced only in 2008 (Knopman et al., 2008). Behavioral disturbances were evaluated by Frontal Behavioral Inventory (Kertesz et al., 1997) and Neuropsychiatry Inventory (Cummings et al., 1994). Patients were also screened for the most common monogenic forms, namely granulin (GRN),
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microtubule associated protein tau (MAPT), 43-kDa transactive response-DNA-binding
protein (TARDBP) and C9orf72 hexanucleotyde expansion, and genotyped for APOE allelic variations, as already reported (Premi et al., 2012). No patient with already known family
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history of monogenic disease was included in the present study.
Stringent exclusion criteria were applied as follows: 1) cerebrovascular disorders, previous
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stroke, normal pressure hydrocephalus, and intra-cranial mass documented by MRI; 2) diagnosis of other type of neurodegenerative disorders; 3) diagnosis of amnestic MCI and cerebrospinal fluid (CSF) /imaging pattern typical for Alzheimer’s Disease (Albert et al., 2011; Dubois et al., 2014) 4) other neurological disorders or significant medical problems (i.e.
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hepatic or renal failure, chronic respiratory insufficiency) potentially responsible for encephalopathy; or 5) bipolar disorder, schizophrenia, substance abuse disorder or mental retardation according to criteria of the DSM-IV.
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Each patient has been followed-up for at least 2 years, and those with diagnosis agreement between two experienced neurologist (B.B. and A.P.), fulfilling probable bvFTD criteria were
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included in the present study. An age-matched group of healthy controls (HC) recruited from spouses or caregivers was introduced for imaging comparisons (n=36, mean age 61.7 + 7.3 years, female 72.2 %). Each HC underwent a brief evaluation of global cognition, which was unremarkable (MMSE>=27/30, preserved IADL and BADL).
Study design. This is a retrospective study aimed at assessing pre-FTD features.
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ACCEPTED MANUSCRIPT As shown in Figure 1, patients with neurodegenerative frontal syndrome were consecutively enrolled and underwent an extensive work-up (n=220). These patients were periodically followed up for at least two years (range 2-9 years), and only those with final diagnosis of probable bvFTD diagnosis were considered in the present study (n=194). Probable bvFTD
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diagnosis was made according to current clinical criteria, with supporting neuroimaging
features of bvFTD. Cerebrospinal fluid (CSF) Abeta/Tau ratio suggestive for AD pathology (3/67 analyses) was considered an adjunctive exclusion criterion (Bian et al., 2008; Padovani
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et al., 2013); patients with any clinical diagnosis other than probable bvFTD at follow-up (n=6) and patients with clinical follow-up evaluation not available (n=17) were not included
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in the present study.
These selected patients were retrospectively classified according to features presented at first admission/baseline. Probable bvFTD diagnosis was made according to current Frontotemporal Dementia Consortium (FTDC) criteria (Rascovsky et al., 2011), in those
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patients with at least 3 out of 6 key-symptoms of current clinical criteria (behavioural disinhibition, apathy/inertia, loss of sympathy/empathy, perseverative/compulsive behavior, hyperorality/dietary changes, and executive deficits), and functional impairment (as measured
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by IADLs and BADLs (Katz et al., 1970; Lawton and Brody, 1969), whilst possible FTD was made in those patients with no impairment in the ADLs.
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An analysis of the clinical features, however, indicated that a subgroup of patients did not fit into the possible bvFTD criteria (at least 3 out of 6 key features). This group of subjects who had less than 3 key-symptoms and preserved ADL was defined as pre-bvFTD. In these subgroups, the characteristics and neuroimaging correlates were assessed.
MRI Acquisition. Over the years of recruitment, 113 images were collected and obtained using two different MR scanners: a) 1.5 T MR scanner (Siemens Symphony, Erlangen, Germany), equipped with a circularly polarized transmit-receive coil to acquire 3D
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ACCEPTED MANUSCRIPT magnetization–prepared rapid gradient echo (MPRAGE) T1-weighted scan (TR=2010 ms, TE=3.93 ms, Matrix=1x1x1x, in-plane field of view FOV=250x250 mm2, slice thickness=1 mm, flip angle =15°); and b) 1.5 T MR scanner (Siemens Avanto, Erlangen, Germany) to acquire 3D MPRAGE T1-weighted scan (TR=2050 ms, TE=2.56 ms, Matrix=1x1x1x, in-
subjects underwent brain MRI by scanner 1 and 46 by scanner 2.
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plane field of view FOV=256x256 mm2, slice thickness=1 mm, flip angle =15°). Sixty-seven
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Voxel-based Morphometry (VBM). MPRAGE data were processed using the VBM protocol in Statistical Parametric Mapping 8 (SPM8 Wellcome Department of Imaging Neuroscience;
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http://www.fil.ion.ucl.ac.uk/spm/) using the “Segment” module, as previously described (Borroni et al., 2012). All data were smoothed using a 10-mm FWHM Gaussian kernel. Modulated and smoothed GM images were analyzed using a one-way ANOVA design. Age, gender and scanner type were added as covariates of no interest (Zhou et al., 2010). The GM
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maps analysis was also adjusted for the total intracranial volume (ICV=GM volume+white matter volume+cerebrospinal fluid volume).
Contrasts were designed to assess: i) probable bvFTD
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iii) pre-bvFTD subgroup
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correction for multiple comparisons at whole brain level (p<0.05).
Statistical analysis. Baseline demographic characteristics, cognitive and behavioural scores have been compared by One-Way ANOVA and Bonferroni post-hoc comparisons or t-test test, as indicated. Results are expressed as mean ± standard deviation. Data analyses were carried out using SPSS 21.0 software (Chicago, USA).
RESULTS
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ACCEPTED MANUSCRIPT Clinical features. One-hundred ninety-four subjects entered the study. Each patient was followed-up for at least 2 years (range 2-9 years), and probable bvFTD diagnosis made according to FTDC criteria (Rascovsky et al., 2011). According to presenting disease features at first visit, the retrospective analysis allowed us to
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classify 136 out of 194 (70%) patients as probable bvFTD, whilst the other 58 patients (30%) did not. Among these, 35 (60%) fulfilled criteria for possible bvFTD and 23 (40%) did not,
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and were herein considered as pre-bvFTD.
Demographic and clinical baseline characteristics of the three groups, namely probable
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bvFTD, possible bvFTD and pre-bvFTD are shown in Table 1. Age at onset, disease duration from the first symptom, family history, and educational levels did not differ between groups, while lower frequency of female patients was found in possible bvFTD. APOE genotype did no differ among groups. UPDRS-III was higher in probable bvFTD, and as defined by
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inclusion criteria probable bvFTD patients were impaired in ADLs. Neuropsychological performances and behavioral assessment in the three subgroups are shown in Table 2. As expected, probable bvFTD scored worse than the other two groups in
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the most of neuropsychological tests and behavioral scales. Possible bvFTD and pre-bvFTD were comparable in term of cognitive impairment and showed the same pattern of deficits,
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with selective impairment in planning and executive functions; possible bvFTD were more severely affected than pre-bvFTD in terms of behavioral abnormalities.
A more detailed analysis in pre-FTD was carried out. As shown in Figure 2 (panel A), 6 keysymptoms of FTDC criteria were analyzed, and compared to possible bvFTD. In 70% of cases, pre-FTD showed executive deficits (comparable to possible bvFTD), followed by apathy, while the other key features were much less represented. Almost 70% of pre-bvFTD cases fulfilled 2 out of 3 diagnostic features of FTDC criteria (see Figure 2, panel A).
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ACCEPTED MANUSCRIPT Further, in pre-bvFTD, the most frequent behavioral disturbances, beside those included in the standardized criteria, were disorganization, inflexibility, irritability, and loss of insight present in more than 30% of cases (see Figure 2, panel B). These symptoms were also found in possible bvFTD.
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Genetic analyses were carried out retrospectively in the selected genes responsible of
monogenic disease. Two out of 35 possible bvFTD were found to carry of GRN T272SfsX10 mutation, and 3 out of 23 pre-bvFTD were found to carry either GRN (p.Q341X and
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T272SfsX10) or TARDBP (p.M359V) mutations. Nine patients with probable bvFTD at baseline carried the T272SfsX10 GRN mutation, while 3 patients carried the C9orf72
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expansion.
Possible bvFTD developed probable bvFTD within 1.4±0.7 years (range 1-3 years), and prebvFTD developed probable bvFTD within 2.1±1.0 years (range 1-4 years).
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Neuroimaging features. MRI scans for VBM-Analyses were available in 113 subjects, namely 44 probable bvFTD, 19 possible bvFTD, 14 pre-bvFTD, and 36 age and gendermatched healthy controls (HC). In Figure 3, the direct comparison between probable bvFTD
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patient and HC showed a significant diffuse frontotemporal grey matter volume reduction,
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according to previous literature; the same pattern of atrophy was found in those patients fulfilling possible bvFTD criteria, even though with less extent from possible bvFTD to prebvFTD. When pre-bvFTD patients were compared to HC, the left superior temporal gyrus (x, y, z: -62,-2,16, T=5.50, 752 voxels), the left medial frontal gyrus (-2,54,8, T=5.52, 245 voxels) and the right insula (46,-4,4, T=5.20, 143 voxels) resulted more affected. The direct comparisons between pre-bvFTD and possible bvFTD did not show any significant clusters at the pre-established threshold.
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ACCEPTED MANUSCRIPT DISCUSSION Identifying very early phases of FTD is still challenging, even though key-symptoms and neuroimaging features of the disease have been carefully described. Since the first descriptions of circumscribed frontotemporal atrophies (Pick’s Disease), and the first
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diagnostic criteria by the Lund and Manchester groups(Lund and Manchester Groups, 1994; Neary et al., 1998), consensus clinical and pathological criteria for FTD have been
increasingly refined (Pasquier, 2013; Piguet et al., 2009) in order to improve diagnostic
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accuracy. The last FTDC clinical criteria for bvFTD (Rascovsky et al., 2011) have been shown to be the most sensitive, operational and reliable, as confirmed by autopsy series
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(Harris et al., 2013; Rascovsky et al., 2011).
However, identification of the switch from the asymptomatic to the symptomatic predementia phase (pre-bvFTD), or from the predementia phase to dementia onset (probable FTD) is still challenging.
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A crucial role in the development of the concept of prodromal Alzheimer’s disease has been played by the definition of MCI. While this is easily applied to non-memory tests in areas such as language, visuo-spatial perception and executive function, behavioural changes are
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typically assessed with informal clinical evaluation or with rating scales. Impairment on executive tests could potentially be considered as an early marker of bvFTD. This is,
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however, only one of the six core criteria for diagnosis, and is not essential for diagnosis. In addition, the sensitivity and, above all, specificity of executive dysfunction for early bvFTD is very low. This has been confirmed by few longitudinal studies assessing progression towards dementia of non-amnesic MCI, the predictive value of executive dysfunction was towards Dementia with Lewy Bodies rather than FTD (Ferman et al., 2013; Huey et al., 2013). Progress has been made with the introduction of the concept of “mild behavioral impairment” (Taragano et al., 2009). This was defined as a) the presence of a major change in patient behavior; b) the change occurs later in life (>60) and is persistent (>6 months); c) there are no
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ACCEPTED MANUSCRIPT complaint of cognitive impairment by patient/informant; d) normal occupational and social functioning, e) normal activities of daily living, f) absence of dementia. The condition was shown to be a significant risk factor for progression to dementia, in particular of the FTD type (Dillon et al., 2013).
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In the present work, we tried to tailor the mild cognitive/behavioural impairment nosology in the FTD field, herein represented by pre-FTD. To this, we considered a large cohort of
patients with clinically proven bvFTD diagnosis at follow-up, corroborated by neuroimaging
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and cerebrospinal fluid analyses, and we retrospectively analyzed presenting features.
In this cohort, 70% of patients already fulfilled current criteria for probable bvFTD at first
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admission, whereas 30% of the sample had no impairment on ADL. Among these, 60% fulfilled current criteria for possible bvFTD, whereas 40% of cases, termed pre-bvFTD, presented progressive cognitive impairment or behavioural abnormalities, without impact on ADLs and with less than 3 diagnostic features of FTDC criteria. Possible bvFTD and pre-
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bvFTD were comparable in terms of duration of first symptoms (see Table 1), neuropsychological profile (see Table 2), and converted to probable bvFTD within four years from admission (on average 1.4 years in possible bvFTD and 2.1 years in pre-bvFTD). The
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difference between possible bvFTD and pre-bvFTD was found in behavioral disturbances, as the latter group was mainly characterized by a different behavioural abnormality pattern,
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namely characterized by disorganization, logopenia and irritability. Althought a standard neuropsychological battery could not detect typical social cognition and executive/control deficits in early bvFTD (Torralva et al., 2009) we showed cognitive deficits in most prebvFTD and possible FTD. The presence of five patients carrying monogenic mutations in these groups may partly explain this aggressive early cognitive involvement and should be replicated in other groups of patients. Interestingly, some patients presented deficits within language and memory function, besides the “classical” executive dysfunction, as suggested by recent studies (Harris et al., 2013).
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ACCEPTED MANUSCRIPT Overall, these results suggest a number of considerations. A giant step forward has been made in the definition of proper clinical and neuroimaging features of bvFTD, ameliorating diagnostic accuracy. It is however true that early diagnosis of bvFTD is mandatory for prognosis (Chow et al., 2006), implication on heritability (Kumar-Singh and Van
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Broeckhoven, 2007), therapeutic purposes (Boxer et al., 2013), and patient management.
Our retrospective analysis showed that a number of patients with bvFTD still come late at first evaluation, as 70% of subjects already fulfilled probable bvFTD criteria when asking for a
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diagnostic work-up. The other 30% of cases did not have any impact on functional abilities, thus not fulfilling diagnosis of dementia (American Psychiatric Association Committee on
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Nomenclature, 2013, 2000). This early stage was largely represented by patients with possible bvFTD, and to a lesser extent by proper pre-bvFTD patients.
Moreover, the retrospective analysis indicated that FTDC criteria were able to detect the majority of the patients with early bvFTD stages, namely possible bvFTD, though we
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identified a group of patients characterized by less severe behavioural abnormalities and with less extent of frontotemporal atrophy. Indeed, it has to be defined whether possible bvFTD and pre-bvFTD represented two phenotypes of very early disease or these were two stages of
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incipient dementia. The main limitation of the study was to effectively rule out other disorders, as, unfortunately, autopsy data were not available and only a small number of
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patients fulfilled criteria for “definite bvFTD” because of the presence of monogenic mutations. However, we excluded the cases with CSF abeta/tau ratio suggestive for Alzheimer’s disease and no patient developed symptoms indicating an underlying αsynucleinopathy at follow-up. Parkinsonism, usually more relevant in some bvFTD patients during late phases, was also more prominent in probable FTD, compared with possible and pre-bvFTD. The three groups differed in the amount of brain atrophy with the probable bvFTD showing the most extensive cortical atrophy. Even though the direct comparison between pre-FTD and
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ACCEPTED MANUSCRIPT possible bvFTD did not show any statistically significant clusters (likely due to the sample size), the pattern of atrophy in different phases of the disease (Figure 3, panels A-C) supported the idea of a progressive impairment of frontotemporal regions. Interestingly, in pre-bvFTD group there was a higher frequency of female patients compared
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to possible FTD patients. This might be due to a different impact that behavioral and
cognitive impairment associated to the early stages of the disease may exert on women given their different social role and domestic duties. All the above findings suggest that the very
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early phases of bvFTD may be missed by current criteria and diagnosed as psychiatric illness (Rascovsky et al., 2011; Varma et al., 1999), but may convert to probable bvFTD during
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follow-up. These preliminary findings should be, however, confirmed by other retrospective series on other bvFTD populations and longitudinal series evaluating subjects with mild behavioral dysfunction in order to define more specific correlates able to predict the conversion to bvFTD.
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In conclusion, we suggest that early stages of FTD comprised patients fulfilling FTDC criteria for possible bvFTD as well as by subjects with other distinctive disease features, hereby defined as pre-bvFTD. These two groups represent the earliest clinically detectable stage of
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the disease, pre-bvFTD likely antedating possible bvFTD. Criteria defining specific features of pre-bvFTD and new diagnostic markers of early frontotemporal disease would be of great
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importance in the future in order to detect all patients with pre-bvFTD symptoms. Our findings should be validated in prospective studies involving larger samples of patients.
Aknowledgements and study funding: the work was supported by grants of Ministry of University (MURST) to A.P. and B.B
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Seelaar, H., Rohrer, J.D., Pijnenburg, Y.A.L., Fox, N.C., van Swieten, J.C., 2011. Clinical, genetic and pathological heterogeneity of frontotemporal dementia: a review. J. Neurol. Neurosurg. Psychiatry 82, 476–86. doi:10.1136/jnnp.2010.212225 Taragano, F.E., Allegri, R.F., Krupitzki, H., Sarasola, D.R., Serrano, C.M., Loñ, L., Lyketsos, C.G., 2009. Mild behavioral impairment and risk of dementia: a prospective cohort study of 358 patients. J. Clin. Psychiatry 70, 584–92.
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Torralva, T., Roca, M., Gleichgerrcht, E., Bekinschtein, T., Manes, F., 2009. A neuropsychological battery to detect specific executive and social cognitive impairments in early frontotemporal dementia. Brain 132, 1299–309. Varma, A.R., Snowden, J.S., Lloyd, J.J., Talbot, P.R., Mann, D.M., Neary, D., 1999. Evaluation of the NINCDS-ADRDA criteria in the differentiation of Alzheimer’s disease and frontotemporal dementia. J. Neurol. Neurosurg. Psychiatry 66, 184– 8. Warren, J.D., Rohrer, J.D., Rossor, M.N., 2013. Clinical review. Frontotemporal dementia. BMJ 347, f4827. Zhou, J., Greicius, M.D., Gennatas, E.D., Growdon, M.E., Jang, J.Y., Rabinovici, G.D., Kramer, J.H., Weiner, M., Miller, B.L., Seeley, W.W., 2010. Divergent network connectivity changes in behavioural variant frontotemporal dementia and Alzheimer’s disease. Brain 133, 1352–67. doi:10.1093/brain/awq075
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ACCEPTED MANUSCRIPT Table 1. Demographic and clinical characteristics of the retrospective study of probable bvFTD, possible bvFTD and pre-FTD Probable
Possible
Pre
bvFTD
bvFTD
FTD
P
136
35
23
-
Gender, F%
48
23
65
0.003^
Positive family history, %
50
40
Age at onset, years
63.7±7.3
Disease duration, years Education, years
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N
0.28^
62.0±7.2
66.2±8.9
0.12
3.0±2.8
2.3±1.9
2.3±3.0
0.35
7.1±3.1
8.1±3.8
7.1±2.9
0.25
APOE, ε4 %
34.2
21.9
UPDRS-III
11.5±13.0
4.5±7.1
IADLs, lost
3.4±2.3
BADLs, lost
1.4±1.8
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35
0.41^
4.6±6.5
0.006
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33.3
0
0
<0.001
0
0
<0.001
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bvFTD, behavioural variant Frontotemporal Dementia; APOE, Apolipoprotein E; UPDRS, Unified Parkinson’s Disease Rating Scale; IADLs, Instrumental Activities of daily Living; BADLs, Basic Activities of Daily Living. *One-Way ANOVA unless specified; ^Chi-Square-test
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P^
Cut-off*
9.0 ± 7.4 b
<0.001
0
16.1 ± 8.7
6.4 ± 5.2 a,b
<0.001
0
15.2 ± 7.4
9.0 ± 4.9
4.6 ± 3.8 a,b
<0.001
0
8.1 ± 6.7
7.1 ± 5.1
2.0 ± 3.4 a,b
<0.001
0
MMSE
18.7±7.5 (62)
24.6±3.3 (14)
23.5±6.3 (20) b
<0.001
>=24
Clock drawing
4.3±3.0 (67)
6.9±2.2 (51)
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Table 2. Baseline neuropsychological and behavioural assessment in probable bvFTD, possible bvFTD and in pre-bvFTD. Variable
Probable bvFTD
Possible bvFTD
Pre-bvFTD
(n=136)
(n=35)
(n=23)
NPI total score
23.5 ± 14.2
16.6 ± 8.4
FBI total score (AB)
23.3 ± 12.1
FBI A FBI B
5.5±3.1 (42)
<0.001
>8
26.4±6.0 (19)
20.0±7.7 (43)
0.20
>18.85
8.7±5.2 (38)
10.4±6.4 (35)
0.07
>7.5
9.7±6.5 (47)
10.3±8.3 (45)
0.18
>10.3
Non-verbal reasoning Raven Matrices
20.1±8.1 (49)
Memory
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Screening for dementia
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Behavioural abnormalities
7.7±4.6 (62)
Rey Figure, recall
7.8±6.1 (74)
Digit span, backward
4.8±1.4 (31)
5.4±1.2 (3)
5.1±1.5 (14)
0.12
>3.75
19.3±10.7 (80)
26.8±7.0 (64)
22.9±9.6 (73)
0.001
>32
19.6±10.8 (50)
21.2±9.7 (35)
26.2±10.6 (22)
0.04
>17.35
23.1±10.1 (60)
29.0±10.8 (32)
25.5±11.2 (26) b
0.001
>25.0
24.8±7.7 (58)
29.4±4.9 (18)
29.3±3.9 (19) b
0.001
>26.5
Trail Making, A
197.3±174.7 (68)
67.6±119.7 (28)
153.5±169.1 (44)
<0.001
<94
Trail Making, B
338.3±134.3 (84)
230.5±168.1 (62)
307.1±174.1 (70)
0.02
<283
Rey Figure, copy Language Phonological fluency
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Semantic fluency
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Visual-construction
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Short Story
Token test
Executive function
bvFTD: behavioural variant Frontotemporal Dementia; MMSE: Mini-Mental State Examination; FBI: Frontal Behavioral Inventory. ^One-Way ANOVA; *Cut-off cores according to Italian normative data. Results are expressed as mean±standard deviation, percentage of subjects with pathological scores (corrected for age and education) between brackets. Tests with more than 50% of subjects within pathological range are underlined. Statistically significant comparisons
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surviving after Bonferroni post-hoc analysis: a pre-bvFTD vs possible bvFTD, P<0.05; b pre-bvFTD vs probable bvFTD, P<0.05
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ACCEPTED MANUSCRIPT Figure captions
Figure 1. Study design. At first admission each subject with suspected Frontotemporal Dementia underwent a standardised
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protocol, and then was followed-up at least for 2 years. Patients with diagnosis of probable bvFTD at follow-up were considered in the present study, and were retrospectively classified according to first admission features into probable bvFTD, possible and pre-bvFTD. These three subgroups were the
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objective of the present study (see Method section, Study design).
Figure 2. Features of pre-bvFTD as compared to possible bvFTD. Panel A. Percentage of possible bvFTD and pre-bvFTD subjects presenting the key-symptoms of FTDC
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bvFTD criteria (Rascovsky et al., 2011)
Panel B. The most frequent behavioural symptoms (>15%) in pre-bvFTD that are not listed in the current
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FTDC criteria, and in possible bvFTD.
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Figure 3. Neuroimaging correlates of bvFTD groups. Voxel-Based Morphometry analyses in all studied groups versus healthy age-matched controls (HC). Panel A: pattern of grey matter (GM) atrophy in probable bvFTD compared to HC (yellow=p<0.0000005 FWE whole-brain; red=p<0.05 FWE whole brain). Panel B: pattern of GM atrophy in possible bvFTD compared to HC (yellow=p<0.0005 FWE whole-brain; red=p<0.05 FWE whole brain). Panel C: pattern of GM atrophy in pre-bvFTD compared to HC (red= p<0.05 FWE whole brain). All results are superimposed on a 2D standardized T1 reference scan. Red and yellow clusters are related to different statistical threshold L=left, R=right. FWE: Family Wise Error.
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ACCEPTED MANUSCRIPT Highlights
Most bvFTD patients fulfil current diagnostic criteria at disease onset A subgroup of patients not fullfilling bvFTD criteria at baseline was defined as pre-FTD Pre-FTD had frontotemporal grey matter atrophy, even though less extensive than bvFTD
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Pre-FTD showed similar neuropsychological pattern compared to bvFTD
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Some pre-FTD behavioural abnormalities are not listed in current criteria for bvFTD
S0197-4580(15)00379-6
DOI:
10.1016/j.neurobiolaging.2015.07.019
Reference:
NBA 9339
To appear in:
Neurobiology of Aging
Received Date: 20 January 2015 Revised Date:
11 July 2015
Accepted Date: 12 July 2015
Please cite this article as: Borroni, B., Cosseddu, M., Pilotto, A., Premi, E., Archetti, S., Gasparotti, R., Cappa, S., Padovani, A., Early stage of behavioral variant Frontotemporal Dementia: clinical and neuroimaging correlates, Neurobiology of Aging (2015), doi: 10.1016/j.neurobiolaging.2015.07.019. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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ACCEPTED MANUSCRIPT Early stage of behavioral variant Frontotemporal Dementia: clinical and neuroimaging correlates
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B. Borronia, M. Cosseddua, A. Pilottoa, E. Premia, S. Archettib, R. Gasparottic, SF. Cappad, A. Padovania
a
Corresponding Author: Barbara Borroni, MD
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Centre for Ageing Brain and Neurodegenerative Disorders, Neurology Unit, University of Brescia, Italy b III Laboratory of Analyses, Brescia Hospital, Brescia, Italy c Neuroradiology Unit, University of Brescia, Brescia, Italy d Institute for Advanced Study IUSS Pavia, Pavia, Italy
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Neurology Unit, University of Brescia
Piazza Spedali Civili 1, Brescia 25125, Italy
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Email: [email protected]
Word counts: Abstract: 189 words; Text: 4149 words Tables/Figures: 5; Supplementary Material: 0; References: 40
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ACCEPTED MANUSCRIPT ABSTRACT
The early stages of behavioural variant Frontotemporal Dementia (bvFTD) are still not
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completely characterised. In a consecutive series of patients with probable bvFTD diagnosis confirmed by follow-up, we retrospectively evaluated the features at onset. Patients were reclassified according to presenting features and current diagnostic criteria into probable and
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possible bvFTD. The term “pre-bvFTD” was adopted for patients with cognitive and/or
behavioural impairment not fulfilling bvFTD criteria and no deficits in activities of daily
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living. One-hundred ninety four subjects were included; at first visit, 70% (n=136) patients were already classified as probable bvFTD. Of the remaining 30% (n=58), 60% fulfilled criteria for possible bvFTD, while 40% did not, and were classified as pre-FTD. The neuropsychological pattern in possible bvFTD and pre-bvFTD was similar, though possible
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bvFTD showed more behavioural abnormalities. Pre-bvFTD subjects had frontotemporal grey matter atrophy, even though less extensive than possible bvFTD. Conclusively, most bvFTD patients fulfil current diagnostic criteria at first admission, whereas a relatively small group is
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characterized by mild behavioural and/or cognitive abnormalities in spite of frontotemporal grey matter atrophy. Our preliminary findings will require a validation in prospective studies
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involving larger samples of patients.
Keywords: Frontotemporal Dementia; prodromal; behavioural variant Frontotemporal Dementia (bvFTD); MRI; Mild Cognitive Impairment (MCI); behavioural impairment, prebvFTD.
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ADL, activities of daily living APOE, Apolipoprotein E BADLs, Basic Activities of Daily Living
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bvFTD, behavioural variant Frontotemporal Dementia CSF, cerebrospinal fluid
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FBI, Frontal Behavioral Inventory FTD frontotemporal dementia
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Abbreviations:
FTD-modified CDR, Frontotemporal Dementia-modified Clinical Dementia Rating scale FTDC, Frontotemporal Dementia Consortium
GM, gray matter GRN, granulin HC, healthy controls
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FWE, family-wise error
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IADLs, Instrumental Activities of Daily Living MAPT, microtubule associated protein tau
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MCI, Mild Cognitive Impairment
MMSE, Mini-Mental State Examination MRI, magnetic resonance imaging
TARDBP, TDP-43 transactive response DNA-binding protein UPDRS, Unified Parkinson’s Disease Rating Scale VBM, Voxel-based Morphometry
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ACCEPTED MANUSCRIPT INTRODUCTION Frontotemporal dementia (FTD) is the second most frequent form of neurodegenerative earlyonset dementia and is the clinical manifestation of progressive nerve cell loss in the frontal and anterior temporal lobes (Seelaar et al., 2011; Warren et al., 2013). Histopathological
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changes are characterised by protein misfoldings, in most cases either Tau or transactive
response DNA-binding protein (TDP-43) (Rademakers et al., 2012). It is generally considered that there is a phase of frontotemporal disease when individuals experience a gradually
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progressive cognitive decline and behavioural change resulting from the accumulation of pathological protein in the brain. When the cognitive impairment and the behavioural
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abnormalities are sufficiently severe, such that there is interference with activities of daily living (ADL) functions, the patient is diagnosed with FTD.
It is important to note that, as FTD is a progressive disorder with no clear-cut fixed events that indicates its onset, on clinical grounds it is particularly challenging to identify transition
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points for the individual patient. In the realm of dementia, prodromal stages have been largely investigated in order to identify markers of early diagnosis and promptly introduce therapeutic interventions when functional disabilities are not yet present. Thus, Mild Cognitive
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Impairment (MCI) has been proposed as a nosological entity useful to identify subjects at higher risk of developing dementia, thus with likely prodromal disease, suffering from
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cognitive complains but with preserved ADLs (American Psychiatric Association Committee on Nomenclature, 2013, 2000; Petersen et al., 1999). Initially developed to detect prodromal stages of Alzheimer’s disease, MCI term has been extended to subjects progressing to different dementing illnesses. Indeed, different MCI subtypes have been described. Whereas amnestic MCI subjects have higher risk of having prodromal AD, non amnestic MCI or multidomain MCI subjects have higher risk of developing other neurodegenerative dementias, i.e. Dementia with Lewy Bodies or FTD (Ferman et al., 2013; Gauthier et al., 2006; Huey et al., 2013; Petersen and Bennett, 2005). If a large body of literature exists on MCI related to
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ACCEPTED MANUSCRIPT Alzheimer disease pathology, no particular attention has been paid to MCI subjects who have pre-FTD and will develop disease over years. Behavioural variant Frontotemporal Dementia (bvFTD) is characterized by executive dysfunction, behavioral disturbances and personality changes (Kertesz et al., 2005; Seelaar et
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al., 2011).
Applying the definition of dementia status, namely the presence of cognitive deficits that impact on ADLs (American Psychiatric Association Committee on Nomenclature, 2013,
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2000) is still challenging in frontotemporal disease. At early FTD disease stages, patients may present preserved ADLs (Gauthier et al., 2006; Huey et al., 2013; Kertesz et al., 2005), thus
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not satisfying diagnosis of dementia, despite significant behavioural disturbances and executive deficits.
Recently, new revised criteria have been developed by Rascovsky and colleagues (Rascovsky et al., 2011) to increase diagnostic accuracy and to capture the early disease stages of FTD.
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The authors required 3 out of 6 clustered key symptoms to reach possible bvFTD diagnosis, and additional impairment of ADLs and compatible features on neuroimaging to reach probable bvFTD diagnosis. Pathologically confirmed series showed the usefulness of these
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criteria in ameliorating diagnostic sensitivity (Harris et al., 2013; Rascovsky et al., 2011). Notwithstanding this, it is still not clear whether these criteria are effective to detect patients
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in the early stages. This would be mandatory for anticipating diagnosis, avoiding medicolegal problems and ensuring early work retirement. Theoretically, the criteria for possible bvFTD might represent a pre-dementia stage giving the requirement of the absence of functional impairments. However, the requirement of 3 out of 6 core symptoms may exclude very early or atypical cases, thus reducing the possibility of identifying patients with early stages of disease. These premises prompted the present work, aimed at identifying the clinical and neuroimaging features associated with early bvFTD. To this end, we considered a large cohort
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ACCEPTED MANUSCRIPT of patients diagnosed as having probable bvFTD diagnosis at follow-up, on the basis of current clinical criteria, neuroimaging and cerebrospinal fluid analysis (Irwin et al., 2013; Rohrer et al., 2011). In this selected cohort, we retrospectively considered features at disease onset, with the aim to i) assess the clinical and behavioural profile of early stage bvFTD, and
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ii) evaluate the neuroimaging correlates, iii) assess the sensitivity of current diagnostic criteria for bvFTD.
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METHODS
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Patient selection. In the present work, we considered a consecutive series of patients with diagnosis of probable bvFTD at follow-up evaluation (range 2-9 years) recruited from January 2001 to April 2014 at the Centre for Ageing Brain and Neurodegenerative Disorders, University of Brescia, Italy.
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At enrollment and at each year follow-up, patients underwent a general medical and neurological evaluation, and neuropsychological assessment. Moreover, at enrollment, each patient underwent a routine laboratory analysis and brain structural imaging study (magnetic
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resonance imaging, MRI).
The comprehensive neuropsychological and behavioral assessment (Borroni et al., 2007)
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included Basic Activities of Daily Living (BADL) and Instrumental Activities of Daily Living (IADL) (Katz et al., 1970; Lawton and Brody, 1969) to test functional abilities. The neuropsychological testing was performed by a standardized neuropsychological battery including Mini-Mental State Examination (MMSE), Raven Colored Progressive Matrices, Controlled Oral Word Association Test and Category Fluency, Clock Drawing Test, Rey Complex Figure Copy and Recall, Story Recall Test, Digit Span, Trail Making Test A and B, Token Test, and De Renzi Imitation Test (Lezak et al., 2012). Frontotemporal Dementiamodified Clinical Dementia Rating scale (FTD-modified CDR) was not available for all the
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ACCEPTED MANUSCRIPT subjects as introduced only in 2008 (Knopman et al., 2008). Behavioral disturbances were evaluated by Frontal Behavioral Inventory (Kertesz et al., 1997) and Neuropsychiatry Inventory (Cummings et al., 1994). Patients were also screened for the most common monogenic forms, namely granulin (GRN),
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microtubule associated protein tau (MAPT), 43-kDa transactive response-DNA-binding
protein (TARDBP) and C9orf72 hexanucleotyde expansion, and genotyped for APOE allelic variations, as already reported (Premi et al., 2012). No patient with already known family
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history of monogenic disease was included in the present study.
Stringent exclusion criteria were applied as follows: 1) cerebrovascular disorders, previous
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stroke, normal pressure hydrocephalus, and intra-cranial mass documented by MRI; 2) diagnosis of other type of neurodegenerative disorders; 3) diagnosis of amnestic MCI and cerebrospinal fluid (CSF) /imaging pattern typical for Alzheimer’s Disease (Albert et al., 2011; Dubois et al., 2014) 4) other neurological disorders or significant medical problems (i.e.
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hepatic or renal failure, chronic respiratory insufficiency) potentially responsible for encephalopathy; or 5) bipolar disorder, schizophrenia, substance abuse disorder or mental retardation according to criteria of the DSM-IV.
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Each patient has been followed-up for at least 2 years, and those with diagnosis agreement between two experienced neurologist (B.B. and A.P.), fulfilling probable bvFTD criteria were
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included in the present study. An age-matched group of healthy controls (HC) recruited from spouses or caregivers was introduced for imaging comparisons (n=36, mean age 61.7 + 7.3 years, female 72.2 %). Each HC underwent a brief evaluation of global cognition, which was unremarkable (MMSE>=27/30, preserved IADL and BADL).
Study design. This is a retrospective study aimed at assessing pre-FTD features.
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ACCEPTED MANUSCRIPT As shown in Figure 1, patients with neurodegenerative frontal syndrome were consecutively enrolled and underwent an extensive work-up (n=220). These patients were periodically followed up for at least two years (range 2-9 years), and only those with final diagnosis of probable bvFTD diagnosis were considered in the present study (n=194). Probable bvFTD
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diagnosis was made according to current clinical criteria, with supporting neuroimaging
features of bvFTD. Cerebrospinal fluid (CSF) Abeta/Tau ratio suggestive for AD pathology (3/67 analyses) was considered an adjunctive exclusion criterion (Bian et al., 2008; Padovani
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et al., 2013); patients with any clinical diagnosis other than probable bvFTD at follow-up (n=6) and patients with clinical follow-up evaluation not available (n=17) were not included
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in the present study.
These selected patients were retrospectively classified according to features presented at first admission/baseline. Probable bvFTD diagnosis was made according to current Frontotemporal Dementia Consortium (FTDC) criteria (Rascovsky et al., 2011), in those
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patients with at least 3 out of 6 key-symptoms of current clinical criteria (behavioural disinhibition, apathy/inertia, loss of sympathy/empathy, perseverative/compulsive behavior, hyperorality/dietary changes, and executive deficits), and functional impairment (as measured
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by IADLs and BADLs (Katz et al., 1970; Lawton and Brody, 1969), whilst possible FTD was made in those patients with no impairment in the ADLs.
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An analysis of the clinical features, however, indicated that a subgroup of patients did not fit into the possible bvFTD criteria (at least 3 out of 6 key features). This group of subjects who had less than 3 key-symptoms and preserved ADL was defined as pre-bvFTD. In these subgroups, the characteristics and neuroimaging correlates were assessed.
MRI Acquisition. Over the years of recruitment, 113 images were collected and obtained using two different MR scanners: a) 1.5 T MR scanner (Siemens Symphony, Erlangen, Germany), equipped with a circularly polarized transmit-receive coil to acquire 3D
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ACCEPTED MANUSCRIPT magnetization–prepared rapid gradient echo (MPRAGE) T1-weighted scan (TR=2010 ms, TE=3.93 ms, Matrix=1x1x1x, in-plane field of view FOV=250x250 mm2, slice thickness=1 mm, flip angle =15°); and b) 1.5 T MR scanner (Siemens Avanto, Erlangen, Germany) to acquire 3D MPRAGE T1-weighted scan (TR=2050 ms, TE=2.56 ms, Matrix=1x1x1x, in-
subjects underwent brain MRI by scanner 1 and 46 by scanner 2.
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plane field of view FOV=256x256 mm2, slice thickness=1 mm, flip angle =15°). Sixty-seven
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Voxel-based Morphometry (VBM). MPRAGE data were processed using the VBM protocol in Statistical Parametric Mapping 8 (SPM8 Wellcome Department of Imaging Neuroscience;
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http://www.fil.ion.ucl.ac.uk/spm/) using the “Segment” module, as previously described (Borroni et al., 2012). All data were smoothed using a 10-mm FWHM Gaussian kernel. Modulated and smoothed GM images were analyzed using a one-way ANOVA design. Age, gender and scanner type were added as covariates of no interest (Zhou et al., 2010). The GM
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maps analysis was also adjusted for the total intracranial volume (ICV=GM volume+white matter volume+cerebrospinal fluid volume).
Contrasts were designed to assess: i) probable bvFTD
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iii) pre-bvFTD subgroup
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correction for multiple comparisons at whole brain level (p<0.05).
Statistical analysis. Baseline demographic characteristics, cognitive and behavioural scores have been compared by One-Way ANOVA and Bonferroni post-hoc comparisons or t-test test, as indicated. Results are expressed as mean ± standard deviation. Data analyses were carried out using SPSS 21.0 software (Chicago, USA).
RESULTS
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ACCEPTED MANUSCRIPT Clinical features. One-hundred ninety-four subjects entered the study. Each patient was followed-up for at least 2 years (range 2-9 years), and probable bvFTD diagnosis made according to FTDC criteria (Rascovsky et al., 2011). According to presenting disease features at first visit, the retrospective analysis allowed us to
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classify 136 out of 194 (70%) patients as probable bvFTD, whilst the other 58 patients (30%) did not. Among these, 35 (60%) fulfilled criteria for possible bvFTD and 23 (40%) did not,
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and were herein considered as pre-bvFTD.
Demographic and clinical baseline characteristics of the three groups, namely probable
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bvFTD, possible bvFTD and pre-bvFTD are shown in Table 1. Age at onset, disease duration from the first symptom, family history, and educational levels did not differ between groups, while lower frequency of female patients was found in possible bvFTD. APOE genotype did no differ among groups. UPDRS-III was higher in probable bvFTD, and as defined by
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inclusion criteria probable bvFTD patients were impaired in ADLs. Neuropsychological performances and behavioral assessment in the three subgroups are shown in Table 2. As expected, probable bvFTD scored worse than the other two groups in
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the most of neuropsychological tests and behavioral scales. Possible bvFTD and pre-bvFTD were comparable in term of cognitive impairment and showed the same pattern of deficits,
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with selective impairment in planning and executive functions; possible bvFTD were more severely affected than pre-bvFTD in terms of behavioral abnormalities.
A more detailed analysis in pre-FTD was carried out. As shown in Figure 2 (panel A), 6 keysymptoms of FTDC criteria were analyzed, and compared to possible bvFTD. In 70% of cases, pre-FTD showed executive deficits (comparable to possible bvFTD), followed by apathy, while the other key features were much less represented. Almost 70% of pre-bvFTD cases fulfilled 2 out of 3 diagnostic features of FTDC criteria (see Figure 2, panel A).
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ACCEPTED MANUSCRIPT Further, in pre-bvFTD, the most frequent behavioral disturbances, beside those included in the standardized criteria, were disorganization, inflexibility, irritability, and loss of insight present in more than 30% of cases (see Figure 2, panel B). These symptoms were also found in possible bvFTD.
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Genetic analyses were carried out retrospectively in the selected genes responsible of
monogenic disease. Two out of 35 possible bvFTD were found to carry of GRN T272SfsX10 mutation, and 3 out of 23 pre-bvFTD were found to carry either GRN (p.Q341X and
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T272SfsX10) or TARDBP (p.M359V) mutations. Nine patients with probable bvFTD at baseline carried the T272SfsX10 GRN mutation, while 3 patients carried the C9orf72
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expansion.
Possible bvFTD developed probable bvFTD within 1.4±0.7 years (range 1-3 years), and prebvFTD developed probable bvFTD within 2.1±1.0 years (range 1-4 years).
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Neuroimaging features. MRI scans for VBM-Analyses were available in 113 subjects, namely 44 probable bvFTD, 19 possible bvFTD, 14 pre-bvFTD, and 36 age and gendermatched healthy controls (HC). In Figure 3, the direct comparison between probable bvFTD
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patient and HC showed a significant diffuse frontotemporal grey matter volume reduction,
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according to previous literature; the same pattern of atrophy was found in those patients fulfilling possible bvFTD criteria, even though with less extent from possible bvFTD to prebvFTD. When pre-bvFTD patients were compared to HC, the left superior temporal gyrus (x, y, z: -62,-2,16, T=5.50, 752 voxels), the left medial frontal gyrus (-2,54,8, T=5.52, 245 voxels) and the right insula (46,-4,4, T=5.20, 143 voxels) resulted more affected. The direct comparisons between pre-bvFTD and possible bvFTD did not show any significant clusters at the pre-established threshold.
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ACCEPTED MANUSCRIPT DISCUSSION Identifying very early phases of FTD is still challenging, even though key-symptoms and neuroimaging features of the disease have been carefully described. Since the first descriptions of circumscribed frontotemporal atrophies (Pick’s Disease), and the first
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diagnostic criteria by the Lund and Manchester groups(Lund and Manchester Groups, 1994; Neary et al., 1998), consensus clinical and pathological criteria for FTD have been
increasingly refined (Pasquier, 2013; Piguet et al., 2009) in order to improve diagnostic
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accuracy. The last FTDC clinical criteria for bvFTD (Rascovsky et al., 2011) have been shown to be the most sensitive, operational and reliable, as confirmed by autopsy series
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(Harris et al., 2013; Rascovsky et al., 2011).
However, identification of the switch from the asymptomatic to the symptomatic predementia phase (pre-bvFTD), or from the predementia phase to dementia onset (probable FTD) is still challenging.
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A crucial role in the development of the concept of prodromal Alzheimer’s disease has been played by the definition of MCI. While this is easily applied to non-memory tests in areas such as language, visuo-spatial perception and executive function, behavioural changes are
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typically assessed with informal clinical evaluation or with rating scales. Impairment on executive tests could potentially be considered as an early marker of bvFTD. This is,
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however, only one of the six core criteria for diagnosis, and is not essential for diagnosis. In addition, the sensitivity and, above all, specificity of executive dysfunction for early bvFTD is very low. This has been confirmed by few longitudinal studies assessing progression towards dementia of non-amnesic MCI, the predictive value of executive dysfunction was towards Dementia with Lewy Bodies rather than FTD (Ferman et al., 2013; Huey et al., 2013). Progress has been made with the introduction of the concept of “mild behavioral impairment” (Taragano et al., 2009). This was defined as a) the presence of a major change in patient behavior; b) the change occurs later in life (>60) and is persistent (>6 months); c) there are no
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ACCEPTED MANUSCRIPT complaint of cognitive impairment by patient/informant; d) normal occupational and social functioning, e) normal activities of daily living, f) absence of dementia. The condition was shown to be a significant risk factor for progression to dementia, in particular of the FTD type (Dillon et al., 2013).
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In the present work, we tried to tailor the mild cognitive/behavioural impairment nosology in the FTD field, herein represented by pre-FTD. To this, we considered a large cohort of
patients with clinically proven bvFTD diagnosis at follow-up, corroborated by neuroimaging
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and cerebrospinal fluid analyses, and we retrospectively analyzed presenting features.
In this cohort, 70% of patients already fulfilled current criteria for probable bvFTD at first
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admission, whereas 30% of the sample had no impairment on ADL. Among these, 60% fulfilled current criteria for possible bvFTD, whereas 40% of cases, termed pre-bvFTD, presented progressive cognitive impairment or behavioural abnormalities, without impact on ADLs and with less than 3 diagnostic features of FTDC criteria. Possible bvFTD and pre-
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bvFTD were comparable in terms of duration of first symptoms (see Table 1), neuropsychological profile (see Table 2), and converted to probable bvFTD within four years from admission (on average 1.4 years in possible bvFTD and 2.1 years in pre-bvFTD). The
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difference between possible bvFTD and pre-bvFTD was found in behavioral disturbances, as the latter group was mainly characterized by a different behavioural abnormality pattern,
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namely characterized by disorganization, logopenia and irritability. Althought a standard neuropsychological battery could not detect typical social cognition and executive/control deficits in early bvFTD (Torralva et al., 2009) we showed cognitive deficits in most prebvFTD and possible FTD. The presence of five patients carrying monogenic mutations in these groups may partly explain this aggressive early cognitive involvement and should be replicated in other groups of patients. Interestingly, some patients presented deficits within language and memory function, besides the “classical” executive dysfunction, as suggested by recent studies (Harris et al., 2013).
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ACCEPTED MANUSCRIPT Overall, these results suggest a number of considerations. A giant step forward has been made in the definition of proper clinical and neuroimaging features of bvFTD, ameliorating diagnostic accuracy. It is however true that early diagnosis of bvFTD is mandatory for prognosis (Chow et al., 2006), implication on heritability (Kumar-Singh and Van
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Broeckhoven, 2007), therapeutic purposes (Boxer et al., 2013), and patient management.
Our retrospective analysis showed that a number of patients with bvFTD still come late at first evaluation, as 70% of subjects already fulfilled probable bvFTD criteria when asking for a
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diagnostic work-up. The other 30% of cases did not have any impact on functional abilities, thus not fulfilling diagnosis of dementia (American Psychiatric Association Committee on
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Nomenclature, 2013, 2000). This early stage was largely represented by patients with possible bvFTD, and to a lesser extent by proper pre-bvFTD patients.
Moreover, the retrospective analysis indicated that FTDC criteria were able to detect the majority of the patients with early bvFTD stages, namely possible bvFTD, though we
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identified a group of patients characterized by less severe behavioural abnormalities and with less extent of frontotemporal atrophy. Indeed, it has to be defined whether possible bvFTD and pre-bvFTD represented two phenotypes of very early disease or these were two stages of
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incipient dementia. The main limitation of the study was to effectively rule out other disorders, as, unfortunately, autopsy data were not available and only a small number of
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patients fulfilled criteria for “definite bvFTD” because of the presence of monogenic mutations. However, we excluded the cases with CSF abeta/tau ratio suggestive for Alzheimer’s disease and no patient developed symptoms indicating an underlying αsynucleinopathy at follow-up. Parkinsonism, usually more relevant in some bvFTD patients during late phases, was also more prominent in probable FTD, compared with possible and pre-bvFTD. The three groups differed in the amount of brain atrophy with the probable bvFTD showing the most extensive cortical atrophy. Even though the direct comparison between pre-FTD and
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ACCEPTED MANUSCRIPT possible bvFTD did not show any statistically significant clusters (likely due to the sample size), the pattern of atrophy in different phases of the disease (Figure 3, panels A-C) supported the idea of a progressive impairment of frontotemporal regions. Interestingly, in pre-bvFTD group there was a higher frequency of female patients compared
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to possible FTD patients. This might be due to a different impact that behavioral and
cognitive impairment associated to the early stages of the disease may exert on women given their different social role and domestic duties. All the above findings suggest that the very
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early phases of bvFTD may be missed by current criteria and diagnosed as psychiatric illness (Rascovsky et al., 2011; Varma et al., 1999), but may convert to probable bvFTD during
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follow-up. These preliminary findings should be, however, confirmed by other retrospective series on other bvFTD populations and longitudinal series evaluating subjects with mild behavioral dysfunction in order to define more specific correlates able to predict the conversion to bvFTD.
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In conclusion, we suggest that early stages of FTD comprised patients fulfilling FTDC criteria for possible bvFTD as well as by subjects with other distinctive disease features, hereby defined as pre-bvFTD. These two groups represent the earliest clinically detectable stage of
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the disease, pre-bvFTD likely antedating possible bvFTD. Criteria defining specific features of pre-bvFTD and new diagnostic markers of early frontotemporal disease would be of great
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importance in the future in order to detect all patients with pre-bvFTD symptoms. Our findings should be validated in prospective studies involving larger samples of patients.
Aknowledgements and study funding: the work was supported by grants of Ministry of University (MURST) to A.P. and B.B
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ACCEPTED MANUSCRIPT Table 1. Demographic and clinical characteristics of the retrospective study of probable bvFTD, possible bvFTD and pre-FTD Probable
Possible
Pre
bvFTD
bvFTD
FTD
P
136
35
23
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Gender, F%
48
23
65
0.003^
Positive family history, %
50
40
Age at onset, years
63.7±7.3
Disease duration, years Education, years
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N
0.28^
62.0±7.2
66.2±8.9
0.12
3.0±2.8
2.3±1.9
2.3±3.0
0.35
7.1±3.1
8.1±3.8
7.1±2.9
0.25
APOE, ε4 %
34.2
21.9
UPDRS-III
11.5±13.0
4.5±7.1
IADLs, lost
3.4±2.3
BADLs, lost
1.4±1.8
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0.41^
4.6±6.5
0.006
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0
0
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0
0
<0.001
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P^
Cut-off*
9.0 ± 7.4 b
<0.001
0
16.1 ± 8.7
6.4 ± 5.2 a,b
<0.001
0
15.2 ± 7.4
9.0 ± 4.9
4.6 ± 3.8 a,b
<0.001
0
8.1 ± 6.7
7.1 ± 5.1
2.0 ± 3.4 a,b
<0.001
0
MMSE
18.7±7.5 (62)
24.6±3.3 (14)
23.5±6.3 (20) b
<0.001
>=24
Clock drawing
4.3±3.0 (67)
6.9±2.2 (51)
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Table 2. Baseline neuropsychological and behavioural assessment in probable bvFTD, possible bvFTD and in pre-bvFTD. Variable
Probable bvFTD
Possible bvFTD
Pre-bvFTD
(n=136)
(n=35)
(n=23)
NPI total score
23.5 ± 14.2
16.6 ± 8.4
FBI total score (AB)
23.3 ± 12.1
FBI A FBI B
5.5±3.1 (42)
<0.001
>8
26.4±6.0 (19)
20.0±7.7 (43)
0.20
>18.85
8.7±5.2 (38)
10.4±6.4 (35)
0.07
>7.5
9.7±6.5 (47)
10.3±8.3 (45)
0.18
>10.3
Non-verbal reasoning Raven Matrices
20.1±8.1 (49)
Memory
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RI PT
Behavioural abnormalities
7.7±4.6 (62)
Rey Figure, recall
7.8±6.1 (74)
Digit span, backward
4.8±1.4 (31)
5.4±1.2 (3)
5.1±1.5 (14)
0.12
>3.75
19.3±10.7 (80)
26.8±7.0 (64)
22.9±9.6 (73)
0.001
>32
19.6±10.8 (50)
21.2±9.7 (35)
26.2±10.6 (22)
0.04
>17.35
23.1±10.1 (60)
29.0±10.8 (32)
25.5±11.2 (26) b
0.001
>25.0
24.8±7.7 (58)
29.4±4.9 (18)
29.3±3.9 (19) b
0.001
>26.5
Trail Making, A
197.3±174.7 (68)
67.6±119.7 (28)
153.5±169.1 (44)
<0.001
<94
Trail Making, B
338.3±134.3 (84)
230.5±168.1 (62)
307.1±174.1 (70)
0.02
<283
Rey Figure, copy Language Phonological fluency
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Short Story
Token test
Executive function
bvFTD: behavioural variant Frontotemporal Dementia; MMSE: Mini-Mental State Examination; FBI: Frontal Behavioral Inventory. ^One-Way ANOVA; *Cut-off cores according to Italian normative data. Results are expressed as mean±standard deviation, percentage of subjects with pathological scores (corrected for age and education) between brackets. Tests with more than 50% of subjects within pathological range are underlined. Statistically significant comparisons
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surviving after Bonferroni post-hoc analysis: a pre-bvFTD vs possible bvFTD, P<0.05; b pre-bvFTD vs probable bvFTD, P<0.05
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Figure 1. Study design. At first admission each subject with suspected Frontotemporal Dementia underwent a standardised
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protocol, and then was followed-up at least for 2 years. Patients with diagnosis of probable bvFTD at follow-up were considered in the present study, and were retrospectively classified according to first admission features into probable bvFTD, possible and pre-bvFTD. These three subgroups were the
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objective of the present study (see Method section, Study design).
Figure 2. Features of pre-bvFTD as compared to possible bvFTD. Panel A. Percentage of possible bvFTD and pre-bvFTD subjects presenting the key-symptoms of FTDC
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Panel B. The most frequent behavioural symptoms (>15%) in pre-bvFTD that are not listed in the current
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FTDC criteria, and in possible bvFTD.
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Figure 3. Neuroimaging correlates of bvFTD groups. Voxel-Based Morphometry analyses in all studied groups versus healthy age-matched controls (HC). Panel A: pattern of grey matter (GM) atrophy in probable bvFTD compared to HC (yellow=p<0.0000005 FWE whole-brain; red=p<0.05 FWE whole brain). Panel B: pattern of GM atrophy in possible bvFTD compared to HC (yellow=p<0.0005 FWE whole-brain; red=p<0.05 FWE whole brain). Panel C: pattern of GM atrophy in pre-bvFTD compared to HC (red= p<0.05 FWE whole brain). All results are superimposed on a 2D standardized T1 reference scan. Red and yellow clusters are related to different statistical threshold L=left, R=right. FWE: Family Wise Error.
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Most bvFTD patients fulfil current diagnostic criteria at disease onset A subgroup of patients not fullfilling bvFTD criteria at baseline was defined as pre-FTD Pre-FTD had frontotemporal grey matter atrophy, even though less extensive than bvFTD
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Pre-FTD showed similar neuropsychological pattern compared to bvFTD
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Some pre-FTD behavioural abnormalities are not listed in current criteria for bvFTD