PMCC PMCC

Search tips
Search criteria

Advanced
Results 1-25 (722692)

Clipboard (0)
None

Related Articles

1.  TDP-43 subtypes are associated with distinct atrophy patterns in frontotemporal dementia 
Neurology  2010;75(24):2204-2211.
Background:
We sought to describe the antemortem clinical and neuroimaging features among patients with frontotemporal lobar degeneration with TDP-43 immunoreactive inclusions (FTLD-TDP).
Methods:
Subjects were recruited from a consecutive series of patients with a primary neuropathologic diagnosis of FTLD-TDP and antemortem MRI. Twenty-eight patients met entry criteria: 9 with type 1, 5 with type 2, and 10 with type 3 FTLD-TDP. Four patients had too sparse FTLD-TDP pathology to be subtyped. Clinical, neuropsychological, and neuroimaging features of these cases were reviewed. Voxel-based morphometry was used to assess regional gray matter atrophy in relation to a group of 50 cognitively normal control subjects.
Results:
Clinical diagnosis varied between the groups: semantic dementia was only associated with type 1 pathology, whereas progressive nonfluent aphasia and corticobasal syndrome were only associated with type 3. Behavioral variant frontotemporal dementia and frontotemporal dementia with motor neuron disease were seen in type 2 or type 3 pathology. The neuroimaging analysis revealed distinct patterns of atrophy between the pathologic subtypes: type 1 was associated with asymmetric anterior temporal lobe atrophy (either left- or right-predominant) with involvement also of the orbitofrontal lobes and insulae; type 2 with relatively symmetric atrophy of the medial temporal, medial prefrontal, and orbitofrontal-insular cortices; and type 3 with asymmetric atrophy (either left- or right-predominant) involving more dorsal areas including frontal, temporal, and inferior parietal cortices as well as striatum and thalamus. No significant atrophy was seen among patients with too sparse pathology to be subtyped.
Conclusions:
FTLD-TDP subtypes have distinct clinical and neuroimaging features, highlighting the relevance of FTLD-TDP subtyping to clinicopathologic correlation.
GLOSSARY
= behavioral variant frontotemporal dementia;
= corticobasal syndrome;
= Clinical Dementia Rating;
= false discovery rate;
= frontotemporal dementia;
= frontotemporal lobar degeneration;
= frontotemporal lobar degeneration with TDP-43 immunoreactive inclusions;
= fused in sarcoma;
= Mini-Mental State Examination;
= motor neuron disease;
= progressive nonfluent aphasia;
= TAR DNA-binding protein of 43 kDa;
= University of California, San Francisco;
= voxel-based morphometry.
doi:10.1212/WNL.0b013e318202038c
PMCID: PMC3013589  PMID: 21172843
2.  Novel CSF biomarkers for frontotemporal lobar degenerations(e–Pub ahead of print) 
Neurology  2010;75(23):2079-2086.
Objective:
To identify antemortem CSF diagnostic biomarkers that can potentially distinguish between the 2 main causes of frontotemporal lobar degeneration (FTLD), i.e., FTLD with TDP-43 pathology (FTLD-TDP) and FTLD with tau pathology (FTLD-tau).
Methods:
CSF samples were collected antemortem from 23 patients with FTLD with known pathology to form a autopsy cohort as part of a comparative biomarker study that additionally included 33 living cognitively normal subjects and 66 patients with autopsy-confirmed Alzheimer disease (AD). CSF samples were also collected from 80 living patients clinically diagnosed with frontotemporal dementia (FTD). Levels of 151 novel analytes were measured via a targeted multiplex panel enriched in neuropeptides, cytokines, and growth factors, along with levels of CSF biomarkers for AD.
Results:
CSF levels of multiple analytes differed between FTLD-TDP and FTLD-tau, including Fas, neuropeptides (agouti-related peptide and adrenocorticotropic hormone), and chemokines (IL-23, IL-17). Classification by random forest analysis achieved high sensitivity for FTLD-TDP (86%) with modest specificity (78%) in the autopsy cohort. When the classification algorithm was applied to a living FTD cohort, semantic dementia was the phenotype with the highest predicted proportion of FTLD-TDP. When living patients with behavioral variant FTD were examined in detail, those predicted to have FTLD-TDP demonstrated neuropsychological differences vs those predicted to have FTLD-tau in a pattern consistent with previously reported trends in autopsy-confirmed cases.
Conclusions:
Clinical cases with FTLD-TDP and FTLD-tau pathology can be potentially identified antemortem by assaying levels of specific analytes that are well-known and readily measurable in CSF.
GLOSSARY
= Alzheimer disease;
= Aguti-related protein;
= angiopoietin-2;
= adrenocorticotropic hormone;
= amyotrophic lateral sclerosis;
= apolipoprotein B;
= behavioral variant FTD;
= corticobasal syndrome;
= frontotemporal dementia;
= frontotemporal lobar degeneration;
= frontotemporal lobar degeneration with tau pathology;
= frontotemporal lobar degeneration with TDP-43 pathology;
= interleukin;
= macrophage-derived chemokine;
= progressive nonfluent aphasia;
= primary progressive aphasia;
= progressive supranuclear palsy;
= S100 calcium binding protein b;
= semantic dementia;
= tumor necrosis factor-related apoptosis-inducing ligand receptor 3.
doi:10.1212/WNL.0b013e318200d78d
PMCID: PMC2995537  PMID: 21048198
3.  Does TDP-43 type confer a distinct pattern of atrophy in frontotemporal lobar degeneration? 
Neurology  2010;75(24):2212-2220.
Objective:
To determine whether TDP-43 type is associated with distinct patterns of brain atrophy on MRI in subjects with pathologically confirmed frontotemporal lobar degeneration (FTLD).
Methods:
In this case-control study, we identified all subjects with a pathologic diagnosis of FTLD with TDP-43 immunoreactive inclusions (FTLD-TDP) and at least one volumetric head MRI scan (n = 42). In each case we applied published criteria for subclassification of FTLD-TDP into FTLD-TDP types 1-3. Voxel-based morphometry was used to compare subjects with each of the different FTLD-TDP types to age- and gender-matched normal controls (n = 30). We also assessed different pathologic and genetic variants within, and across, the different types.
Results:
Twenty-two subjects were classified as FTLD-TDP type 1, 9 as type 2, and 11 as type 3. We identified different patterns of atrophy across the types with type 1 showing frontotemporal and parietal atrophy, type 2 predominantly anterior temporal lobe atrophy, and type 3 predominantly posterior frontal atrophy. Within the FTLD-TDP type 1 group, those with a progranulin mutation had significantly more lateral temporal lobe atrophy than those without. All type 2 subjects were diagnosed with semantic dementia. Subjects with a pathologic diagnosis of FTLD with motor neuron degeneration had a similar pattern of atrophy, regardless of whether they were type 1 or type 3.
Conclusions:
Although there are different patterns of atrophy across the different FTLD-TDP types, it appears that genetic and pathologic factors may also affect the patterns of atrophy.
GLOSSARY
= Alzheimer disease;
= Alzheimer's Disease Research Center;
= behavioral variant frontotemporal dementia;
= corticobasal syndrome;
= Clinical Dementia Rating scale sum of boxes;
= frontotemporal lobar degeneration;
= frontotemporal lobar degeneration with motor neuron degeneration;
= frontotemporal lobar degeneration with TDP-43 immunoreactive inclusions;
= Mini-Mental State Examination;
= neuronal cytoplasmic inclusion;
= progressive nonfluent aphasia;
= semantic dementia;
= Short Test of Mental Status;
= voxel-based morphometry.
doi:10.1212/WNL.0b013e31820203c2
PMCID: PMC3013590  PMID: 21172844
4.  Frequency of ubiquitin and FUS-positive, TDP-43-negative frontotemporal lobar degeneration 
Journal of Neurology  2009;257(5):747-753.
Frontotemporal lobar degeneration (FTLD) is a clinically, genetically and pathologically heterogeneous disorder. Within FTLD with ubiquitin-positive inclusions (FTLD-U), a new pathological subtype named FTLD-FUS was recently found with fused in sarcoma (FUS) positive, TDP-43-negative inclusions, and striking atrophy of the caudate nucleus. The aim of this study was to determine the frequency of FTLD-FUS in our pathological FTLD series, and to describe the clinical, neuroimaging and neuropathological features of FTLD-FUS, especially caudate atrophy. Demographic and clinical data collected prospectively from 387 patients with frontotemporal dementia (FTD) yielded 74 brain specimens. Immunostaining was carried out using a panel of antibodies, including AT-8, ubiquitin, p62, FUS, and TDP-43. Cortical and caudate atrophy on MRI (n = 136) was rated as normal, mild-moderate or severe. Of the 37 FTLD-U cases, 33 were reclassified as FTLD-TDP and four (0.11, 95%: 0.00–0.21) as FTLD-FUS, with ubiquitin and FUS-positive, p62 and TDP-43-negative neuronal intranuclear inclusions (NII). All four FTLD-FUS cases had a negative family history, behavioural variant FTD (bvFTD), and three had an age at onset ≤40 years. MRI revealed mild-moderate or severe caudate atrophy in all, with a mean duration from onset till MRI of 63 months (range 16–119 months). In our total clinical FTD cohort, we found 11 patients (0.03; 95% CI: 0.01–0.05) with bvFTD, negative family history, and age at onset ≤40 years. Caudate atrophy was present in 10 out of 136 MRIs, and included all four FUS-cases. The newly identified FTLD-FUS has a frequency of 11% in FTLD-U, and an estimated frequency of three percent in our clinical FTD cohort. The existence of this pathological subtype can be predicted with reasonable certainty by age at onset ≤40 years, negative family history, bvFTD and caudate atrophy on MRI.
doi:10.1007/s00415-009-5404-z
PMCID: PMC2864899  PMID: 19946779
Frontotemporal lobar degeneration (FTLD); Ubiquitin; p62; TDP-43; FUS
5.  Caudate atrophy on MRI is a characteristic feature of FTLD-FUS 
Background and Purpose
Frontotemporal lobar degeneration (FTLD) can be subdivided into those in which the abnormal protein is tau (FTLD-TAU), the TAR DNA binding protein 43 (FTLD-TDP) and the fused in sarcoma protein (FTLD-FUS). We have observed severe caudate atrophy at autopsy in FTLD-FUS, and hence we aimed to determine whether caudate atrophy on MRI is a feature that can distinguish FTLD-FUS from FTLD-TDP and FTLD-TAU.
Methods
From a cohort of 207 cases of FTLD we identified all cases of FTLD-FUS that had a volumetric antemortem head MRI (n=3). Caudate and frontal lobe volumes were measured in all three cases using atlas based parcellation and SPM5, and were compared to 10 randomly selected cases of FTLD-TDP and 10 randomly selected cases of FTLD-TAU. Total grey matter volumes were also calculated for all cases.
Results
The FTLD-FUS cases had significantly smaller caudate volumes (p=0.02) yet similar frontal lobe grey matter volumes (p=0.12) compared to FTLD-TDP and FTLD-TAU. Caudate volumes when corrected for total grey matter volume (p=0.01) or frontal lobe grey matter volume (p=0.01) were significantly smaller in FTLD-FUS than FTLD-TDP and FTLD-TAU, and showed no overlap with the other two groups.
Conclusions
Caudate atrophy on MRI appears to be significantly greater in FTLD-FUS compared with FTLD-TDP and FTLD-TAU suggesting that severe caudate atrophy may be a useful clinical feature to predict FTLD-FUS pathology.
doi:10.1111/j.1468-1331.2010.02975.x
PMCID: PMC2989679  PMID: 20236174
TDP-43; FTLD-TAU; FTLD-FUS; atlas based parcellation; caudate atrophy
6.  MRI Correlates of Protein Deposition and Disease Severity in Postmortem Frontotemporal Lobar Degeneration 
Neuro-degenerative diseases  2009;6(3):106-117.
Background
Frontotemporal lobar degeneration (FTLD) can be classified based on the presence of the microtubule-associated protein tau and the TAR DNA binding protein-43 (TDP-43). Future treatments will likely target these proteins, therefore it is important to identify biomarkers to help predict protein biochemistry.
Objective
To determine whether there is an MRI signature pattern of tau or TDP-43 using a large cohort of FTLD subjects and to investigate how patterns of atrophy change according to disease severity using a large autopsy-confirmed cohort of FTLD subjects.
Methods
Patterns of gray matter loss were assessed using voxel-based morphometry in 37 tau-positive and 44 TDP-43-positive subjects compared to 35 age and gender-matched controls, and compared to each other. Comparisons were also repeated in behavioral variant frontotemporal dementia (bvFTD) subjects (n = 15 tau-positive and n = 30 TDP-43-positive). Patterns of atrophy were also assessed according to performance on the Clinical Dementia Rating (CDR) scale and Mini-Mental State Examination (MMSE).
Results
The tau-positive and TDP-43-positive groups showed patterns of frontotemporal gray matter loss compared to controls with no differences observed between the groups, for all subjects and for bvFTD subjects. Patterns of gray matter loss increased in a graded manner by CDR and MMSE with loss in the frontal lobes, insula and hippocampus in mild subjects, spreading to the temporal and parietal cortices and striatum in more advanced disease.
Conclusion
There is no signature pattern of atrophy for tau or TDP-43; however, patterns of atrophy in FTLD progress with measures of clinical disease severity.
doi:10.1159/000209507
PMCID: PMC2745704  PMID: 19299900
Frontotemporal lobar degeneration; Autopsy; Tau; TAR DNA binding protein-43; Voxel-based morphometry; Clinical Dementia Rating Scale; Mini-Mental State Examination
7.  Progressive aphasia secondary to Alzheimer disease pathology: A clinicopathologic and MRI study 
Neurology  2008;70(1):25-34.
Background
The pathology causing progressive aphasia is typically a variant of frontotemporal lobar degeneration, especially with ubiquitin-positive-inclusions (FTLD-U). Less commonly the underlying pathology is Alzheimer disease (AD).
Objective
To compare clinicopathological and MRI features of subjects with progressive aphasia and AD pathology, to subjects with aphasia and FTLD-U pathology, and subjects with typical AD.
Methods
We identified 5 subjects with aphasia and AD pathology and 5 with aphasia and FTLD-U pathology with an MRI from a total of 216 aphasia subjects. Ten subjects with typical AD clinical features and AD pathology were also identified. All subjects with AD pathology underwent pathological re-analysis with TDP-43 immunohistochemistry. Voxel-based morphometry (VBM) was used to assess patterns of grey matter atrophy in the aphasia cases with AD pathology, aphasia cases with FTLD-U, and typical AD cases with AD pathology, compared to a normal control group.
Results
All aphasic subjects had fluent speech output. However, those with AD pathology had better processing speed than those with FTLD-U pathology. Immunohistochemistry with TDP-43 antibodies was negative. VBM revealed grey matter atrophy predominantly in the temporoparietal cortices with notable sparing of the hippocampus in the aphasia with AD subjects. In comparison, the aphasic subjects with FTLD-U showed sparing of the parietal lobe. Typical AD subjects showed temporoparietal and hippocampal atrophy.
Conclusions
A temporoparietal pattern of atrophy on MRI in patients with progressive fluent aphasia and relatively preserved processing speed is suggestive of underlying AD pathology rather than FTLD-U.
doi:10.1212/01.wnl.0000287073.12737.35
PMCID: PMC2749307  PMID: 18166704
Primary progressive aphasia; Progressive non-fluent aphasia; Logopenic progressive aphasia; frontotemporal lobar degeneration with ubiquitin-only-immunoreactive changes; Voxel based morphometry
8.  Rates of cerebral atrophy differ in different degenerative pathologies 
Brain : a journal of neurology  2007;130(Pt 4):1148-1158.
SUMMARY
Neurodegenerative disorders are pathologically characterized by the deposition of abnormal proteins in the brain. It is likely that future treatment trials will target the underlying protein biochemistry and it is therefore increasingly important to be able to distinguish between different pathologies during life. The aim of this study was to determine whether rates of brain atrophy differ in neurodegenerative dementias that vary by pathological diagnoses and characteristic protein biochemistry. Fifty-six autopsied subjects were identified with a clinical diagnosis of dementia and two serial head MRI. Subjects were subdivided based on pathological diagnoses into Alzheimer's disease (AD), dementia with Lewy bodies (DLB), mixed AD/DLB, frontotemporal lobar degeneration with ubiquitin-only-immunoreactive changes (FTLD-U), corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP). Twenty-five controls were matched by age, gender, and scan interval, to the study cohort. The boundary-shift integral was used to calculate change over time in whole brain (BBSI) and ventricular volume (VBSI). All BSI results were annualized by adjusting for scan interval. The rates of whole brain atrophy and ventricular expansion were significantly increased compared to controls in the AD, mixed AD/DLB, FTLD-U, CBD and PSP groups. However, atrophy rates in the DLB group were not significantly different from control rates of atrophy. The largest rates of atrophy were observed in the CBD group which had a BBSI of 2.3% and VBSI of 16.2%. The CBD group had significantly greater rates of BBSI and VBSI than the DLB, mixed AD/DLB, AD and PSP groups, with a similar trend observed when compared to the FTLD-U group. The FTLD-U group showed the next largest rates with a BBSI of 1.7% and VBSI of 9.6% which were both significantly greater than the DLB group. There was no significant difference in the rates of atrophy between the AD, mixed AD/DLB and PSP groups, which all showed similar rates of atrophy; BBSI of 1.1, 1.3 and 1.0% and VBSI of 8.3, 7.2 and 10.9% respectively. Rates of atrophy therefore differ according to the pathological diagnoses and underlying protein biochemistry. While rates are unlikely to be useful in differentiating AD from cases with mixed AD/DLB pathology, they demonstrate important pathophysiological differences between DLB and those with mixed AD/DLB and AD pathology, and between those with CBD and PSP pathology.
doi:10.1093/brain/awm021
PMCID: PMC2752409  PMID: 17347250
magnetic resonance imaging; Alzheimer's disease; dementia with Lewy bodies; frontotemporal lobar degeneration; progressive supranuclear palsy
9.  Ultrastructural Localization of TDP-43 in Filamentous Neuronal Inclusions in Various Neurodegenerative Diseases 
Acta neuropathologica  2008;116(2):205-213.
Using post-embedding immunogold electron microscopy, TAR DNA-binding protein of 43 kDa (TDP-43) was localized to neuronal cytoplasmic (NCI) and intranuclear (NII) inclusions, as well as unmyelinated neurites, in frontotemporal lobar degeneration with ubiquitinated inclusions (FTLD-U), amyotrophic lateral sclerosis (ALS), Alzheimer’s (AD), Pick’s disease (PiD) and Lewy body disease (LBD). The TDP-43 immunoreactive structures were morphologically heterogeneous. The most common was characterized by bundles of 10–20 nm diameter straight filaments with electron dense granular material within NCI, NII and neurites. This type of pathology was found in FTLD-U, ALS and some cases of AD. Less often inclusions in neuritic processes of FTLD-U and some cases of AD contained 10–17 nm diameter straight filaments without granular material. A final type of TDP-43 immunoreactivity was labeling of filaments and granular material associated tau filaments in neurofibrillary tangles of AD and Pick bodies of PiD or α-synuclein filaments in Lewy bodies of LBD. The results suggest that TDP-43 is the primary component of the granulofilamentous inclusions in FTLD-U and ALS. Similar inclusions sometimes accompany filamentous aggregates composed of other abnormal proteins in AD, PiD and LBD.
doi:10.1007/s00401-008-0408-9
PMCID: PMC2706695  PMID: 18607609
Alzheimer's disease; amyotrophic lateral sclerosis; frontotemporal lobar degeneration with ubiquitinated inclusions; immunoelectron microscopy; Lewy body disease; Pick's disease; TAR DNA-binding protein of 43 kDa (TDP-43)
10.  MRI correlates of protein deposition and disease severity in postmortem frontotemporal lobar degeneration 
Neuro-degenerative diseases  2009;6(3):106-117.
Background
Frontotemporal lobar degeneration (FTLD) can be classified based on the presence of the microtubule associated protein tau and the TAR DNA binding protein-43 (TDP-43). Future treatments will likely target these proteins; therefore it is important to identify biomarkers to help predict protein biochemistry.
Objective
To determine whether there is an MRI signature pattern of tau or TDP-43 using a large cohort of FTLD subjects and to investigate how patterns of atrophy change according to disease severity using a large autopsy-confirmed cohort of FTLD subjects.
Methods
Patterns of grey matter loss were assessed using voxel-based morphometry in 37 tau-positive and 44 TDP-43 positive subjects compared to 35 age and gender-matched controls, and compared to each other. Comparisons were also repeated in behavioral variant frontotemporal dementia (bvFTD) subjects (n=15 tau-positive and n=30 TDP-43 positive). Patterns of atrophy were also assessed according to performance on the clinical dementia rating (CDR) scale and mini-mental state examination (MMSE).
Results
The tau-positive and TDP-43 positive groups showed patterns of frontotemporal grey matter loss compared to controls with no differences observed between the groups, for all subjects and for bvFTD subjects. Patterns of grey matter loss increased in a graded manner by CDR and MMSE with loss in the frontal lobes, insula and hippocampus in mild subjects, spreading to the temporal and parietal cortices and striatum in more advanced disease.
Conclusion
There is no signature pattern of atrophy for tau or TDP-43; however patterns of atrophy in FTLD progress with measures of clinical disease severity.
doi:10.1159/000209507
PMCID: PMC2745704  PMID: 19299900
frontotemporal lobar degeneration; autopsy; tau; TAR DNA binding protein-43; voxel-based morphometry; Clinical Dementia Rating Scale; Mini-Mental State Examination
11.  Imaging signatures of molecular pathology in behavioral variant frontotemporal dementia 
Journal of Molecular Neuroscience  2011;45(3):372-378.
Pathology underlying behavioral variant frontotemporal dementia (bvFTD) is heterogeneous, with the most common pathologies being Pick’s disease (PiD), corticobasal degeneration (CBD), and FTLD-TDP type 1. Clinical features are unhelpful in differentiating these pathologies. We aimed to determine whether imaging atrophy patterns differ across these pathologies in bvFTD subjects. We identified 15 bvFTD subjects that had volumetric MRI during life and autopsy: five with PiD, five CBD and five FTLD-TDP type 1. Voxel-based morphometry was used to assess atrophy patterns in each bvFTD group compared to 20 age and gender-matched controls. All three pathological groups showed grey matter loss in frontal lobes, although specific patterns of atrophy differed across groups: PiD showed widespread loss in frontal lobes with additional involvement of anterior temporal lobes; CBD showed subtle patterns of loss involving posterior lateral and medial superior frontal lobe; FTLD-TDP type 1 showed widespread loss in frontal, temporal and parietal lobes. Greater parietal loss was observed in FTLD-TDP type 1 compared to both other groups, and greater anterior temporal and medial frontal loss was observed in PiD compared to CBD. Imaging patterns of atrophy in bvFTD vary according to pathological diagnosis and may therefore be helpful in predicting these pathologies in bvFTD.
doi:10.1007/s12031-011-9533-3
PMCID: PMC3401589  PMID: 21556732
Frontotemporal dementia; behavioral variant; Pick’s disease; corticobasal degeneration; TDP-43; atrophy; voxel-based morphometry; MRI
12.  TAR DNA-binding protein 43 in neurodegenerative disease 
Nature reviews. Neurology  2010;6(4):211-220.
In 2006, TAR DNA-binding protein 43 (TDP-43), a highly conserved nuclear protein, was identified as the major disease protein in amyotrophic lateral sclerosis (ALS) and in the most common variant of frontotemporal lobar degeneration (FTLD), FTLD-U, which is characterized by cytoplasmic inclusions that stain positive for ubiquitin but negative for tau and α-synuclein. Since then, rapid advances have been made in our understanding of the physiological function of TDP-43 and the role of this protein in neurodegeneration. These advances link ALS and FTLD-U (now designated FTLD-TDP) to a shared mechanism of disease. In this Review, we summarize the current evidence regarding the normal function of TDP-43 and the TDP-43 pathology observed in FTLD-TDP, ALS, and other neurodegenerative diseases wherein TDP-43 pathology co-occurs with other disease-specific lesions (for example, with amyloid plaques and neurofibrillary tangles in Alzheimer disease). Moreover, we discuss the accumulating data that support our view that FTLD-TDP and ALS represent two ends of a spectrum of primary TDP-43 proteinopathies. Finally, we comment on the importance of recent advances in TDP-43-related research to neurological practice, including the new opportunities to develop better diagnostics and disease-modifying therapies for ALS, FTLD-TDP, and related disorders exhibiting TDP-43 pathology.
doi:10.1038/nrneurol.2010.18
PMCID: PMC2892118  PMID: 20234357
13.  Biomarkers in Frontotemporal Lobar Degenerations – Progress and Challenges 
Progress in neurobiology  2011;95(4):636-648.
Neuronal and glial changes associated with tau, TAR DNA binding protein of ~43 kD (TDP-43), and fused in sarcoma (FUS) together constitute the pathologic spectrum of frontotemporal lobar degeneration (FTLD). Most patients with FTLD present with prominent behavior or language changes, sometimes accompanied by extrapyramidal symptoms or motor neuron disease. Identification of FTLD patients with mutations in genes for tau, TDP-43, and FUS lends strong support for their pathogenic roles in FTLD, and elucidation of their dysfunction will pave the way for development of substrate specific therapy. However, there remains no reliable biomarker for early detection of FTLD or prediction of underlying FTLD pathologic change. Clinical syndromes usually reflects the earliest affected brain regions where atrophy can be visualized on structural MRI, but neither clinical nor structural imaging-based biomarkers has been accurately correlated with underlying pathology on the individual patient level. Biochemical markers in the cerebrospinal fluid (CSF) have also been investigated in FTLD and related disorders, including amyotrophic lateral sclerosis (ALS) and progressive supranuclear palsy (PSP). However, their accuracy and pathologic significance need to be confirmed in future multi-center studies. Here we review the progress made in FTLD biomarkers, including clinical phenotype/feature characterization, neuropsychological analysis, CSF and plasma analytes, and patterns of brain atrophy and network dysfunction detectable on brain imaging. Given the pathologic overlap of FTLD with ALS and PSP, collaboration with specialists in those fields will be essential in the translation of promising FTLD biomarkers into clinical practice.
doi:10.1016/j.pneurobio.2011.04.012
PMCID: PMC3173583  PMID: 21554923
Biomarker; diagnosis; frontotemporal dementia; tau; tauopathy; TDP-43
14.  Imaging correlates of pathology in corticobasal syndrome(Podcast) 
Neurology  2010;75(21):1879-1887.
Background:
Corticobasal syndrome (CBS) can be associated with different underlying pathologies that are difficult to predict based on clinical presentation. The aim of this study was to determine whether patterns of atrophy on imaging could be useful to help predict underlying pathology in CBS.
Methods:
This was a case-control study of 24 patients with CBS who had undergone MRI during life and came to autopsy. Pathologic diagnoses included frontotemporal lobar degeneration (FTLD) with TDP-43 immunoreactivity in 5 (CBS-TDP), Alzheimer disease (AD) in 6 (CBS-AD), corticobasal degeneration in 7 (CBS-CBD), and progressive supranuclear palsy in 6 (CBS-PSP). Voxel-based morphometry and atlas-based parcellation were used to assess atrophy across the CBS groups and compared to 24 age- and gender-matched controls.
Results:
All CBS pathologic groups showed gray matter loss in premotor cortices, supplemental motor area, and insula on imaging. However, CBS-TDP and CBS-AD showed more widespread patterns of loss, with frontotemporal loss observed in CBS-TDP and temporoparietal loss observed in CBS-AD. CBS-TDP showed significantly greater loss in prefrontal cortex than the other groups, whereas CBS-AD showed significantly greater loss in parietal lobe than the other groups. The focus of loss was similar in CBS-CBD and CBS-PSP, although more severe in CBS-CBD.
Conclusions:
Imaging patterns of atrophy in CBS vary according to pathologic diagnosis. Widespread atrophy points toward a pathologic diagnosis of FTLD-TDP or AD, with frontotemporal loss suggesting FTLD-TDP and temporoparietal loss suggesting AD. On the contrary, more focal atrophy predominantly involving the premotor and supplemental motor area suggests CBD or PSP pathology.
GLOSSARY
= automated anatomic labeling;
= Alzheimer disease;
= corticobasal degeneration;
= corticobasal syndrome;
= Clinical Dementia Rating sum of boxes;
= false discovery rate;
= frontotemporal lobar degeneration;
= Mini-Mental State Examination;
= progressive supranuclear palsy;
= region of interest;
= supplemental motor area;
= TDP-43 immunoreactivity;
= total intracranial volume;
= voxel-based morphometry.
doi:10.1212/WNL.0b013e3181feb2e8
PMCID: PMC2995388  PMID: 21098403
15.  Hippocampal atrophy on MRI in frontotemporal lobar degeneration and Alzheimer's disease 
Background
Hippocampal atrophy on magnetic resonance imaging (MRI) is an early characteristic of Alzheimer's disease. However, hippocampal atrophy may also occur in other dementias, such as frontotemporal lobar degeneration (FTLD).
Objective
To investigate hippocampal atrophy on MRI in FTLD and its three clinical subtypes, in comparison with Alzheimer's disease, using volumetry and a visual rating scale.
Methods
42 patients with FTLD (17 frontotemporal dementia, 13 semantic dementia, and 12 progressive non‐fluent aphasia), 103 patients with Alzheimer's disease, and 73 controls were included. Hippocampal volumetry and the easily applicable medial temporal lobe atrophy (MTA) rating scale were applied to assess hippocampal atrophy.
Results
Multivariate analysis of variance for repeated measures showed an effect of diagnostic group on hippocampal volume. There was a significant diagnosis by side (left v right) interaction. Both FTLD and Alzheimer's disease showed hippocampal atrophy compared with controls. Results of the visual MTA rating scale confirmed these findings. Within the FTLD subtypes there were marked differences in hippocampal atrophy. Frontotemporal dementia and semantic dementia showed bilateral hippocampal atrophy, and in semantic dementia the left hippocampus was smaller than in Alzheimer's disease. No significant hippocampal atrophy was detected in non‐fluent progressive aphasia.
Conclusions
Hippocampal atrophy is not only a characteristic of Alzheimer's disease but also occurs in FTLD. The three clinical subtypes of FTLD show different patterns of hippocampal atrophy.
doi:10.1136/jnnp.2005.075341
PMCID: PMC2077497  PMID: 16306153
hippocampus; Alzheimer's disease; frontotemporal lobar degeneration; MRI
16.  Acute and chronically increased immunoreactivity to phosphorylation-independent but not pathological TDP-43 after a single traumatic brain injury in humans 
Acta neuropathologica  2011;122(6):715-726.
The pathologic phosphorylation and sub-cellular translocation of neuronal transactive response-DNA binding protein (TDP-43) was identified as the major disease protein in frontotemporal lobar degeneration (FTLD) with ubiquitinated inclusions, now termed FTLD-TDP, and amyotrophic lateral sclerosis (ALS). More recently, TDP-43 proteinopathy has been reported in dementia pugilistica or chronic traumatic encephalopathy caused by repetitive traumatic brain injury (TBI). While a single TBI has been linked to the development of Alzheimer’s disease and an increased frequency of neurofibrillary tangles, TDP-43 proteinopathy has not been examined with survival following a single TBI. Using immunohistochemistry specific for both pathological phosphorylated TDP-43 (p-TDP-43) and phosphorylation-independent TDP-43 (pi-TDP-43), we examined acute (n = 23: Survival < 2 weeks) and long-term (n = 39; 1–47 years survival) survivors of a single TBI versus age-matched controls (n = 47). Multiple regions were examined including the hippocampus, medial temporal lobe, cingulate gyrus, superior frontal gyrus and brainstem. No association was found between a history of single TBI and abnormally phosphorylated TDP-43 (p-TDP-43) inclusions. Specifically, just 3 of 62 TBI cases displayed p-TDP-43 pathology versus 2 of 47 control cases. However, while aggregates of p-TDP-43 were not increased acutely or long-term following TBI, immunoreactivity to phosphorylation-independent TDP-43 was commonly increased in the cytoplasm following TBI with both acute and long-term survival. Moreover, while single TBI can induce multiple long-term neurodegenerative changes, the absence of TDP-43 proteinopathy may indicate a fundamental difference in the processes induced following single TBI from those of repetitive TBI.
doi:10.1007/s00401-011-0909-9
PMCID: PMC3979333  PMID: 22101322
TDP-43; 43 kDa transactive response (TAR) DNA binding protein; Traumatic brain injury; Head injury; Diffuse axonal injury; DAI; Neurodegeneration; Dementia; Alzheimer’s disease; Long-term survival; Single versus repetitive TBI
17.  Simulated brain biopsy for diagnosing neurodegeneration using autopsy-confirmed cases 
Acta neuropathologica  2011;122(6):737-745.
Risks associated with brain biopsy limit availability of tissues and the role of brain biopsy in diagnosing neurodegeneration is unclear. We developed a simulated brain biopsy paradigm to comprehensively evaluate potential accuracy of detecting neurodegeneration in biopsies. Postmortem tissue from the frontal, temporal and parietal cortices and basal ganglia from 73 cases including Alzheimer’s disease (AD), Lewy body disease (LBD), frontotemporal lobar degeneration-TDP43 (FTLD-TDP), multiple system atrophy (MSA), Pick’s disease (PiD), corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP) were evaluated using H&E and immunostains. Brain biopsy was simulated in a blinded manner by masking each slide with opaque tape except for an area measuring 10 mm in diameter. Diagnoses obtained from frontal cortex only or all 4-brain regions were then compared with autopsy diagnoses. Diagnostic sensitivity in frontal cortex was highest in FTLD-TDP (88%), AD (80%) and LBD (79%); intermediate for MSA (71%), CBD (66%) and PiD (66%) and lowest for PSP (0%) (average 64%). Specificity was 43%. Sensitivities were enhanced with all 4-brain regions: FTLD-TDP (100%), AD (80%), LBD (100%), MSA (100%), CBD (83%), PiD (100%) and PSP (88%) (average 92%). Specificity was 71%. Simulated brain biopsy addressed limitations of standard brain biopsies such as tissue availability and lack of autopsy confirmation of diagnoses. These data could inform efforts to establish criteria for biopsy diagnosis of neurodegenerative disorders to guide care of individuals who undergo biopsy for enigmatic causes of cognitive impairment or when evidence of an underlying neurodegenerative disease may influence future therapy.
doi:10.1007/s00401-011-0880-5
PMCID: PMC3575084  PMID: 21959586
Neurodegeneration; Biopsy; Diagnosis; Alzheimer’s disease; Tauopathies; Synucleinopathies
18.  White Matter Imaging Helps Dissociate Tau from TDP-43 in Frontotemporal Lobar Degeneration 
Background
Frontotemporal lobar degeneration (FTLD) is most commonly associated with TAR-DNA binding protein (TDP-43) or tau pathology at autopsy, but there are no in vivo biomarkers reliably discriminating between sporadic cases. As disease-modifying treatments emerge, it is critical to accurately identify underlying pathology in living patients so that they can be entered into appropriate etiology-directed clinical trials. Patients with tau inclusions (FTLD-TAU) appear to have relatively greater white matter (WM) disease at autopsy than those patients with TDP-43 (FTLD-TDP). In this paper, we investigate the ability of white matter (WM) imaging to help discriminate between FTLD-TAU and FTLD-TDP during life using diffusion tensor imaging (DTI).
Methods
Patients with autopsy-confirmed disease or a genetic mutation consistent with FTLD-TDP or FTLD-TAU underwent multimodal T1 volumetric MRI and diffusion weighted imaging scans. We quantified cortical thickness in GM and fractional anisotropy (FA) in WM. We performed Eigenanatomy, a statistically robust dimensionality reduction algorithm, and used leave-one-out cross-validation to predict underlying pathology. Neuropathological assessment of GM and WM disease burden was performed in the autopsy-cases to confirm our findings of an ante-mortem GM and WM dissociation in the neuroimaging cohort.
Results
ROC curve analyses evaluated classification accuracy in individual patients and revealed 96% sensitivity and 100% specificity for WM analyses. FTLD-TAU had significantly more WM degeneration and inclusion severity at autopsy relative to FTLD-TDP.
Conclusions
These neuroimaging and neuropathological investigations provide converging evidence for greater WM burden associated with FTLD-TAU, and emphasize the role of WM neuroimaging for in vivo discrimination between FTLD-TAU and FTLD-TDP.
doi:10.1136/jnnp-2012-304418
PMCID: PMC3737288  PMID: 23475817
19.  Neuropathologic diagnostic and nosologic criteria for frontotemporal lobar degeneration: consensus of the Consortium for Frontotemporal Lobar Degeneration 
Acta Neuropathologica  2007;114(1):5-22.
The aim of this study was to improve the neuropathologic recognition and provide criteria for the pathological diagnosis in the neurodegenerative diseases grouped as frontotemporal lobar degeneration (FTLD); revised criteria are proposed. Recent advances in molecular genetics, biochemistry, and neuropathology of FTLD prompted the Midwest Consortium for Frontotemporal Lobar Degeneration and experts at other centers to review and revise the existing neuropathologic diagnostic criteria for FTLD. The proposed criteria for FTLD are based on existing criteria, which include the tauopathies [FTLD with Pick bodies, corticobasal degeneration, progressive supranuclear palsy, sporadic multiple system tauopathy with dementia, argyrophilic grain disease, neurofibrillary tangle dementia, and FTD with microtubule-associated tau (MAPT) gene mutation, also called FTD with parkinsonism linked to chromosome 17 (FTDP-17)]. The proposed criteria take into account new disease entities and include the novel molecular pathology, TDP-43 proteinopathy, now recognized to be the most frequent histological finding in FTLD. TDP-43 is a major component of the pathologic inclusions of most sporadic and familial cases of FTLD with ubiquitin-positive, tau-negative inclusions (FTLD-U) with or without motor neuron disease (MND). Molecular genetic studies of familial cases of FTLD-U have shown that mutations in the progranulin (PGRN) gene are a major genetic cause of FTLD-U. Mutations in valosin-containing protein (VCP) gene are present in rare familial forms of FTD, and some families with FTD and/or MND have been linked to chromosome 9p, and both are types of FTLD-U. Thus, familial TDP-43 proteinopathy is associated with defects in multiple genes, and molecular genetics is required in these cases to correctly identify the causative gene defect. In addition to genetic heterogeneity amongst the TDP-43 proteinopathies, there is also neuropathologic heterogeneity and there is a close relationship between genotype and FTLD-U sub-type. In addition to these recent significant advances in the neuropathology of FTLD-U, novel FTLD entities have been further characterized, including neuronal intermediate filament inclusion disease. The proposed criteria incorporate up-to-date neuropathology of FTLD in the light of recent immunohistochemical, biochemical, and genetic advances. These criteria will be of value to the practicing neuropathologist and provide a foundation for clinical, clinico-pathologic, mechanistic studies and in vivo models of pathogenesis of FTLD.
doi:10.1007/s00401-007-0237-2
PMCID: PMC2827877  PMID: 17579875
Frontotemporal dementia; Semantic dementia; Progressive non-Xuent aphasia; Frontotemporal lobar degeneration; Motor neuron disease; Tauopathy; Ubiquitin; TDP-43 proteinopathy; Progranulin; Valosin-containing protein; Charged multivesicular body protein 2B; Neuronal intermediate filament inclusion disease; Neuropathologic diagnosis
20.  TDP-43 protein in plasma may index TDP-43 brain pathology in Alzheimer’s disease and frontotemporal lobar degeneration 
Acta Neuropathologica  2008;116(2):141-146.
Autopsy studies have shown that about 55% of patients with frontotemporal lobar degeneration (FTLD) and 25% of patients with Alzheimer’s disease (AD) harbour TDP-43 immunoreactive pathological changes in their brains. Using ELISA, we investigated whether we could detect the presence, or increased amounts, of TDP-43 in plasma of patients with FTLD and AD compared to normal control subjects. We detected elevated levels of TDP-43 protein in plasma of 46% patients with FTLD with clinical frontotemporal dementia (FTD) and 22% patients with AD, compared to 8% of control subjects. The proportions of patients with FTD and AD showing raised plasma TDP-43 levels correspond closely to those proportions known from autopsy studies to contain TDP-43 pathological changes in their brains. Raised TDP-43 plasma levels may thereby index TDP-43 pathology within the brain. Plasma TDP-43 levels may be a biomarker that can provide a laboratory test capable of identifying the presence of TDP-43 brain pathology in neurodegenerative disease during life. It may help to distinguish those cases of FTLD with ubiquitin/TDP-43 pathology in their brains from those with tauopathy. As a predictive test, plasma TDP-43 level may have great practical value in directing therapeutic strategies aimed at preventing or removing tau or TDP-43 pathological changes from the brain in FTLD and AD.
doi:10.1007/s00401-008-0389-8
PMCID: PMC2464623  PMID: 18506455
Frontotemporal lobar degeneration; Alzheimer’s disease; TDP-43; Plasma; Biomarker
21.  Different molecular pathologies result in similar spatial patterns of cellular inclusions in neurodegenerative disease: a comparative study of eight disorders 
Journal of neural transmission (Vienna, Austria : 1996)  2012;119(12):10.1007/s00702-012-0838-3.
Recent research suggests cell-to-cell transfer of pathogenic proteins such as tau and α-synuclein may play a role in neurodegeneration. Pathogenic spread along neural pathways may give rise to specific spatial patterns of the neuronal cytoplasmic inclusions (NCI) characteristic of these disorders. Hence, the spatial patterns of NCI were compared in four tauopathies, viz., Alzheimer’s disease, Pick’s disease, corticobasal degeneration, and progressive supranuclear palsy, two synucleinopathies, viz., dementia with Lewy bodies and multiple system atrophy, the ‘fused in sarcoma’ (FUS)-immunoreactive inclusions in neuronal intermediate filament inclusion disease, and the transactive response DNA-binding protein (TDP-43)-immunoreactive inclusions in frontotemporal lobar degeneration, a TDP-43 proteinopathy (FTLD-TDP). Regardless of molecular group or morphology, NCI were most frequently aggregated into clusters, the clusters being regularly distributed parallel to the pia mater. In a significant proportion of regions, the regularly distributed clusters were in the size range 400–800 μm, approximating to the dimension of cell columns associated with the cortico-cortical pathways. The data suggest that cortical NCI in different disorders exhibit a similar spatial pattern in the cortex consistent with pathogenic spread along anatomical pathways. Hence, treatments designed to protect the cortex from neurodegeneration may be applicable across several different disorders.
doi:10.1007/s00702-012-0838-3
PMCID: PMC3863379  PMID: 22678700
Tauopathy; Synucleinopathy; FUS proteinopathy; TDP-43 proteinopathy; Spatial patterns; Neuronal cytoplasmic inclusions (NCI); Cell to cell transfer
22.  Characterization of DCTN1 genetic variability in neurodegeneration 
Neurology  2009;72(23):2024-2028.
Objective:
Recently, mutations in DCTN1 were found to cause Perry syndrome, a parkinsonian disorder with TDP-43-positive pathology. Previously, mutations in DCTN1 were identified in a family with lower motor neuron disease, in amyotrophic lateral sclerosis (ALS), and in a family with ALS/frontotemporal dementia (FTD), suggesting a central role for DCTN1 in neurodegeneration.
Methods:
In this study we sequenced all DCTN1 exons and exon-intron boundaries in 286 samples diagnosed with Parkinson disease (PD), frontotemporal lobar degeneration (FTLD), or ALS.
Results:
This analysis revealed 36 novel variants (9 missense, 5 silent, and 22 noncoding). Segregation analysis in families and association studies in PD, FTLD, and ALS case–control series did not identify any variants segregating with disease or associated with increased disease risk.
Conclusions:
This study suggests that pathogenic mutations in DCTN1 are rare and do not play a common role in the development of Parkinson disease, frontotemporal lobar degeneration, or amyotrophic lateral sclerosis.
GLOSSARY
= Alzheimer disease;
= amyotrophic lateral sclerosis;
= cytoskeleton-associated protein-glycine-rich;
= frontotemporal dementia;
= frontotemporal lobar degeneration;
= motor neuron disease;
= Parkinson disease.
doi:10.1212/WNL.0b013e3181a92c4c
PMCID: PMC2692178  PMID: 19506225
23.  Patterns of MRI atrophy in tau-positive and ubiquitin-positive frontotemporal lobar degeneration 
We applied optimized voxel-based morphometry (VBM) to brain MRIs from autopsy-proven cases of tau-positive frontotemporal lobar degeneration (FTLD-T, N = 6), ubiquitin and TDP-43-positive/tau-negative FTLD (FTLD-U, N = 8) and cognitively normal controls (N = 61). The analysis revealed that FTLD-T and FTLD-U both show atrophy in the frontal cortex and striatum, but striatal atrophy is more severe in FTLD-T. Manual region-of-interest (ROI) tracing of caudate and putamen volumes confirmed the VBM findings. These anatomic differences may help distinguish between FTLD spectrum pathologic subtypes in vivo.
doi:10.1136/jnnp.2006.114231
PMCID: PMC2095621  PMID: 17615169
Tau-positive frontotemporal lobar degeneration; Ubiquitin and TDP-43-positive/tau-negative frontotemproal lobar degeneration; Voxel-based morphometry; Region-of-interest; Basal ganglia
24.  Patterns of MRI atrophy in tau positive and ubiquitin positive frontotemporal lobar degeneration 
We applied optimised voxel based morphometry (VBM) to brain MRIs from autopsy proven cases of tau positive frontotemporal lobar degeneration (FTLD‐T, n = 6), ubiquitin and TDP‐43 positive/tau negative FTLD (FTLD‐U, n = 8) and cognitively normal controls (n = 61). The analysis revealed that FTLD‐T and FTLD‐U both show atrophy in the frontal cortex and striatum, but striatal atrophy is more severe in FTLD‐T. Manual region of interest tracing of caudate and putamen volumes confirmed the VBM findings. These anatomical differences may help distinguish between FTLD spectrum pathological subtypes in vivo.
doi:10.1136/jnnp.2006.114231
PMCID: PMC2095621  PMID: 17615169
25.  Delusions in frontotemporal lobar degeneration 
Journal of Neurology  2009;256(4):600-607.
We assessed the significance and nature of delusions in frontotemporal lobar degeneration (FTLD), an important cause of young-onset dementia with prominent neuropsychiatric features that remain incompletely characterised. The case notes of all patients meeting diagnostic criteria for FTLD attending a tertiary level cognitive disorders clinic over a three year period were retrospectively reviewed and eight patients with a history of delusions were identified. All patients underwent detailed clinical and neuropsychological evaluation and brain MRI. The diagnosis was confirmed pathologically in two cases. The estimated prevalence of delusions was 14 %. Delusions were an early, prominent and persistent feature. They were phenomenologically diverse; however paranoid and somatic delusions were prominent. Behavioural variant FTLD was the most frequently associated clinical subtype and cerebral atrophy was bilateral or predominantly right-sided in most cases. We conclude that delusions may be a clinical issue in FTLD, and this should be explored further in future work.
doi:10.1007/s00415-009-0128-7
PMCID: PMC2756566  PMID: 19365594
delusions; frontotemporal lobar degeneration; Pick’s disease; dementia

Results 1-25 (722692)