Abstract
Frontotemporal dementia (FTD) is characterized by executive dysfunctions, behavioral disturbances, language deficits and extrapyramidal symptoms. Frontotemporal lobar degeneration-modified Clinical Dementia Rating Scale (FTLD modified-CDR) has been proposed to measure disease severity in behavioral variant FTD (bvFTD). No tools of global disease severity are available in the other FTLD phenotypes [primary progressive aphasias (PPAs), progressive supranuclear palsy (PSP), and corticobasal syndrome (CBS)]. This would be strategic as outcome measures in clinical trials. To this aim, we evaluated the association between brain volume (voxel based morphometry) and available clinical scales in FTD. In 176 FTD patients (64 bvFTD, 40 PPAs, 32 PSP, 40 CBS), instrumental activities of daily living (ADLs), FTLD-modified CDR, Mini-Mental State Examination (MMSE), Frontal Behavioral Inventory (FBI), and Neuropsychiatry Inventory (NPI) were administered and MRI performed. Whole-brain linear correlation between each clinical rating scale and brain volume was performed. In bvFTD and PPAs, FTLD-modified CDR was associated with regional brain volume, thereby providing evidence for validity of the FTLD-modified CDR. In PSP, none of the clinical indicators were associated with regional brain volume. In CBS, ADLs and MMSE correlated with frontotemporal lower volume. Considering monogenic disease, FTLD-modified CDR was the best measure. In FTD continuum, different measures able to correlate with brain damage should be considered for the different clinical phenotypes or genetic traits.
Keywords
INTRODUCTION
Frontotemporal dementia (FTD) represents a continuum of clinically heterogeneous conditions, primarily characterized by behavioral abnormalities, language disturbances, and executive dysfunctions [1]. Moreover, in a number of cases parkinsonism and motor neuron disease may be observed.
Even considering the clinical phenotypes of FTD spectrum individually, the clinical picture is widely variable. In behavioral variant FTD (bvFTD), behavioral disturbances and executive impairment are predominant, while in primary progressive aphasias (PPAs) severe language deficits represent the key associated symptoms. Furthermore, in corticobasal syndrome (CBS) and progressive supranuclear palsy (PSP), which are often considered under the same label of FTD, extrapyramidal features and cognitive decline are consistent [2 –5].
In FTD, to overcome the heterogeneous picture [2 , 7], the Clinical Dementia Rating for FTD (FTLD-modified CDR) has been developed, considering behavioral disturbances and language impairment as additional items to the CDR scale [8]. The FTLD-modified CDR has been demonstrated to measure disease progression in a multicenter longitudinal study [8] and its scores correlate with frontotemporal hypoperfusion [9] in both bvFTD and PPA. However, no data on bvFTD and PPA, considered as individual subgroups, and in the other clinical phenotypes, i.e., CBS and PSP, are available yet.
Nevertheless, the feasibility of the other clinical scales widely used on clinical grounds, and the comparison of each other to assess the best global rating measure in the context of FTD continuum, have not been tested.
On the basis of clinical trial inclusion criteria, we might need either clinical markers useful in different FTD subtypes simultaneously, as well as in a single specific clinical phenotype [8]. Indeed, clinical trials targeting genetic trait or pathogenic background will include patients with different clinical phenotypes, while those on clinical or behavioral symptoms will include patients with unique phenotypes.
In the present work, we aimed to explore the role of clinical and functional scales as markers of brain volume reduction in the FTLD spectrum. In a complex disease like FTD, a number of variables are implied in determining disease severity at each stage, as well as the progression of the disease. The association between the score of a clinical scale (like FTLD-modified CDR) and the neuroimaging alterations is not enough to explain (and to represent) all this complexity but, as in the case of FTLD-modified CDR, the presence of a significant correlation with neuroimaging alterations strengthened the potential role of FTLD-modified CDR in FTD. From this point of view, this correlation itself could be considered as a surrogate marker in testing other potentially useful clinical scales, as well as a tool to explore damage modulation in the different stages of the disease, even using a cross-sectional framework [10 –12]. To this end, in a large sample of FTD patients, grouped according to each clinical phenotype, we evaluated the correlation between grey matter (GM) density by means of voxel-based morphometry (VBM) and a) scales of functional impairment, i.e., basic activity of daily living (BADL) and instrumental activity of daily living (IADL); b) scales of global cognitive impairment, i.e., FTLD-modified CDR and Mini-Mental State Examination (MMSE); and c) scales of behavioral disturbances, i.e., Frontal Behavioral Inventory (FBI) and Neuropsychiatric Inventory (NPI).
METHODS
Subjects
Subjects entering the present study were recruited from the Centre for Ageing Brain and Neurodegenerative Disorders at University of Brescia (Brescia, Italy). The studied sample included 176 FTD patients, namely 64 with a diagnosis of probable bvFTD [2], 40 with PPAs (28 agrammatic variant PPA and 12 semantic variant PPA) [3]), 40 patients with a diagnosis of CBS [4] and 32 patients diagnosed with PSP [5].
Patients were also screened for the most common monogenic forms, namely granulin (GRN), microtubule associated protein tau (MAPT), 43-kDa transactive response-DNA-binding protein (TARDBP), and C9orf72 hexanucleotide expansion, as already reported [13].
Stringent exclusion criteria were applied as follows: 1) cerebrovascular disorders, previous stroke, normal pressure hydrocephalus, and intra-cranial mass documented by MRI; 2) diagnosis of other types of neurodegenerative disorders; 3) diagnosis of amnestic mild cognitive impairment and cerebrospinal/imaging pattern typical for AD [14, 15]; 4) other neurological disorders or significant medical problems (i.e., 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.
Written informed consent (from the subject or from the responsible guardian if the subject was incapable, as demonstrated by clinical and neuropsychological evaluation, showing functional impairment in ADL) was obtained, for each procedure, before study initiation, including MRI scanning. The research protocol has been approved by the Ethics Committee of the Brescia Hospital, Brescia, Italy. The work was conformed to the Helsinki Declaration.
Clinical and behavioral assessment
Each patient underwent evaluation of functional impairment by BADL, a 6 item-scale considering the impairment in self-care activities (i.e., bathing and showering, dressing, personal hygiene, functional mobility, continence, eating) [16] and IADL, a 8-item scale that measures the ability to perform instrumental activities related to daily life (i.e., using telephone, going shopping, food preparation, housekeeping, laundry, mode of transportation, responsibility for own medications, ability to handle finances) [17]. When considering IADLs, we took into account the gender effect, thus defining the number of IADLs lost out of the number of IADLs performed. As indexes of global cognitive impairment, we used FTLD-modified CDR [8] and MMSE [18], and to measure behavioral disturbances, we considered FBI [19] and NPI [20] scales.
MRI acquisition
In the present study, 176 images were collected 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 magnetization–prepared rapid gradient echo (MPRAGE) T1-weighted scan (TR = 2010 ms, TE = 3.93 ms, Matrix = 1×1×1×, in-plane field of view FOV = 250×250 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 = 1×1×1×, in-plane field of view FOV = 256×256 mm2, slice thickness = 1 mm, flip angle = 15°). One-hundred nineteen subjects underwent brain MRI by scanner 1 and 57 by scanner 2.
Voxel-based morphometry
MPRAGE data were processed using the VBM protocol in Statistical Parametric Mapping 8 (SPM8 Wellcome Department of Imaging Neuroscience; http://www.fil.ion.ucl.ac.uk/spm/) using the “Segment” module, as previously described [21]. All data were smoothed using a 10-mm FWHM Gaussian kernel. We considered clinical scale scores to test the association with brain volume in FTLD. At this purpose, we performed a whole-brain linear correlation analysis (Multiple Regression) between each clinical rating scale and modulated and smoothed GM density images. Age, gender, scanner type, and educational level (as years of formal schooling) were entered as nuisance variables; the total intracranial volume (TIV) (GM volume + white matter volume + cerebrospinal fluid volume) was included as global regressor in the statistical design. The presence of at least one significant cluster (considering two different statistical threshold: 1) p < 0.001 uncorrected, FWE 0.05 cluster level, voxel threshold = 200 voxels; and 2) p < 0.05 FWE whole brain), in regions usually impaired in the different clinical FTLD phenotypes was used as criterion to define good performance of the selected scale in depicting the association with a reduced brain volume, considering two different threshold to underline the strength of the correlation even at the highest whole-brain statistical threshold (FWE 0.05 whole-brain) [22, 23].
Statistical analysis
SPSS package (v. 17.0, Chicago, IL, USA) was employed to run statistics for group differences in demographic and clinical characteristics. Group comparisons were assessed by One-Way ANOVA for continuous variables and by Kruskal-Wallis forcategorical variables, setting the statistical threshold to p-values Bonferroni’s corrected≤0.05 for post-hoc analysis (One-Way ANOVA) and to p < 0.05 for pairwise comparisons after Kruskal-Wallis test.
RESULTS
Subjects
In Table 1, the demographic and clinical characteristics of FTD patients were reported. In line with literature data, PSP and CBS were older compared to the other groups. Furthermore, CBS had the longest disease duration. bvFTD and PPA had the highest number of cases with positive family history for dementia, as well as the highest number of cases with monogenic disease. Twenty-three patients carried GRN mutations (14 bvFTD, 7 PPAs, and 2 CBS), 2 had TARDBP mutations (bvFTD), and 1 carried C9orf72 expansion (bvFTD).
bvFTD and PPA were more impaired than the other groups.
MRI analyses
The patterns of brain volume reduction in each clinical phenotype, when compared to a group of healthy volunteers (n = 32, age: 64.1±7.1 years, % female: 65.6%), resembled those reported in the current literature (see Supplementary Figure 1), and it was consistent with bilateral frontotemporal lower brain volume in bvFTD, and left predominance in PPAs. CBS patients showed greater involvement of motor and premotor cortex, bilaterally, whereas PSP patients showed widespread lower brain volume in cortical and subcortical regions, especially in frontotemporal areas.
In bvFTD group, all scales but MMSE showed significant association with lower GM volume in frontotemporal regions, mainly on the right side (p < 0.05 FWE whole brain, Figs. 1 and 2).
In PPA patients, only FTLD-modified CDR scale correlated with lower brain volume in the left inferior frontal gyrus (see Figs. 1 and 3).
In CBS, a significant correlation between BADL and MMSE and GM lower brain volume in frontotemporal regions was reported (see Figs. 1 and 3).
The aforementioned correlation analysis in PPA and CBS was obtained using a less stringent threshold (p < 0.001, FWE cluster-level), due to the lower number of patients.
No significant correlation between any of the studied scales and GM lower brain volume was detected in PSP.
Then, to identify the proper measure to be used in trials targeting genetic traits, we considered patients with GRN mutations (n = 23; 14 bvFTD, 7 PPA, 2 CBS). As shown in Fig. 4, the best marker of brain volume was the FTLD-modified CDR; even measures of functional impairment, i.e., IADLs and BADLs, were significantly correlated with frontotemporal lower brain volume.
DISCUSSION
In the present work, we aimed at assessing possible clinical markers of brain volume reduction in the FTD continuum to be used in pharmacological and non-pharmacological trials. To this end, we evaluated the relationship between the lower volume in the key-regions involved in FTD and the clinical rating scale scores used in clinical practice [9]. As future clinical trials in FTD might target either the key-clinical symptoms of each phenotype or the molecular bases of underlying pathogenic mechanism, we considered both.
In a large group of patients, encompassing all the clinical phenotypes, we were able to test the correlation of functional, cognitive, and behavioral clinical rating scales and the structural damage in the most affected regions of the FTD spectrum. As demonstrated in Fig. 1, in bvFTD all scales with the exception of MMSE presented a good correlation with frontotemporal lower brain volume. Otherwise, in PPAs only FTLD-modified CDR was able to significantly detect brain volume reduction [8, 9].
Thus, considering both bvFTD and PPAs and the high degree of correlation with the specific key-regions of each phenotype, FTLD-modified CDR may be considered the best measure to set brain volume modulation in both. Notwithstanding, in the other phenotypes belonging to the FTD spectrum, FTLD-modified CDR was not found a reliable measure of brain damage. In CBS, the functional impairment as measured by BADLs was strictly correlated with the brain structural damage, and MMSE scores significantly correlated with a well-defined pattern of frontotemporal regions only in this group, as already reported [24, 25].
Interestingly, ADLs (BADL and/or IADL) correlated with neuroanatomical alterations only in bvFTD and CBS, where cognitive, behavioral, and motor symptoms were all present, rather than in PPA (predominant language disturbances with little cognitive and motor impairment in the initial phase of the disease) or PSP (predominant motor symptoms with lower cognitive/behavioral impairment at disease onset).
Finally, the scales used herein were not useful in detecting brain volume reduction in PSP patients. This is in line with previous literature data [26 –29], and suggests that other specific instruments, such as the PSP Rating Scale [30, 31], may capture the disease severity in PSP.
Overall, these data support the view that different scales should be used in the different clinical phenotypes, with FTLD-modified CDR being useful in both bvFTD and PPAs, while BADLs being considered in CBS. Finally, in PSP an initial report supported the correlation between the newly developed measures of disease severity, such as PSP Rating Scale, and the degree of brain damage [32].
When we moved from clinical phenotypes to monogenic disease, such as GRN-related FTD, we found that FTLD-modified CDR and ADLs were the best markers of brain volume reduction, arguing for its use in trials on genetic cases [8].
Our work presents several limitations. First of all, the cross-sectional approach did not allow a direct correlation between each clinical scale and the neuroimaging alterations, considering longitudinal performances for each scale, as well as longitudinal neuroimaging evaluation of MRI parameters during the course of the disease, for a direct correlation with disease severity. Furthermore, we did not include any clinical scale for motor symptoms (i.e., UPDRS-III of PSP rating scale), considering the partial inhomogeneity of the motor evaluation in our, that did not allow a linear correlation of these scales in all phenotypes.
In conclusion, we defined the usefulness of each scale in FTD phenotypes (i.e., bvFTD, PPAs, CBS, and PSP) as well as in monogenic disease (i.e., GRN) independently of clinical features, suggesting which scales should be considered in future trials. In keeping with the wide heterogeneity of FTD continuum, the concept of a single ideal clinical rating scale should be overcome, and different indexes should be used on the basis of clinical examination.
