Insights gained over 60 years on factors shaping post-stroke aphasia recovery: A commentary on Vignolo (1964).

Aphasia is an acquired language disorder resulting from brain injury, including strokes which is the most common etiology, neurodegenerative diseases, tumors, traumatic brain injury, and resective surgery. Aphasia affects a significant portion of stroke survivors, with approximately one third experiencing its debilitating effects in the long term. Despite its challenges, there is growing evidence that recovery from aphasia is possible, even in the chronic phase of stroke. Sixty years ago, Vignolo (1964) outlined the primary challenges confronted by researchers in this field. These challenges encompassed the absence of an objective evaluation of language difficulties, the scarcity of evidence regarding spontaneous aphasia recovery, and the presence of numerous variables that could potentially influence the process of aphasia recovery. In this paper, we discuss the remarkable progress that has been made in the assessment of language and communication in aphasia as well as in understanding the factors influencing post-stroke aphasia recovery.

Improved prediction of glioma-related aphasia by diffusion MRI metrics, machine learning, and automated fiber bundle segmentation.

White matter impairments caused by gliomas can lead to functional disorders. In this study, we predicted aphasia in patients with gliomas infiltrating the language network using machine learning methods. We included 78 patients with left-hemispheric perisylvian gliomas. Aphasia was graded preoperatively using the Aachen aphasia test (AAT). Subsequently, we created bundle segmentations based on automatically generated tract orientation mappings using TractSeg. To prepare the input for the support vector machine (SVM), we first preselected aphasia-related fiber bundles based on the associations between relative tract volumes and AAT subtests. In addition, diffusion magnetic resonance imaging (dMRI)-based metrics [axial diffusivity (AD), apparent diffusion coefficient (ADC), fractional anisotropy (FA), and radial diffusivity (RD)] were extracted within the fiber bundles' masks with their mean, standard deviation, kurtosis, and skewness values. Our model consisted of random forest-based feature selection followed by an SVM. The best model performance achieved 81% accuracy (specificity = 85%, sensitivity = 73%, and AUC = 85%) using dMRI-based features, demographics, tumor WHO grade, tumor location, and relative tract volumes. The most effective features resulted from the arcuate fasciculus (AF), middle longitudinal fasciculus (MLF), and inferior fronto-occipital fasciculus (IFOF). The most effective dMRI-based metrics were FA, ADC, and AD. We achieved a prediction of aphasia using dMRI-based features and demonstrated that AF, IFOF, and MLF were the most important fiber bundles for predicting aphasia in this cohort.

Disparity of Primary and Secondary Language Outcomes in Bilingual Patients Undergoing Resection of Glioma of the Speech-Related Regions.

BACKGROUND: The existing data about language recovery in bilingual patients come from few studies on acute lesional deficits like stroke or traumatic injury. Still, little is known about the neuroplasticity potential of bilingual patients who undergo resection of gliomas affecting language-eloquent brain regions. In this study, we prospectively evaluated the pre- and postoperative language functions among bilinguals with eloquent region gliomas. METHODS: We have prospectively collected the preoperative, 3-month and 6-month postoperative data from patients with tumors infiltrating the dominant hemisphere language areas during a 15-month period. Validated Persian/Turkish version of Western Aphasia Battery test and Addenbrooke Cognitive Examination were assessed for main language (L1) and second acquired languages (L2) in each visit. RESULTS: Twenty-two right-handed bilingual patients were enrolled, and language proficiencies were assessed using mixed model analysis. On baseline and postoperative points, L1 had higher scores in all Addenbrooke Cognitive Examination and Western Aphasia Battery subdomains than L2. Both languages had deterioration at 3-month visit; however, L2 was significantly more deteriorated in all domains. At 6-month visit, both L1 and L2 showed recovery; however, L2 recovered to a less extent than L1. The single most parameter affecting the ultimate language outcome in this study was the preoperative functional level of L1. CONCLUSIONS: This study shows L1 is less vulnerable to operative insults and L2 may be damaged even when L1 is preserved. We would suggest the more sensitive L2 be used as the screening tool and L1 be used for confirmation of positive responses during language mapping.

Decreasing distance from tumor to the language network causes language deficit.

Preoperative language deficits are associated with alterations in the language networks of patients with gliomas. This study investigated how gliomas affect language performance by altering the language network. Ninety patients with lower-grade gliomas were included, and their preoperative language performance was evaluated using the Western Aphasia Battery. We also calculated the topological properties based on resting state functional magnetic resonance imaging. All patients were classified according to aphasia quotient (AQ) into the aphasia (AQ < 93.8), mild anomia (AQ > 93.8 and naming section <9.8), and normal groups (AQ > 93.8). The shortest distance from the tumor to the language network (SDTN) was evaluated to identify the effect on language performance induced by the tumor. One-way analysis of variance and post hoc analysis with Sidak correction were used to analyze the differences in topological properties among the three groups. Causal mediation analysis was used to identify indirectly affected mediators. Compared with the mild anomia group, longer shortest path length (p = .0016), lower vulnerability (p = .0331), and weaker nodal efficiencies of three nodes (right caudal Brodmann area [BA] 45, right caudal BA 22, and left BA 41/42, all p < .05) were observed in the aphasia group. The SDTN mediated nodal degree centrality and nodal vulnerability (left rostroventral BA 39), which negatively affected the AQs. Conventional language eloquent and mirrored areas participated in the language network alterations induced by gliomas. The SDTN was a mediator that affected the preoperative language status in patients with gliomas.

Preoperative language tract integrity is a limiting factor in recovery from aphasia after glioma surgery.

Aphasia can occur in a broad range of pathological conditions that affect cortical or subcortical structures. Here we test the hypothesis that white matter integrity of language pathways assessed by preoperative diffusion tensor imaging (DTI) is associated with language performance and its recovery after glioma resection. 27 patients with preoperative DTI were included. Segmentation of the arcuate fascicle (AF), the inferior fronto-occipital fascicle (IFOF), the inferior longitudinal fascicle (ILF), the superior longitudinal fascicle (SLF), and the uncinate fascicle (UF) was performed with a fully-connected neural network (FCNN, TractSeg). Median fractional anisotropy (FA) was extracted from the resulting volumes as surrogate marker for white matter integrity and tested for correlation with clinical parameters. After correction for demographic data and multiple testing, preoperative white matter integrity of the IFOF, the ILF, and the UF in the left hemisphere were independently and significantly associated with aphasia three months after surgery. Comparison between patients with and without aphasia three months after surgery revealed significant differences in preoperative white matter integrity of the left AF (p = 0.021), left IFOF (p = 0.015), left ILF (p = 0.003), left SLF (p = 0.001, p = 0.021, p = 0.043 for respective sub-bundles 1-3), left UF (p = 0.041) and the right AF (p = 0.027). Preoperative assessment of white matter integrity of the language network by time-efficient MRI protocols and FCNN-driven segmentation may assist in the evaluation of postoperative rehabilitation potential in glioma patients.

Distinct brain iron profiles associated with logopenic progressive aphasia and posterior cortical atrophy.

Quantitative susceptibility mapping (QSM) can detect iron distribution in the brain by estimating local tissue magnetic susceptibility properties at every voxel. Iron deposition patterns are well studied in typical Alzheimer's disease (tAD), but little is known about these patterns in atypical clinical presentations of AD such as logopenic progressive aphasia (LPA) and posterior cortical atrophy (PCA). Seventeen PCA patients and eight LPA patients were recruited by the Neurodegenerative Research Group at Mayo Clinic, Rochester, MN, and underwent MRI that included a five-echo gradient echo sequence for calculation of QSM. Mean QSM signal was extracted from gray and white matter for regions-of-interest across the brain using the Mayo Clinic Adult Lifespan Template. Bayesian hierarchical models were fit per-region and per-hemisphere to compare PCA, LPA, 63 healthy controls, and 20 tAD patients. Strong evidence (posterior probability > 0.99) was observed for greater susceptibility in the middle occipital gyrus and amygdala in both LPA and PCA, and in the right inferior parietal, inferior temporal, and angular gyri in PCA and the caudate and substantia nigra in LPA compared to controls. Moderate evidence for greater susceptibility (posterior probability > 0.90) was also observed in the inferior occipital gyrus, precuneus, putamen and entorhinal cortex in both LPA and PCA, along with superior frontal gyrus in PCA and inferior temporal gyri, insula and basal ganglia in LPA, when compared to controls. Between phenotypic comparisons, LPA had greater susceptibility in the caudate, hippocampus, and posterior cingulate compared to PCA, while PCA showed greater susceptibility in the right superior frontal and middle temporal gyri compared to LPA. Both LPA and PCA showed moderate and strong evidence for greater susceptibility than tAD, particularly in medial and lateral parietal regions, while tAD showed greater susceptibility in the hippocampus and basal ganglia. This study proposes the possibility of unique iron profiles existing between LPA and PCA within cortical and subcortical structures. These changes match well with the disease-related changes of the clinical phenotypes, suggesting that QSM could be an informative candidate marker to study iron deposition in these patients.

Formal language assessment in low-educated persons with aphasia: can the lesion effect be distinguished from the education effect? / Avaliação da linguagem em pacientes afásicos com baixa escolaridade: o impacto da lesão neurológica pode ser discriminado da baixa escolaridade?

ABSTRACT Background: Language tests are important in the assessment and follow up of people with aphasia (PWA). However, language assessment in the low literacy population is still a challenge. Objective: To investigate whether a formal evaluation of aphasia is able to distinguish the neurological effect from the effect of low educational level in people with post-stroke aphasia. Methods: The sample consisted of a group of 30 aphasic subjects (AG) and a control group (CG) of 36 individuals, both with an educational level of 1-4 years. The Brazilian Montreal-Toulouse Language Assessment battery was applied to all subjects. Results: There were statistically significant differences between the groups in 19 out of the 20 tasks analyzed. Conclusions: These results suggest that formal evaluation procedures are able to detect language disorders resulting from stroke, even in subjects with low educational level.

RESUMO Antecedentes: Os testes de linguagem são importantes para a avaliação e o acompanhamento de pacientes afásicos. Apesar disso, a avaliação de linguagem em indivíduos com baixa escolaridade ainda é um desafio. Objetivo: Investigar se a avaliação formal da afasia é capaz de diferenciar o efeito da lesão neurológica versus o efeito da baixa escolaridade em pacientes afásicos, acometidos por acidente vascular cerebral (AVC). Métodos: A amostra foi composta de um grupo de 30 sujeitos afásicos (AG) e um grupo controle (CG) de 36 indivíduos, todos com um a quatro anos de escolaridade. A Bateria Montreal-Toulouse de Avaliação da Linguagem foi administrada a todos os participantes. Resultados: Das 20 tarefas analisadas, 19 apresentaram diferenças significativas entre os grupos. Conclusões: Os resultados sugerem que procedimentos formais de avaliação são capazes de identificar as alterações linguísticas ocasionadas por um AVC, também em pacientes com baixa escolaridade.

Changes in white matter microstructure related to non-linguistic cognitive impairment in post-stroke aphasia.

OBJECTS: Post-stroke aphasia (PSA) often have non-linguistic cognitive impairment. We aimed to ascertain its characteristics of non-linguistic cognitive impairment and the corresponding changes in white matter microstructures. METHODS: Ten patients with PSA and 17 healthy controls (HCs) were enrolled. Loewenstein occupational therapy cognitive assessment (LOTCA) were used to assess non-linguistic cognitive function. Summary T-test was performed to compare the LOTCA scores between PSA and the Chinese norm. Tract-based spatial statistics (TBSS) was used to calculate fractional anisotropy (FA), mean diffusivity (MD), and radial diffusivity (RD) after collecting diffusion tensor imaging data. Correlation analysis was performed between these metrics and LOTCA scores. RESULTS: The days after stroke onset of PSA was 428.0±52.0. The total LOTCA score of PSA (78.20±22.63) was lower than the Chinese norm (97.65±16.24, P=0.003), as well as the scores of orientation, spatial perception (SP), motor praxis (MP), and attention (P<0.05). Lower FA and higher MD/RD in bilateral inferior fronto-occipital fasciculus (IFOF), inferior longitudinal fasciculus (ILF), and left superior longitudinal fasciculus (SLF) were found in PSA compared with HCs. The MD and RD of the right uncinate fasciculus (UF) was negatively correlated with SP and MP scores (r=-0.787, r=-0.733, r=-0.726; P<0.05). The FA of left UF was negatively correlated with orientation score (r=-0.690, P=0.04). CONCLUSION: Patients with PSA have non-linguistic cognitive impairment. The integrity of the white matter microstructures can be extensively damaged. Impaired SP and MP in patients with PSA are related to UF damage.

Thalamic aphasia secondary to glioblastoma multiforme.

BACKGROUND: Thalamic aphasia is an unusual clinical presentation of brain neoplasm with few cases reported. Herein, we present a case of an adult woman with thalamic aphasia due to glioblastoma of the thalamus. CASE PRESENTATION: A 57-year-old female patient presented with difficulty walking, slow speech and cognition and altered mental status. At baseline, she was conversant and interactive. Physical examination showed right hemiparesis in addition to word finding difficulties, an impaired naming of objects and semantic paraphasia but preserved repetition and comprehension. The remaining neurological exam was otherwise unremarkable. Brain CT and brain MRI scans showed a left thalamic lesion that is centrally necrotic and peripherally enhancing suggestive of a high-grade neoplasm. Eventually, histopathological examination of brain biopsy confirmed the diagnosis of glioblastoma multiforme. Thalamic aphasia was proposed as an explanation for the neurological symptoms observed in this patient. CONCLUSIONS: This patient demonstrates an unusual presentation of glioblastoma multiforme as thalamic aphasia. It may also point to the potential contribution of the understanding of how thalamic aphasia evolves to characterize the role of the thalamus in language functions.

Disruption of Frontal Aslant Tract Is Not Associated with Long-Term Postoperative Language Deficits.

BACKGROUND: The frontal aslant tract (FAT) is a white matter fiber pathway connecting the superior frontal gyrus to the Broca area. This tract in the dominant hemisphere has been shown to play a role in speech initiation and production, and direct subcortical stimulation can induce stuttering and speech arrest in a patient. However, controversy remains as to whether disruption of this pathway will lead to a permanent language deficit and if it is even necessary to map this tract during tumor resections of the dominant frontal lobe. CASE DESCRIPTION: Here, we report a case of a patient with a lower-grade diffuse glioma invading the dominant FAT that was removed with an asleep craniotomy. In the immediate postoperative state, the patient had a transcortical motor dysphasia and was unable to initiate speech. These immediate language deficits quickly recovered, and the patient was neurologically intact at the time of discharge a few days after surgery. CONCLUSIONS: Given the high likelihood for a complete neurologic recovery including transient aphasia, we propose that awake mapping for the purpose of identifying the dominant FAT is unnecessary during tumor resection and that disruption of this tract is not associated with any long-term language deficits.

The white matter architecture underlying semantic processing: A systematic review.

From a holistic point of view, semantic processes are subserved by large-scale subcortico-cortical networks. The dynamic routing of information between grey matter structures depends on the integrity of subcortical white matter pathways. Nonetheless, controversy remains on which of these pathways support semantic processing. Therefore, a systematic review of the literature was performed with a focus on anatomo-functional correlations obtained from direct electrostimulation during awake tumor surgery, and conducted between diffusion tensor imaging metrics and behavioral semantic performance in healthy and aphasic individuals. The 43 included studies suggest that the left inferior fronto-occipital fasciculus contributes to the essential connectivity that allows semantic processing. However, it remains uncertain whether its contributive role is limited to the organization of semantic knowledge or extends to the level of semantic control. Moreover, the functionality of the left uncinate fasciculus, inferior longitudinal fasciculus and the posterior segment of the indirect arcuate fasciculus in semantic processing has to be confirmed by future research.

Degenerative and Vascular Fluent Aphasia: Looking for Differences.

OBJECTIVE: To investigate whether the characteristics of language disorders of degenerative and vascular aphasias depend on the underlying neuropathology. METHODS: Logopenic variant/mixed primary progressive aphasics (lvmPPA; n=18) and poststroke fluent aphasics (PSA; n=11) underwent a neuropsychological examination and an assessment of the macro- and microlinguistic aspects of language. A principal component analysis and a cluster analysis applying a two-group solution were performed on the scores obtained from the neuropsychological and language examination. RESULTS: Global cognition, lexical-semantic, and morphosyntactic components, and two components loading macrolinguistic variables, were extracted by the principal component analysis. A first cluster of 18 participants (14 lvmPPA and 4 PSA) and a second cluster of 11 participants (4 lvmPPA and 7 PSA) were identified. Participants in the first cluster were significantly more impaired than those in the second cluster in global cognition, lexical-semantic, and morphosyntactic components. Macrolinguistic components did not differentiate the two clusters. lvmPPA in the first cluster showed bilateral cortical thinning (greater on the left), whereas lvmPPA in the second cluster showed atrophy only in the left. Participants with PSA in both clusters showed vascular lesions encompassing the posterior left perisylvian regions. Underestimation of the severity of the leukoencephalopathy and damage of the interhemispheric connectivity might be responsible for the inclusion of PSA individuals in the first cluster, despite a unilateral lesion. CONCLUSIONS: Lesion localization is the main factor that determines the characteristics of aphasic deficits. Etiology indirectly acts through a different sensitivity of the brain regions to various pathologies.

Aphasia outcome: the interactions between initial severity, lesion size and location.

OBJECTIVES: The outcome of aphasia at 3 months is variable in patients with moderate/severe stroke. The aim was to predict 3-month aphasia outcome using prediction models including initial severity in addition to the interaction between lesion size and location at the acute phase. METHODS: Patients with post-stroke aphasia (assessed by the Aphasia Rapid Test at day 7-ART D7) and MRI performed at day 1 were enrolled (n = 73). Good outcome at 3-months was defined by an Aphasia Handicap Score of 0-2. Each infarct lesion was overlapped with an area of interest in the left temporo-parietal region to compute an intersection index (proportion of the critical region damaged by the infarct). We tested ART D7, age, lesion volume, and intersection index as well as a combined variable lesion volume*intersection in a univariate analysis. Then, we performed a multivariate analysis to investigate which variables were independent predictors of good outcome. RESULTS: ART at D7, infarct volume, and the intersection index were univariate predictors of good outcome. In the multivariate analysis, ART D7 and "volume ≥ 50 ml or intersection index ≥ 20%" correctly classified 89% of the patients (p < 0.0001). When added to the model, the interaction between both variables was significant indicating that the impact of the size or site variable depends on the initial severity of aphasia. CONCLUSION: In patients with initially severe aphasia, large infarct size or critical damage in left temporoparietal junction is associated with poor language outcome at 3 months.

The Artery of Aphasia, A Uniquely Sensitive Posterior Temporal Middle Cerebral Artery Branch that Supplies Language Areas in the Brain: Anatomy and Report of Four Cases.

BACKGROUND: Arterial disruption during brain surgery can cause devastating injuries to wide expanses of white and gray matter beyond the tumor resection cavity. Such damage may occur as a result of disrupting blood flow through en passage arteries. Identification of these arteries is critical to prevent unforeseen neurologic sequelae during brain tumor resection. In this study, we discuss one such artery, termed the artery of aphasia (AoA), which when disrupted can lead to receptive and expressive language deficits. METHODS: We performed a retrospective review of all patients undergoing an awake craniotomy for resection of a glioma by the senior author from 2012 to 2018. Patients were included if they experienced language deficits secondary to postoperative infarction in the left posterior temporal lobe in the distribution of the AoA. The gross anatomy of the AoA was then compared with activation likelihood estimations of the auditory and semantic language networks using coordinate-based meta-analytic techniques. RESULTS: We identified 4 patients with left-sided posterior temporal artery infarctions in the distribution of the AoA on diffusion-weighted magnetic resonance imaging. All 4 patients developed substantial expressive and receptive language deficits after surgery. Functional language improvement occurred in only 2/4 patients. Activation likelihood estimations localized parts of the auditory and semantic language networks in the distribution of the AoA. CONCLUSIONS: The AoA is prone to blood flow disruption despite benign manipulation. Patients seem to have limited capacity for speech recovery after intraoperative ischemia in the distribution of this artery, which supplies parts of the auditory and semantic language networks.

Left Sylvian Fissure Epidermoid Cyst Presenting with Progressive Aphasia.

INTRODUCTION: Epidermoid cysts within the sylvian fissure are extremely rare. Expressive aphasia and neurocognitive dysfunction because of mass effect have never been reported previously. CASE PRESENTATION: We discuss the case of a 53-year-old male who presented with an acute episode of expressive aphasia and vision changes along with progressive headaches and cognitive slowing over the 2.5 years prior to presentation. A detailed neurologic examination revealed subtle conductive aphasia, as well as mild short-term memory dysfunction. Magnetic resonance imaging revealed a cystic mass consistent with epidermoid cyst within the left sylvian fissure. High-definition fiber tractography showed that the arcuate fasciculus was stretched by the tumor. A left frontotemporal craniotomy allowed for near-total excision of the cyst and led to rapid and complete resolution of symptoms. CONCLUSION: Although rare, epidermoid cysts of the dominant sylvian fissure can present with progressive aphasia due to mass effect on the arcuate fasciculus. Despite the long-standing symptoms, surgical resection can lead to their complete resolution.

Mixed language dominance: insights from a case of unexpected fluent aphasia with semantic jargon resulting from massive left perisylvian lesion.

We report a right-handed patient with a massive lesion in left perisylvian language cortex, who unexpectedly presented with fluent aphasia with semantic jargon. Language deficits were assessed with a comprehensive battery of language tests. Comprehension, naming, reading, and writing were severely impaired, and verbal expression was moderately fluent with semantic jargon. Although the patient's lesion included brain areas typically essential for motor speech coordination, he was neither nonfluent nor apraxic. He exhibited strikingly unexpected aphasia with semantic jargon and prominent comprehension deficits, suggesting that this is a case of mixed dominance: the right hemisphere likely controls motor speech and basic syntactic skills, while the severely damaged left hemisphere controls semantic processing, predictably severely impaired.

Cognitive dysfunction in corticobasal degeneration / Disfunção cognitiva na degeneração corticobasal

ABSTRACT Corticobasal degeneration (CBD) was originally described as a distinct clinicopathological entity in 1967. Since then, different phenotypic presentations have emerged as possible manifestations of CBD histopathological findings. In addition, pathophysiological findings and the molecular basis have been delineated and several aspects of its cognitive manifestations have been clarified. Thus, not only the spectrum of what is currently designated as CBD has expanded, but overlap with other degenerative and even secondary disorders has made clinical diagnostic certainty even more challenging in the absence of specific and readily-available markers. Cognitive deficits in CBD are now recognized as a frequent initial presentation and may appear up to eight years before the motor symptoms, depending on the phenotypic variant. Characteristic cognitive features of CBD involve language deficits, visuospatial and executive dysfunctions, apraxia, and behavioral disorders. Semantic and episodic memories are usually preserved, while language is often impaired in the early stages.

RESUMO A degeneração corticobasal (DCB) foi originalmente descrita como uma entidade clínico-patológica distinta em 1967. Desde então, nossa compreensão sobre DCB evoluiu substancialmente. Diferentes apresentações fenotípicas emergiram refletindo possíveis manifestações das anormalidades histopatológicos da DCB. Adicionalmente, dados fisiopatológicos e moleculares foram delineados e aspectos das manifestações cognitivas foram explorados. Assim, não só o espectro do que é atualmente designado DCB foi expandido, mas a sobreposição com outras doenças degenerativas e até mesmo secundárias tornaram o diagnóstico clínico ainda mais desafiador na ausência de marcadores específicos e prontamente disponíveis. Déficits cognitivos na DCB são agora reconhecidos frequentemente como apresentações iniciais e podem surgir até 8 anos antes dos sintomas motores, dependendo da variante fenotípica. O quadro cognitivo envolve característicamente déficits de linguagem, disfunção visuoespacial e executiva, apraxia, e distúrbios comportamentais. Anormalidades da linguagem são frequentemente descritas nos estágios iniciais da DCB.

Frontotemporal lobar degeneration: Pathogenesis, pathology and pathways to phenotype.

Frontotemporal Lobar Degeneration (FTLD) is a clinically, pathologically and genetically heterogeneous group of disorders that affect principally the frontal and temporal lobes of the brain. There are three major associated clinical syndromes, behavioral variant frontotemporal dementia (bvFTD), semantic dementia (SD) and progressive non-fluent aphasia (PNFA); three principal histologies, involving tau, TDP-43 and FUS proteins; and mutations in three major genes, MAPT, GRN and C9orf72, along with several other less common gene mutations. All three clinical syndromes can exist separately or in combination with Amyotrophic Lateral Sclerosis (ALS). SD is exclusively a TDP-43 proteinopathy, and PNFA may be so, with both showing tight clinical, histological and genetic inter-relationships. bvFTD is more of a challenge with overlapping histological and genetic features, involvement of any of the three aggregating proteins, and changes in any of the three major genes. However, when ALS is present, all cases show a clear histological phenotype with TDP-43 aggregated proteins, and familial forms are associated with expansions in C9orf72. TDP-43 and FUS are nuclear carrier proteins involved in the regulation of RNA metabolism, whereas tau protein - the product of MAPT - is responsible for the assembly/disassembly of microtubules, which are vital for intracellular transport. Mutations in TDP-43 and FUS genes are linked to clinical ALS rather than FTLD (with or without ALS), suggesting that clinical ALS may be a disorder of RNA metabolism. Conversely, the protein products of GRN and C9orf72, along with those of the other minor genes, appear to form part of the cellular protein degradation machinery. It is possible therefore that FTLD is a reflection of dysfunction within lysosomal/proteasomal systems resulting in failure to remove potentially neurotoxic (TDP-43 and tau) aggregates, which ultimately overwhelm capacity to function. Spread of aggregates along distinct pathways may account for the different clinical phenotypes, and patterns of progression of disease.