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White matter damage in posterior cortical atrophy assessed in vivo using diffusion tensor magnetic resonance imaging
P176
Poster Presentations: P1
PCA patients (5 women; 59.8 6 4.8 years old) and 16 controls (12 women; 52.1 6 13.2 years old) were studied. All subjects had two DTI scans with an interval of 13.4 6 2.1 months. Definition of regions of interest (ROI) were performed having first co-registered the serial DTI in order to improve consistency of the ROIs and precision of longitudinal measure. All affine and non-linear registrations were performed using DTI-TK, a state-of-the-art tool for spatial normalization of DTI data, which uses the whole-tensor information for optimal white matter alignment. For each subject (“nest”), a subject-specific template was created by groupwise registration (affine, then non-linear) between each subject’s two time-points. An average tensor image was created for each nest. FA maps were then created from the average tensor image and each registered tensor image. Eight specific WM ROIs were defined by non-rigidly propagating the JHU-ICBM WM atlas to the template FA images. Linear regression models were used to make comparisons between groups adjusting for age and gender. Results: Significant cross-sectional differences in FA between PCA and control groups are seen at baseline in the genu, body and splenium of corpus callosum, cingulum bundle, fornix and posterior thalamic radiation (Table). The change in FA between baseline and followup was significantly different between PCA and controls for the genu and splenium of corpus callosum, right superior longitudinal fasciculus and left inferior fronto-occipital/inferior longitudinal fasciculus. Conclusions: Using an automatic tensor-based DTI registration technique to improve ROI consistency, we showed statistically significant decreases of FA in WM tracts of PCA patients over 12 months, suggesting a decline in WM integrity. Interestingly the cross-sectional differences accord with the longitudinal changes and imply several years of gradual changes. Evidence of longitudinal change in the genu may reflect increasing disruption of progressively more anterior structures in patients with more advanced disease. Table Descriptive statistics of FA (mean 6 SD) of two time points for PCA patients and Controls (CON); Each difference score (Baseline – Follow-up) was divided by the interscan interval to create a rate of change (slope), absolute change is reported
White matter ROIs Genu (CC) Body (CC) Splenium (CC) Fornix Cingulum bundle R Cingulum bundle L Posterior thalamic radiation R Posterior thalamic radiation L IFO/ILF R IFO/ILF L SLF R SLF L
Baseline Mean (SD)
Annualised change Mean (SD)
CON (n ¼ 16)
PCA (n ¼ 11)
CON (n ¼ 16)
PCA (n ¼ 11)
.597 (.028) .598 (.027) .668 (.023) .460 (.038) .484 (.027) .466 (.024) .528 (.024)
.564 (.028)* .568 (.029)* .627 (.027)** .391 (.042)** .425 (.036)** .408 (.031)** .496 (.026)*
.004 (.003) .007 (.006) .005 (.004) .025 (.016) .008 (.005) .007 (.005) .006 (.006)
.011 (.005) ** .011 (.005) .010 (.007) * .033 (.030) .014 (.011) .010 (.007) .011 (.008)
.512 (.024)
.483 (.025)**
.009 (.008)
.008 (.006)
.525 (.020) .509 (.020) .448 (.020) .449 (.023)
.512 (.021) .494 (.023) .431 (.025) .430 (.024)
.009 (.006) .009 (.006) .005 (.004) .006 (.004)
.014 (.008) .023 (.013)* .010 (.009) ** .006 (.004)
Manja Lehmann2, John Thornton4, Jason Warren2, David Cash5, Sebastian Crutch1, Sebastien Ourselin2, Nick Fox1, 1UCL Institute of Neurology, London, United Kingdom; 2University College London, London, United Kingdom; 3London School of Hygiene and Tropical Medicine, London, United Kingdom; 4National Hospital for Neurology and Neurosurgery, London, United Kingdom; 5University College of London, London, United Kingdom. Background: White matter (WM) damage has been reported in Alzheimer’s disease (AD) patients studied with diffusion tensor imaging (DTI). However, few group studies have investigated WM involvement in Posterior Cortical Atrophy (PCA). We explored whether there is WM tract degeneration in PCA using a tensor-based registration technique on atlas-based regions of interest (ROI). Methods: Twenty patients with PCA (11 women; mean 6 SD age ¼ 61.6 6 5.9yrs; MMSE score ¼ 16.6 6 5.9) and twenty controls (13 women; mean 6 SD age ¼ 54.9 6 13.3 yrs) were studied. All PCA subjects fulfilled the clinical criteria proposed by Mendez et al. (2002) and Tang-Wai et al. (2004). All registrations were performed using DTI-Toolkit, a state-of-the-art tool for spatial normalization of DTI data, which uses the whole-tensor information for optimal white matter alignment. First, a study-specific template was created by non-linearly registering all data to the groupwise space. A fractional anisotropy (FA) map was then created for both the groupwise template and each individual registered image. Eight specific WM ROIs were defined by segmentation propagation of the JHU-ICBM WM atlas to the groupwise template. The mean and standard deviation FA was calculated in each ROI. Results: Linear regression models were used to assess differences in FA of WM tracts between populations, adjusting for age and gender. PCA patients showed significantly lower FA than controls in the corpus callosum, fornix, bilateral cingulum, posterior thalamic radiations, inferior fronto-occipital/inferior longitudinal fasciculi and superior longitudinal fasciculi. A positive correlation was found between MMSE score and FA value in the right posterior thalamic radiation (r ¼ .60, P ¼ .006), inferior fronto-occipital/inferior longitudinal fasciculi (r ¼ .50, P ¼ .03) and superior longitudinal fasciculus (r ¼ .47, P ¼ .03) (Figure). Conclusions: Results suggest selective disruption of posterior WM tracts in PCA. Tract damage is significantly associated with disease severity, as measured by the MMSE. The posterior focus of WM damage is consistent with established evidence of occipito-parietal cortical dysfunction and atrophy in PCA. Given that PCA patients typically present with higher visual
SLF, Superior longitudinal fasciculi; IFO/ILF, Inferior fronto-occipital/ inferior longitudinal fasciculi; CC, Corpus Callosum; L, Left; R, Right; *, P <.05; **, P <.01, between group differences adjusted for age and gender.
P1-198
WHITE MATTER DAMAGE IN POSTERIOR CORTICAL ATROPHY ASSESSED IN VIVO USING DIFFUSION TENSOR MAGNETIC RESONANCE IMAGING
Shiva Keihaninejad1, Hui Zhang2, Tim Shakespeare1, Natalie Ryan1, Ian Malone1, Chris Frost3, Manuel Cardoso2, Marc Modat2,
Figure. Scatterplots of the white matter fractional anisotropy (FA) value versus mini mental state examination (MMSE) scores in patients with PCA. SLF, Superior longitudinal fasciculus; R, Right; L, Left.
Poster Presentations: P1
P177
Table Descriptive statistics of FA (mean 6 SD); significance for comparison between subject groups; the 95% confidence intervals (CI) for the adjusted differences between group means (the mean for the patient group minus the mean for the healthy group) White matter ROIs
CON (n ¼ 20)
PCA (n ¼ 20)
Adjusted difference (95%CI)
P-value
Genu (CC) Body (CC) Splenium (CC) Fornix Cingulum bundle R Cingulum bundle L Posterior thalamic radiation R Posterior thalamic radiation L Inferior frontooccipital/ inferior longitudinal fasciculi R Inferior frontooccipital/ inferior longitudinal fasciculi L Superior longitudinal fasciculus R Superior longitudinal fasciculus L
.596 6 .033 .604 6 .032 .669 6 .029 .405 6 .043 .470 6 .031 .452 6 .032 .537 6 .029 .521 6 .021 .540 6 .032 .519 6 .036 .444 6 .022 .450 6 .020
.569 6 .024 .570 6 .026 .622 6 .033 .338 6 .036 .412 6 .040 .394 6 .038 .485 6 .031 .482 6 .034 .489 6 .042 .467 6 .040 .419 6 .026 .423 6 .023
.022 (.056, .009) .028 (.047, .009) .040 (.061, .020) .055 (.080, .030) .053 (.078, .029) .058 (.082, .034) .049 (.069, .029) .037 (.056, .018) .045 (.069, .021) .043 (.066, .020) .026 (.041, .011) .027 (.041, .012)
.028 .004 <.001 <.001 <.001 <.001 <.001 <.001 <.001 <.001 <.001 <.001
Abbreviations: CC, Corpus Callosum; L, Left; R, Right
processing deficits, the involvement of the optic radiation is of particular note as this tract represents the major sensory input pathway to visual cortex. FA measures of WM tract integrity in PCA patients may have value as surrogate markers for monitoring disease progression.
P1-199
A CLINICAL STUDY ON EVENT-RELATED POTENTIAL N400 IN PATIENTS WITH ALZHEIMER’S DISEASE AND MILD COGNITIVE IMPAIRMENT
Su Ning, Fu Xiao, Shanghai Jiaotong University School of Medicine, Shanghai, China. Background: To explore the event related potential N400 of patients with Alzheimer’s disease and mild cognitive impairment, analyzed the diagnostic value of N400 for AD and MCI. Methods: 26 patients with Alzheimer’s disease patients (AD group), 22 mild cognitive impairment (MCI group) and 24 normal controls (control group) were investigated. All subjects were measured with event-related potential N400 and administered with MMSE, MoCA, ADAS-cog, ADL. The correlation between eventrelated potential N400 and cognition, and the diagnostic value of N400 for AD and MCI were analyzed. Results: 1. The N400 latencies of Fz, Pz, C3, C4 in mismatching sentence and Pz in matching sentence showed statistically significant diffrences among three groups (P<0.05). N400 latencies in MCI group were longer than those in control group, N400 latencies were longer in AD group than those in MCI group. 2. The N400 amplitudes of Pz in mismatching sentence and matching sentence showed statistically significant diffrences among three groups (P<0.05). The N400 amplitudes of C3 in mismatching sentence, C4 in matching sentence were both statistically significant diffrences in three groups (P<0.05). The amplitudes were decreased in AD and MCI group. Conclusions: 1. The patients with AD and MCI have impairment in their cognitive function and N400. 2. The latency and amplitude of N400 significantly correlated to the score of MMSE, MoCA, ADAS-Cog and ADL. 3. Event related potential N400 is valuable in the early diagnosis of AD and MCI.
P1-200
SCREENING OF THE SOD1, TARDBP AND FUS MUTATIONS AND THE PATHOLOGICAL STUDIES IN JAPANESE CASES WITH FAMILIAL AND SPORADIC AMYOTROPHIC LATERAL SCLEROSIS
Tetsuaki Arai1, Makoto Arai2, Masanari Itokawa2, Mari Yoshida3, Akira Tamaoka4, Zen Kobayashi5, Masato Hosokawa2, Masato Hasegawa2,
Takashi Nonaka2, Hiroshi Tsuji4, Masahito Yamada6, Makoto Matsui6, Ryuji Kaji7, Kenji Nakajima8, Ryozo Kuwano9, Sho Takahashi1, Takash Asada1, Haruhiko Akiyama2, 1University of Tsukuba, Ibaraki, Japan; 2Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan; 3 Aichi Medical University, Aichi, Japan; 4University of Tsukuba, Tsukuba, Japan; 5JA Toride Medical Center, Ibaraki, Japan; 6Kanazawa Medical University, Kanazawa, Japan; 7University of Tokushima, Tokushima, Japan; 8 Tottori University, Yonago-shi ,Tottori, Japan; 9Niigata University, Niigata, Japan.
Background: About 10% of amyotrophic lateral sclerosis (ALS) cases are known to be familial (FALS), and pathogenic mutations are found in 30% of FALS patients. Until recently, mutations in SOD1 are the most frequent cause of ALS, accounting for 20% of FALS and 3% of sporadic ALS (SALS) cases. Mutations in TARDBP and FUS are both estimated to cause 5% of FALS cases. Recent studies have found that the C9ORF72 mutations are the most common genetic abnormality in FALS and SALS. However, there are few reports on the frequency of these mutations in Japanese cases with ALS and the pathology of these cases. Methods: We screened mutations in the SOD1, TARDBP and FUS genes in 32 cases with FALS and 279 cases with SALS in Japan. The samples are supposed to be screened for the C9ORF72 mutations in the future. In addition, we performed pathological and biochemical analyses of autopsied brains of a case with G298S mutation in TARDBP and a case with R521C mutation in FUS. Results: In FALS cases, fourteen different mutations, including 8 in SOD1, 3 in TARDBP, and 3 in FUS were identified. Mutations in SOD1, TARDBP and FUS account for 25%, 9.4%, and 9.4% of FALS, respectively. In SALS cases, only 2 mutations in SOD1 (0.72%) were found. Pathologically, in a case with G298S mutation in TARDBP, TDP-43 positive neuronal and glial inclusions in the spinal cord, hippocampal region, internal capsule and thalamus. Accumulated TDP-43 was phosphorylated and cleaved as previously reported in SALS. In a case with R521C mutation in FUS, FUS positive neuronal cytoplasmic inclusions, glial cytoplasmic inclusions and dystrophic neurites were more abundantly occurring than basophilic inclusions, especially in the cuneate nucleus and globus pallidus. Conclusions: The present study suggest that the frequency of the mutations in SOD1, TARDBP and FUS in Japan is comparable to data previously published, and that in addition to mutations in SOD1, those in TARDBP and FUS are a widespread cause of FALS. Mutations in TARDBP and FUS cause the wide distribution of intracellular protein aggregates beyond the motor system, which are regarded as multisystem neuroglial proteinopathy.
Poster Presentations: P1
PCA patients (5 women; 59.8 6 4.8 years old) and 16 controls (12 women; 52.1 6 13.2 years old) were studied. All subjects had two DTI scans with an interval of 13.4 6 2.1 months. Definition of regions of interest (ROI) were performed having first co-registered the serial DTI in order to improve consistency of the ROIs and precision of longitudinal measure. All affine and non-linear registrations were performed using DTI-TK, a state-of-the-art tool for spatial normalization of DTI data, which uses the whole-tensor information for optimal white matter alignment. For each subject (“nest”), a subject-specific template was created by groupwise registration (affine, then non-linear) between each subject’s two time-points. An average tensor image was created for each nest. FA maps were then created from the average tensor image and each registered tensor image. Eight specific WM ROIs were defined by non-rigidly propagating the JHU-ICBM WM atlas to the template FA images. Linear regression models were used to make comparisons between groups adjusting for age and gender. Results: Significant cross-sectional differences in FA between PCA and control groups are seen at baseline in the genu, body and splenium of corpus callosum, cingulum bundle, fornix and posterior thalamic radiation (Table). The change in FA between baseline and followup was significantly different between PCA and controls for the genu and splenium of corpus callosum, right superior longitudinal fasciculus and left inferior fronto-occipital/inferior longitudinal fasciculus. Conclusions: Using an automatic tensor-based DTI registration technique to improve ROI consistency, we showed statistically significant decreases of FA in WM tracts of PCA patients over 12 months, suggesting a decline in WM integrity. Interestingly the cross-sectional differences accord with the longitudinal changes and imply several years of gradual changes. Evidence of longitudinal change in the genu may reflect increasing disruption of progressively more anterior structures in patients with more advanced disease. Table Descriptive statistics of FA (mean 6 SD) of two time points for PCA patients and Controls (CON); Each difference score (Baseline – Follow-up) was divided by the interscan interval to create a rate of change (slope), absolute change is reported
White matter ROIs Genu (CC) Body (CC) Splenium (CC) Fornix Cingulum bundle R Cingulum bundle L Posterior thalamic radiation R Posterior thalamic radiation L IFO/ILF R IFO/ILF L SLF R SLF L
Baseline Mean (SD)
Annualised change Mean (SD)
CON (n ¼ 16)
PCA (n ¼ 11)
CON (n ¼ 16)
PCA (n ¼ 11)
.597 (.028) .598 (.027) .668 (.023) .460 (.038) .484 (.027) .466 (.024) .528 (.024)
.564 (.028)* .568 (.029)* .627 (.027)** .391 (.042)** .425 (.036)** .408 (.031)** .496 (.026)*
.004 (.003) .007 (.006) .005 (.004) .025 (.016) .008 (.005) .007 (.005) .006 (.006)
.011 (.005) ** .011 (.005) .010 (.007) * .033 (.030) .014 (.011) .010 (.007) .011 (.008)
.512 (.024)
.483 (.025)**
.009 (.008)
.008 (.006)
.525 (.020) .509 (.020) .448 (.020) .449 (.023)
.512 (.021) .494 (.023) .431 (.025) .430 (.024)
.009 (.006) .009 (.006) .005 (.004) .006 (.004)
.014 (.008) .023 (.013)* .010 (.009) ** .006 (.004)
Manja Lehmann2, John Thornton4, Jason Warren2, David Cash5, Sebastian Crutch1, Sebastien Ourselin2, Nick Fox1, 1UCL Institute of Neurology, London, United Kingdom; 2University College London, London, United Kingdom; 3London School of Hygiene and Tropical Medicine, London, United Kingdom; 4National Hospital for Neurology and Neurosurgery, London, United Kingdom; 5University College of London, London, United Kingdom. Background: White matter (WM) damage has been reported in Alzheimer’s disease (AD) patients studied with diffusion tensor imaging (DTI). However, few group studies have investigated WM involvement in Posterior Cortical Atrophy (PCA). We explored whether there is WM tract degeneration in PCA using a tensor-based registration technique on atlas-based regions of interest (ROI). Methods: Twenty patients with PCA (11 women; mean 6 SD age ¼ 61.6 6 5.9yrs; MMSE score ¼ 16.6 6 5.9) and twenty controls (13 women; mean 6 SD age ¼ 54.9 6 13.3 yrs) were studied. All PCA subjects fulfilled the clinical criteria proposed by Mendez et al. (2002) and Tang-Wai et al. (2004). All registrations were performed using DTI-Toolkit, a state-of-the-art tool for spatial normalization of DTI data, which uses the whole-tensor information for optimal white matter alignment. First, a study-specific template was created by non-linearly registering all data to the groupwise space. A fractional anisotropy (FA) map was then created for both the groupwise template and each individual registered image. Eight specific WM ROIs were defined by segmentation propagation of the JHU-ICBM WM atlas to the groupwise template. The mean and standard deviation FA was calculated in each ROI. Results: Linear regression models were used to assess differences in FA of WM tracts between populations, adjusting for age and gender. PCA patients showed significantly lower FA than controls in the corpus callosum, fornix, bilateral cingulum, posterior thalamic radiations, inferior fronto-occipital/inferior longitudinal fasciculi and superior longitudinal fasciculi. A positive correlation was found between MMSE score and FA value in the right posterior thalamic radiation (r ¼ .60, P ¼ .006), inferior fronto-occipital/inferior longitudinal fasciculi (r ¼ .50, P ¼ .03) and superior longitudinal fasciculus (r ¼ .47, P ¼ .03) (Figure). Conclusions: Results suggest selective disruption of posterior WM tracts in PCA. Tract damage is significantly associated with disease severity, as measured by the MMSE. The posterior focus of WM damage is consistent with established evidence of occipito-parietal cortical dysfunction and atrophy in PCA. Given that PCA patients typically present with higher visual
SLF, Superior longitudinal fasciculi; IFO/ILF, Inferior fronto-occipital/ inferior longitudinal fasciculi; CC, Corpus Callosum; L, Left; R, Right; *, P <.05; **, P <.01, between group differences adjusted for age and gender.
P1-198
WHITE MATTER DAMAGE IN POSTERIOR CORTICAL ATROPHY ASSESSED IN VIVO USING DIFFUSION TENSOR MAGNETIC RESONANCE IMAGING
Shiva Keihaninejad1, Hui Zhang2, Tim Shakespeare1, Natalie Ryan1, Ian Malone1, Chris Frost3, Manuel Cardoso2, Marc Modat2,
Figure. Scatterplots of the white matter fractional anisotropy (FA) value versus mini mental state examination (MMSE) scores in patients with PCA. SLF, Superior longitudinal fasciculus; R, Right; L, Left.
Poster Presentations: P1
P177
Table Descriptive statistics of FA (mean 6 SD); significance for comparison between subject groups; the 95% confidence intervals (CI) for the adjusted differences between group means (the mean for the patient group minus the mean for the healthy group) White matter ROIs
CON (n ¼ 20)
PCA (n ¼ 20)
Adjusted difference (95%CI)
P-value
Genu (CC) Body (CC) Splenium (CC) Fornix Cingulum bundle R Cingulum bundle L Posterior thalamic radiation R Posterior thalamic radiation L Inferior frontooccipital/ inferior longitudinal fasciculi R Inferior frontooccipital/ inferior longitudinal fasciculi L Superior longitudinal fasciculus R Superior longitudinal fasciculus L
.596 6 .033 .604 6 .032 .669 6 .029 .405 6 .043 .470 6 .031 .452 6 .032 .537 6 .029 .521 6 .021 .540 6 .032 .519 6 .036 .444 6 .022 .450 6 .020
.569 6 .024 .570 6 .026 .622 6 .033 .338 6 .036 .412 6 .040 .394 6 .038 .485 6 .031 .482 6 .034 .489 6 .042 .467 6 .040 .419 6 .026 .423 6 .023
.022 (.056, .009) .028 (.047, .009) .040 (.061, .020) .055 (.080, .030) .053 (.078, .029) .058 (.082, .034) .049 (.069, .029) .037 (.056, .018) .045 (.069, .021) .043 (.066, .020) .026 (.041, .011) .027 (.041, .012)
.028 .004 <.001 <.001 <.001 <.001 <.001 <.001 <.001 <.001 <.001 <.001
Abbreviations: CC, Corpus Callosum; L, Left; R, Right
processing deficits, the involvement of the optic radiation is of particular note as this tract represents the major sensory input pathway to visual cortex. FA measures of WM tract integrity in PCA patients may have value as surrogate markers for monitoring disease progression.
P1-199
A CLINICAL STUDY ON EVENT-RELATED POTENTIAL N400 IN PATIENTS WITH ALZHEIMER’S DISEASE AND MILD COGNITIVE IMPAIRMENT
Su Ning, Fu Xiao, Shanghai Jiaotong University School of Medicine, Shanghai, China. Background: To explore the event related potential N400 of patients with Alzheimer’s disease and mild cognitive impairment, analyzed the diagnostic value of N400 for AD and MCI. Methods: 26 patients with Alzheimer’s disease patients (AD group), 22 mild cognitive impairment (MCI group) and 24 normal controls (control group) were investigated. All subjects were measured with event-related potential N400 and administered with MMSE, MoCA, ADAS-cog, ADL. The correlation between eventrelated potential N400 and cognition, and the diagnostic value of N400 for AD and MCI were analyzed. Results: 1. The N400 latencies of Fz, Pz, C3, C4 in mismatching sentence and Pz in matching sentence showed statistically significant diffrences among three groups (P<0.05). N400 latencies in MCI group were longer than those in control group, N400 latencies were longer in AD group than those in MCI group. 2. The N400 amplitudes of Pz in mismatching sentence and matching sentence showed statistically significant diffrences among three groups (P<0.05). The N400 amplitudes of C3 in mismatching sentence, C4 in matching sentence were both statistically significant diffrences in three groups (P<0.05). The amplitudes were decreased in AD and MCI group. Conclusions: 1. The patients with AD and MCI have impairment in their cognitive function and N400. 2. The latency and amplitude of N400 significantly correlated to the score of MMSE, MoCA, ADAS-Cog and ADL. 3. Event related potential N400 is valuable in the early diagnosis of AD and MCI.
P1-200
SCREENING OF THE SOD1, TARDBP AND FUS MUTATIONS AND THE PATHOLOGICAL STUDIES IN JAPANESE CASES WITH FAMILIAL AND SPORADIC AMYOTROPHIC LATERAL SCLEROSIS
Tetsuaki Arai1, Makoto Arai2, Masanari Itokawa2, Mari Yoshida3, Akira Tamaoka4, Zen Kobayashi5, Masato Hosokawa2, Masato Hasegawa2,
Takashi Nonaka2, Hiroshi Tsuji4, Masahito Yamada6, Makoto Matsui6, Ryuji Kaji7, Kenji Nakajima8, Ryozo Kuwano9, Sho Takahashi1, Takash Asada1, Haruhiko Akiyama2, 1University of Tsukuba, Ibaraki, Japan; 2Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan; 3 Aichi Medical University, Aichi, Japan; 4University of Tsukuba, Tsukuba, Japan; 5JA Toride Medical Center, Ibaraki, Japan; 6Kanazawa Medical University, Kanazawa, Japan; 7University of Tokushima, Tokushima, Japan; 8 Tottori University, Yonago-shi ,Tottori, Japan; 9Niigata University, Niigata, Japan.
Background: About 10% of amyotrophic lateral sclerosis (ALS) cases are known to be familial (FALS), and pathogenic mutations are found in 30% of FALS patients. Until recently, mutations in SOD1 are the most frequent cause of ALS, accounting for 20% of FALS and 3% of sporadic ALS (SALS) cases. Mutations in TARDBP and FUS are both estimated to cause 5% of FALS cases. Recent studies have found that the C9ORF72 mutations are the most common genetic abnormality in FALS and SALS. However, there are few reports on the frequency of these mutations in Japanese cases with ALS and the pathology of these cases. Methods: We screened mutations in the SOD1, TARDBP and FUS genes in 32 cases with FALS and 279 cases with SALS in Japan. The samples are supposed to be screened for the C9ORF72 mutations in the future. In addition, we performed pathological and biochemical analyses of autopsied brains of a case with G298S mutation in TARDBP and a case with R521C mutation in FUS. Results: In FALS cases, fourteen different mutations, including 8 in SOD1, 3 in TARDBP, and 3 in FUS were identified. Mutations in SOD1, TARDBP and FUS account for 25%, 9.4%, and 9.4% of FALS, respectively. In SALS cases, only 2 mutations in SOD1 (0.72%) were found. Pathologically, in a case with G298S mutation in TARDBP, TDP-43 positive neuronal and glial inclusions in the spinal cord, hippocampal region, internal capsule and thalamus. Accumulated TDP-43 was phosphorylated and cleaved as previously reported in SALS. In a case with R521C mutation in FUS, FUS positive neuronal cytoplasmic inclusions, glial cytoplasmic inclusions and dystrophic neurites were more abundantly occurring than basophilic inclusions, especially in the cuneate nucleus and globus pallidus. Conclusions: The present study suggest that the frequency of the mutations in SOD1, TARDBP and FUS in Japan is comparable to data previously published, and that in addition to mutations in SOD1, those in TARDBP and FUS are a widespread cause of FALS. Mutations in TARDBP and FUS cause the wide distribution of intracellular protein aggregates beyond the motor system, which are regarded as multisystem neuroglial proteinopathy.