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C9ORF72 and the FTD-ALS spectrum: a systematic review of neuroimaging studies

MUTAÇÕES NO CROMOSSOMA 9 E O ESPECTRO DFT-ELA: REVISÃO SISTEMÁTICA DE ESTUDOS DE NEUROIMAGEM

ABSTRACT

OBJECTIVE:

To perform a systematic review of the literature on the neuroimaging investigation of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) associated with C9ORF72 mutation.

METHODS:

The search was performed on PubMed and LILACS with the following terms:C9ORF72, MRI, SPECT, PET, ALS, FTD. No filters were added.

RESULTS

Twenty articles were selected. Most studies found consistent involvement of frontotemporal regions in C9ORF72 carriers, including prefrontal cortex, and also cingulate, subcortical regions, especially the thalami, and posterior regions such as the parietal and occipital lobes. Functional connectivity was also explored and impaired sensorimotor connectivity in striatum and thalami was found in behavioral variant FTDC9ORF72 carriers. Some papers have reported an absence of significant abnormalities on brain imaging.

CONCLUSION

The inclusion of patients at different stages of the disease, differences in neuroimaging methods across studies, and distinct clinical phenotypes associated with C9ORF72 may account for the heterogeneity of results.

Key words:
amyotrophic lateral sclerosis; frontotemporal dementia; C9ORF72 repeat expansion; neuroimaging.

RESUMO

OBJETIVO

Realizar uma revisão sistemática da literatura sobre os estudos de neuroimagem da demência frontotemporal (DFT) e esclerose lateral amiotrófica (ELA), associadas à mutação C9ORF72.

Métodos

A pesquisa foi realizada nas bases PubMed e LILACS com os seguintes termos:C9ORF72, MRI, SPECT, PET, ALS, FTD. Nenhum filtro foi utilizado.

RESULTADOS

Vinte artigos foram incluídos. A maioria dos estudos encontrou, nos portadores da expansão C9ORF72, envolvimento significativo das regiões frontotemporais, incluindo o córtex pré-frontal e também o cíngulo, regiões subcorticais (especialmente o tálamo) e regiões posteriores, como os lobos parietal e occipital. A conectividade funcional também foi investigada e disfunção sensório-motora foi demonstrada no estriado e no tálamo em pacientes com a variante comportamental da DFT associada à expansão C9ORF72. Alguns trabalhos não evidenciaram alterações significativas na neuroimagem.

CONCLUSÃO

A inclusão de pacientes em diferentes estágios da doença, a variabilidade dos métodos de neuroimagem utilizados nos estudos e os distintos fenótipos de C9ORF72 podem contribuir para a heterogeneidade dos resultados.

Palavras-chave:
esclerose lateral amiotrófica; demência frontotemporal; expansão C9ORF72; neuroimagem

INTRODUCTION

Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) share common clinical, pathological and genetic features. FTD encompasses a heterogeneous group of clinical presentations, with variable phenotypes including behavioral changes and deficits in language and other cognitive functions.11. Pressman PS, Miller BL. Diagnosis and management of behavioral variant frontotemporal dementia. Biol Psychiatry. 2014;75:574-581. 22. Piguet O, Hornberger M, Mioshi E, Hodges JR. Behavioural-variant frontotemporal dementia: diagnosis, clinical staging, and management. Lancet Neurol 2011;10:162-172. On the other hand, besides motor symptoms, ALS is also characterized by cognitive impairment and behavioral disorders, overlapping with the cognitive profile of FTD.3 Indeed, the association between dementia and ALS has been recognized since the nineteenth century and almost 50% of ALS patients are believed to have cognitive impairment and up to 15% of these fulfill criteria for FTD.33. Goldstein LH, Abrahams S. Changes in cognition and behaviour in amyotrophic lateral sclerosis: nature of impairment and implications for assessment. Lancet Neurol 2013;12:368-380. 44. Lomen-Hoerth C, Murphy J, Langmore S, Kramer JH, Olney RK, Miller B. Are amyotrophic lateral sclerosis patients cognitively normal? Neurology 2003;60:1094-1097. Conversely, motor neuron disease can appear during the course of FTD in up to 15% of patients.55. Solje E, Aaltokallio H, Koivumaa-Honkanen H, et al. The Phenotype of the C9ORF72 Expansion Carriers According to Revised Criteria for bvFTD. PLoS One. 2015;10:e0131817. Therefore there is a clinical and pathophysiological continuum between FTD and ALS.

The recent discovery that an expanded hexanucleotide (GGGGCC) repeat insertion in a noncoding promoter region of open-reading frame 72 (C9ORF72) is a cause of familial FTD and ALS opened a promising window for the understanding of the FTD-ALS spectrum.66. Renton AE, Majounie E, Waite A, et al. A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron 2011;72:257-268. 77. DeJesus-Hernandez M, Mackenzie IR, Boeve BF, et al. Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron. 2011;72:245-256. The neurobiological functions ofC9ORF72 and the pathophysiological mechanisms by which it participates in neurodegenerative processes are unknown.88. Takada LT. The Genetics of Monogenic Frontotemporal Dementia. Dement Neuropsychol 2015;9:219-229. The C9ORF72 genotype may account for 10-50% of familial cases of behavioral variant FTD (bvFTD).11. Pressman PS, Miller BL. Diagnosis and management of behavioral variant frontotemporal dementia. Biol Psychiatry. 2014;75:574-581. 88. Takada LT. The Genetics of Monogenic Frontotemporal Dementia. Dement Neuropsychol 2015;9:219-229. Conversely, up to 41% of familial ALS and 5% of sporadic ALS cases may have C9ORF72 mutation.99. Byrne S, Elamin M, Bede P, et al. Cognitive and clinical characteristics of patients with amyotrophic lateral sclerosis carrying a C9orf72 repeat expansion: a population-based cohort study. Lancet Neurol 2012; 11:232-240. Co-morbid FTD is more common in ALS patients with the C9ORF72 genotype, and these patients may have faster disease progression and more pronounced cognitive and behavioral disorders.99. Byrne S, Elamin M, Bede P, et al. Cognitive and clinical characteristics of patients with amyotrophic lateral sclerosis carrying a C9orf72 repeat expansion: a population-based cohort study. Lancet Neurol 2012; 11:232-240. 1010. Irwin DJ, McMillan CT, Brettschneider J, et al. Cognitive decline and reduced survival in C9orf72 expansion frontotemporal degeneration and amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry 2013; 84:163-169.

Since its discovery, there has been an intense research effort to investigate the clinical phenotypes associated with C9ORF72 repeat expansion. More specifically, neuroimaging methods have been employed to investigate neuroanatomical features of FTD and/or ALS patients with C9ORF72 mutation. Brain imaging may provide clinical markers for both the diagnosis and/or the follow-up of these patients, and may also shed light on the pathophysiological mechanisms of neurodegeneration associated with C9ORF72 repeat expansion. In the current paper, we aimed to review the literature on neuroimaging studies of FTD and/or ALS patients with C9ORF72 mutation.

METHODS

We conducted a systematic review of the literature according to a predetermined protocol as described elsewhere.1111. Vargas C, Lopez-Jaramillo C, Vieta E. A systematic literature review of resting state network--functional MRI in bipolar disorder. J Affect Disord 2013;150:727-735. The search aimed to identify original papers reporting neuroimaging data in FTD and/or ALS patients with C9ORF72 repeat expansion.

The search was performed in July 26th 2015 on two electronic databases: PubMed and LILACS. The following terms (alone and in combination) were employed for the search on PubMed: C9ORF72, MRI, SPECT, PET, ALS, FTD. The same keywords were entered for the search on the LILACS database. We did not employ language or chronological filters in the search.

Titles and abstracts of the papers retrieved in the initial search were screened according to the following eligibility criteria: [1] original research, [2] case series, cohort or cross-sectional design, and [3] imaging methods (MRI, PET and/or SPECT). Abstracts with insufficient information, individual case reports and review articles were not included in the final selection. Disagreements on eligibility were resolved through discussion among the authors.

RESULTS

Table 1 presents findings reported in the selected studies, including the number of patients, neuroimaging technique, and main results.

Table 1
Synthesis of articles included in the present review.

The initial search resulted in 110 and 69 papers retrieved on PubMed and LILACS, respectively. After this initial screening, papers were selected according to the aforementioned inclusion criteria and duplicate articles removed. The final selection comprised twenty articles (Figure 1).

Figure 1
Flowchart depicting selection of items for systematic review on PubMed and Lilacs databases using the terms C9ORF72, ALS, FTD, MRI, SPECT and PET.

Selected publications are presented below in three parts: Part I, comprising studies which included FTD patients only; Part II, which describes studies limited to ALS patients; and Part III, which presents studies that included ALS, FTD and FTD-ALS patients.

Part I: FTD Patients. A series of studies assessed the pattern of brain atrophy in FTD patients with C9ORF721010. Irwin DJ, McMillan CT, Brettschneider J, et al. Cognitive decline and reduced survival in C9orf72 expansion frontotemporal degeneration and amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry 2013; 84:163-169. 1212. Lee SE, Khazenzon AM, Trujillo AJ, et al. Altered network connectivity in frontotemporal dementia with C9orf72 hexanucleotide repeat expansion. Brain 2014;137:3047-3060. 2121. Mahoney CJ, Ridgway GR, Malone IB, et al. Profiles of white matter tract pathology in frontotemporal dementia. Hum Brain Mapp 2014; 35:4163-4179. using mainly MRI volumetric analysis.

A widespread, symmetrical pattern of brain atrophy was reported in FTD-C9ORF72 patients compared with healthy controls.1212. Lee SE, Khazenzon AM, Trujillo AJ, et al. Altered network connectivity in frontotemporal dementia with C9orf72 hexanucleotide repeat expansion. Brain 2014;137:3047-3060. 1313. Whitwell JL, Weigand SD, Boeve BF, et al. Neuroimaging signatures of frontotemporal dementia genetics: C9ORF72, tau, progranulin and sporadics. Brain 2012;135:794-806. The more atrophic compromised areas were the anterior brain regions, including temporal lobes and all the main subregions of the prefrontal cortex (dorsolateral, orbitofrontal and medial regions). Atrophy in posterior regions (parietal and occipital regions) was also observed inC9ORF72 carriers.1313. Whitwell JL, Weigand SD, Boeve BF, et al. Neuroimaging signatures of frontotemporal dementia genetics: C9ORF72, tau, progranulin and sporadics. Brain 2012;135:794-806. 1414. Mahoney CJ, Downey LE, Ridgway GR, et al. Longitudinal neuroimaging and neuropsychological profiles of frontotemporal dementia with C9ORF72 expansions. Alzheimers Res Ther 2012;4:41. However, these findings were not replicated in a series of C9ORF72 FTD patients in which brain atrophy was assessed using a visual rating scale, and which failed to find significant differences in atrophy patterns between carriers and healthy controls in prefrontal regions (orbitofrontal cortex, anterior cingulate) or temporal regions.1616. Devenney E, Hornberger M, Irish M, et al. JAMA Neurology. 2014;71: 331-339. A recent study reported that carriers of C9ORF72 repeat expansion exhibited significant atrophy in specific brain regions in the pre-symptomatic phase of FTD (before the onset of clinical symptoms).1919. Rohrer JD, Nicholas JM, Cash DM, et al. Presymptomatic cognitive and neuroanatomical changes in genetic frontotemporal dementia in the Genetic Frontotemporal dementia Initiative (GENFI) study: a cross-sectional analysis. Lancet Neurol 2015;14:253-262. Compared to healthy controls, C9ORF72 carriers had marked atrophy in subcortical (thalamus, e.g.) and cortical regions (including frontal, temporal and parietal regions) 20-25 years prior to expected disease onset.1919. Rohrer JD, Nicholas JM, Cash DM, et al. Presymptomatic cognitive and neuroanatomical changes in genetic frontotemporal dementia in the Genetic Frontotemporal dementia Initiative (GENFI) study: a cross-sectional analysis. Lancet Neurol 2015;14:253-262.

Investigating white matter tract changes in different genetic groups of bvFTD2121. Mahoney CJ, Ridgway GR, Malone IB, et al. Profiles of white matter tract pathology in frontotemporal dementia. Hum Brain Mapp 2014; 35:4163-4179. compared with healthy controls,C9ORF72 carriers had altered diffusivity in the corpus callosum and cingulum bundle. However, these data are limited by the small size of the sample (only four bvFTD carriers).

Some studies compared neuroimaging features of C9ORF72-bvFTD with sporadic bvFTD and other mutations. C9ORF72-bvFTD patients had less gray matter loss than sporadic bvFTD in the anterior cingulate, orbitofrontal cortex, anterior temporal lobe and insula.1616. Devenney E, Hornberger M, Irish M, et al. JAMA Neurology. 2014;71: 331-339.Another study reported that the majority of subjects with mutation in the microtubule associated protein tau gene (MAPT) andC9ORF72 subjects had symmetric frontal atrophy, while most subjects with mutation in the progranulin gene (GRN) had asymmetric atrophy.1313. Whitwell JL, Weigand SD, Boeve BF, et al. Neuroimaging signatures of frontotemporal dementia genetics: C9ORF72, tau, progranulin and sporadics. Brain 2012;135:794-806.C9ORF72 carriers had greater atrophy in posterior (parietal and occipital) lobes in comparison with MAPT and sporadic bvFTD groups, while patients with MAPT mutations had greater impairment in temporal poles, compared with the C9ORF72 group.1313. Whitwell JL, Weigand SD, Boeve BF, et al. Neuroimaging signatures of frontotemporal dementia genetics: C9ORF72, tau, progranulin and sporadics. Brain 2012;135:794-806. Patients with GRN mutation had more loss in parietal lobes than C9ORF72 carriers.1313. Whitwell JL, Weigand SD, Boeve BF, et al. Neuroimaging signatures of frontotemporal dementia genetics: C9ORF72, tau, progranulin and sporadics. Brain 2012;135:794-806. In the same study, by applying a multinomial logistic regression model based on atrophic patterns, it was possible to classify FTD patients with different genotypes with 93% accuracy, suggesting that neuroimaging may be useful to distinguish C9ORF72-FTD patients from patients with other mutations at a single-subject level.1313. Whitwell JL, Weigand SD, Boeve BF, et al. Neuroimaging signatures of frontotemporal dementia genetics: C9ORF72, tau, progranulin and sporadics. Brain 2012;135:794-806.

Only one study investigated white matter patterns across bvFTD patients grouped according to genetic status.2121. Mahoney CJ, Ridgway GR, Malone IB, et al. Profiles of white matter tract pathology in frontotemporal dementia. Hum Brain Mapp 2014; 35:4163-4179. There were no differences between C9ORF72 and sporadic bvFTD cases, butMAPT patients had abnormal fractional anisotropy in the anterior region of the left temporal lobe, compared with theC9ORF72 group.

The integrity of the intrinsic connectivity network in bvFTD was explored in a group of 14 bvFTD C9ORF72 carriers and 14 bvFTD non-carriers.1212. Lee SE, Khazenzon AM, Trujillo AJ, et al. Altered network connectivity in frontotemporal dementia with C9orf72 hexanucleotide repeat expansion. Brain 2014;137:3047-3060. These groups were compared against healthy controls. Patients with C9ORF72 did not exhibit differences in the default mode network compared to controls. Conversely, bvFTD non-carriers exhibited a different pattern, presenting both impaired (in striatum and thalamus) and enhanced (in precuneus and posterior cingulate) connectivity compared with controls.1212. Lee SE, Khazenzon AM, Trujillo AJ, et al. Altered network connectivity in frontotemporal dementia with C9orf72 hexanucleotide repeat expansion. Brain 2014;137:3047-3060. In the same study, it was reported that C9ORF72 carriers had impaired sensorimotor connectivity in striatum and thalami, compared with bvFTD non-carriers. There was no difference in the salience network connectivity between carriers and non-carriers.1212. Lee SE, Khazenzon AM, Trujillo AJ, et al. Altered network connectivity in frontotemporal dementia with C9orf72 hexanucleotide repeat expansion. Brain 2014;137:3047-3060.

The progression of brain atrophy in bvFTD patients with different genetic status was assessed in a longitudinal study.1818. Whitwell JL, Boeve BF, Weigand SD, et al. Brain atrophy over time in genetic and sporadic frontotemporal dementia: a study of 198 serial magnetic resonance images. Eur J Neurol 2015;22:745-752.GRN patients had greater rates of atrophy than sporadic,MAPT and C9ORF72 groups. Sporadic bvFTD patients had greater rates of gray matter loss in anterior cingulate thanC9ORF72 carriers, while the latter had greater rates of atrophy in cerebellum and occipital lobes, compared with MAPTcarriers.1818. Whitwell JL, Boeve BF, Weigand SD, et al. Brain atrophy over time in genetic and sporadic frontotemporal dementia: a study of 198 serial magnetic resonance images. Eur J Neurol 2015;22:745-752. Another study found thatC9ORF72-bvFTD patients had increased rates of brain atrophy and ventricular expansion compared with healthy controls.1414. Mahoney CJ, Downey LE, Ridgway GR, et al. Longitudinal neuroimaging and neuropsychological profiles of frontotemporal dementia with C9ORF72 expansions. Alzheimers Res Ther 2012;4:41.

In summary, widespread brain atrophy was reported in FTD C9ORF72patients, mostly in anterior brain regions, but also with possible damage in posterior cortical areas. Brain atrophy may be identified before disease onset. However, the absence of significant changes in FTD C9ORF72 carriers has also been reported.

Part II: ALS Patients. Five articles investigated neuroimaging features of ALS patients with C9ORF72 expansion. Four of these studies employed the MRI technique99. Byrne S, Elamin M, Bede P, et al. Cognitive and clinical characteristics of patients with amyotrophic lateral sclerosis carrying a C9orf72 repeat expansion: a population-based cohort study. Lancet Neurol 2012; 11:232-240. 2222. Snowden JS, Rollinson S, Thompson JC, et al. Distinct clinical and pathological characteristics of frontotemporal dementia associated with C9ORF72 mutations. Brain 2012;135:693-708. 2424. Bede P, Elamin M, Byrne S, et al. Basal ganglia involvement in amyotrophic lateral sclerosis. Neurology 2013;81:2107-2115. while the remainder used FDG-PET.2525. Van Laere K, Vanhee A, Verschueren J, et al. Value of 18fluorodeoxyglucose-positron-emission tomography in amyotrophic lateral sclerosis: a prospective study. JAMA Neurology 2014;71:553-561.

ALS patients with C9ORF72 mutation had greater atrophy in prefrontal regions, including frontal gyri and the anterior cingulate, compared to those with sporadic ALS.99. Byrne S, Elamin M, Bede P, et al. Cognitive and clinical characteristics of patients with amyotrophic lateral sclerosis carrying a C9orf72 repeat expansion: a population-based cohort study. Lancet Neurol 2012; 11:232-240. 2222. Snowden JS, Rollinson S, Thompson JC, et al. Distinct clinical and pathological characteristics of frontotemporal dementia associated with C9ORF72 mutations. Brain 2012;135:693-708. The right precentral gyrus was also affected in one study.99. Byrne S, Elamin M, Bede P, et al. Cognitive and clinical characteristics of patients with amyotrophic lateral sclerosis carrying a C9orf72 repeat expansion: a population-based cohort study. Lancet Neurol 2012; 11:232-240. Mild hypometabolism in the thalamus and posterior cingulate was found on PET-FDG in ALS carriers compared with non-carriers.2525. Van Laere K, Vanhee A, Verschueren J, et al. Value of 18fluorodeoxyglucose-positron-emission tomography in amyotrophic lateral sclerosis: a prospective study. JAMA Neurology 2014;71:553-561. Compared with ALS non-carriers, C9ORF72 carriers had more cortical and subcortical involvement, affecting both cortical (fusiform, supramarginal, and orbitofrontal cortex and Broca's area) and subcortical regions (thalamus).2323. Bede P, Bokde AL, Byrne S, et al. Multiparametric MRI study of ALS stratified for the C9orf72 genotype. Neurology 2013;81:361-369. Interestingly, in the same study, white matter abnormalities in ALS non-carriers were relatively limited to corticospinal and cerebellar pathways, while carriers had more widespread involvement. These data suggested that non-motor changes (e.g. cognitive impairment) in ALS could be largely driven byC9ORF72 repeat expansion.2323. Bede P, Bokde AL, Byrne S, et al. Multiparametric MRI study of ALS stratified for the C9orf72 genotype. Neurology 2013;81:361-369. Basal ganglia involvement was also more extensive in ALS patients with C9ORF72 mutation than in non-carriers.2424. Bede P, Elamin M, Byrne S, et al. Basal ganglia involvement in amyotrophic lateral sclerosis. Neurology 2013;81:2107-2115.

In short, ALS C9ORF72 carriers had greater atrophy, with predominance in prefrontal regions, compared to sporadic ALS patients. Mild hypometabolism in the thalamus and posterior cingulate, more widespread abnormalities of white matter, and greater basal ganglia involvement has also been demonstrated in ALS carriers compared with non-carriers.

Part III: FTD, ALS and FTD-ALS patients. The imaging patterns of patients with ALS, FTD or FTD-ALS according to their genetic status were compared in a series of studies.55. Solje E, Aaltokallio H, Koivumaa-Honkanen H, et al. The Phenotype of the C9ORF72 Expansion Carriers According to Revised Criteria for bvFTD. PLoS One. 2015;10:e0131817. 1010. Irwin DJ, McMillan CT, Brettschneider J, et al. Cognitive decline and reduced survival in C9orf72 expansion frontotemporal degeneration and amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry 2013; 84:163-169. 2020. Hsiung GY, DeJesus-Hernandez M, Feldman HH, et al. Clinical and pathological features of familial frontotemporal dementia caused by C9ORF72 mutation on chromosome 9p. Brain 2012;135:709-722. 2222. Snowden JS, Rollinson S, Thompson JC, et al. Distinct clinical and pathological characteristics of frontotemporal dementia associated with C9ORF72 mutations. Brain 2012;135:693-708. 2626. Boeve BF, Boylan KB, Graff-Radford NR, et al. Characterization of frontotemporal dementia and/or amyotrophic lateral sclerosis associated with the GGGGCC repeat expansion in C9ORF72. Brain 2012;13:765-783. 2727. Sha SJ, Takada LT, Rankin KP, et al. Frontotemporal dementia due to C9ORF72 mutations: clinical and imaging features. Neurology 2012;79: 1002-1011. Most of the papers employed structural brain MRI.

In a group of eighteen patients with C9ORF72 repeat expansion (fourteen bvFTD, three with FTD/ALS and one with ALS), gray matter loss was found in cortical areas including frontotemporal regions,2626. Boeve BF, Boylan KB, Graff-Radford NR, et al. Characterization of frontotemporal dementia and/or amyotrophic lateral sclerosis associated with the GGGGCC repeat expansion in C9ORF72. Brain 2012;13:765-783. in a similar pattern to that reported by others.1010. Irwin DJ, McMillan CT, Brettschneider J, et al. Cognitive decline and reduced survival in C9orf72 expansion frontotemporal degeneration and amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry 2013; 84:163-169. 2020. Hsiung GY, DeJesus-Hernandez M, Feldman HH, et al. Clinical and pathological features of familial frontotemporal dementia caused by C9ORF72 mutation on chromosome 9p. Brain 2012;135:709-722. 2222. Snowden JS, Rollinson S, Thompson JC, et al. Distinct clinical and pathological characteristics of frontotemporal dementia associated with C9ORF72 mutations. Brain 2012;135:693-708. Most studies reported symmetrical patterns of brain atrophy, except for patients presenting with predominant language deficit. Some patients may have parietal cortical atrophy and thalamic involvement.1010. Irwin DJ, McMillan CT, Brettschneider J, et al. Cognitive decline and reduced survival in C9orf72 expansion frontotemporal degeneration and amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry 2013; 84:163-169. 2626. Boeve BF, Boylan KB, Graff-Radford NR, et al. Characterization of frontotemporal dementia and/or amyotrophic lateral sclerosis associated with the GGGGCC repeat expansion in C9ORF72. Brain 2012;13:765-783. These studies are limited by the absence of direct comparisons between bvFTD and FTD-ALS.

A group of patients with C9ORF72 expansion (15 bvFTD, 11 FTD-ALS and 5 ALS) was compared against 48 sporadic non-carrier patients (48 bvFTD, 19 FTD-ALS and 6 ALS).2727. Sha SJ, Takada LT, Rankin KP, et al. Frontotemporal dementia due to C9ORF72 mutations: clinical and imaging features. Neurology 2012;79: 1002-1011. The authors found that bvFTD-C9 patients had more parietal and bilateral thalamic atrophy and less medial frontal atrophy compared to sporadic bvFTD patients. FTD-ALS C9ORF72 patients had more dorsal frontal and bilateral posterior cortical atrophy and less damage to the temporal pole than sporadic FTD-ALS patients.2727. Sha SJ, Takada LT, Rankin KP, et al. Frontotemporal dementia due to C9ORF72 mutations: clinical and imaging features. Neurology 2012;79: 1002-1011.

Conversely, some studies reported that C9ORF72 carriers may not have brain atrophy.2222. Snowden JS, Rollinson S, Thompson JC, et al. Distinct clinical and pathological characteristics of frontotemporal dementia associated with C9ORF72 mutations. Brain 2012;135:693-708. 2626. Boeve BF, Boylan KB, Graff-Radford NR, et al. Characterization of frontotemporal dementia and/or amyotrophic lateral sclerosis associated with the GGGGCC repeat expansion in C9ORF72. Brain 2012;13:765-783. These findings were expanded by a recent study, which demonstrated that almost 18% of bvFTD cases withC9ORF72 mutation had no abnormalities on PET/SPECT.55. Solje E, Aaltokallio H, Koivumaa-Honkanen H, et al. The Phenotype of the C9ORF72 Expansion Carriers According to Revised Criteria for bvFTD. PLoS One. 2015;10:e0131817.

In a study that investigated the metabolic patterns of C9ORF72carriers on PET-FDG, ALS carriers of C9ORF72 had more pronounced hypometabolism in cortical (cingulate cortex, and frontotemporal regions) and subcortical structures (caudate and thalami) compared with sporadic ALS patients.2828. Cistaro A, Pagani M, Montuschi A, et al. The metabolic signature of C9ORF72-related ALS: FDG PET comparison with nonmutated patients. Eur J Nucl Med Mol Imaging 2014;41:844-852. In the same study, ALS patients with C9ORF72 expansion had impaired metabolism in the left temporal cortex, compared with the ALS-FTD group.2828. Cistaro A, Pagani M, Montuschi A, et al. The metabolic signature of C9ORF72-related ALS: FDG PET comparison with nonmutated patients. Eur J Nucl Med Mol Imaging 2014;41:844-852. Accordingly, ALS C9ORF72 patients may have a more severe clinical picture and more widespread central nervous system involvement than sporadic ALS patients, regardless of the association with bvFTD.

Taken together, C9ORF72 carriers had symmetrical gray matter loss in cortical regions, except for patients with predominant language deficit, who demonstrated asymmetrical cortical involvement. ALS C9ORF72patients had more widespread central nervous system involvement than sporadic ALS and/or FTD groups. Some studies have reported an absence of abnormalities on structural and functional neuroimaging.

DISCUSSION

For many years, neuroimaging was of limited applicability in the everyday evaluation of neurodegenerative disorders. For instance, the exclusion of focal lesions or hydrocephalus as causes of cognitive deficits was the main utility of imaging exploration in patients suffering from cognitive disorders. This picture has changed, with modern imaging techniques which provide useful and specific markers for the diagnosis and the follow-up of neurodegenerative diseases, such as ALS and FTD.2929. de Souza LC, Lehericy S, Dubois B, Stella F, Sarazin M. Neuroimaging in dementias. Curr Opin Psychiatry 2012;25:473-479. In this paper we systematically reviewed neuroimaging data in FTD and/or ALS patients with C9ORF72repeat expansion.

Most studies that investigated the neuroimaging features of C9ORF72carriers found consistent involvement of frontotemporal regions, including prefrontal cortex, (dorsolateral, orbitofrontal and medial regions), and also cingulate and posterior regions such as the parietal and occipital lobes.1010. Irwin DJ, McMillan CT, Brettschneider J, et al. Cognitive decline and reduced survival in C9orf72 expansion frontotemporal degeneration and amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry 2013; 84:163-169. 1212. Lee SE, Khazenzon AM, Trujillo AJ, et al. Altered network connectivity in frontotemporal dementia with C9orf72 hexanucleotide repeat expansion. Brain 2014;137:3047-3060.-15 Subcortical regions, especially thalami, may also be affected inC9ORF72 carriers.1010. Irwin DJ, McMillan CT, Brettschneider J, et al. Cognitive decline and reduced survival in C9orf72 expansion frontotemporal degeneration and amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry 2013; 84:163-169. 1919. Rohrer JD, Nicholas JM, Cash DM, et al. Presymptomatic cognitive and neuroanatomical changes in genetic frontotemporal dementia in the Genetic Frontotemporal dementia Initiative (GENFI) study: a cross-sectional analysis. Lancet Neurol 2015;14:253-262. 2222. Snowden JS, Rollinson S, Thompson JC, et al. Distinct clinical and pathological characteristics of frontotemporal dementia associated with C9ORF72 mutations. Brain 2012;135:693-708. It is of note that some studies reported that patients with C9ORF72 mutation may not have abnormalities on structural and functional brain imaging.55. Solje E, Aaltokallio H, Koivumaa-Honkanen H, et al. The Phenotype of the C9ORF72 Expansion Carriers According to Revised Criteria for bvFTD. PLoS One. 2015;10:e0131817. 1616. Devenney E, Hornberger M, Irish M, et al. JAMA Neurology. 2014;71: 331-339. 2222. Snowden JS, Rollinson S, Thompson JC, et al. Distinct clinical and pathological characteristics of frontotemporal dementia associated with C9ORF72 mutations. Brain 2012;135:693-708. 2626. Boeve BF, Boylan KB, Graff-Radford NR, et al. Characterization of frontotemporal dementia and/or amyotrophic lateral sclerosis associated with the GGGGCC repeat expansion in C9ORF72. Brain 2012;13:765-783. These disparate patterns may be due to a number of different reasons. The inclusion of patients at different stages of disease and differences in neuroimaging methods across studies may account for the variability of results. One factor that may partially account for these disparate findings is that different phenotypes are associated with C9ORF72and heterogeneity may occur even among patients with the same clinical phenotype.2222. Snowden JS, Rollinson S, Thompson JC, et al. Distinct clinical and pathological characteristics of frontotemporal dementia associated with C9ORF72 mutations. Brain 2012;135:693-708. Besides ALS, bvFTD and ALS/FTD, C9ORF72 mutation has also been associated with primary progressive aphasia, Huntington's disease-like syndrome, and atypical parkinsonism syndromes, such as corticobasal degeneration and progressive supranuclear palsy.2222. Snowden JS, Rollinson S, Thompson JC, et al. Distinct clinical and pathological characteristics of frontotemporal dementia associated with C9ORF72 mutations. Brain 2012;135:693-708. 3030. Simon-Sanchez J, Dopper EG, Cohn-Hokke PE, et al. The clinical and pathological phenotype of C9ORF72 hexanucleotide repeat expansions. Brain 2012;135:723-735. 3333. Beck J, Poulter M, Hensman D, et al. Large C9orf72 hexanucleotide repeat expansions are seen in multiple neurodegenerative syndromes and are more frequent than expected in the UK population. Am J Hum Genet 2013;92:345-353. Repeated expansion inC9ORF72 may also contribute to Alzheimer's disease.3333. Beck J, Poulter M, Hensman D, et al. Large C9orf72 hexanucleotide repeat expansions are seen in multiple neurodegenerative syndromes and are more frequent than expected in the UK population. Am J Hum Genet 2013;92:345-353. 3434. Kohli MA, John-Williams K, Rajbhandary R, et al. Repeat expansions in the C9ORF72 gene contribute to Alzheimer's disease in Caucasians. Neurobiol Aging 2013;34:1519 e1515-1512. In summary, although FTD and/or ALS are the most common phenotypes of C9ORF72 repeat expansion, other clinical presentations may occur, with different neuroimaging patterns. It remains unclear why some patients with the C9ORF72 expansion have minimal atrophy on neuroimaging studies. The possible pathways by which C9ORF72mutation participates in the pathophysiological process associated with different neurodegenerative diseases also remain elusive.

From a clinical perspective, the variability of clinical findings associated withC9ORF72 limits the interpretation of neuroimaging features at an individual level. A single-center study reported the utility of a multinomial regression model to accurately identify C9ORF72 patients based on patterns of brain atrophy1313. Whitwell JL, Weigand SD, Boeve BF, et al. Neuroimaging signatures of frontotemporal dementia genetics: C9ORF72, tau, progranulin and sporadics. Brain 2012;135:794-806. at single-subject level. However, this strategy seems limited to research centers with advanced expertise in neuroimaging techniques. Moreover, C9ORF72 carriers may have no structural abnormalities on brain MRI.1616. Devenney E, Hornberger M, Irish M, et al. JAMA Neurology. 2014;71: 331-339. 2222. Snowden JS, Rollinson S, Thompson JC, et al. Distinct clinical and pathological characteristics of frontotemporal dementia associated with C9ORF72 mutations. Brain 2012;135:693-708. 2626. Boeve BF, Boylan KB, Graff-Radford NR, et al. Characterization of frontotemporal dementia and/or amyotrophic lateral sclerosis associated with the GGGGCC repeat expansion in C9ORF72. Brain 2012;13:765-783. Therefore, atrophic features in brain MRI are of limited value for identification of C9ORF72 carriers in clinical practice.

On the other hand, neuroimaging assessment may be useful for the follow-up of patients with C9ORF72 repeat expansion and for suggesting prognostic aspects. FTD and/or ALS patients with C9ORF72 mutation may have faster disease progression and shorter survival than non-carriers,1010. Irwin DJ, McMillan CT, Brettschneider J, et al. Cognitive decline and reduced survival in C9orf72 expansion frontotemporal degeneration and amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry 2013; 84:163-169. 1616. Devenney E, Hornberger M, Irish M, et al. JAMA Neurology. 2014;71: 331-339. even though this is not consistent across studies.2727. Sha SJ, Takada LT, Rankin KP, et al. Frontotemporal dementia due to C9ORF72 mutations: clinical and imaging features. Neurology 2012;79: 1002-1011. In this scenario, neuroimaging can identify markers of disease progression, such as the rate of brain atrophy and ventricular expansion.1414. Mahoney CJ, Downey LE, Ridgway GR, et al. Longitudinal neuroimaging and neuropsychological profiles of frontotemporal dementia with C9ORF72 expansions. Alzheimers Res Ther 2012;4:41. These markers could help track disease changes and guide clinical management, especially in the prospect of disease-modifying drugs that will target the pathophysiological process of neurodegenerative disorders.

New modern neuroimaging techniques may provide useful biomarkers for the diagnosis and follow-up of C9ORF72 carriers. Disruption of functional connectivity may be seen in the absence of brain atrophy and could be regarded as an early marker of disease.1212. Lee SE, Khazenzon AM, Trujillo AJ, et al. Altered network connectivity in frontotemporal dementia with C9orf72 hexanucleotide repeat expansion. Brain 2014;137:3047-3060. Only one study to date explored functional connectivity in C9ORF72 carriers, and found that there is a convergent, large-scale, disrupted network among different patterns of brain atrophy.1212. Lee SE, Khazenzon AM, Trujillo AJ, et al. Altered network connectivity in frontotemporal dementia with C9orf72 hexanucleotide repeat expansion. Brain 2014;137:3047-3060. The investigation of functional connectivity may enhance our understanding about the neural networks compromised by C9ORF72 mutation, thus providing valuable information for the comprehension of the pathophysiology of the FTD-ALS spectrum.

Techniques exploring the integrity of the white matter tract may also be of clinical value in the assessment of patients with C9ORF72 repeat expansion. Degeneration of the corticospinal tract is a hallmark of ALS, and disruption of this tract can differentiate ALS patients from bvFTD and ALS-FTD patients.2323. Bede P, Bokde AL, Byrne S, et al. Multiparametric MRI study of ALS stratified for the C9orf72 genotype. Neurology 2013;81:361-369. 3535. Lillo P, Mioshi E, Burrell JR, Kiernan MC, Hodges JR, Hornberger M. Grey and white matter changes across the amyotrophic lateral sclerosis-frontotemporal dementia continuum. PLoS One 2012;7:e43993. Further studies are needed to describe putative white matter changes associated withC9ORF72 mutation.

Besides its value for diagnostic purposes, neuroimaging is also important for the understanding of the neural basis of cognitive and behavioral disorders observed in the FTD-ALS spectrum. ALS and bvFTD patients with C9ORF72 mutation have a greater frequency of psychiatric disorders, especially psychotic symptoms, such as delusions, paranoid ideation and hallucinations.55. Solje E, Aaltokallio H, Koivumaa-Honkanen H, et al. The Phenotype of the C9ORF72 Expansion Carriers According to Revised Criteria for bvFTD. PLoS One. 2015;10:e0131817. 1616. Devenney E, Hornberger M, Irish M, et al. JAMA Neurology. 2014;71: 331-339. 2222. Snowden JS, Rollinson S, Thompson JC, et al. Distinct clinical and pathological characteristics of frontotemporal dementia associated with C9ORF72 mutations. Brain 2012;135:693-708. 3636. DOBSON-STONE C, HALLUPP M, BARTLEY L, ET AL. C9ORF72 REPEAT EXPANSION IN CLINICAL AND NEUROPATHOLOGIC FRONTOTEMPORAL DEMENTIA COHORTS. NEUROLOGY 2012;79:995-1001. Indeed, almost 40% of FTD patients withC9ORF72 repeat expansion presented psychotic symptoms.22 Paranoid or irrational thinking were also frequent in the same study.2222. Snowden JS, Rollinson S, Thompson JC, et al. Distinct clinical and pathological characteristics of frontotemporal dementia associated with C9ORF72 mutations. Brain 2012;135:693-708. The neuropsychological profile of bvFTD patients with C9ORF72 expansion is similar to non-carrier bvFTD patients,1616. Devenney E, Hornberger M, Irish M, et al. JAMA Neurology. 2014;71: 331-339. with comparable performance in memory, language and executive skills. Deficits in executive functions are the most common observed feature in ALS-FTD patients33. Goldstein LH, Abrahams S. Changes in cognition and behaviour in amyotrophic lateral sclerosis: nature of impairment and implications for assessment. Lancet Neurol 2013;12:368-380. and can also be associated with prefrontal dysfunction.

Taken together, these data emphasize the complex interaction between C9ORF72mutation and clinical presentations of neurodegenerative diseases, especially the FTD-ALS spectrum. The discovery of the C9ORF72repeat expansion has opened a window for the understanding of the continuum between FTD and ALS. The next advances in neuroimaging investigation may provide valuable markers for the diagnosis and follow-up of these patients, and may also clarify the common pathophysiological pathways between ALS and FTD, with possible clinical outcomes.

Acknowledgments

This study was partly funded by CNPq. We thank the reviewers for their valuable comments on the paper

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    This study was conducted at the Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, MG, Brazil

Publication Dates

  • Publication in this collection
    Oct-Dec 2015

History

  • Received
    01 Aug 2015
  • Accepted
    10 Oct 2015
Academia Brasileira de Neurologia, Departamento de Neurologia Cognitiva e Envelhecimento R. Vergueiro, 1353 sl.1404 - Ed. Top Towers Offices, Torre Norte, São Paulo, SP, Brazil, CEP 04101-000, Tel.: +55 11 5084-9463 | +55 11 5083-3876 - São Paulo - SP - Brazil
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