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1.  Chronic traumatic encephalopathy and other neurodegenerative proteinopathies 
“Chronic traumatic encephalopathy” (CTE) is described as a slowly progressive neurodegenerative disease believed to result from multiple concussions. Traditionally, concussions were considered benign events and although most people recover fully, about 10% develop a post-concussive syndrome with persisting neurological, cognitive and neuropsychiatric symptoms. CTE was once thought to be unique to boxers, but it has now been observed in many different athletes having suffered multiple concussions as well as in military personal after repeated blast injuries. Much remains unknown about the development of CTE but its pathological substrate is usually tau, similar to that seen in Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD). The aim of this “perspective” is to compare and contrast clinical and pathological CTE with the other neurodegenerative proteinopathies and highlight that there is an urgent need for understanding the relationship between concussion and the development of CTE as it may provide a window into the development of a proteinopathy and thus new avenues for treatment.
doi:10.3389/fnhum.2014.00030
PMCID: PMC3907709  PMID: 24550810
concussions; chronic traumatic encephalopathy; neurodegenerative disease; Alzheimer's disease; frontotemporal lobar degeneration; tau
2.  Pathological Evidence that the T188R Mutation in PRNP Is Associated with Prion Disease 
Human prion diseases can be caused by mutations in the prion protein gene PRNP. Prion disease with mutations at codon 188 has been reported in 6 cases, but only 1 had the T188R mutation and it was not pathologically confirmed. We report the clinical, neuropsychological, imaging, genetic, and neuropathological features of a patient with familial Creutzfeldt-Jakob Disease (CJD), associated with a very rare PRNP mutation at T188R. The patient presented with prominent behavioral changes in addition to the more typical cognitive and motor impairments seen in sporadic CJD. The autopsy confirmed prion disease pathology. This case supports the pathogenicity of the T188 PRNP mutation, demonstrates the variability of clinical phenotypes associated with certain mutations and emphasizes the importance of testing for genetic prion disease in cases of apparently sporadic atypical dementia.
doi:10.1097/NEN.0b013e3181ffc39c
PMCID: PMC3136530  PMID: 21107135
Codon 188; Creutzfeldt-Jakob disease; Dementia; Genetic; Prion
3.  Neurodegenerative disease phenotypes in carriers of MAPT p.A152T, a risk factor for frontotemporal dementia spectrum disorders and Alzheimer's disease 
Alzheimer disease and associated disorders  2013;27(4):10.1097/WAD.0b013e31828cc357.
Recently, Coppola and colleagues demonstrated that a rare MAPT sequence variant, c.454G>A (p.A152T), significantly increases the risk of frontotemporal dementia (FTD) spectrum disorders and Alzheimer's disease (AD) in a screen of 15,369 subjects1. We describe clinical features of 9 patients with neurodegenerative disease (4 women) harboring p.A152T, aged 51 to 79 years at symptom onset. Seven developed FTD spectrum clinical syndromes, including progressive supranuclear palsy syndrome (PSP, n=2), behavioral variant FTD (bvFTD, n=1), nonfluent variant primary progressive aphasia (nfvPPA, n=2), and corticobasal syndrome (CBS, n=2); two patients were diagnosed with clinical AD. Thus, MAPT p.A152T is associated with a variety of FTD spectrum clinical presentations, although patients with clinical AD are also identified. These data warrant larger studies with clinicopathological correlation to elucidate the influence of this genetic variant on neurodegenerative disease.
doi:10.1097/WAD.0b013e31828cc357
PMCID: PMC3796183  PMID: 23518664
All Cognitive Disorders/Dementia; Alzheimer's disease; Frontotemporal Dementia; Corticobasal degeneration; Progressive Supranuclear Palsy
4.  The neural basis of syntactic deficits in primary progressive aphasia 
Brain and language  2012;122(3):190-198.
Patients with primary progressive aphasia (PPA) vary considerably in terms of which brain regions are impacted, as well as in the extent to which syntactic processing is impaired. Here we review the literature on the neural basis of syntactic deficits in PPA. Structural and functional imaging studies have most consistently associated syntactic deficits with damage to left inferior frontal cortex. Posterior perisylvian regions have been implicated in some studies. Damage to the superior longitudinal fasciculus, including its arcuate component, has been linked with syntactic deficits, even after gray matter atrophy is taken into account. These findings suggest that syntactic processing depends on left frontal and posterior perisylvian regions, as well as intact connectivity between them. In contrast, anterior temporal regions, and the ventral tracts that link frontal and temporal language regions, appear to be less important for syntax, since they are damaged in many PPA patients with spared syntactic processing.
doi:10.1016/j.bandl.2012.04.005
PMCID: PMC3418470  PMID: 22546214
syntax; primary progressive aphasia; voxel-based morphometry; functional MRI; diffusion tensor imaging
5.  MRI Signatures of Brain Macrostructural Atrophy and Microstructural Degradation in Frontotemporal Lobar Degeneration Subtypes 
Brain magnetic resonance imaging (MRI) studies have demonstrated regional patterns of brain macrostructural atrophy and white matter microstructural alterations separately in the three major subtypes of frontotemporal lobar degeneration (FTLD), which includes behavioral variant frontotemporal dementia (bvFTD), semantic dementia (SD), and progressive nonfluent aphasia (PNFA). This study was to investigate to what extent the pattern of white matter microstructural alterations in FTLD subtypes mirrors the pattern of brain atrophy, and to compare the ability of various diffusion tensor imaging (DTI) indices in characterizing FTLD patients, as well as to determine whether DTI measures provide greater classification power for FTLD than measuring brain atrophy. Twenty-five patients with FTLD (13 with bvFTD, 6 with SD, and 6 with PNFA) and 19 healthy age-matched control subjects underwent both structural MRI and DTI scans. Measurements of regional brain atrophy were based on T1-weighted MRI data and voxel-based morphometry. Measurements of regional white matter degradation were based on voxelwise as well as regions-of-interest tests of DTI variations, expressed as fractional anisotropy, axial diffusivity, and radial diffusivity. Compared to controls, bvFTD, SD, and PNFA patients each exhibited characteristic regional patterns of brain atrophy and white matter damage. DTI overall provided significantly greater accuracy for FTLD classification than brain atrophy. Moreover, radial diffusivity was more sensitive in assessing white matter damage in FTLD than other DTI indices. The findings suggest that DTI in general and radial diffusivity in particular are more powerful measures for the classification of FTLD patients from controls than brain atrophy.
doi:10.3233/JAD-2012-121156
PMCID: PMC3738303  PMID: 22976075
Behavioral variant frontotemporal dementia; diffusion tensor imaging; frontotemporal lobar degeneration; multimodality MRI; progressive nonfluent aphasia; semantic dementia
6.  Clinical overlap between Jakob-Creutzfeldt disease and Lewy Body Disease 
Objective
Sporadic Jakob-Creutzfeldt disease (sCJD) and dementia with Lewy bodies (DLB) have overlapping clinical symptoms that can lead to their misdiagnosis. We delineated the clinical overlap between sCJD and DLB, and assessed the value of MRI to differentiate between them.
Methods
Medical records, MRI, EEG and CSF were reviewed from 56 sCJD and 30 DLB subjects.
Results
46% of sCJD subjects met probable DLB criteria and 40% of DLB subjects met probable CJD criteria. A greater proportion of sCJD subjects had cerebellar signs (66% vs. 10%, p<0.001), myoclonus (64% vs. 30%, p=0.002), and visual symptoms (other than hallucinations) (61% vs. 7%, p<0.001), whereas more DLB subjects had hallucinations (70% vs. 39%, p=0.007) and fluctuations (57% vs. 23%, p=0.002). Cortical and/or basal ganglia MRI DWI hyperintensities consistent with sCJD were seen in 96% of sCJD subjects but in none with DLB. Logistic regression in sCJD revealed that those meeting probable DLB criteria were more likely to have occipital lobe involvement on MRI (OR 1.4, p=0.058, model p=0.022). Parietal lobe involvement on MRI was a predictor of “Other Focal Cortical signs” (OR 1.9, p=0.021) in sCJD. EEG and CSF assessments lacked sensitivity for sCJD as 48% of sCJD patients had a negative EEG and 67% of the 36 sCJD patents with a CSF evaluation, had a negative or inconclusive result. Too few DLB patients had EEG or CSF to assess their utility.
Conclusion
Sporadic CJD and DLB have significant symptom overlap. MRI helps differentiate these diseases and is related to the signs/symptoms observed in sCJD.
PMCID: PMC3590309  PMID: 22547509
Creutzfeldt-Jakob disease; Lewy body disease; Lewy body dementia; diffusion-weighted imaging; DWI
7.  Syntactic processing depends on dorsal language tracts 
Neuron  2011;72(2):397-403.
Frontal and temporal language areas involved in syntactic processing are connected by several dorsal and ventral tracts, but the functional roles of the different tracts are not well understood. To identify which white matter tract(s) are important for syntactic processing, we examined the relationship between white matter damage and syntactic deficits in patients with primary progressive aphasia, using multimodal neuroimaging and neurolinguistic assessment. Diffusion tensor imaging showed that microstructural damage to left hemisphere dorsal tracts—the superior longitudinal fasciculus including its arcuate component—was strongly associated with deficits in comprehension and production of syntax. Damage to these dorsal tracts predicted syntactic deficits after gray matter atrophy was taken into account, and fMRI confirmed that these tracts connect regions modulated by syntactic processing. In contrast, damage to ventral tracts—the extreme capsule fiber system or the uncinate fasciculus—was not associated with syntactic deficits. Our findings show that syntactic processing depends primarily on dorsal language tracts.
doi:10.1016/j.neuron.2011.09.014
PMCID: PMC3201770  PMID: 22017996
8.  White matter damage in primary progressive aphasias: a diffusion tensor tractography study 
Brain  2011;134(10):3011-3029.
Primary progressive aphasia is a clinical syndrome that encompasses three major phenotypes: non-fluent/agrammatic, semantic and logopenic. These clinical entities have been associated with characteristic patterns of focal grey matter atrophy in left posterior frontoinsular, anterior temporal and left temporoparietal regions, respectively. Recently, network-level dysfunction has been hypothesized but research to date has focused largely on studying grey matter damage. The aim of this study was to assess the integrity of white matter tracts in the different primary progressive aphasia subtypes. We used diffusion tensor imaging in 48 individuals: nine non-fluent, nine semantic, nine logopenic and 21 age-matched controls. Probabilistic tractography was used to identify bilateral inferior longitudinal (anterior, middle, posterior) and uncinate fasciculi (referred to as the ventral pathway); and the superior longitudinal fasciculus segmented into its frontosupramarginal, frontoangular, frontotemporal and temporoparietal components, (referred to as the dorsal pathway). We compared the tracts’ mean fractional anisotropy, axial, radial and mean diffusivities for each tract in the different diagnostic categories. The most prominent white matter changes were found in the dorsal pathways in non-fluent patients, in the two ventral pathways and the temporal components of the dorsal pathways in semantic variant, and in the temporoparietal component of the dorsal bundles in logopenic patients. Each of the primary progressive aphasia variants showed different patterns of diffusion tensor metrics alterations: non-fluent patients showed the greatest changes in fractional anisotropy and radial and mean diffusivities; semantic variant patients had severe changes in all metrics; and logopenic patients had the least white matter damage, mainly involving diffusivity, with fractional anisotropy altered only in the temporoparietal component of the dorsal pathway. This study demonstrates that both careful dissection of the main language tracts and consideration of all diffusion tensor metrics are necessary to characterize the white matter changes that occur in the variants of primary progressive aphasia. These results highlight the potential value of diffusion tensor imaging as a new tool in the multimodal diagnostic evaluation of primary progressive aphasia.
doi:10.1093/brain/awr099
PMCID: PMC3187537  PMID: 21666264
primary progressive aphasia; progressive non-fluent aphasia; semantic dementia; logopenic progressive aphasia; diffusion tensor imaging
9.  Abhorring the vacuum: use of Alzheimer’s disease medications in frontotemporal dementia 
There is no dedicated therapy for frontotemporal dementia (FTD). In order to treat the often devastating behavioral disturbances that interfere with both normal social functioning and the ability of caregivers to provide needed support, off-label medication usage is frequent. In addition to antidepressant and antipsychotic medications, which afford some benefits, US FDA-approved treatments for Alzheimer’s disease are often used, including both cholinesterase inhibitors and memantine. Here, we review the various clinical manifestations of FTD, a general approach to treatment and the goals of any potential therapies. We review all of the existing literature on the use of cholinesterase inhibitors and memantine in FTD. While cholinesterase inhibitors do not currently have a place in FTD treatment, memantine may be helpful, although the results of two placebo-controlled trials with this agent are not yet available. Finally, we discuss our view that such approaches will probably become supplanted by rational, molecularly-based therapies currently in development.
PMCID: PMC3136916  PMID: 21728274
Alzheimer’s disease; frontotemporal dementia; frontotemporal lobar degeneration; FUS; progressive nonfluent aphasia; semantic dementia; Tau; TDP-43
10.  Sporadic Corticobasal Syndrome due to FTLD-TDP 
Acta neuropathologica  2009;119(3):365-374.
Sporadic corticobasal syndrome (CBS) has been associated with diverse pathological substrates, but frontotemporal lobar degeneration with TDP-43 immunoreactive inclusions (FTLD-TDP) has only been linked to CBS among progranulin mutation carriers. We report the clinical, neuropsychological, imaging, genetic, and neuropathological features of GS, a patient with sporadic corticobasal syndrome. Genetic testing revealed no mutations in the microtubule associated protein tau (MAPT) or progranulin (PGRN) genes, but GS proved homozygous for the T allele of the rs5848 PGRN variant. Autopsy showed ubiquitin and TDP-43 pathology most similar to a pattern previously associated with PGRN mutation carriers. These findings confirm that FTLD-TDP should be included in the pathological differential diagnosis for sporadic CBS.
doi:10.1007/s00401-009-0605-1
PMCID: PMC2832091  PMID: 19876635
corticobasal degeneration; TDP-43; frontotemporal lobar degeneration; progranulin
11.  Neuroimaging in Dementia 
Neurotherapeutics  2011;8(1):82-92.
Summary
Dementia is a common illness with an incidence that is rising as the aged population increases. There are a number of neurodegenerative diseases that cause dementia, including Alzheimer’s disease, dementia with Lewy bodies, and frontotemporal dementia, which is subdivided into the behavioral variant, the semantic variant, and nonfluent variant. Numerous other neurodegenerative illnesses have an associated dementia, including corticobasal degeneration, Creutzfeldt–Jakob disease, Huntington’s disease, progressive supranuclear palsy, multiple system atrophy, Parkinson’s disease dementia, and amyotrophic lateral sclerosis. Vascular dementia and AIDS dementia are secondary dementias. Diagnostic criteria have relied on a constellation of symptoms, but the definite diagnosis remains a pathologic one. As treatments become available and target specific molecular abnormalities, differentiating amongst the various primary dementias early on becomes essential. The role of imaging in dementia has traditionally been directed at ruling out treatable and reversible etiologies and not to use imaging to better understand the pathophysiology of the different dementias. Different brain imaging techniques allow the examination of the structure, biochemistry, metabolic state, and functional capacity of the brain. All of the major neurodegenerative disorders have relatively specific imaging findings that can be identified. New imaging techniques carry the hope of revolutionizing the diagnosis of neurodegenerative disease so as to obtain a complete molecular, structural, and metabolic characterization, which could be used to improve diagnosis and to stage each patient and follow disease progression and response to treatment. Structural and functional imaging modalities contribute to the diagnosis and understanding of the different dementias.
Electronic supplementary material
The online version of this article (doi:10.1007/s13311-010-0012-2) contains supplementary material, which is available to authorized users.
doi:10.1007/s13311-010-0012-2
PMCID: PMC3026935  PMID: 21274688
Dementia; MRI; PET; Alzheimer’s disease; frontotemporal dementia
12.  Neuroimaging in Dementia 
Summary
Dementia is a common illness with an incidence that is rising as the aged population increases. There are a number of neurodegenerative diseases that cause dementia, including Alzheimer’s disease, dementia with Lewy bodies, and frontotemporal dementia, which is subdivided into the behavioral variant, the semantic variant, and nonfluent variant. Numerous other neurodegenerative illnesses have an associated dementia, including corticobasal degeneration, Creutzfeldt–Jakob disease, Huntington’s disease, progressive supranuclear palsy, multiple system atrophy, Parkinson’s disease dementia, and amyotrophic lateral sclerosis. Vascular dementia and AIDS dementia are secondary dementias. Diagnostic criteria have relied on a constellation of symptoms, but the definite diagnosis remains a pathologic one. As treatments become available and target specific molecular abnormalities, differentiating amongst the various primary dementias early on becomes essential. The role of imaging in dementia has traditionally been directed at ruling out treatable and reversible etiologies and not to use imaging to better understand the pathophysiology of the different dementias. Different brain imaging techniques allow the examination of the structure, biochemistry, metabolic state, and functional capacity of the brain. All of the major neurodegenerative disorders have relatively specific imaging findings that can be identified. New imaging techniques carry the hope of revolutionizing the diagnosis of neurodegenerative disease so as to obtain a complete molecular, structural, and metabolic characterization, which could be used to improve diagnosis and to stage each patient and follow disease progression and response to treatment. Structural and functional imaging modalities contribute to the diagnosis and understanding of the different dementias.
Electronic supplementary material
The online version of this article (doi:10.1007/s13311-010-0012-2) contains supplementary material, which is available to authorized users.
doi:10.1007/s13311-010-0012-2
PMCID: PMC3026935  PMID: 21274688
Dementia; MRI; PET; Alzheimer’s disease; frontotemporal dementia
13.  Interrater reliability of the new criteria for behavioral variant frontotemporal dementia 
Neurology  2013;80(21):1973-1977.
Objective:
To evaluate the interrater reliability of the new International Behavioural Variant FTD Criteria Consortium (FTDC) criteria for behavioral variant frontotemporal dementia (bvFTD).
Methods:
Twenty standardized clinical case modules were developed for patients with a range of neurodegenerative diagnoses, including bvFTD, primary progressive aphasia (nonfluent, semantic, and logopenic variant), Alzheimer disease, and Lewy body dementia. Eighteen blinded raters reviewed the modules and 1) rated the presence or absence of core diagnostic features for the FTDC criteria, and 2) provided an overall diagnostic rating. Interrater reliability was determined by κ statistics for multiple raters with categorical ratings.
Results:
The mean κ value for diagnostic agreement was 0.81 for possible bvFTD and 0.82 for probable bvFTD (“almost perfect agreement”). Interrater reliability for 4 of the 6 core features had “substantial” agreement (behavioral disinhibition, perseverative/compulsive, sympathy/empathy, hyperorality; κ = 0.61–0.80), whereas 2 had “moderate” agreement (apathy/inertia, neuropsychological; κ = 0.41–0.6). Clinician years of experience did not significantly influence rater accuracy.
Conclusions:
The FTDC criteria show promise for improving the diagnostic accuracy and reliability of clinicians and researchers. As disease-altering therapies are developed, accurate differential diagnosis between bvFTD and other neurodegenerative diseases will become increasingly important.
doi:10.1212/WNL.0b013e318293e368
PMCID: PMC3716343  PMID: 23635967

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