European Journal of Neurology 2008, 15: 1412–1415
doi:10.1111/j.1468-1331.2008.02338.x
SHORT COMMUNICATION
Is early-onset clinically different from late-onset frontotemporal dementia? B. Borronia, C. Agostia, G. Bellellib and A. Padovania a
Department of Neurology, University of Brescia, Center for Aging Brain and Dementia, Brescia, Italy; and bRehabilitation and Geriatric Unit, ÔAncelle della Carita`Õ Hospital, Cremona, Italy
Keywords:
age at onset, behavioural disturbances, frontotemporal dementia, neuropshychological assessment Received 24 July 2008 Accepted 4 September 2008
Background and purpose: Frontotemporal dementia (FTD) is the second most common neurodegenerative dementia in the young age after Alzheimer disease. Recent improvement in diagnostic assessment suggests that it is more common than previously, although with a great heterogeneity in clinical presentation. The different clinical patterns related to age of disease onset in behavioural variant FTD (bvFTD) have been fairly studied. Aim of the study was to evaluate whether age at disease onset modulate the heterogeneity of either cognitive impairment or behavioural disturbances in patients affected by bvFTD. Methods: One hundred and thirty-four patients with bvFTD entered the study. Age at onset and demographic characteristics were carefully recorded. Each patient underwent a wide neuropsychological and behavioural standardized assessment, as well as a brain SPECT perfusion imaging study. Results: Behavioural variant FTD were subdivided into four groups according to the age at onset. The four quartile groups did not differ for demographic characteristics and family history for dementia. Global cognitive impairment as well as analysis of the different cognitive domains and behavioural patterns were comparable. Conclusions: These findings provide evidence that the clinical heterogeneity of bvFTD is not explained by age at disease onset. Further studies are needed.
Introduction Frontotemporal dementia (FTD) is the second most common neurodegenerative dementia in the young age after Alzheimer disease, and it refers to a spectrum of heterogeneous conditions [1]. Different clinical phenotypes have been included, and the behavioural variant FTD (bvFTD), the semantic dementia (SD), the progressive non-fluent aphasia represent the most frequently recognized clinical syndromes [2,3]. Despite these different classifications, literature work suggests that changes in behaviour and personality overlap disease course, and that bvFTD is the most common clinical phenotype [4]. The age at disease onset in bvFTD is usually within 50 and 65 years, as FTD account for up to 20% of all presenile dementia cases [5–7]. Notwithstanding, the improvement of clinical diagnostic criteria and advanced neuroimaging techniques highlighted that FTD is more common than previously thought and several studies have observed late-onset cases [8–12]. Correspondence: Barbara Borroni, MD, Clinica Neurologica, Universita` degli Studi di Brescia, Pza Spedali Civili, 1 - 25100 Brescia, Italy (tel.: +39-0303995632; fax: +39-0303995027; e-mail:
[email protected]).
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Whether age at symptom onset might explain disease heterogeneity is the matter of debates. To the best of our knowledge, there is only a work that investigated the neuropsychological and behavioural profile in earlyversus late-onset bvFTD, and they found significant differences between the two groups [10]. With this aim in mind, we aimed at evaluating disease heterogeneity of cognitive deficits and behavioural disturbances in bvFTD patients stratified by different age at disease onset.
Methods Subjects
Patients were consecutively enrolled from March 2003 to March 2008 from the ÔCenter for Aging Brain and Neurodegenerative DiseasesÕ, University of Brescia, Italy. All included individuals met the Neary et al. [2] and McKhann et al. [3] criteria for bvFTD. All subjects underwent a somatic and neurological evaluation, routine laboratory examination. A brain structural and functional study confirmed the clinical diagnosis. The diagnostic assessment involved a review of full medical history, a semi-structured neurological
Ó 2008 The Author(s) Journal compilation Ó 2008 EFNS
Age at onset in frontotemporal dementia
examination and a complete mental status evaluation by two independent and experienced reviewers (B.B., A.P.). The estimated age at symptom onset was referred by the proxy caregiver by a semi-structured interview and carefully recorded. Global cognitive function assessment was made according to a standardized battery (see Table 2). Instrumental activities of daily living (IADL) and basic activities of daily living (BADL) were assessed as well. Behavioural disturbances were evaluated by Neuropsychiatry Inventory (NPI) and Frontal Behavioural Inventory (FBI). Patients considered to have a positive family history were those who had a first-degree relative with dementia, Parkinsonism or motor neuron disease. No patients belonging to the same family were included. All participants were made fully aware of the research goals and the signature of an informed consent was required from all subjects. The work was approved by Ethics Committee of Brescia Hospital. Statistical analysis
We divided the patients according to the four quartiles of age at symptom onset, i.e. very early-onset (46– 58 years), early-onset (59–63 years), late-onset (64– 71 years) and very late-onset (70–79 years). Differences in demographic and clinical characteristics were evaluated by either one-way ANOVA test and Turkey post hoc analysis or chi-squared test and FisherÕs post hoc test, as appropriate. Results are expressed as percentage or mean ± SD. The significant level was set at P < 0.05.
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Data were analysed using the SPSS software, version 11.1 (SPSS, Chicago, IL, USA).
Results One hundred and thirty-four patients with the clinical diagnosis of bvFTD were consecutively enrolled and entered the study. The mean age at onset was 63.2 ± 7.5 years and 40% of the patients were over 65 years at disease onset. As shown in Table 1, bvFTD showed a mild cognitive and functional decline. The most frequent behavioural disturbances (present in more than 50% of the patients), as measured by FBI, were apathy (61.5%), aspontaneity (54.4%), disorganization (55.9%) and irritability (53.5%). Behavioural variant FTD patients were sub grouped according to the age at symptom onset. The four quartile groups were comparable either for disease duration at the time of evaluation or for demographical characteristics, but for gender. The prevalence of family history for dementia did not significantly differ across groups. They were comparable for global cognitive decline and for functional impairment, as measured by IADL and BADL. As shown in Table 2, neuropsychological pattern demonstrated comparable scores. The severity of behavioural disturbances as measured by FBI and NPI did not differ. The analysis of sub items of FBI did not show any statistical significance difference. The same results were obtained, when patients were subdivided into two groups according to the age at onset 65 years old respectively.
Table 1 Demographical and clinical characteristics of FTD patients according to age at disease onset bvFTD – disease onset quartiles Variable
bvFTD Overall
Very early-onset
Early-onset
Late-onset FTD
Very late-onset
P
n Age at onset, years Age at evaluation, years Disease duration, years Gender, F% FHa, % positive Education, years UPDRS-III MMSE BADL IADL
134 63.2 ± 7.5 65.9 ± 7.5 2.5 ± 2.7 43.3 (58) 47.1 (57) 7.00 ± 3.46 8.59 ± 10.30 21.69 ± 6.45 0.58 ± 1.34 1.5 ± 2.14
36 53.9 ± 4.3 56.0 ± 3.5 2.1 ± 1.7 47.2 (17) 46.9 (15) 8.15 ± 3.92 7.10 ± 11.48 22.90 ± 5.93 0.41 ± 1.10 0.78 ± 1.49
33 61.5 ± 2.6 63.7 ± 2.0 2.4 ± 2.0 33.3 (11) 58.1 (18) 7.25 ± 3.57 10.67 ± 12.34 20.18 ± 7.96 0.75 ± 1.68 2.00 ± 2.37
36 66.5 ± 4.1 69.0 ± 2.9 2.8 ± 4.4 27.8 (10) 50.0 (16) 6.15 ± 2.38 8.74 ± 7.86 21.89 ± 6.39 0.65 ± 1.47 1.39 ± 1.90
29 71.9 ± 3.4 75.1 ± 3.2 2.8 ± 2.3 69.0 (20) 30.8 (8) 6.48 ± 3.56 7.54 ± 8.48 21.85 ± 5.19 0.50 ± 1.07 2.06 ± 2.46
0.000 0.000 n.s. 0.005 n.s. n.s. n.s. n.s. n.s. n.s.
Number of subjects between brackets; n, number; FTD, frontotemporal dementia; bvFTD, behavioural variant FTD; F, female; FH, family history; UPDRS, Unified Parkinson Disease Rating Scale; MMSE, mini-mental state examination; BADL, basic activities of daily living; IADL, instrumental activities of daily living. aMissed values are due to unknown FH.
Ó 2008 The Author(s) Journal compilation Ó 2008 EFNS European Journal of Neurology 15, 1412–1415
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Table 2 Cognitive and behavioural profile in FTD patients according to age at disease onset Variable Neuropsychological assessment Short story Raven coloured progressive matrices Rey complex figure, copy Rey complex figure, recall Digit span Semantic fluency Verbal fluency Token test ClockÕs drawing test Trail making A test Trail making B test Behaviour disturbances NPI FBI-A FBI-B FBI-AB
Very early-onset
7.7 21.7 23.6 9.8 5.2 29.0 21.8 29.3
± ± ± ± ± ± ± ±
Early-onset
4.4 8.3 9.7 7.8 1.0 12.3 13.1 3.9
9.8 22.9 22.7 10.6 5.1 28.4 22.2 27.7
116.4 ± 142.6 268.3 ± 185.6 14.1 7.6 4.1 11.8
± ± ± ±
± ± ± ± ± ± ± ±
4.8 6.6 10.5 7.2 1.3 11.1 10.1 7.5
171.0 ± 191.0 286.5 ± 158.2
12.4 7.3 4.8 11.2
20.3 12.8 7.0 19.8
± ± ± ±
14.3 9.4 7.0 15.0
Late-onset
9.6 20.7 24.4 10.8 5.6 31.7 25.1 30.3
± ± ± ± ± ± ± ±
5.0 7.0 9.3 6.2 1.4 14.0 7.9 4.3
165.8 ± 189.2 306.3 ± 150.1 17.0 9.9 6.3 16.3
± ± ± ±
9.8 7.1 5.5 11.4
Very late-onset FTD
9.0 20.7 21.3 10.1 5.0 26.5 25.2 29.2
± ± ± ± ± ± ± ±
5.1 6.5 11.3 7.1 1.9 13.0 11.0 4.2
222.4 ± 200.1 290.2 ± 144.5 19.8 8.5 6.4 14.9
± ± ± ±
15.5 7.5 6.8 12.3
P
n.s. n.s. n.s. n.s. n.s. n.s. n.s. n.s. n.s. n.s. n.s. n.s. n.s. n.s.
NPI, Neuropsychiatry Inventory; FBI, Frontal Behavioural Inventory.
Discussion Frontotemporal dementia has gained a lot of interest in the last decade as recent findings suggested that it may be more common than previously considered [6]. We showed that applying current clinical criteria for bvFTD [2,3], the average onset of our sample was typical for presenile form of dementia, although 40% of the patients were over 65 years at disease onset. Previous studies on this topic found that the oldest FTD patients were significantly more impaired in memory function when compared with presenile FTD [10]. In our bvFTD sample, we did not find any significant difference in the pattern of cognitive deficits and behavioural abnormalities in early- versus late-onset bvFTD patients. Even if bvFTD is generally thought to be a disorder of the adulthood, we confirmed the previous literature as the disease with onset in older age is frequent. A multicentre study performed on 200 bvFTD patients reported that 23% of the sample was over 65 years old at disease onset [9], and a Japanese work on 35 bvFTD showed comparable results herein presented, with 40% of the patients with an onset over 65 years old [10]. Finally, a population-based study demonstrated that the prevalence of bvFTD was 3% in 85 year olds, which is higher than previously expected in this group [11]. The evidence of a wide range of age at disease onset opens several questions. bvFTD has always been considered a disorder characterized by a younger age of symptom onset compared with other neurodegenerative dementias, in whom the genetic background plays a crucial role. The importance of genetic determinants is
also supported by the high prevalence of positive family history for dementia usually found in these patients. In our sample, we confirmed the high prevalence of positive family history, being interestingly found also in late-onset bvFTD patients. Thus, we can speculate that bvFTD might have either monogenic disease cause, or genetic predisposing factors, these latter probably playing a key-role in predisposing to late-onset disease as well. The interaction between genetic modulators and environment in timing the onset of symptoms should be matter of interest in future research. In the present study, each patient underwent an extensive standardized neuropsychological assessment, and we did not find any difference in global cognitive deficits and functional impairment among groups. The observation of the same disease severity along with the same disease duration is in line with the few literature works that found that the age at disease onset is not a predictor of worse prognosis over time [13]. In fact, the patients belonging to each group were evaluated after 2.5 mean years from estimated disease onset and they showed no significant differences in disease severity. Furthermore, the detailed analysis of different cognitive domains did not demonstrate any specific different neuropsychological pattern in early- versus late-onset. The severity and the pattern of behavioural disturbances measured by NPI and FBI were comparable as well. Conversely to our results, it has been previously claimed by Shinagawa et al. [10] that lateonset bvFTD had memory and visuospatial deficits. The assessment administered was different from ours, and their sample differed for mini-mental state examination total score at evaluation. Even if current clinical
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criteria excluded memory deficits in the diagnosis of FTD, autopsy studies demonstrated that these patients may have memory impairment [14]. Our group has previously reported that the presence of memory impairment in FTD patients is related to apolipoprotein E status, epsilon 4 carriers reporting memory deficits compared with no-carriers [15]; it should be of interest the genotyping of apolipoprotein E to address whether it might account for the differences in memory performances highlighted by Shinagawa et al. Finally, in keeping with previous studies, we found that the most prevalent behavioural disturbance was apathy, but no differences across disease onset groups were found. Shinagawa et al. [10] found that apathy was more prevalent in late-onset bvFTD patients, but these also had more severe behavioural abnormalities associated with greater cognitive decline; in our sample, patientÕs groups showed the same severity of behavioural abnormalities. Some limitations of the study should be acknowledged. Neuropathological examination would be mandatory as well as a more extensive testing of the cognitive and behavioural deficits. Further, age at symptom onset might be not always accurate, because it strictly depends on caregiversÕ interview. In conclusion, bvFTD is known to be heterogeneous for clinical and behavioural presentation, but the present findings suggest that age at disease onset does not predict a specific phenotype. Future confirmatory studies are needed.
Acknowledgement The authors wish to thank the patients and their families for taking part into this study. The authors are indebted to Antonella Alberici for editing the manuscript.
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Ó 2008 The Author(s) Journal compilation Ó 2008 EFNS European Journal of Neurology 15, 1412–1415
