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1.  Core features of frontotemporal dementia recapitulated in progranulin knockout mice 
Neurobiology of disease  2011;45(1):395-408.
Frontotemporal dementia (FTD) is typified by behavioral and cognitive changes manifested as altered social comportment and impaired memory performance. To investigate the neurodegenerative consequences of progranulin gene (GRN) mutations, which cause an inherited form of FTD, we used previously generated progranulin knockout mice (Grn-/-). Specifically, we characterized two cohorts of early and later middle-age wild type and knockout mice using a battery of tests to assess neurological integrity and behavioral phenotypes analogous to FTD. The Grn-/- mice exhibited reduced social engagement and learning and memory deficits. Immunohistochemical approaches were used to demonstrate the presence of lesions characteristic of frontotemporal lobar degeneration (FTLD) with GRN mutation including ubiquitination, microgliosis, and reactive astrocytosis, the pathological substrate of FTD. Importantly, Grn-/- mice also have decreased overall survival compared to Grn+/+ mice. These data suggest that the Grn-/- mouse reproduces some core features of FTD with respect to behavior, pathology, and survival. This murine model may serve as a valuable in vivo model of FTLD with GRN mutation through which molecular mechanisms underlying the disease can be further dissected.
doi:10.1016/j.nbd.2011.08.029
PMCID: PMC3225509  PMID: 21933710
Frontotemporal lobar degeneration; frontotemporal dementia; knockout mouse; neurodegeneration; social behavior; memory; ubiquitin; progranulin
2.  Clinical and neuropathologic variation in neuronal intermediate filament inclusion disease 
Neurology  2004;63(8):1376-1384.
Background
Recently described neuronal intermediate filament inclusion disease (NIFID) shows considerable clinical heterogeneity.
Objective
To assess the spectrum of the clinical and neuropathological features in 10 NIFID cases.
Methods
Retrospective chart and comprehensive neuropathological review of these NIFID cases was conducted.
Results
The mean age at onset was 40.8 (range 23 to 56) years, mean disease duration was 4.5 (range 2.7 to 13) years, and mean age at death was 45.3 (range 28 to 61) years. The most common presenting symptoms were behavioral and personality changes in 7 of 10 cases and, less often, memory loss, cognitive impairment, language deficits, and motor weakness. Extrapyramidal features were present in 8 of 10 patients. Language impairment, perseveration, executive dysfunction, hyperreflexia, and primitive reflexes were frequent signs, whereas a minority had buccofacial apraxia, supranuclear ophthalmoplegia, upper motor neuron disease (MND), and limb dystonia. Frontotemporal and caudate atrophy were common. Histologic changes were extensive in many cortical areas, deep gray matter, cerebellum, and spinal cord. The hallmark lesions of NIFID were unique neuronal IF inclusions detected most robustly by antibodies to neurofilament triplet proteins and α-internexin.
Conclusion
NIFID is a neuropathologically distinct, clinically heterogeneous variant of frontotemporal dementia (FTD) that may include parkinsonism or MND. Neuronal IF inclusions are the neuropathological signatures of NIFID that distinguish it from all other FTD variants including FTD with MND and FTD tauopathies.
PMCID: PMC3516854  PMID: 15505152
3.  In vivo amyloid imaging in autopsy-confirmed Parkinson disease with dementia 
Neurology  2010;74(1):77-84.
Objective:
To investigate the specificity of in vivo amyloid imaging with [11C]–Pittsburgh Compound B (PIB) in Parkinson disease dementia (PDD).
Methods:
We performed detailed neuropathologic examination for 3 individuals with PDD who had PIB PET imaging within 15 months of death.
Results:
We observed elevated cortical uptake of [11C]-PIB on in vivo PET imaging in 2 of the 3 cases. At autopsy, all 3 individuals had abundant cortical Lewy bodies (Braak PD stage 6), and were classified as low-probability Alzheimer disease (AD) based on NIA-Reagan criteria. The 2 PIB-positive individuals had abundant diffuse Aβ plaques but only sparse neuritic plaques and intermediate neurofibrillary tangle pathology. The PIB-negative individual had rare diffuse plaques, no neuritic plaques, and low neurofibrillary tangle burden.
Conclusions:
[11C]–Pittsburgh Compound B (PIB) PET is specific for fibrillar Aβ molecular pathology but not for pathologic diagnosis of comorbid Alzheimer disease in individuals with Parkinson disease dementia. The ability to specifically identify fibrillar Aβ amyloid in the setting of α-synucleinopathy makes [11C]-PIB PET a valuable tool for prospectively evaluating how the presence of Aβ amyloid influences the clinical course of dementia in patients with Lewy body disorders.
GLOSSARY
= Alzheimer disease;
= binding potentials;
= Clinical Dementia Rating;
= dementia of the Alzheimer type;
= dementia with Lewy bodies;
= distribution volume;
= Mental State Examination;
= Neuropsychiatric Inventory Questionnaire;
= Parkinson disease dementia;
= Pittsburgh Compound B;
= Unified Parkinson's Disease Rating Scale.
doi:10.1212/WNL.0b013e3181c7da8e
PMCID: PMC2809026  PMID: 20038776
4.  TDP-43 proteinopathy in familial motor neuron disease with TARDBP A315T mutation: a case report 
doi:10.1111/j.1365-2990.2010.01121.x
PMCID: PMC2978282  PMID: 20819167
TARDBP; TDP-43; FUS; motor neuron disease; amyotrophic lateral sclerosis; frontotemporal lobar degeneration; Alzheimer’s disease; mutation
5.  Amyloid imaging of Lewy body-associated disorders 
Background
Clinicopathologic studies of Parkinson disease dementia (PDD) and dementia with Lewy bodies (DLB) commonly reveal abnormal β-amyloid deposition in addition to diffuse Lewy bodies (α-synuclein aggregates), but the relationship among these neuropathologic features and the development of dementia in these disorders remains uncertain.
Objective
To determine whether amyloid-βdeposition detected by PET imaging with Pittsburgh Compound B (PIB) distinguishes clinical subtypes of Lewy body-associated disorders.
Methods
Nine healthy controls (HC), eight PD with no cognitive impairment (PD-noCI), nine PD with mild cognitive impairment (PD-MCI), six dementia with Lewy bodies (DLB) and fifteen PD with dementia (PDD) patients underwent [11C]-PIB PET imaging, clinical examination, and cognitive testing. The binding potential (BP) of PIB for predefined regions and the mean cortical BP (MCBP) were calculated for each participant. Annual longitudinal follow-up and postmortem examinations were performed on a subset of participants.
Results
Regional PIB BPs and the proportion of individuals with abnormally elevated MCBP were not significantly different across participant groups. Elevated PIB binding was associated with worse global cognitive impairment in participants with Lewy body disorders but was not associated with any other clinical or neuropsychological features, including earlier onset or faster rate of progression of cognitive impairment.
Conclusions
These results suggest that the presence of fibrillar amyloid-βdoes not distinguish between clinical subtypes of Lewy body-associated disorders, although larger numbers are needed to more definitively rule out this association. Amyloid-βmay modify the severity of global cognitive impairment in individuals with Lewy body-associated dementia.
doi:10.1002/mds.23393
PMCID: PMC2978796  PMID: 20922808
Parkinson’s disease; Parkinson’s disease with dementia; Dementia with Lewy bodies; PET
6.  ANALYSIS OF β-AMYLOID (Aβ) DEPOSITION IN THE TEMPORAL LOBE IN ALZHEIMER’S DISEASE USING FOURIER (SPECTRAL) ANALYSIS 
Aim
To determine the spatial pattern of β-amyloid (Aβ) deposition throughout the temporal lobe in Alzheimer’s disease (AD).
Methods
Sections of the complete temporal lobe from six cases of sporadic AD were immunolabelled with antibody against Aβ. Fourier (spectral) analysis was used to identify sinusoidal patterns in the fluctuation of Aβ deposition in a direction parallel to the pia mater or alveus.
Results
Significant sinusoidal fluctuations in density were evident in 81/99 (82%) analyses. In 64% of analyses, two frequency components were present with density peaks of Aβ deposits repeating every 500–1000μm and at distances greater than 1000μm. In 25% of analyses, three or more frequency components were present. The estimated period or wavelength (number of sample units to complete one full cycle) of the first and second frequency components did not vary significantly between gyri of the temporal lobe, but there was evidence that the fluctuations of the classic deposits had longer periods than the diffuse and primitive deposits.
Conclusions
(i) Aβ deposits exhibit complex sinusoidal fluctuations in density in the temporal lobe in AD, (ii) fluctuations in Aβ deposition may reflect the formation of Aβ deposits in relation to the modular and vascular structure of the cortex, and (iii) Fourier analysis may be a useful statistical method for studying the patterns of Aβ deposition both in AD and in transgenic models of disease.
doi:10.1111/j.1365-2990.2010.01071.x
PMCID: PMC2972722  PMID: 20132489
Alzheimer’s disease; Fourier (spectral) analysis; β-amyloid (Aβ) deposits; Spatial pattern; Spectral density; Wavelength
7.  PRESENILIN1 G217R MUTATION LINKED TO ALZHEIMER DISEASE WITH COTTON WOOL PLAQUES 
Neurology  2009;73(6):480-482.
doi:10.1212/WNL.0b013e3181b163ba
PMCID: PMC2727146  PMID: 19667325
8.  ALS and FTLD: two faces of TDP-43 proteinopathy 
European Journal of Neurology  2008;15(8):772-780.
Major discoveries have been made in the recent past in the genetics, biochemistry and neuropathology of frontotemporal lobar degeneration (FTLD). TAR DNA-binding protein 43 (TDP-43), encoded by the TARDBP gene, has been identified as the major pathological protein of FTLD with ubiquitin-immunoreactive (ub-ir) inclusions (FTLD-U) with or without amyotrophic lateral sclerosis (ALS) and sporadic ALS. Recently, mutations in the TARDBP gene in familial and sporadic ALS have been reported which demonstrate that abnormal TDP-43 alone is sufficient to cause neurodegeneration. Several familial cases of FTLD-U, however, are now known to have mutations in the progranulin (GRN) gene, but granulin is not a component of the TDP-43- and ub-ir inclusions. Further, TDP-43 is found to be a component of the inclusions of an increasing number of neurodegenerative diseases. Other FTLD-U entities with TDP-43 proteinopathy include: FTLD-U with valosin-containing protein (VCP) gene mutation and FTLD with ALS linked to chromosome 9p. In contrast, chromosome 3-linked dementia, FTLD-U with chromatin modifying protein 2B (CHMP2B) mutation, has ub-ir, TDP-43-negative inclusions. In summary, recent discoveries have generated new insights into the pathogenesis of a spectrum of disorders called TDP-43 proteinopathies including: FTLD-U, FTLD-U with ALS, ALS, and a broadening spectrum of other disorders. It is anticipated that these discoveries and a revised nosology of FTLD will contribute toward an accurate diagnosis, and facilitate the development of new diagnostic tests and therapeutics.
doi:10.1111/j.1468-1331.2008.02195.x
PMCID: PMC2801606  PMID: 18684309
amyotrophic lateral sclerosis; frontotemporal dementia; frontotemporal lobar degeneration; granulin; motor neuron disease; TARDBP; TDP-43; ubiquitin; valosin-containing protein
10.  The butyrylcholinesterase K variant and susceptibility to Alzheimer's disease. 
Journal of Medical Genetics  1998;35(12):1034-1035.
Previous work has shown an association between the K variant of the butyrylcholinesterase (BCHE) gene and Alzheimer's disease (AD) in patients carrying the epsilon4 allele of ApoE. We attempted to replicate this finding in 181 UK white AD cases and 71 controls. No difference was found in BCHE-K genotypes (p=0.75) or alleles (p=0.70) between patients and controls. Moreover, despite a significant excess of ApoE epsilon4 in patients versus controls (p<0.0001), we found no evidence to support previous reports of an interaction between ApoE and BCHE-K (chi2=1.49, df=4, p=0.83).
PMCID: PMC1051518  PMID: 9863603

Results 1-10 (10)