Email updates

Keep up to date with the latest news and content from Alzheimer's Research & Therapy and BioMed Central.

This article is part of the series The new FTD mutation on chromosome 9.

Review

Cognitive and behavioral features of c9FTD/ALS

Bradley F Boeve1* and Neill R Graff-Radford2

Author Affiliations

1 Department of Neurology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA

2 Department of Neurology, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA

For all author emails, please log on.

Alzheimer's Research & Therapy 2012, 4:29  doi:10.1186/alzrt132


The electronic version of this article is the complete one and can be found online at: http://alzres.com/content/4/4/29


Published:20 July 2012

© 2012 BioMed Central Ltd

Abstract

Numerous kindreds with familial frontotemporal dementia or amyotrophic lateral sclerosis or both have been linked to chromosome 9 (c9FTD/ALS), and an expansion of the GGGGCC hexanucleotide repeat in the non-coding region of chromosome 9 open reading frame 72 (C9ORF72) was identified in the summer of 2011 as the pathogenic mechanism. An avalanche of papers on this disorder is in progress, and a relatively distinctive phenotype is taking form. In this review, we present an illustrative case and summarize the demographic, inheritance, clinical, and behavioral aspects and presumed pathologic underpinnings of c9FTD/ALS on the basis of the available data on more than 250 patients with frontotemporal lobar degeneration syndromes, parkinsonism, or ALS or a combination of these disorders.

Introduction

Familial frontotemporal dementia (FTD) with or without parkinsonism has been associated with mutations in genes encoding microtubule-associated protein tau (MAPT), progranulin (PGRN), and less commonly valosin-containing protein (VCP), TAR DNA-binding protein (TARDBP), and fused in sarcoma (FUS), whereas familial amyotrophic lateral sclerosis (ALS) has been associated with mutations in genes encoding Cu/Zn superoxide dismutase-1 (SOD1), TARDBP, and FUS [1-9]. Although the phenotype of familial FTD or ALS linked to chromosome 9 or both has been appreciated for many years [10-17], the pathogenic genetic mutation remained elusive until two teams of investigators discovered the mechanism in the summer of 2011 and published their findings shortly thereafter [18,19]. The mutation is an expansion of the GGGGCC hexanucleotide repeat in the non-coding intronic region of the chromosome 9 open reading frame 72 (C9ORF72) gene [18,19], and the disease is known as frontotemporal dementia or amyotrophic lateral sclerosis (or both) linked to chromosome 9 (c9FTD/ALS) [18,20]. A number of papers on c9FTD/ALS have already been published, and a relatively distinctive phenotype is becoming clear. In this review, we present an illustrative case from our index kindred and then summarize the demographic, inheritance, clinical, and behavioral aspects of c9FTD/ALS on the basis of the available data.

Illustrative case from index kindred

The identification of the mutation in our index kindred known as the Vancouver-San Francisco-Mayo Clinic family 20 reflects collaborative work that was conducted by several groups of investigators over the course of almost two decades [16]. One case we have followed over the course of seven years illustrates many of the core cognitive, behavioral, neuropsychological, and neuro-imaging features that cases with c9FTD/ALS frequently exhibit.

A right-handed male began experiencing depression and apathy at age 49. He is patient III.2 in the report by Boxer and colleagues [16]. His father developed ALS at age 35 and died after a two-and-a-half-year course. His paternal aunt presented with behavioral variant fronto-temporal dementia (bvFTD) features at age 46 and shortly thereafter with parkinsonism and ALS and died after a nine-year course. His brother had bvFTD, which was diagnosed at age 49, and parkinsonism, which was diagnosed four years later, and is currently residing in a skilled nursing care facility after a seven-year course. Five other relatives have or had FTD, ALS, or parkinsonism or a combination of these disorders.

The patient presented to our institution at age 53, complaining of severe depression and 'lack of pep'. He had lost his job because of apathy and poor decisions. He lived in a rural area and remarked that, owing to boredom since he could not find work, a favorite activity was to sit in a lawn chair in his yard with a cooler of beer adjacent to him, hold a rifle in each arm, and 'shoot anything that moves'. The targets included squirrels, birds, and insects. Despite his wife's best efforts to curb this activity and keep him from consuming alcohol, he continued to do so. This eventually led to a drunk driving charge, and as a result, all weapons were removed from his residence. His driver's license was temporarily suspended, yet he was able to evade the local police and drive his own or friends' cars, apparently never getting lost or having any accidents. After a six-month period with no driving privileges, he successfully completed a driving safety examination. On one occasion, he picked up a hitchhiker who was seeking shelter, brought him home, but refused to allow the hitchhiker in his home and an altercation ensued.

The patient became increasingly suspicious of his family, neighbors, and local police and health-care providers. Owing to his obstinacy, his wife chose to reside in a separate home and his children chose to no longer interact with him. He remarked that he often heard voices, but other than stating that the Lord was telling him to do good deeds, he would not elaborate on the content of these auditory hallucinations as 'you guys will lock me up and throw away the keys'.

His only source of income was disability benefits. His home was in disarray, and he would drive around town obtaining food from fast-food restaurants, but he managed to live independently. He gained more than 50 pounds since the onset of his symptoms because of hyperphagia and the tendency to consume large quantities of potato chips. His family has worked with the local legal authorities in an attempt to transfer oversight of his medical and financial affairs to his wife, but when he went before a judge, the patient successfully argued that he was competent and absolutely did not want anyone overseeing his affairs.

The longitudinal clinical, behavioral, neuropsychological, and neuroimaging findings in this patient are shown in Figures 1 to 3. His presenting features were typical of bvFTD, followed shortly thereafter with left hemiparkinsonism that has evolved to an asymmetric akinetic-rigid syndrome without tremor. Asymmetric corticospinal tract signs have also evolved but without features of lower motor neuron dysfunction. His course has been remarkably slowly progressive. As reflected in his neuropsychological performance over time, his episodic memory and visuospatial functions have remained relatively preserved and this likely has allowed him to live independently despite his psychomotor slowing, executive dysfunction, delusions, hallucinations, apathy, and mild parkinsonism.

thumbnailFigure 1. Longitudinal cognitive, motor, functional, and neuropsychiatric data in an illustrative case in the VSM-20 kindred with c9FTD/ALS. (a) Graphs of longitudinal scores on the Mini-Mental State Exam (MMSE) (maximum of 30) and Kokmen Short Test of Mental Status (STMS) (maximum of 36) of a patient from ages 50 to 57. (b) Global scores on the Clinical Dementia Rating (CDR) scale (maximum of 3) and CDR sum of the boxes (CDR-SOB) (maximum of 18) from ages 50 to 57. (c) Longitudinal summed scores for each assessment on the motor subtest of the Unified Parkinson's Disease Rating Scale (UPDRS) (maximum of 108) from ages 50 to 57. (d) Longitudinal scores and Neuropsychiatric Inventory (NPI) from ages 50 to 55. (At age 57, the patient was estranged from his wife.) The NPI-Present score represents the summed score for the presence (score = 1) or absence (score = 0) of each domain across the 12 domains (maximum of 12), and the NPI-Severity score represents the summed score for the severity rating by the informant (mild = 1, moderate = 2, and severe = 3) for each domain across the 12 domains (maximum of 36). Given that scores of less than 24 on the MMSE and of less than 29 on the STMS are viewed as abnormal, this patient has declined minimally on these screening/global measures of mental status. He has hovered in the very mild (0.5) to mild (1) range on the global CDR, whereas the CDR-SOB score shows the accumulating functional impairment across the six domains measured on the CDR. The UPDRS graph reflects that, at age 50, the patient had subtle parkinsonism that increased in severity through age 52 and that has registered scores of around 30 to 33 in the past five years. His parkinsonian features began as left hemiparkinsonism, which has since evolved to an asymmetric akinetic-rigid syndrome without tremor. None of his parkinsonian features responded to carbidopa-levodopa (750 mg of levodopa per day in divided doses). As reflected in the NPI graph, apathy, depression, and appetite/eating change have been confirmed by his wife to have been present throughout his course (he has gained more than 50 pounds over his illness due to hyperphagia), and the severity of most features has increased in recent years. The dips in frequency and severity on the NPI at age 52 may reflect the effects of quetiapine, which was commenced at age 51. However, despite upward titrations of this agent and many other pharmacologic adjustments, his neuropsychiatric morbidity continues to escalate. c9FTD/ALS, frontotemporal dementia or amyotrophic lateral sclerosis (or both) linked to chromosome 9; VSM-20, Vancouver-San Francisco-Mayo Clinic family 20.

thumbnailFigure 2. Graph of the neuropsychological test scores of the patient at ages 53, 54, 55, and 57. Note the poorer performance on measures of attention/executive functioning and letter fluency, which are typically impaired in those with behavioral variant frontotemporal dementia. Note also the relative stability of performance across most measures. He has been at the 'floor' in letter fluency and Trail Making Test (TMT) forms A and B for the past few years. AVLT, Auditory Verbal Learning Test; BNT, Boston Naming Test; Categ flu, category fluency; DRS 2, Dementia Rating Scale 2; Letter flu, letter fluency; MOANS, Mayo Older American Normative Studies; Rey O, Rey-Osterreith Complex Figure; SD, standard deviation; Stroop CW, Stroop Color-Word Test; WAIS-BD, Wechsler Adult Intelligence Scale-Block Design; WAIS-PC, Wechsler Adult Intelligence Scale-Picture Completion; WMS-R LM % R, Wechsler Memory Scale-Revised, Logical Memory, percentage retention; WMS-R VR % R, Wechsler Memory Scale-Revised, Visual Reproduction, percentage retention.

thumbnailFigure 3. Neuroimaging findings in an illustrative case in the VSM-20 kindred with c9FTD/ALS. (a) Axial fluid attenuation inversion recovery magnetic resonance images (top row) and coronal T1-weighted magnetic resonance images (bottom row) demonstrating the minimal atrophy in the frontal and temporal lobes at ages 50, 53, and 57. (b) Flourodeoxyglucose positron emission tomography scan images of the brain at age 57. The color scheme on the left side of the set of images shows the relative degree of hypometabolism. Areas in black and blue are considered to be within normal limits, areas in green are considered mildly abnormal, areas in yellow are considered moderately abnormal, and areas in orange and red are considered markedly abnormal. Note the relatively mild and symmetric hypometabolism in the frontal, temporal, parietal, and cingulate cortices; this is remarkable given that this scan was performed eight years after the onset of symptoms. c9FTD/ALS, frontotemporal dementia or amyotrophic lateral sclerosis (or both) linked to chromosome 9; VSM-20, Vancouver-San Francisco-Mayo Clinic family 20.

Neuroimaging findings mirror this remarkably slow clinical progression. Very minimal atrophy has evolved over the course of seven years of serial magnetic resonance imaging (MRI) scans. A flourodeoxyglucose positron emission tomography (FDG-PET) scan image of the brain, performed eight years after the onset of his symptoms, shows relatively mild frontal, parietal, and cingulate cortex hypometabolism.

Literature review

We reviewed reports with ample numbers of cases having a dementia-predominant phenotype, published through March 2012. Reports focused on ALS with cognitive and behavioral data were also included. We identified nine recent publications meeting these criteria [20-28], and a summary of the core features associated with c9FTD/ALS is shown in Table 1.

Table 1. Key features of c9FTD/ALS due to the GGGGCC hexanucleotide repeat expansion in C9ORF72 across published series with ample numbers of cases with the FTD ± ALS phenotype

Cohort characteristics

More than 250 subjects among more than 230 kindreds with sufficient cognitive/behavioral data are included in these reports to be summarized and reviewed for general consistencies [20-22,24-29]. This accumulation of hundreds of subjects is in itself striking given that these data have been published within seven months since the publication of the landmark papers on the C9ORF72 mutation [18,19]; similar data exist for FTD associated with mutations in the gene encoding MAPT among 134 kindreds since the original report on MAPT mutations in 1996 [1] and in the gene encoding PGRN among 231 kindreds since the original reports on PGRN mutations in 2006 [2,3,30].

Among those series in which the frequency of the C9ORF72 mutation was assessed (some also compared this frequency with the frequency of mutations in MAPT and PGRN), the frequency was calculated as sporadic or familial or both; also, the frequency of FTD ± parkinsonism ± ALS was calculated [21,22,24-29]. Most reports state that the C9ORF72 mutation frequency is in the 7% to 12% range compared with the 6% to 10% range for MAPT and the 4% to 7% range for PGRN. These frequencies increase to 13% to 26% for C9ORF72, 11% to 22% for MAPT, and 6% to 22% for PGRN when the frequencies of mutations among familial FTD cases are considered. Importantly, despite the recruitment and analyses of familial FTD cases during at least the past 20 years among several teams focused on this issue, the frequency of familial cases without an identified genetic mechanism is in the 45% to 66% range, thereby providing ample reasons to continue research in familial FTD.

Demographic characteristics

The male-to-female ratio on cumulative cases among FTD ± parkinsonism ± ALS suggests a slight male predominance (129:105 or 1.23:1). In different series, the mean/median age of onset is in the 52- to 65-year age range, and the range of age of onset is wide (33 to 78 years). Survival mean/median values are in the 5- to 9-year range, and the range of survival also is wide (1 to 22 years). The illustrative case above exemplifies the slow course and long survival of some individuals. In the reports in which this was assessed, those with FTD and concomitant ALS tended to have shorter survival, as one would expect.

Inheritance characteristics

The disorder of c9FTD/ALS is inherited in an autosomal dominant fashion with high but not complete penetrance, and sporadic cases have been identified in every report published to date. Many reports document families in which succeeding generations appear to have a younger age of onset; hence, these reports suggest genetic anticipation [21,25,29]. Given that c9FTD/ALS involves a polynucleotide repeat expansion mechanism, it stands to reason that anticipation could occur. The challenge among geneticists is to resolve the technical aspects of quantifying the number of repeats in this mutation but this has been difficult. One can easily hypothesize that, with increasing numbers of repeats, an earlier age of onset would occur, but this awaits confirmation.

Clinical phenotype

Clearly, the predominant dementia phenotype is the classic bvFTD syndrome [31,32]. Many have some degree of parkinsonism, which is typically of the akinetic-rigid type without tremor and is levodopa-unresponsive [21]. Others have elements or the full clinical picture of ALS. This phenotype has not yet been reported in c9FTD/ALS, in contrast to FTD with or without parkinsonism associated with MAPT and PGRN mutations, in which a primary parkinsonian phenotype can occur. Most series do not have any cases with a primary progressive aphasia (PPA) phenotype, although this has been encountered rarely in some series [25-28]. Only one case of the corticobasal syndrome phenotype [33] has been reported in c9FTD/ALS [16]. Though rare, the amnestic presentation diagnosed clinically as probable Alzheimer's disease has been observed across many in the series [20,21,25,26], including one analysis focused on late-onset Alzheimer's disease [34]. The phenotype of dementia with Lewy bodies was reported in a few cases in one series [20]. These observations suggest that the C9ORF72 mutation can manifest as a variety of dementia phenotypes as well as pure ALS, but the vast majority have the core syndrome of bvFTD ± parkinsonism ± ALS.

Cognitive features

The classic bvFTD phenotype involves executive dysfunction and word retrieval difficulties with relative sparing of memory and visuospatial functioning [31,32], as exemplified by our illustrative case. Degeneration of the dorsomedial and dorsolateral cortices and their afferent and efferent connections - two of the critical frontosubcortical neural networks involved in executive functioning, word retrieval, psychomotor speed, motivation, and so on - is the likely substrate underlying the typical bvFTD cognitive features. In some c9FTD/ALS cases, this classic phenotype is not always exhibited, owing mainly to memory being impaired [20,21,25-28]. Visuo-spatial dysfunction is present in a minority of cases [21,25-28]. In addition to bifrontal and cingulate cortex atrophy, parietal cortex atrophy is part of the signature pattern on MRI [35] and this likely explains visuospatial dysfunction, but memory impairment is harder to explain. The determination of whether memory is impaired varies on the basis of clinical evaluation, neuropsychological testing, and which tests are used. For example, one can consider the older and more simplistic rubric that memory impairment is due to an encoding versus retrieval deficit. A deficit in encoding implicates the mesial temporal lobe structures with or without other structures in the limbic system such as the medial thalamus, whereas a retrieval deficit implicates the frontosubcortical neural networks. Most cases of c9FTD/ALS have clinical, neuropsychological, and neuroimaging features implicating the frontosubcortical neural networks, and thus a retrieval deficit would be expected, and in one study in which neuropsychological tests were performed in many c9FTD/ALS subjects, performance on delayed recall measures was usually normal [21]. Yet many cases exhibit poor performance on delayed recall measures as well as on recognition of stimuli [26-28], suggesting an encoding deficit, yet the medial temporal lobes tend to be relatively spared, according to neuroimaging studies conducted thus far [21,26,35]. However, pathologic studies show that hippocampal sclerosis is frequent and associated with those presenting with an amnestic disorder [20]. This issue is reviewed in more detail in the section on 'Neuropathologic features and their clinical relevance'.

Another challenge is understanding the executive dysfunction in mutation carriers who have the bvFTD phenotype yet no apparent frontotemporal atrophy on MRI or hypometabolism on FDG-PET [21]. The pathologic findings, however, provide evidence that frontal atrophy is indeed more frequent with this phenotype. One hypothesis is that the executive deficits are due, in part, to primary cerebellar dysfunction akin to the cerebellar cognitive affective syndrome [36-38]. All pathologic studies in c9FTD/ALS have shown widespread ubiquitin-positive inclusions in the cerebellum, and this could contribute to 'frontal' dysfunction (see section on 'Neuropathologic features and their clinical relevance'). Furthermore, while neuroimaging studies clearly include the cerebellum as part of the signature pattern of atrophy [26,35], cerebellar degeneration per se tends to be minimal on pathologic analyses, and other clinical features of cerebellar dysfunction, such as limb or truncal ataxia, limb dysmetria, ataxic dysarthria, and nystagmus, have not been appreciated in affected cases. Understanding the mechanism for executive dysfunction in c9FTD/ALS cases with minimal or no frontotemporal atrophy will require further study.

Language impairment is relatively common in c9FTD/ALS but is rarely the predominant phenotype; aphasia typically evolves as the illness progresses. When the primary progressive aphasia syndrome is the predominant phenotype, it is typically of the non-fluent/agrammatic type [25-28]. Non-fluent/agrammatic aphasia relates to degeneration of Broca's area or the insula in the dominant hemisphere or both, and in those with a predominant non-fluent/agrammatic PPA phenotype, neuroimaging studies demonstrate this topography of atrophy or hypometabolism [39-44]. However, such PPA phenotype cases in c9FTD/ALS have not been well characterized with detailed speech/language assessments and neuroimaging studies, and so this remains to be seen. Furthermore, symmetric neuroimaging abnormalities are the rule and asymmetric findings are the exception [21,26,35], and so these PPA cases could be the exceptions with focal/asymmetric dominant hemisphere degeneration. One might also predict that if a bilateral and relatively symmetric pattern of degeneration has ensued and if the key anterior language networks are affected, then a non-fluent/agrammatic phenotype could be present. Also, the dominant hemisphere supplementary motor area has recently been implicated in the primary progressive apraxia of speech phenotype [45,46], and this could easily be construed to represent non-fluent aphasia; mesial frontal atrophy/hypoperfusion/hypometabolism is part of the signature pattern of topography in c9FTD/ALS [21,26,35], and so this mechanism is quite plausible. This is yet another area worthy of further research.

Behavioral features

The overwhelming majority of cases with a dementia syndrome-predominant phenotype as part of c9FTD/ALS manifest the full spectrum of the bvFTD features [31,32]: early behavioral disinhibition, early apathy or inertia, early loss of sympathy or empathy, and hyperorality and dietary changes. The dorsolateral prefrontal cortex, orbitofrontal cortex, and anterior cingulate cortex are typically affected, according to neuroimaging and neuropathologic studies [20,21,26,35], and this topography readily explains the full bvFTD spectrum of behavioral features. Yet there are those who do not have neuroimaging evidence of frontal atrophy or hypometabolism [21], and as noted above, perhaps the cerebellar degeneration contributes to these behavioral features similar to the hypothesis that such degeneration might explain executive dysfunction. These 'frontally impaired but frontally normal on neuroimaging' cases clearly deserve ample study, as understanding the neuroanatomic correlates of their impairment will not only aid in understanding the disease of c9FTD/ALS but also enhance our understanding of brain-behavior correlations in general.

A few investigators have observed that some c9FTD/ALS cases exhibit the most bizarre behavioral manifestations they have ever witnessed among all of the bvFTD patients they have cared for [21,28]. Psychotic features, obsessive-compulsive behaviors, odd ritualistic behaviors, and so on are often striking. A summary of observations by clinicians is presented in Table 2.

Table 2. Descriptions of dramatic behavioral manifestations associated with c9FTD/ALS

Other clinical features

Whereas the documentation of other clinical features varied across reports, many cases with frontal release signs, parkinsonism, upper or lower motor neuron dysfunction (or both) not fulfilling criteria for ALS, and the full ALS phenotype were observed. Limb apraxia was rarely documented.

Atypical features

Atypical features are already emerging. A very interesting (and, for many clinicians, somewhat frightening) finding is the identification of the C9ORF72 mutation in rare cases of the FTD phenocopy syndrome [47]. The FTD phenocopy refers to those individuals who clearly exhibit cognitive and behavioral changes suggestive of bvFTD, but neuropsychological tests and neuroimaging studies tend to be more normal than not during the initial years of symptoms [48,49]. The 'typical' FTD phenocopy patient does not show progression on longitudinal clinical, neuropsychological, and neuroimaging evaluations, and such cases are now considered to usually have a non-degenerative substrate for their features. When first encountering patients who clearly have bvFTD features but no corroborating evidence of an underlying neurodegenerative disorder, the clinician is faced with the obvious challenge of establishing a confident diagnosis and predicting what the future holds. And since so few cases have come to autopsy, the underlying substrate for their symptoms has not been well characterized. The two cases recently reported with the FTD phenocopy associated with the C9ORF72 mutation are very intriguing [47], not only because such atypical FTD cases do have a neurodegenerative disorder underlying their symptoms but also because of the number of atypical FTD cases who have surely been suspected by seasoned clinicians to have a primary psychiatric disorder. Clinical testing is now commercially available for C9ORF72 mutation detection, and more FTD phenocopy and other atypical neurobehavioral syndromes will undoubtedly be identified with this mutation.

Neuropathologic features and their clinical relevance

Neuropathologic studies in c9FTD/ALS have shown many consistent findings yet also some unexpected, variable, and curious findings. All cases studied to date - except one (see below) - have had TDP-43 pathology associated with frontal and variable parietal or temporal cortical atrophy (or both) and microscopic evidence of neurodegeneration [20,21,25-28,50-55]. Many have evidence of upper or lower motor neuron degeneration (or both) that may or may not have been appreciated antemortem, but this finding underscores the involvement of the brain and spinal cord motor systems in this disease and also emphasizes the overlapping spectrum of FTD and ALS. Degeneration of the substantia nigra is also common and likely explains the presence of parkinsonism in the significant minority of cases who have parkinsonism. A few cases have had coexisting Alzheimer's disease pathology. One case with an apparent hexanucleotide expansion has been described in association with corticobasal degeneration pathology [28]; hopefully, additional details will be presented in the future to better understand this single case with non-TDP pathology.

Unexpected findings in c9FTD/ALS are the variable histologic features across cases [20,21,25,27,51-53]. Earlier studies suggested that all chromosome 9-linked FTD/ALS cases had a moderate degree of cortical neurons with neuronal cytoplasmic inclusions and relatively few dystrophic neurites across all cortical layers (which is characteristic of Mackenzie type 3, Sampathu type 2, and harmonized type B FTLD-TDP pathology) [56,57], yet approximately half of c9FTD/ALS cases have had many neurons with neuronal cytoplasmic inclusions and many dystrophic neurites in the cortex, especially in layer 2 (which is characteristic of Mackenzie type 1, Sampathu type 3, and harmonized type A FTLD-TDP pathology and most often associated with mutations in PGRN) [20,21,57]. Why this variability exists is not understood, but this finding suggests that there is not a distinctive set of histologic features for c9FTD/ALS based on TDP-positive inclusions alone.

One of the most unexpected and still curious findings in c9FTD/ALS cases is the predominance of ubiquitin-positive inclusions in the cerebellum, which far exceeds the density of TDP-positive inclusions [20,21,50,51,53,58]. The ubiquitin-positive inclusions also stain positively for ubiquilin and p62 immunohistochemistry, suggesting a pathophysiological link between C9ORF72 expansions and ubiquilin proteins in ALS and FTLD-TDP [20,50,51,53,58]. Yet the degree of neuronal loss in cerebellar structures has been mild to negligible and this may explain why classic cerebellar signs such as ataxia, dysmetria, and nystagmus have not been appreciated or reported. However, the finding of ubiquitin-, ubiquilin-, and p62-positive inclusions in the cerebellum has been present in almost every case in which such immuno-histochemistry has been used. Hence, these cerebellar inclusions are now viewed as a highly sensitive and specific marker for the presence of the C9ORF72 mutation.

The cognitive and behavioral features and their known or presumed neuropathologic substrates are described above in the respective sections, but again, the typical cognitive features (executive dysfunction and word retrieval deficits) likely relate to degeneration in the dorsomedial and dorsolateral frontosubcortical networks, and the typical behavioral features (impaired social cognition, prominent apathy, and so on) likely relate to these and other frontosubcortical networks such as the orbitomedial frontal and anterior cingulate circuits. Furthermore, the von Economo neurons in the anterior cingulate and insular regions have been implicated in impaired social cognition [59-61]. These clinical-topography associations are very plausible when abnormalities on MRI, single-photon emission computed tomography, or PET correspond to the specific features that are present in individual cases.

The more challenging circumstance is when obvious cognitive or behavioral changes or both are present and the neuroimaging studies are normal regardless of whether any patient has an obvious neurologic cause or has the less obvious FTD phenocopy syndrome. Memory impairment is not typical of the bvFTD syndrome but is often present in c9FTD/ALS cases; as discussed above, this could relate to hippocampal sclerosis or a retrieval-based deficit due to frontosubcortical dysfunction. Also, even when hippocampal sclerosis is not present, an encoding deficit could relate to dysfunction associated with ubiquitin-, ubiquilin-, and p62-positive inclusions in the hippocampus [53]. Dysfunction associated with these inclusions in the cerebellum as part of the cerebellar cognitive affective syndrome is also possible. This will be challenging to prove or disprove until radioligands that tag these key proteins are available for functional neuroimaging studies [47].

Summary

A summary of the salient features of the FTD-predominant phenotype of c9FTD/ALS due to the GGGGCC hexanucleotide repeat expansion in C9ORF72 is presented in Table 3.

Table 3. Salient features of the FTD-predominant phenotype of c9FTD/ALS due to the GGGGCC hexanucleotide repeat expansion in C9ORF72

Clues for the clinician to suspect the C9ORF72 mutation

An important consideration for any clinician evaluating a patient for changes in cognition, behavior, or neuromuscular functioning is when to be suspicious of the mutation in C9ORF72. Clinical clues that should raise suspicion are listed in Table 4.

Table 4. Clues that should alert clinicians to suspect the hexanucleotide repeat expansion in C9ORF72 in individual patients

Future directions

With any discovery, 'one question answered poses ten new questions' and this is clearly the case in many aspects of c9FTD/ALS. A list of some issues worthy of further study is presented in Table 5. Our hope is that the observations in this review based on what has been published thus far help steer investigators to answer these and other questions associated with this fascinating disorder.

Table 5. Issues worthy of further study in c9FTD/ALS

Abbreviations

ALS: amyotrophic lateral sclerosis; bvFTD: behavioral variant frontotemporal dementia; c9FTD/ALS: frontotemporal dementia or amyotrophic lateral sclerosis (or both) linked to chromosome 9; C9ORF72: (gene encoding the mutation in) chromosome 9 open reading frame 72; FDG-PET: flourodeoxyglucose positron emission tomography; FTD: frontotemporal dementia; FTD/ALS: frontotemporal dementia or amyotrophic lateral sclerosis or both; FTLD-MND: frontotemporal lobar degeneration with motor neuron disease; FUS: fused in sarcoma; GGGGCC: (the hexanucleotide expansion of ) guanine-guanine-guanine-guanine-cytosine-cytosine; MAPT: microtubule-associated protein tau; MRI: magnetic resonance imaging; PET: positron emission tomography; PGRN: progranulin; PPA: primary progressive aphasia; TARDBP: TAR DNA-binding protein.

Competing interests

This paper was supported by P50 AG016574. Ronald C Petersen is the principal investigator. BFB declares that he has no competing interests. He has served as an investigator for clinical trials sponsored by Cephalon, Inc. (Frazer, PA, USA), Allon Pharmaceuticals Inc. (Vancouver, BC, Canada), and GE Healthcare (Little Chalfont, Buckinghamshire, UK). He receives royalties from the publication of a book entitled the Behavioral Neurology of Dementia (Cambridge: Cambridge University Press; 2009). He has received honoraria from the American Academy of Neurology. NRG-R declares that he has no competing interests. He is on the scientific advisory board of Codman (part of DePuy Orthopaedics, Inc, Warsaw, IN, USA) and is chair of the data and safety monitoring board of Baxter (Deerfield, IL, USA) regarding an IGIV (immune globulin administered intravenously) trial in Alzheimer's disease, an editor for the Neurologist, and part of multicenter trials for Allon Pharmaceuticals Inc. (progressive supranuclear palsy), Janssen (Titusville, NJ, USA), Pfizer Inc (New York, NY, USA) (bapineuzumab for Alzheimer's disease), and Forest Laboratories, Inc. (New York, NY, USA) using memantine in frontotemporal dementia.

Authors' contributions

Both authors contributed to the analysis and views expressed in this review. BFB drafted the manuscript, and NRG-R revised it critically. Both authors read and approved the final manuscript.

Acknowledgements

This work was supported by the 'Mayo Alzheimer's Disease Research Center' (P50 AG016574), the 'Mayo Alzheimer's Disease Patient Registry' (UO1 AG006786), 'Identifying Mechanisms of Dementia: Role for MRI in the Era of Molecular Imaging' (RO1 AG011378), and the Robert H. and Clarice Smith and Abigail Van Buren Alzheimer's Disease Research Program of the Mayo Foundation. We thank our many collaborators across the Mayo Clinic sites in Rochester, MN; Jacksonville, FL; and Scottsdale, AZ. We thank Ian Mackenzie, Adam Boxer, and Bruce Miller for collaborating on the VSM-20 (Vancouver-San Francisco-Mayo Clinic family 20) kindred. We particularly thank the patients and their families for participating in aging and neurodegenerative disease research.

References

  1. Hutton M, Lendon CL, Rizzu P, Baker M, Froelich S, Houlden H, Pickering-Brown S, Chakraverty S, Isaacs A, Grover A, Hackett J, Adamson J, Lincoln S, Dickson D, Davies P, Petersen RC, Stevens M, de Graaff E, Wauters E, van Baren J, Hillebrand M, Joosse M, Kwon JM, Nowotny P, Che LK, Norton J, Morris JC, Reed LA, Trojanowski J, Basun H, et al.: Association of missense and 5'-splicesite mutations in tau with the inherited dementia FTDP-17.

    Nature 1998, 393:702-705. PubMed Abstract | Publisher Full Text OpenURL

  2. Baker M, Mackenzie IR, Pickering-Brown SM, Gass J, Rademakers R, Lindholm C, Snowden J, Adamson J, Sadovnick AD, Rollinson S, Cannon A, Dwosh E, Neary D, Melquist S, Richardson A, Dickson D, Berger Z, Eriksen J, Robinson T, Zehr C, Dickey CA, Crook R, McGowan E, Mann D, Boeve B, Feldman H, Hutton M: Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17.

    Nature 2006, 442:916-919. PubMed Abstract | Publisher Full Text OpenURL

  3. Cruts M, Gijselinck I, van der Zee J, Engelborghs S, Wils H, Pirici D, Rademakers R, Vandenberghe R, Dermaut B, Martin JJ, van Duijn C, Peeters K, Sciot R, Santens P, De Pooter T, Mattheijssens M, Van den Broeck M, Cuijt I, Vennekens K, De Deyn PP, Kumar-Singh S, Van Broeckhoven C: Null mutations in progranulin cause ubiquitin positive frontotemporal dementia linked to chromosome 17q21.

    Nature 2006, 442:920-924. PubMed Abstract | Publisher Full Text OpenURL

  4. Watts G, Wymer J, Kovach M, Mehta S, Mumm S, Darvish D, Pestronk A, Whyte M, Kimonis V: Inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia is caused by mutant valosin-containing protein.

    Nat Genet 2004, 36:377-381. PubMed Abstract | Publisher Full Text OpenURL

  5. Sreedharan J, Blair IP, Tripathi VB, Hu X, Vance C, Rogelj B, Ackerley S, Durnall JC, Williams KL, Buratti E, Baralle F, de Belleroche J, Mitchell JD, Leigh PN, Al-Chalabi A, Miller CC, Nicholson G, Shaw CE: TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis.

    Science 2008, 319:1668-1672. PubMed Abstract | Publisher Full Text OpenURL

  6. Kabashi E, Valdmanis PN, Dion P, Spiegelman D, McConkey BJ, Vande Velde C, Bouchard JP, Lacomblez L, Pochigaeva K, Salachas F, Pradat PF, Camu W, Meininger V, Dupre N, Rouleau GA: TARDBP mutations in individuals with sporadic and familial amyotrophic lateral sclerosis.

    Nat Genet 2008, 40:572-574. PubMed Abstract | Publisher Full Text OpenURL

  7. Kwiatkowski TJ Jr, Bosco DA, Leclerc AL, Tamrazian E, Vanderburg CR, Russ C, Davis A, Gilchrist J, Kasarskis EJ, Munsat T, Valdmanis P, Rouleau GA, Hosler BA, Cortelli P, de Jong PJ, Yoshinaga Y, Haines JL, Pericak-Vance MA, Yan J, Ticozzi N, Siddique T, McKenna-Yasek D, Sapp PC, Horvitz HR, Landers JE, Brown RH Jr: Mutations in the FUS/TLS gene on chromosome 16 cause familial amyotrophic lateral sclerosis.

    Science 2009, 323:1205-1208. PubMed Abstract | Publisher Full Text OpenURL

  8. Vance C, Rogelj B, Hortobágyi T, De Vos KJ, Nishimura AL, Sreedharan J, Hu X, Smith B, Ruddy D, Wright P, Ganesalingam J, Williams KL, Tripathi V, Al-Saraj S, Al-Chalabi A, Leigh PN, Blair IP, Nicholson G, de Belleroche J, Gallo JM, Miller CC, Shaw CE: Mutations in FUS, an RNA processing protein, cause familial amyotrophic lateral sclerosis type 6.

    Science 2009, 323:1208-1211. PubMed Abstract | Publisher Full Text OpenURL

  9. Rosen DR, Siddique T, Patterson D, Figlewicz DA, Sapp P, Hentati A, Donaldson D, Goto J, O'Regan JP, Deng HX, Rahmani Z, Krizus A, McKenna-Yasek D, Cayabyab A, Gaston SM, Berger R, Tanzi RE, Halperin JJ, Herzfeldt B, Van den Bergh R, Hung WY, Bird T, Deng G, Mulder DW, Smyth C, Laing NG, Soriano E, Pericak-Vance MA, Haines J, Rouleau GA, et al.: Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis.

    Nature 1993, 362:59-62. PubMed Abstract | Publisher Full Text OpenURL

  10. Morita M, Al-Chalabi A, Andersen PM, Hosler B, Sapp P, Englund E, Mitchell JE, Habgood JJ, de Belleroche J, Xi J, Jongjaroenprasert W, Horvitz HR, Gunnarsson LG, Brown RH Jr: A locus on chromosome 9p confers susceptibility to ALS and frontotemporal dementia.

    Neurology 2006, 66:839-844. PubMed Abstract | Publisher Full Text OpenURL

  11. Vance C, Al-Chalabi A, Ruddy D, Smith BN, Hu X, Sreedharan J, Siddique T, Schelhaas HJ, Kusters B, Troost D, Baas F, de Jong V, Shaw CE: Familial amyotrophic lateral sclerosis with frontotemporal dementia is linked to a locus on chromosome 9p13.2-21.3.

    Brain 2006, 129:868-876. PubMed Abstract | Publisher Full Text OpenURL

  12. Valdmanis P, Dupre N, Bouchard J, Camu W, Salachas F, Meininger V, Strong M, Rouleau G: Three families with amyotrophic lateral sclerosis and frontotemporal dementia with evidence of linkage to chromosome 9p.

    Arch Neurol 2007, 64:240-245. PubMed Abstract | Publisher Full Text OpenURL

  13. Luty AA, Kwok JB, Thompson EM, Blumbergs P, Brooks WS, Loy CT, Dobson-Stone C, Panegyres PK, Hecker J, Nicholson GA, Halliday GM, Schofield PR: Pedigree with frontotemporal lobar degeneration--motor neuron disease and Tar DNA binding protein-43 positive neuropathology: genetic linkage to chromosome 9.

    BMC Neurol 2008, 8:32. PubMed Abstract | BioMed Central Full Text | PubMed Central Full Text OpenURL

  14. Le Ber I, Camuzat A, Berger E, Hannequin D, Laquerrière A, Golfier V, Seilhean D, Viennet G, Couratier P, Verpillat P, Heath S, Camu W, Martinaud O, Lacomblez L, Vercelletto M, Salachas F, Sellal F, Didic M, Thomas-Anterion C, Puel M, Michel BF, Besse C, Duyckaerts C, Meininger V, Campion D, Dubois B, Brice A, French Research Network on FTD/FTD-MND: Chromosome 9p-linked families with frontotemporal dementia associated with motor neuron disease.

    Neurology 2009, 72:1669-1676. PubMed Abstract | Publisher Full Text OpenURL

  15. Gijselinck I, Engelborghs S, Maes G, Cuijt I, Peeters K, Mattheijssens M, Joris G, Cras P, Martin JJ, De Deyn PP, Kumar-Singh S, Van Broeckhoven C, Cruts M: Identification of 2 Loci at chromosomes 9 and 14 in a multiplex family with frontotemporal lobar degeneration and amyotrophic lateral sclerosis.

    Arch Neurol 2010, 67:606-616. PubMed Abstract | Publisher Full Text OpenURL

  16. Boxer AL, Mackenzie IR, Boeve BF, Baker M, Seeley WW, Crook R, Feldman H, Hsiung GY, Rutherford N, Laluz V, Whitwell J, Foti D, McDade E, Molano J, Karydas A, Wojtas A, Goldman J, Mirsky J, Sengdy P, Dearmond S, Miller BL, Rademakers R: Clinical, neuroimaging and neuropathological features of a new chromosome 9p-linked FTD-ALS family.

    J Neurol Neurosurg Psychiatry 2011, 82:196-203. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  17. Pearson JP, Williams NM, Majounie E, Waite A, Stott J, Newsway V, Murray A, Hernandez D, Guerreiro R, Singleton AB, Neal J, Morris HR: Familial frontotemporal dementia with amyotrophic lateral sclerosis and a shared haplotype on chromosome 9p.

    J Neurol 2011, 258:647-655. PubMed Abstract | Publisher Full Text OpenURL

  18. DeJesus-Hernandez M, Mackenzie IR, Boeve BF, Boxer AL, Baker M, Rutherford NJ, Nicholson AM, Finch NA, Flynn H, Adamson J, Kouri N, Wojtas A, Sengdy P, Hsiung GY, Karydas A, Seeley WW, Josephs KA, Coppola G, Geschwind DH, Wszolek ZK, Feldman H, Knopman DS, Petersen RC, Miller BL, Dickson DW, Boylan KB, Graff-Radford NR, Rademakers R: Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS.

    Neuron 2011, 72:245-256. PubMed Abstract | Publisher Full Text OpenURL

  19. Renton AE, Majounie E, Waite A, Simón-Sánchez J, Rollinson S, Gibbs JR, Schymick JC, Laaksovirta H, van Swieten JC, Myllykangas L, Kalimo H, Paetau A, Abramzon Y, Remes AM, Kaganovich A, Scholz SW, Duckworth J, Ding J, Harmer DW, Hernandez DG, Johnson JO, Mok K, Ryten M, Trabzuni D, Guerreiro RJ, Orrell RW, Neal J, Murray A, Pearson J, Jansen IE, et al.: A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD.

    Neuron 2011, 72:257-268. PubMed Abstract | Publisher Full Text OpenURL

  20. Murray ME, DeJesus-Hernandez M, Rutherford NJ, Baker M, Duara R, Graff-Radford NR, Wszolek ZK, Ferman TJ, Josephs KA, Boylan KB, Rademakers R, Dickson DW: Clinical and neuropathologic heterogeneity of c9FTD/ALS associated with hexanucleotide repeat expansion in C9ORF72.

    Acta Neuropathol 2011, 122:673-690. PubMed Abstract | Publisher Full Text OpenURL

  21. Boeve BF, Boylan KB, Graff-Radford NR, DeJesus-Hernandez M, Knopman DS, Pedraza O, Vemuri P, Jones D, Lowe V, Murray ME, Dickson DW, Josephs KA, Rush BK, Machulda MM, Fields JA, Ferman TJ, Baker M, Rutherford NJ, Adamson J, Wszolek ZK, Adeli A, Savica R, Boot B, Kuntz KM, Gavrilova R, Reeves A, Whitwell J, Kantarci K, Jack CR Jr, Parisi JE, et al.: Characterization of frontotemporal dementia and/or amyotrophic lateral sclerosis associated with the GGGGCC repeat expansion in C9ORF72.

    Brain 2012, 135:765-783. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  22. Byrne S, Elamin M, Bede P, Shatunov A, Walsh C, Corr B, Heverin M, Jordan N, Kenna K, Lynch C, McLaughlin RL, Iyer PM, O'Brien C, Phukan J, Wynne B, Bokde AL, Bradley DG, Pender N, Al-Chalabi A, Hardiman O: 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. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  23. Chiò A, Borghero G, Restagno G, Mora G, Drepper C, Traynor BJ, Sendtner M, Brunetti M, Ossola I, Calvo A, Pugliatti M, Sotgiu MA, Murru MR, Marrosu MG, Marrosu F, Marinou K, Mandrioli J, Sola P, Caponnetto C, Mancardi G, Mandich P, La Bella V, Spataro R, Conte A, Monsurrò MR, Tedeschi G, Pisano F, Bartolomei I, Salvi F, Lauria Pinter G, et al.: Clinical characteristics of patients with familial amyotrophic lateral sclerosis carrying the pathogenic GGGGCC hexanucleotide repeat expansion of C9ORF72.

    Brain 2012, 135:784-793. PubMed Abstract | Publisher Full Text OpenURL

  24. Gijselinck I, Van Langenhove T, van der Zee J, Sleegers K, Philtjens S, Kleinberger G, Janssens J, Bettens K, Van Cauwenberghe C, Pereson S, Engelborghs S, Sieben A, De Jonghe P, Vandenberghe R, Santens P, De Bleecker J, Maes G, Bäumer V, Dillen L, Joris G, Cuijt I, Corsmit E, Elinck E, Van Dongen J, Vermeulen S, Van den Broeck M, Vaerenberg C, Mattheijssens M, Peeters K, Robberecht W, et al.: A C9orf72 promoter repeat expansion in a Flanders-Belgian cohort with disorders of the frontotemporal lobar degeneration-amyotrophic lateral sclerosis spectrum: a gene identification study.

    Lancet Neurol 2012, 11:54-65. PubMed Abstract | Publisher Full Text OpenURL

  25. Hsiung GY, DeJesus-Hernandez M, Feldman HH, Sengdy P, Bouchard-Kerr P, Dwosh E, Butler R, Leung B, Fok A, Rutherford NJ, Baker M, Rademakers R, Mackenzie IR: Clinical and pathological features of familial frontotemporal dementia caused by C9ORF72 mutation on chromosome 9p.

    Brain 2012, 135:709-722. PubMed Abstract | Publisher Full Text OpenURL

  26. Mahoney CJ, Beck J, Rohrer JD, Lashley T, Mok K, Shakespeare T, Yeatman T, Warrington EK, Schott JM, Fox NC, Rossor MN, Hardy J, Collinge J, Revesz T, Mead S, Warren JD: Frontotemporal dementia with the C9ORF72 hexanucleotide repeat expansion: clinical, neuroanatomical and neuropathological features.

    Brain 2012, 135:736-750. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  27. Simón-Sánchez J, Dopper EG, Cohn-Hokke PE, Hukema RK, Nicolaou N, Seelaar H, de Graaf JR, de Koning I, van Schoor NM, Deeg DJ, Smits M, Raaphorst J, van den Berg LH, Schelhaas HJ, De Die-Smulders CE, Majoor-Krakauer D, Rozemuller AJ, Willemsen R, Pijnenburg YA, Heutink P, van Swieten JC: The clinical and pathological phenotype of C9ORF72 hexanucleotide repeat expansions.

    Brain 2012, 135:723-735. PubMed Abstract | Publisher Full Text OpenURL

  28. Snowden JS, Rollinson S, Thompson JC, Harris JM, Stopford CL, Richardson AM, Jones M, Gerhard A, Davidson YS, Robinson A, Gibbons L, Hu Q, DuPlessis D, Neary D, Mann DM, Pickering-Brown SM: Distinct clinical and pathological characteristics of frontotemporal dementia associated with C9ORF72 mutations.

    Brain 2012, 135:693-708. PubMed Abstract | Publisher Full Text OpenURL

  29. Ferrari R, Mok K, Moreno JH, Cosentino S, Goldman J, Pietrini P, Mayeux R, Tierney MC, Kapogiannis D, Jicha GA, Murrell JR, Ghetti B, Wassermann EM, Grafman J, Hardy J, Huey ED, Momeni P: Screening for C9ORF72 repeat expansion in FTLD.

    Neurobiol Aging 2012, 33:1850.e1-1850.e11. PubMed Abstract | Publisher Full Text OpenURL

  30. Alzheimer Disease & Frontotemporal Dementia Mutation Database [http://www.molgen.ua.ac.be/Admutations/] webcite

  31. Neary D, Snowden JS, Gustafson L, Passant U, Stuss D, Black S, Freedman M, Kertesz A, Robert PH, Albert M, Boone K, Miller BL, Cummings J, Benson DF: Frontotemporal lobar degeneration: a consensus on clinical diagnostic criteria.

    Neurology 1998, 51:1546-1554. PubMed Abstract | Publisher Full Text OpenURL

  32. Rascovsky K, Hodges JR, Knopman D, Mendez MF, Kramer JH, Neuhaus J, van Swieten JC, Seelaar H, Dopper EG, Onyike CU, Hillis AE, Josephs KA, Boeve BF, Kertesz A, Seeley WW, Rankin KP, Johnson JK, Gorno-Tempini ML, Rosen H, Prioleau-Latham CE, Lee A, Kipps CM, Lillo P, Piguet O, Rohrer JD, Rossor MN, Warren JD, Fox NC, Galasko D, Salmon DP, et al.: Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia.

    Brain 2011, 134:2456-2477. PubMed Abstract | Publisher Full Text OpenURL

  33. Boeve B, Lang A, Litvan I: Corticobasal degeneration and its relationship to progressive supranuclear palsy and frontotemporal dementia.

    Ann Neurol 2003, 54:S15-S19. PubMed Abstract | Publisher Full Text OpenURL

  34. Majounie E, Abramzon Y, Renton AE, Perry R, Bassett SS, Pletnikova O, Troncoso JC, Hardy J, Singleton AB, Traynor BJ: Repeat expansion in C9ORF72 in Alzheimer's disease.

    N Engl J Med 2012, 366:283-284. PubMed Abstract | Publisher Full Text OpenURL

  35. Whitwell JL, Weigand SD, Boeve BF, Senjem ML, Gunter JL, DeJesus-Hernandez M, Rutherford NJ, Baker M, Knopman DS, Wszolek ZK, Parisi JE, Dickson DW, Petersen RC, Rademakers R, Jack CR Jr, Josephs KA: Neuroimaging signatures of frontotemporal dementia genetics: C9ORF72, tau, progranulin and sporadics.

    Brain 2012, 135:794-806. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  36. Schmahmann JD, Sherman JC: The cerebellar cognitive affective syndrome.

    Brain 1998, 121(Pt 4):561-579. PubMed Abstract | Publisher Full Text OpenURL

  37. Schmahmann JD, Weilburg JB, Sherman JC: The neuropsychiatry of the cerebellum - insights from the clinic.

    Cerebellum 2007, 6:254-267. PubMed Abstract | Publisher Full Text OpenURL

  38. Schmahmann JD: The role of the cerebellum in cognition and emotion: personal reflections since 1982 on the dysmetria of thought hypothesis, and its historical evolution from theory to therapy.

    Neuropsychol Rev 2010, 20:236-260. PubMed Abstract | Publisher Full Text OpenURL

  39. Josephs KA, Duffy JR, Strand EA, Whitwell JL, Layton KF, Parisi JE, Hauser MF, Witte RJ, Boeve BF, Knopman DS, Dickson DW, Jack CR Jr, Petersen RC: Clinicopathological and imaging correlates of progressive aphasia and apraxia of speech.

    Brain 2006, 129:1385-1398. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  40. Josephs KA, Whitwell JL, Duffy JR, Vanvoorst WA, Strand EA, Hu WT, Boeve BF, Graff-Radford NR, Parisi JE, Knopman DS, Dickson DW, Jack CR Jr, Petersen RC: Progressive aphasia secondary to Alzheimer disease vs FTLD pathology.

    Neurology 2008, 70:25-34. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  41. Gorno-Tempini M, Dronkers N, Rankin K, Ogar J, Phengrasamy L, Rosen H, Johnson J, Weiner M, Miller B: Cognition and anatomy in three variants of primary progressive aphasia.

    Ann Neurol 2004, 55:335-346. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  42. Gorno-Tempini ML, Hillis AE, Weintraub S, Kertesz A, Mendez M, Cappa SF, Ogar JM, Rohrer JD, Black S, Boeve BF, Manes F, Dronkers NF, Vandenberghe R, Rascovsky K, Patterson K, Miller BL, Knopman DS, Hodges JR, Mesulam MM, Grossman M: Classification of primary progressive aphasia and its variants.

    Neurology 2011, 76:1006-1014. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  43. Bonner MF, Ash S, Grossman M: The new classification of primary progressive aphasia into semantic, logopenic, or nonfluent/agrammatic variants.

    Curr Neurol Neurosci Rep 2010, 10:484-490. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  44. Grossman M: Primary progressive aphasia: clinicopathological correlations.

    Nat Rev Neurol 2010, 6:88-97. PubMed Abstract | Publisher Full Text OpenURL

  45. Josephs KA, Duffy JR, Fossett TR, Strand EA, Claassen DO, Whitwell JL, Peller PJ: Fluorodeoxyglucose F18 positron emission tomography in progressive apraxia of speech and primary progressive aphasia variants.

    Arch Neurol 2010, 67:596-605. PubMed Abstract | Publisher Full Text OpenURL

  46. Josephs KA, Duffy JR, Strand EA, Machulda MM, Senjem ML, Master AV, Lowe VJ, Jack CR Jr, Whitwell JL: Characterizing a neurodegenerative syndrome: primary progressive apraxia of speech.

    Brain 2012, 135(Pt 5):1522-36. PubMed Abstract | Publisher Full Text OpenURL

  47. Khan BK, Yokoyama JS, Takada LT, Sha SJ, Rutherford NJ, Fong JC, Karydas AM, Wu T, Ketelle RS, Baker MC, Hernandez MD, Coppola G, Geschwind DH, Rademakers R, Lee SE, Rosen HJ, Rabinovici GD, Seeley WW, Rankin KP, Boxer AL, Miller BL: Atypical, slowly progressive behavioural variant frontotemporal dementia associated with C9ORF72 hexanucleotide expansion.

    J Neurol Neurosurg Psychiatry 2012, 83:358-364. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  48. Kipps CM, Nestor PJ, Fryer TD, Hodges JR: Behavioural variant frontotemporal dementia: not all it seems?

    Neurocase 2007, 13:237-247. PubMed Abstract | Publisher Full Text OpenURL

  49. Kipps CM, Hodges JR, Fryer TD, Nestor PJ: Combined magnetic resonance imaging and positron emission tomography brain imaging in behavioural variant frontotemporal degeneration: refining the clinical phenotype.

    Brain 2009, 132:2566-2578. PubMed Abstract | Publisher Full Text OpenURL

  50. Al-Sarraj S, King A, Troakes C, Smith B, Maekawa S, Bodi I, Rogelj B, Al-Chalabi A, Hortobagyi T, Shaw CE: p62 positive, TDP-43 negative, neuronal cytoplasmic and intranuclear inclusions in the cerebellum and hippocampus define the pathology of C9orf72-linked FTLD and MND/ALS.

    Acta Neuropathol 2011, 122:691-702. PubMed Abstract | Publisher Full Text OpenURL

  51. Brettschneider J, Van Deerlin VM, Robinson JL, Kwong L, Lee EB, Ali YO, Safren N, Monteiro MJ, Toledo JB, Elman L, McCluskey L, Irwin DJ, Grossman M, Molina-Porcel L, Lee VM, Trojanowski JQ: Pattern of ubiquilin pathology in ALS and FTLD indicates presence of C9ORF72 hexanucleotide expansion.

    Acta Neuropathol 2012, 123:825-839. PubMed Abstract | Publisher Full Text OpenURL

  52. Cooper-Knock J, Hewitt C, Highley JR, Brockington A, Milano A, Man S, Martindale J, Hartley J, Walsh T, Gelsthorpe C, Baxter L, Forster G, Fox M, Bury J, Mok K, McDermott CJ, Traynor BJ, Kirby J, Wharton SB, Ince PG, Hardy J, Shaw PJ: Clinico-pathological features in amyotrophic lateral sclerosis with expansions in C9ORF72.

    Brain 2012, 135:751-764. PubMed Abstract | Publisher Full Text OpenURL

  53. Stewart H, Rutherford NJ, Briemberg H, Krieger C, Cashman N, Fabros M, Baker M, Fok A, DeJesus-Hernandez M, Eisen A, Rademakers R, Mackenzie IR: Clinical and pathological features of amyotrophic lateral sclerosis caused by mutation in the C9ORF72 gene on chromosome 9p.

    Acta Neuropathol 2012, 123:409-417. PubMed Abstract | Publisher Full Text OpenURL

  54. Troakes C, Maekawa S, Wijesekera L, Rogelj B, Siklós L, Bell C, Smith B, Newhouse S, Vance C, Johnson L, Hortobágyi T, Shatunov A, Al-Chalabi A, Leigh N, Shaw CE, King A, Al-Sarraj S: An MND/ALS phenotype associated with C9orf72 repeat expansion: Abundant p62-positive, TDP-43-negative inclusions in cerebral cortex, hippocampus and cerebellum but without associated cognitive decline.

    Neuropathology 2011.

    [Epub ahead of print]

    PubMed Abstract | Publisher Full Text OpenURL

  55. van Langenhove T, van der Zee J, van Broeckhoven C: The molecular basis of the frontotemporal lobar degeneration-amyotrophic lateral sclerosis spectrum.

    Ann Med 2012.

    [Epub ahead of print]

    PubMed Abstract | Publisher Full Text OpenURL

  56. Mackenzie IR: The neuropathology of FTD associated With ALS.

    Alzheimer Dis Assoc Disord 2007, 21:S44-49. PubMed Abstract | Publisher Full Text OpenURL

  57. Mackenzie I, Neumann M, Baborie A, Sampathu D, Du Plessis D, Jaros E, Perry R, Trojanowski J, Mann D, Lee V: A harmonized classification system for FTLD-TDP pathology.

    Acta Neuropathol 2011, 122:111-113. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  58. Lin W, Dickson DW: Ultrastructure of ubiquitin-positive, TDP-43-negative neuronal inclusions in cerebral cortex of C9ORF72-linked frontotemporal lobar degeneration/amyotrophic lateral sclerosis.

    Neuropathology 2012, in press. OpenURL

  59. Seeley WW, Carlin DA, Allman JM, Macedo MN, Bush C, Miller BL, Dearmond SJ: Early frontotemporal dementia targets neurons unique to apes and humans.

    Ann Neurol 2006, 60:660-667. PubMed Abstract | Publisher Full Text OpenURL

  60. Seeley WW: Selective functional, regional, and neuronal vulnerability in frontotemporal dementia.

    Curr Opin Neurol 2008, 21:701-707. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  61. Kim EJ, Sidhu M, Gaus SE, Huang EJ, Hof PR, Miller BL, DeArmond SJ, Seeley WW: Selective frontoinsular von Economo neuron and fork cell loss in early behavioral variant frontotemporal dementia.

    Cereb Cortex 2012, 22:251-259. PubMed Abstract | Publisher Full Text OpenURL