- Email: [email protected]
Characterizing abnormal white matter structure in primary progressive aphasia
S180
Poster Presentations P1
prion protein gene (PRNP). The phenotypes associated with these genetic forms are Creutzfeldt-Jakob disease (CJD), Gerstmann-Strau¨ssler-Scheinker (GSS) and fatal familial insomnia (FFI). P102L mutation is usually associated with GSS phenotype. Objective: To describe the phenotypic heterogeneity in a Brazilian family with P102L mutation. Methods: Patient 1 was seen in the Cognitive and Behavioral Neurology Unit of the Hospital das Clinicas of the University of Sa˜o Paulo School of Medicine in 2002 with an atypical and probably genetic dementia. We tracked all clinical, laboratory, neuroimaging and pathological data from the other affected members of the family. Results: Patient 1: woman, age at onset: 27 yo; memory and attention deficits, gate disturbance, progression to severe dementia in 2 years. MRI: brain atrophy. CSF 14.3.3: negative. EEG: excess of lower frequencies. PRNP: P102L, M129V. Patient 2 (uncle of #1): age at onset: 53 yo, rapidly progressive dementia; death in 8 months. Frontal and extrapyramidal syndromes and myoclonias. MRI: frontal atrophy. EEG: non specific changes. Clinical diagnosis of possible CJD; brain biopsy: spongiform encephalopathy. PRNP: not available. Patient 3 (sister of #2): age of onset: 54 yo; dizziness, cognitive decline, gate disturbance and blindness; death after 4 years. MRI: brain atrophy; hyperintensities in frontal and parietal cortex on DWI. PRNP: P102L, M129M. Patient 4 (daughter of #3): age of onset: 36 yo; progressive ataxia, spasticity, back pain, and feet numbness. Mild executive function deficit after 2 years. Severe dementia 7 years after onset. MRI: cerebellar atrophy. PRNP: P102L, M129V. Conclusions: Prion disease associated with P102L mutation presented with high phenotypic heterogeneity in this Brazilian family. P1-022
CHARACTERIZING ABNORMAL WHITE MATTER STRUCTURE IN PRIMARY PROGRESSIVE APHASIA
Graeme Schwindt1,2, Naida Graham3,4, Elizabeth Rochon3,4, David TangWai5,6, Sandra E. Black1,2, 1Institute of Medical Science, University of Toronto, Toronto, ON, Canada; 2LC Campbell Cognitive Neurology Research Unit, Sunnybrook Health Sciences Centre, Toronto, ON, Canada; 3 Department of Speech-Language Pathology, University of Toronto, Toronto, ON, Canada; 4Toronto Rehabilitation Institute, Toronto, ON, Canada; 5 Department of Medicine, University of Toronto, Toronto, ON, Canada; 6 Division of Neurology, Toronto Western Hospital, University Health Network, Toronto, ON, Canada. Contact e-mail: [email protected] Background: Primary progressive aphasia (PPA) shows early selective language impairment, and relative sparing of other cognitive domains. Cortical atrophy is noted in the left perisylvian language areas, though different PPA subtypes may have additional areas involved. To date, little work has examined the integrity of white matter tracts in PPA, but there is some suggestion that the arcuate region of the left superior longitudinal fasciculus (SLF) may be involved. The present study uses diffusion tensor imaging (DTI) and tract-based spatial statistics (TBSS)5 to examine differences in fractional anisotropy (FA), radial (DR), and axial diffusivity (DA) between a group of PPA patients and healthy controls. Methods: 10 patients with PPA (3 non-fluent, 7 semantic dementia) were recruited from two clinical sites in Toronto. 17 healthy controls were matched to patients for age and education. Diffusion weighted images were collected on a 3.0T GE Signa scanner with 23 directions and two repetitions. Analysis was carried out using TBSS within the FSL package. FA, DA, and DR images were calculated for each individual. Images were transformed into MNI space using the FMRIB58 FA template and nonlinear registration. FA images were skeletonised to define a search space for voxel-wise comparisons. 2-sample ttests compared FA, DR, and DA between groups, with randomise for non-parametric estimation and threshold-free cluster enhancement for multiple-comparisons correction. Results: FA values were higher in controls across a number of territories, including left SLF, bilateral inferior longitudinal fasciculi (ILF) and uncinate fasciculi (UF). Patients showed higher DR overlapping these changes in FA, while DA was not reduced in patients. DA was higher in patients than controls within voxels contributing to the left UF and forceps major. Conclusions: Results suggest white matter disruption is widespread in PPA, but includes left-hemisphere SLF/arcuate involvement. This disruption is marked by an increase in radial diffusivity without loss of
axial diffusivity and may reflect demyelination in multiple tracts. Increased DA and DR in left UF may represent a unique degenerative process in this tract which could relate to loss of semantic memory in PPA. Future work will examine differences between PPA subtypes and clinical correlates of these findings. P1-023
RAPAMYCIN RESCUES TDP-43 MISLOCALIZATION AND THE ASSOCIATED LOW MOLECULAR WEIGHT NEUROFILAMENT INSTABILITY
Antonella Caccamo, Smita Majumder, Salvatore Oddo, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA. Contact e-mail: [email protected] Background: Transactive response DNA-binding protein 43 (TDP-43) is a nuclear protein involved in exon skipping and alternative splicing. Recently, TDP-43 has been identified as the pathological signature protein in frontotemporal lobar degeneration with ubiquitin positive inclusions and in amyotrophic lateral sclerosis. In addition, TDP-43 positive inclusions are present in Parkinson’s disease, dementia with Lewy bodies and in 30% of Alzheimer’s disease cases. Pathological TDP-43 is redistributed from the nucleus to the cytoplasm, where it accumulates. Particularly, a w25 kDa C-terminal fragment of TDP-43 accumulate in affected brain regions suggesting that it may be involved in the disease pathogenesis. Methods: We use two different cells lines, N2A and SH-SY5Y cells, to study the cell biology of TDP-43 and its 25KDa C-terminal fragment. Specifically we use pulse-chase experiments to study TDP-43 turnover. Results: Here we show that overexpression of the 25 kDa C-terminal fragment is sufficient to cause the mislocalization and cytoplasmic accumulation of endogenous full length TDP-43 in two different cell lines, thus recapitulating a key biochemical characteristic of TDP-43 proteinopathies. We also found that TDP-43 mislocalization is associated with a reduction in the low molecular weight neurofilament (NFL) mRNA levels. Notably, we show that the autophagic system plays a role in TDP-43 metabolism. Specifically, we found that autophagy inhibition increases the accumulation of the C-terminal fragments of TDP-43 while inhibition of the mammalian target of rapamycin, a key protein kinase involved in autophagy regulation, reduces the 25 kDa C-terminal fragment accumulation and restores TDP-43 localization. Conclusions: Our results suggest that autophagy induction may be a valid therapeutic target for TDP-43 proteinopathies. P1-024
VISUAL AND COGNITIVE IMPAIRMENT IN PATIENTS WITH DEMENTIA WITH LEWY BODIES AND ALZHEIMER’S DISEASE
Ana Rodrigues1, Isabel Santana1, Joana Sampaio2, Fernando Silva3, Miguel Castelo-Branco2, 1Faculty of Medicine, University of Coimbra, Coimbra, Portugal; 2Institute of Biomedical Research in Light and Image Faculty of Medicine, University of Coimbra, Coimbra, Portugal; 3Department of Neurology, University Hospital of Coimbra, Coimbra, Portugal. Contact e-mail: [email protected] Background: Dementia with Lewy Bodies (DLB) patients often exhibit attentional, visuospatial and executive deficits, consistent with frontal and parieto-occipital neuropathological abnormalities well described in this disease. Less is known about the impairment of eye movement control, as well as of early and dorsal visual functions and the specificity of this kind of disregulation in DLB. Using a battery of neuropsychological and psychophysical tests, we aim to explore cognitive and visual abnormalities in patients with DLB and compare them with Alzheimer’s Disease (AD). Methods: Twenty DLB patients, previously diagnosed following international consensus criteria (McKeith, et. al, 1996), twenty AD patients diagnosed according NINCDS-ADRDA, as well as a control group (N ¼ 20), were recruited. Both groups of patients were matched for age, educational level and severity of the disease. All subjects were assessed with a battery of cognitive tests: Stroop Colour Test, Trail Making Test, Verbal Fluency Test, Luria’s Graphmotor Sequences and Reaction Time Test (RTI)-CANTAB. Participants without retinal pathology underwent visual function assessment with psychophysical
Poster Presentations P1
prion protein gene (PRNP). The phenotypes associated with these genetic forms are Creutzfeldt-Jakob disease (CJD), Gerstmann-Strau¨ssler-Scheinker (GSS) and fatal familial insomnia (FFI). P102L mutation is usually associated with GSS phenotype. Objective: To describe the phenotypic heterogeneity in a Brazilian family with P102L mutation. Methods: Patient 1 was seen in the Cognitive and Behavioral Neurology Unit of the Hospital das Clinicas of the University of Sa˜o Paulo School of Medicine in 2002 with an atypical and probably genetic dementia. We tracked all clinical, laboratory, neuroimaging and pathological data from the other affected members of the family. Results: Patient 1: woman, age at onset: 27 yo; memory and attention deficits, gate disturbance, progression to severe dementia in 2 years. MRI: brain atrophy. CSF 14.3.3: negative. EEG: excess of lower frequencies. PRNP: P102L, M129V. Patient 2 (uncle of #1): age at onset: 53 yo, rapidly progressive dementia; death in 8 months. Frontal and extrapyramidal syndromes and myoclonias. MRI: frontal atrophy. EEG: non specific changes. Clinical diagnosis of possible CJD; brain biopsy: spongiform encephalopathy. PRNP: not available. Patient 3 (sister of #2): age of onset: 54 yo; dizziness, cognitive decline, gate disturbance and blindness; death after 4 years. MRI: brain atrophy; hyperintensities in frontal and parietal cortex on DWI. PRNP: P102L, M129M. Patient 4 (daughter of #3): age of onset: 36 yo; progressive ataxia, spasticity, back pain, and feet numbness. Mild executive function deficit after 2 years. Severe dementia 7 years after onset. MRI: cerebellar atrophy. PRNP: P102L, M129V. Conclusions: Prion disease associated with P102L mutation presented with high phenotypic heterogeneity in this Brazilian family. P1-022
CHARACTERIZING ABNORMAL WHITE MATTER STRUCTURE IN PRIMARY PROGRESSIVE APHASIA
Graeme Schwindt1,2, Naida Graham3,4, Elizabeth Rochon3,4, David TangWai5,6, Sandra E. Black1,2, 1Institute of Medical Science, University of Toronto, Toronto, ON, Canada; 2LC Campbell Cognitive Neurology Research Unit, Sunnybrook Health Sciences Centre, Toronto, ON, Canada; 3 Department of Speech-Language Pathology, University of Toronto, Toronto, ON, Canada; 4Toronto Rehabilitation Institute, Toronto, ON, Canada; 5 Department of Medicine, University of Toronto, Toronto, ON, Canada; 6 Division of Neurology, Toronto Western Hospital, University Health Network, Toronto, ON, Canada. Contact e-mail: [email protected] Background: Primary progressive aphasia (PPA) shows early selective language impairment, and relative sparing of other cognitive domains. Cortical atrophy is noted in the left perisylvian language areas, though different PPA subtypes may have additional areas involved. To date, little work has examined the integrity of white matter tracts in PPA, but there is some suggestion that the arcuate region of the left superior longitudinal fasciculus (SLF) may be involved. The present study uses diffusion tensor imaging (DTI) and tract-based spatial statistics (TBSS)5 to examine differences in fractional anisotropy (FA), radial (DR), and axial diffusivity (DA) between a group of PPA patients and healthy controls. Methods: 10 patients with PPA (3 non-fluent, 7 semantic dementia) were recruited from two clinical sites in Toronto. 17 healthy controls were matched to patients for age and education. Diffusion weighted images were collected on a 3.0T GE Signa scanner with 23 directions and two repetitions. Analysis was carried out using TBSS within the FSL package. FA, DA, and DR images were calculated for each individual. Images were transformed into MNI space using the FMRIB58 FA template and nonlinear registration. FA images were skeletonised to define a search space for voxel-wise comparisons. 2-sample ttests compared FA, DR, and DA between groups, with randomise for non-parametric estimation and threshold-free cluster enhancement for multiple-comparisons correction. Results: FA values were higher in controls across a number of territories, including left SLF, bilateral inferior longitudinal fasciculi (ILF) and uncinate fasciculi (UF). Patients showed higher DR overlapping these changes in FA, while DA was not reduced in patients. DA was higher in patients than controls within voxels contributing to the left UF and forceps major. Conclusions: Results suggest white matter disruption is widespread in PPA, but includes left-hemisphere SLF/arcuate involvement. This disruption is marked by an increase in radial diffusivity without loss of
axial diffusivity and may reflect demyelination in multiple tracts. Increased DA and DR in left UF may represent a unique degenerative process in this tract which could relate to loss of semantic memory in PPA. Future work will examine differences between PPA subtypes and clinical correlates of these findings. P1-023
RAPAMYCIN RESCUES TDP-43 MISLOCALIZATION AND THE ASSOCIATED LOW MOLECULAR WEIGHT NEUROFILAMENT INSTABILITY
Antonella Caccamo, Smita Majumder, Salvatore Oddo, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA. Contact e-mail: [email protected] Background: Transactive response DNA-binding protein 43 (TDP-43) is a nuclear protein involved in exon skipping and alternative splicing. Recently, TDP-43 has been identified as the pathological signature protein in frontotemporal lobar degeneration with ubiquitin positive inclusions and in amyotrophic lateral sclerosis. In addition, TDP-43 positive inclusions are present in Parkinson’s disease, dementia with Lewy bodies and in 30% of Alzheimer’s disease cases. Pathological TDP-43 is redistributed from the nucleus to the cytoplasm, where it accumulates. Particularly, a w25 kDa C-terminal fragment of TDP-43 accumulate in affected brain regions suggesting that it may be involved in the disease pathogenesis. Methods: We use two different cells lines, N2A and SH-SY5Y cells, to study the cell biology of TDP-43 and its 25KDa C-terminal fragment. Specifically we use pulse-chase experiments to study TDP-43 turnover. Results: Here we show that overexpression of the 25 kDa C-terminal fragment is sufficient to cause the mislocalization and cytoplasmic accumulation of endogenous full length TDP-43 in two different cell lines, thus recapitulating a key biochemical characteristic of TDP-43 proteinopathies. We also found that TDP-43 mislocalization is associated with a reduction in the low molecular weight neurofilament (NFL) mRNA levels. Notably, we show that the autophagic system plays a role in TDP-43 metabolism. Specifically, we found that autophagy inhibition increases the accumulation of the C-terminal fragments of TDP-43 while inhibition of the mammalian target of rapamycin, a key protein kinase involved in autophagy regulation, reduces the 25 kDa C-terminal fragment accumulation and restores TDP-43 localization. Conclusions: Our results suggest that autophagy induction may be a valid therapeutic target for TDP-43 proteinopathies. P1-024
VISUAL AND COGNITIVE IMPAIRMENT IN PATIENTS WITH DEMENTIA WITH LEWY BODIES AND ALZHEIMER’S DISEASE
Ana Rodrigues1, Isabel Santana1, Joana Sampaio2, Fernando Silva3, Miguel Castelo-Branco2, 1Faculty of Medicine, University of Coimbra, Coimbra, Portugal; 2Institute of Biomedical Research in Light and Image Faculty of Medicine, University of Coimbra, Coimbra, Portugal; 3Department of Neurology, University Hospital of Coimbra, Coimbra, Portugal. Contact e-mail: [email protected] Background: Dementia with Lewy Bodies (DLB) patients often exhibit attentional, visuospatial and executive deficits, consistent with frontal and parieto-occipital neuropathological abnormalities well described in this disease. Less is known about the impairment of eye movement control, as well as of early and dorsal visual functions and the specificity of this kind of disregulation in DLB. Using a battery of neuropsychological and psychophysical tests, we aim to explore cognitive and visual abnormalities in patients with DLB and compare them with Alzheimer’s Disease (AD). Methods: Twenty DLB patients, previously diagnosed following international consensus criteria (McKeith, et. al, 1996), twenty AD patients diagnosed according NINCDS-ADRDA, as well as a control group (N ¼ 20), were recruited. Both groups of patients were matched for age, educational level and severity of the disease. All subjects were assessed with a battery of cognitive tests: Stroop Colour Test, Trail Making Test, Verbal Fluency Test, Luria’s Graphmotor Sequences and Reaction Time Test (RTI)-CANTAB. Participants without retinal pathology underwent visual function assessment with psychophysical