%0 Book Section
%A Sutherland, Greg
%A Kril, Jillian
%T Alzheimer’s Disease: Approaches
to Pathogenesis in the Genomic Age
%B Neuroscience - Dealing With Frontiers
%D 2012
%C Croatia
%I InTech
%V 
%N 
%P 389-428
%@ 9789535102076
%E Contreras, Carlos M.
%X 
%Z FOR Codes: 110904


%0 Journal Article
%~ PubMed
%A Sheedy, Donna
%A Harding, Antony
%A Say, Meichien
%A Stevens, Julia
%A Kril, Jillian J
%T Histological assessment of cerebellar granule cell layer in postmortem brain; a useful marker of tissue integrity?
%B Cell and Tissue Banking
%D 2012
%C Netherlands
%I Springer Netherlands
%V 13
%N 4
%P 521-527
%@ 1573-6814
%X Tissue quality control measures are routinely performed in brain banks with the assessment of brain pH being the most common measure. In some brain banks the assessment of the RNA integrity number is also performed, although this requires access to specialised equipment and is more expensive. The aim of this study is to determine if there is a correlation between the visual assessment of cerebellar granule cell integrity and brain pH or RIN. One hundred and five consecutive cases from the NSW Tissue Resource Centre, Sydney, Australia were accessed. The cerebrum was hemisected and one hemisphere sliced parasagittally at approximately 1-2??cm intervals and frozen. The other hemisphere was fixed in 15% buffered formalin for 2-3??weeks. The contralateral cerebellar hemisphere was preserved in the same manner as the cerebral hemisphere. Samples of fixed tissue were embedded in paraffin, 7????m sections cut and stained routinely with hematoxylin and eosin. The granular cell layer (GCL) was assessed microscopically to determine the degree of autolytic degradation. Degradation was graded as nil, mild, moderate or severe. Brain tissue pH and RIN were measured using standardised protocols. This study showed that both brain pH and RIN significantly correlated with the severity of the degradation of the cerebellar granule cell layer. This additional screening tool can be performed during routine histological review of the cerebellar tissue to assess the suitability for further investigation of tissue quality.
%Z FOR Codes: 110903 110316


%0 Journal Article
%~ PubMed
%A Hornberger, Michael
%A Wong, Stephanie
%A Tan, Rachel
%A Irish, Muireann
%A Piguet, Olivier
%A Kril, Jillian
%A Hodges, John R
%A Halliday, Glenda
%T In vivo and post-mortem memory circuit integrity in frontotemporal dementia and Alzheimer's disease.
%B Brain
%D 2012
%C United Kingdom
%I Oxford University Press
%V 135
%N Pt 10
%P 3015-3025
%@ 1460-2156
%X 
%Z FOR Codes: 110316 110903


%0 Journal Article
%~ PubMed
%A Sheedy, Donna
%A Say, Meichien
%A Stevens, Julia
%A Harper, Clive G
%A Kril, Jillian J
%T Influence of Liver Pathology on Markers of Postmortem Brain Tissue Quality.
%B Alcoholism, clinical and experimental research
%D 2012
%C United States
%I Wiley-Blackwell Publishing, Inc.
%V 36
%N 1
%P 55-60
%@ 1530-0277
%X Postmortem brain tissue provides an important resource to investigate various brain disorders, including those resulting from the effects of alcohol abuse. Unlike the traditionally recognized confounders to tissue quality (e.g., coma, hypoxia), our understanding of the effects of liver disease is incomplete. The aim of this study was to determine the effects of liver pathology, and in particular cirrhosis resulting in hepatic encephalopathy (HE), on 2 postmortem brain tissue quality markers, brain pH and RNA integrity.
%Z FOR Codes: 1109


%0 Journal Article
%~ PubMed
%A Valenzuela, Michael J
%A Matthews, Fiona E
%A Brayne, Carol
%A Ince, Paul
%A Halliday, Glenda
%A Kril, Jillian J
%A Dalton, Marshall A
%A Richardson, Kathryn
%A Forster, Gill
%A Sachdev, Perminder S
%A , Medical Research Council Cognitive Function and Ageing Study
%T Multiple Biological Pathways Link Cognitive Lifestyle to Protection from Dementia.
%B Biological Psychiatry
%D 2012
%C United States
%I Elsevier Inc.
%V 71
%N 9
%P 783-791
%@ 1873-2402
%X BACKGROUND: An active cognitive lifestyle is linked to diminished dementia risk, but the underlying mechanisms are poorly understood. Potential mechanisms include disease modification, neuroprotection, and compensation. Prospective, population-based brain series provide the rare opportunity to test the plausibility of these mechanisms in humans. METHODS: Participants came from the United Kingdom Medical Research Council Cognitive Function and Ageing Study, comprising 13,004 individuals aged over 65 years and followed for 14 years. In study 1, a Cognitive Lifestyle Score (CLS) was computed on all Cognitive Function and Ageing Study subjects to define low, middle, and high groups. By August 2004, 329 individuals with CLS data had come to autopsy and underwent Consortium to Establish a Registry of Alzheimer''s Disease assessment. Study 2 involved more detailed quantitative histology in the hippocampus and Brodmann area 9 in 72 clinically matched individuals with high and low CLS. RESULTS: CLS groups did not differ on several Alzheimer disease neuropathologic measures; however, high CLS men had less cerebrovascular disease after accounting for vascular risk factors, and women had greater brain weight. No group differences were evident in hippocampal neuronal density. In Brodmann area 9, cognitively active individuals had significantly greater neuronal density, as well as correlated increases in cortical thickness. CONCLUSIONS: An active cognitive lifestyle was associated with protection from cerebrovascular disease in men, but there was no evidence for Alzheimer disease modification or hippocampal neuroprotection. Men and women both exhibited neurotrophic changes in the prefrontal lobe linked to cognitive lifestyle, consistent with a compensatory process. Lifespan complex cognitive activity may therefore protect against dementia through multiple biological pathways.
%Z FOR Codes: 110903


%0 Journal Article
%~ PubMed
%A Kril, Jillian J
%A Harper, Clive G
%T Neuroanatomy and Neuropathology Associated with Korsakoff's Syndrome.
%B Neuropsychology Review
%D 2012
%C United States
%I Springer New York LLC
%V 22
%N 2
%P 72-80
%@ 1573-6660
%X Although the neuropathology of Korsakoff''s syndrome (KS) was first described well over a century ago and the characteristic brain pathology does not pose a diagnostic challenge to pathologists, there is still controversy over the neuroanatomical substrate of the distinctive memory impairment in these patients. Cohort studies of KS suggest a central role for the mammillary bodies and mediodorsal thalamus, and quantitative studies suggest additional damage to the anterior thalamus is required. Rare cases of KS caused by pathologies other than those of nutritional origin provide support for the role of the anterior thalamus and mammillary bodies. Taken together the evidence to date shows that damage to the thalamus and hypothalamus is required, in particular the anterior thalamic nucleus and the medial mammillary nucleus of the hypothalamus. As these nuclei form part of wider memory circuits, damage to the inter-connecting white matter tracts can also result in a similar deficit as direct damage to the nuclei. Although these nuclei and their connections appear to be the primary site of damage, input from other brain regions within the circuits, such as the frontal cortex and hippocampus, or more distant regions, including the cerebellum and amygdala, may have a modulatory role on memory function. Further studies to confirm the precise site(s) and extend of brain damage necessary for the memory impairment of KS are required.
%Z FOR Codes: 110903 110316


%0 Journal Article
%~ PubMed
%A Schwartz, Raymond S
%A Halliday, Glenda M
%A Cordato, Dennis J
%A Kril, Jillian J
%T Small-vessel disease in patients with Parkinson's disease: A clinicopathological study.
%B Movement Disorders
%D 2012
%C United States
%I John Wiley & Sons, Inc.
%V 27
%N 12
%P 1506-1512
%@ 1531-8257
%X 
%Z FOR Codes: 110316 110903


%0 Journal Article
%~ PubMed
%A Ke, Yazi
%A Dramiga, Joe
%A Sch??tz, Ulrich
%A Kril, Jillian J
%A Ittner, Lars M
%A Schr??der, Hannsj??rg
%A G??tz, J??rgen
%T Tau-Mediated Nuclear Depletion and Cytoplasmic Accumulation of SFPQ in Alzheimer's and Pick's Disease.
%B PLoS One
%D 2012
%C United States
%I Public Library of Science
%V 7
%N 4
%P e35678
%@ 1932-6203
%X Tau dysfunction characterizes neurodegenerative diseases such as Alzheimer''s disease (AD) and frontotemporal lobar degeneration (FTLD). Here, we performed an unbiased SAGE (serial analysis of gene expression) of differentially expressed mRNAs in the amygdala of transgenic pR5 mice that express human tau carrying the P301L mutation previously identified in familial cases of FTLD. SAGE identified 29 deregulated transcripts including Sfpq that encodes a nuclear factor implicated in the splicing and regulation of gene expression. To assess the relevance for human disease we analyzed brains from AD, Pick''s disease (PiD, a form of FTLD), and control cases. Strikingly, in AD and PiD, both dementias with a tau pathology, affected brain areas showed a virtually complete nuclear depletion of SFPQ in both neurons and astrocytes, along with cytoplasmic accumulation. Accordingly, neurons harboring either AD tangles or Pick bodies were also depleted of SFPQ. Immunoblot analysis of human entorhinal cortex samples revealed reduced SFPQ levels with advanced Braak stages suggesting that the SFPQ pathology may progress together with the tau pathology in AD. To determine a causal role for tau, we stably expressed both wild-type and P301L human tau in human SH-SY5Y neuroblastoma cells, an established cell culture model of tau pathology. The cells were differentiated by two independent methods, mitomycin C-mediated cell cycle arrest or neuronal differentiation with retinoic acid. Confocal microscopy revealed that SFPQ was confined to nuclei in non-transfected wild-type cells, whereas in wild-type and P301L tau over-expressing cells, irrespective of the differentiation method, it formed aggregates in the cytoplasm, suggesting that pathogenic tau drives SFPQ pathology in post-mitotic cells. Our findings add SFPQ to a growing list of transcription factors with an altered nucleo-cytoplasmic distribution under neurodegenerative conditions.
%Z FOR Codes: 110903


%0 Journal Article
%~ PubMed
%A Piguet, O
%A Halliday, G M
%A Reid, W G J
%A Casey, B
%A Carman, R
%A Huang, Y
%A Xuereb, J H
%A Hodges, J R
%A Kril, J J
%T Clinical phenotypes in autopsy-confirmed Pick disease.
%B Neurology
%D 2011
%C United States
%I Lippincott Williams & Wilkins
%V 76
%N 3
%P 253-259
%@ 1526-632X
%X Neuropathology of frontotemporal lobar degeneration is variable and relationship between the pathology and the clinical presentation remains uncertain. Abnormal deposits of hyperphosphorylated and ubiquitinated tau protein are present in 30% of cases, which include the classic presentation of Pick disease with argyrophilic, intraneuronal inclusions known as Pick bodies. This study aimed to improve sensitivity of clinicopathologic relations in cases with neuropathologically confirmed Pick disease and to identify clinical symptoms and signs predictive of disease progression.
%Z FOR Codes: 110902 110316 110308


%0 Journal Article
%~ PubMed
%A Schofield, Emma C
%A Hodges, John R
%A Macdonald, Virginia
%A Cordato, Nicholas J
%A Kril, Jillian J
%A Halliday, Glenda M
%T Cortical atrophy differentiates Richardson's syndrome from the parkinsonian form of progressive supranuclear palsy.
%B Movement Disorders
%D 2011
%C United States
%I John Wiley & Sons, Inc.
%V 26
%N 2
%P 256-263
%@ 0885-3185
%X To determine whether brain atrophy differs between the two subtypes of progressive supranuclear palsy (PSP), Richardson''s syndrome (PSP-RS), and PSP parkinsonism (PSP-P), and whether such atrophy directly relates to clinical deficits and the severity of tau deposition. We compared 24 pathologically confirmed PSP cases (17 PSP-RS and 7 PSP-P) with 22 controls from a Sydney brain donor program. Volume loss was analyzed in 29 anatomically discrete brain regions using a validated point-counting technique, and tau-immunoreactive neurons, astrocytes and oligodendrocytes/threads semiquantified. Correlations between the two pathological measures and the presence or absence of cardinal PSP symptoms were investigated. Cortical atrophy was more severe in PSP-RS than PSP-P and affected more frontal lobe regions (frontal pole, inferior frontal gyrus). The supramarginal gyrus was atrophic in both subtypes. Additionally, atrophy of the internal globus pallidus, amygdala, and thalamus was more severe in PSP-RS. As expected, more severe frontal lobe tau pathology differentiated PSP-RS from PSP-P. No correlations were found between the degree of atrophy and severity of tau pathology in any region assessed, or between the severity of atrophy or tau pathology and the presence or absence of cardinal PSP symptoms. Our study shows that thalamocortical atrophy is a defining feature of PSP-RS, but this atrophy does not correlate with the presence of any specific cardinal clinical feature. Interestingly, there is a disassociation between tau pathology and atrophy in the brain regions affected in PSP-RS that requires further investigation.
%Z FOR Codes: 110903 110316 110308


%0 Journal Article
%~ PubMed
%A van Eersel, Janet
%A Ke, Yazi D
%A Gladbach, Amadeus
%A Bi, Mian
%A Götz, Jürgen
%A Kril, Jillian J
%A Ittner, Lars M
%T Cytoplasmic Accumulation and Aggregation of TDP-43 upon Proteasome Inhibition in Cultured Neurons.
%B PloS One
%D 2011
%C United States
%I Public Library of Science
%V 6
%N 7
%P e22850
%@ 1932-6203
%X Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are characterized by intraneuronal deposition of the nuclear TAR DNA-binding protein 43 (TDP-43) caused by unknown mechanisms. Here, we studied TDP-43 in primary neurons under different stress conditions and found that only proteasome inhibition by MG-132 or lactacystin could induce significant cytoplasmic accumulation of TDP-43, a histopathological hallmark in disease. This cytoplasmic accumulation was accompanied by phosphorylation, ubiquitination and aggregation of TDP-43, recapitulating major features of disease. Proteasome inhibition produced similar effects in both hippocampal and cortical neurons, as well as in immortalized motor neurons. To determine the contribution of TDP-43 to cell death, we reduced TDP-43 expression using small interfering RNA (siRNA), and found that reduced levels of TDP-43 dose-dependently rendered neurons more vulnerable to MG-132. Taken together, our data suggests a role for the proteasome in subcellular localization of TDP-43, and possibly in disease.
%Z FOR Codes: 110902


%0 Journal Article
%~ PubMed
%A Chen-Plotkin, Alice S
%A Martinez-Lage, Maria
%A Sleiman, Patrick M A
%A Hu, William
%A Greene, Robert
%A Wood, Elisabeth McCarty
%A Bing, Shaoxu
%A Grossman, Murray
%A Schellenberg, Gerard D
%A Hatanpaa, Kimmo J
%A Weiner, Myron F
%A White, Charles L
%A Brooks, William S
%A Halliday, Glenda M
%A Kril, Jillian J
%A Gearing, Marla
%A Beach, Thomas G
%A Graff-Radford, Neill R
%A Dickson, Dennis W
%A Rademakers, Rosa
%A Boeve, Bradley F
%A Pickering-Brown, Stuart M
%A Snowden, Julie
%A van Swieten, John C
%A Heutink, Peter
%A Seelaar, Harro
%A Murrell, Jill R
%A Ghetti, Bernardino
%A Spina, Salvatore
%A Grafman, Jordan
%A Kaye, Jeffrey A
%A Woltjer, Randall L
%A Mesulam, Marsel
%A Bigio, Eileen
%A Lladó, Albert
%A Miller, Bruce L
%A Alzualde, Ainhoa
%A Moreno, Fermin
%A Rohrer, Jonathan D
%A Mackenzie, Ian R A
%A Feldman, Howard H
%A Hamilton, Ronald L
%A Cruts, Marc
%A Engelborghs, Sebastiaan
%A De Deyn, Peter P
%A Van Broeckhoven, Christine
%A Bird, Thomas D
%A Cairns, Nigel J
%A Goate, Allison
%A Frosch, Matthew P
%A Riederer, Peter F
%A Bogdanovic, Nenad
%A Lee, Virginia M Y
%A Trojanowski, John Q
%A Van Deerlin, Vivianna M
%T Genetic and clinical features of progranulin-associated frontotemporal lobar degeneration.
%B Archives of Neurology
%D 2011
%C United States
%I American Medical Association
%V 68
%N 4
%P 488-497
%@ 0003-9942
%X To assess the relative frequency of unique mutations and their associated characteristics in 97 individuals with mutations in progranulin (GRN), an important cause of frontotemporal lobar degeneration (FTLD). Participants and
%Z FOR Codes: 110902 110311 110308


%0 Journal Article
%~ PubMed
%A Sutherland, Greg T
%A Siebert, Gerhard A
%A Kril, Jillian J
%A Mellick, George D
%T Knowing Me, Knowing You: Can Knowledge of Risk Factors for Alzheimer's Disease Prove Useful in Understanding the Pathogenesis of Parkinson's Disease?
%B Journal of Alzheimer's disease : JAD
%D 2011
%C Netherlands
%I IOS Press
%V 25
%N 3
%P 395-415
%@ 1875-8908
%X Alzheimer''s disease (AD) and Parkinson''s disease (PD) are the two most common neurodegenerative disorders. Why some individuals develop one disease rather than the other is not clear. Association studies with a case-control design are the time-honored approach to identifying risk factors. Extensive association studies have been carried out in both diseases creating a large knowledge database, however, reproducible risk factors remain rare. This general lack of knowledge of pathogenesis prevents us from reducing the worldwide burden of these diseases. Case-control studies are reductionist paradigms that assume, for maximum power, that the two populations being compared are exclusive and homogenous. The common occurrence of incidental AD and PD-type pathology combined with ''intermediate phenotypes'' such as dementia with Lewy bodies suggest that aging itself, AD, and PD are part of a complex continuum characterized by variable amounts of amyloid-??, tau, and ??-synuclein pathology. This heterogeneity may be a contributor to the lack of reproducibility in association studies to date. Here, we speculate on alternative experimental approaches to the case-control paradigm and consider how the association-study literature for AD and PD might be re-interpreted in terms of a disease spectrum.
%Z FOR Codes: 110904


%0 Journal Article
%~ PubMed
%A Masters, Colin L
%A Kril, Jillian J
%A Halliday, Glenda M
%A Pamphlett, Roger
%A Collins, Steven
%A Hill, Andrew F
%A McLean, Catriona
%T Overview and recent advances in neuropathology. Part 2: Neurodegeneration.
%B Pathology
%D 2011
%C United Kingdom, Australia
%I Wolters Kluwer UK Ltd.
%V 43
%N 2
%P 93-102
%@ 0031-3025
%X The sections in the following review cover six main neurodegenerative diseases. The first article on Alzheimer''s disease (AD) outlines the major evidence available to date that links A?-amyloid peptide as a proximal cause of AD. The article also highlights how an initial finding of the protein content of the amyloid plaque seen in the brains of patients with AD has led to many very significant findings in the neuroscience field. The next section outlines the many and recent advances that have occurred in the field of frontotemporal lobar degeneration (FTLD), including the most recent finding related to the fused sarcoma gene (FUS) and the newest nomenclature whereby the FTLD is subtyped according to the presence of specific proteins seen at a microscopic level. The section on Lewy bodies outlines the latest advances in the relationship between the anatomical distribution of Lewy bodies and disease phenotype. The following section includes an overview of current known genetic links with familial causes of motor neuron disease (MND) and an update on the areas being researched into the causes of sporadic MND. The presence of TDP-43 within inclusions and its new diagnostic role in MND are discussed. The final article on prion diseases gives an overview of human prion diseases, including the phenotypic spectrum, epidemiology and diagnostic investigations relevant to disease.
%Z FOR Codes: 110903 110316 110308


%0 Journal Article
%~ PubMed
%A Kril, Jillian J
%A Halliday, Glenda M
%T Pathological Staging of Frontotemporal Lobar Degeneration.
%B Journal of molecular neuroscience : MN
%D 2011
%C United States
%I Humana Press, Inc.
%V 45
%N 3
%P 379-83
%@ 0895-8696
%X We developed a staging scheme for assessing pathology in frontotemporal lobar degeneration (FTLD), which relates to atrophy and accounts for the large variability seen at postmortem (Broe et al. 2003;60:1005-11). Atrophy of the temporal lobe has the most linear relationship to disease stage. We review how this simple staging technique has been applied in clinical settings, where it is the best predictor of survival and discriminates semantic dementia and behavioural phenocopies. Patients with clinical presentations of motor neuron disease or progressive supranuclear palsy have significantly lower disease stages than other FTLD syndromes. We also review the pathologies relating to disease stage. There is no significant difference in the overall distribution of stages between the different pathological subtypes of FTLD, indicating a similar underlying disease process. The cellular variables relating independently to increasing disease stage are (1) increasing neuronal loss, astrocytosis and microvacuolation, and (2) increasing glial apoptosis. Of note, the degree of protein deposition does not relate to disease stage.
%Z FOR Codes: 110903 110316 110308


%0 Journal Article
%A Schwartz, RS
%A Cordato, DJ
%A Masters, LT
%A Joseph, MD
%A Kril, Jillian
%T Small-vessel disease: The predominant cerebrovascular subtype in patients with traumatic neck of femur fracture
%B European Geriatric Medicine
%D 2011
%C United Kingdom
%I Elsevier Ltd
%V 2
%N 3
%P 150-154
%@ 1878-7649
%X 
%Z FOR Codes: 110202 110902


%0 Journal Article
%~ PubMed
%A Sutherland, Greg T
%A Janitz, Michal
%A Kril, Jillian J
%T Understanding the pathogenesis of Alzheimer's disease: Will RNA-Seq realize the promise of transcriptomics?
%B Journal of neurochemistry
%D 2011
%C United Kingdom, United States
%I Wiley-Blackwell Publishing Ltd.
%V 116
%N 6
%P 937-46
%@ 0022-3042
%X The prevalence of Alzheimer''s disease (AD) is increasing rapidly in the western world and is poised to have a significant economic and societal impact. Current treatments do not alter the underlying disease processes meaning new treatments are required if this imminent epidemic is to be averted. The clinical manifestations of AD are secondary to a substantial loss of cortical neurons. To be effective, neuroprotective strategies will need to be implemented prior to this cell loss. However, this requires the discovery of both pre-clinical markers to identify susceptible patients and the early pathogenic mechanisms to serve as therapeutic targets. Although the biomarkers and pathogenic mechanisms may overlap, it is likely that new approaches are required to identify novel elements of the disease. Transcriptomic analyses, that assume no a priori etiological hypotheses, promise much in elucidating the pathogenesis of complex diseases like AD. Microarrays are the most popular platform for transcriptomic analysis and have been applied across AD models, patient samples and postmortem brain tissue. The results of these studies have been largely discordant which could, to some extent, reflect the limitations of this probe-hybridization-based methodology. In comparison, whole transcriptome sequencing (RNA-Seq) utilizes a highly efficient, next-generation DNA sequencing method with improved dynamic range and scope of transcript detection. RNA-Seq is not only highly suited to investigations of the genomically complex human brain tissue but it can potentially overcome technical issues inherent to case-control comparisons of postmortem brain tissue in neurodegenerative diseases. The volume of data generated by this platform looms as the major logistical hurdle and a systematic experimental approach will be required to maximise the detection of pathogenically relevant signals. Nevertheless, RNA-Seq looks set to deliver a quantum leap forward in our understanding of AD pathogenesis.
%Z FOR Codes: 110902 60405


%0 Journal Article
%~ PubMed
%A Van Deerlin, Vivianna M
%A Sleiman, Patrick M A
%A Martinez-Lage, Maria
%A Chen-Plotkin, Alice
%A Wang, Li-San
%A Graff-Radford, Neill R
%A Dickson, Dennis W
%A Rademakers, Rosa
%A Boeve, Bradley F
%A Grossman, Murray
%A Arnold, Steven E
%A Mann, David M A
%A Pickering-Brown, Stuart M
%A Seelaar, Harro
%A Heutink, Peter
%A van Swieten, John C
%A Murrell, Jill R
%A Ghetti, Bernardino
%A Spina, Salvatore
%A Grafman, Jordan
%A Hodges, John
%A Spillantini, Maria Grazia
%A Gilman, Sid
%A Lieberman, Andrew P
%A Kaye, Jeffrey A
%A Woltjer, Randall L
%A Bigio, Eileen H
%A Mesulam, Marsel
%A Al-Sarraj, Safa
%A Troakes, Claire
%A Rosenberg, Roger N
%A White, Charles L
%A Ferrer, Isidro
%A Lladó, Albert
%A Neumann, Manuela
%A Kretzschmar, Hans A
%A Hulette, Christine Marie
%A Welsh-Bohmer, Kathleen A
%A Miller, Bruce L
%A Alzualde, Ainhoa
%A de Munain, Adolfo Lopez
%A McKee, Ann C
%A Gearing, Marla
%A Levey, Allan I
%A Lah, James J
%A Hardy, John
%A Rohrer, Jonathan D
%A Lashley, Tammaryn
%A Mackenzie, Ian R A
%A Feldman, Howard H
%A Hamilton, Ronald L
%A Dekosky, Steven T
%A van der Zee, Julie
%A Kumar-Singh, Samir
%A Van Broeckhoven, Christine
%A Mayeux, Richard
%A Vonsattel, Jean Paul G
%A Troncoso, Juan C
%A Kril, Jillian J
%A Kwok, John B J
%A Halliday, Glenda M
%A Bird, Thomas D
%A Ince, Paul G
%A Shaw, Pamela J
%A Cairns, Nigel J
%A Morris, John C
%A McLean, Catriona Ann
%A DeCarli, Charles
%A Ellis, William G
%A Freeman, Stefanie H
%A Frosch, Matthew P
%A Growdon, John H
%A Perl, Daniel P
%A Sano, Mary
%A Bennett, David A
%A Schneider, Julie A
%A Beach, Thomas G
%A Reiman, Eric M
%A Woodruff, Bryan K
%A Cummings, Jeffrey
%A Vinters, Harry V
%A Miller, Carol A
%A Chui, Helena C
%A Alafuzoff, Irina
%A Hartikainen, Päivi
%A Seilhean, Danielle
%A Galasko, Douglas
%A Masliah, Eliezer
%A Cotman, Carl W
%A Tuñón, M Teresa
%A Martínez, M Cristina Caballero
%A Munoz, David G
%A Carroll, Steven L
%A Marson, Daniel
%A Riederer, Peter F
%A Bogdanovic, Nenad
%A Schellenberg, Gerard D
%A Hakonarson, Hakon
%A Trojanowski, John Q
%A Lee, Virginia M-Y
%T Common variants at 7p21 are associated with frontotemporal lobar degeneration with TDP-43 inclusions.
%B Nature Genetics
%D 2010
%C United States
%I Nature Publishing Group
%V 42
%N 3
%P 234-239
%@ 1061-4036
%X Frontotemporal lobar degeneration (FTLD) is the second most common cause of presenile dementia. The predominant neuropathology is FTLD with TAR DNA-binding protein (TDP-43) inclusions (FTLD-TDP). FTLD-TDP is frequently familial, resulting from mutations in GRN (which encodes progranulin). We assembled an international collaboration to identify susceptibility loci for FTLD-TDP through a genome-wide association study of 515 individuals with FTLD-TDP. We found that FTLD-TDP associates with multiple SNPs mapping to a single linkage disequilibrium block on 7p21 that contains TMEM106B. Three SNPs retained genome-wide significance following Bonferroni correction (top SNP rs1990622, P = 1.08 x 10(-11); odds ratio, minor allele (C) 0.61, 95% CI 0.53-0.71). The association replicated in 89 FTLD-TDP cases (rs1990622; P = 2 x 10(-4)). TMEM106B variants may confer risk of FTLD-TDP by increasing TMEM106B expression. TMEM106B variants also contribute to genetic risk for FTLD-TDP in individuals with mutations in GRN. Our data implicate variants in TMEM106B as a strong risk factor for FTLD-TDP, suggesting an underlying pathogenic mechanism.
%Z FOR Codes: 60405 110903 110316


%0 Journal Article
%~ PubMed
%A Urwin, Hazel
%A Josephs, Keith A
%A Rohrer, Jonathan D
%A Mackenzie, Ian R
%A Neumann, Manuela
%A Authier, Astrid
%A Seelaar, Harro
%A Van Swieten, John C
%A Brown, Jeremy M
%A Johannsen, Peter
%A Nielsen, Jorgen E
%A Holm, Ida E
%A , FReJA Consortium
%A Dickson, Dennis W
%A Rademakers, Rosa
%A Graff-Radford, Neill R
%A Parisi, Joseph E
%A Petersen, Ronald C
%A Hatanpaa, Kimmo J
%A White, Charles L
%A Weiner, Myron F
%A Geser, Felix
%A Van Deerlin, Vivianna M
%A Trojanowski, John Q
%A Miller, Bruce L
%A Seeley, William W
%A van der Zee, Julie
%A Kumar-Singh, Samir
%A Engelborghs, Sebastiaan
%A De Deyn, Peter P
%A Van Broeckhoven, Christine
%A Bigio, Eileen H
%A Deng, Han-Xiang
%A Halliday, Glenda M
%A Kril, Jillian J
%A Munoz, David G
%A Mann, David M
%A Pickering-Brown, Stuart M
%A Doodeman, Valerie
%A Adamson, Gary
%A Ghazi-Noori, Shabnam
%A Fisher, Elizabeth M C
%A Holton, Janice L
%A Revesz, Tamas
%A Rossor, Martin N
%A Collinge, John
%A Mead, Simon
%A Isaacs, Adrian M
%T FUS pathology defines the majority of tau- and TDP-43-negative frontotemporal lobar degeneration.
%B Acta Neuropathologica
%D 2010
%C Germany, United King
%I Springer
%V 120
%N 1
%P 33-41
%@ 1432-0533
%X Through an international consortium, we have collected 37 tau- and TAR DNA-binding protein 43 (TDP-43)-negative frontotemporal lobar degeneration (FTLD) cases, and present here the first comprehensive analysis of these cases in terms of neuropathology, genetics, demographics and clinical data. 92% (34/37) had fused in sarcoma (FUS) protein pathology, indicating that FTLD-FUS is an important FTLD subtype. This FTLD-FUS collection specifically focussed on aFTLD-U cases, one of three recently defined subtypes of FTLD-FUS. The aFTLD-U subtype of FTLD-FUS is characterised clinically by behavioural variant frontotemporal dementia (bvFTD) and has a particularly young age of onset with a mean of 41 years. Further, this subtype had a high prevalence of psychotic symptoms (36% of cases) and low prevalence of motor symptoms (3% of cases). We did not find FUS mutations in any aFTLD-U case. To date, the only subtype of cases reported to have ubiquitin-positive but tau-, TDP-43- and FUS-negative pathology, termed FTLD-UPS, is the result of charged multivesicular body protein 2B gene (CHMP2B) mutation. We identified three FTLD-UPS cases, which are negative for CHMP2B mutation, suggesting that the full complement of FTLD pathologies is yet to be elucidated.
%Z FOR Codes: 110904 110903


%0 Journal Article
%~ PubMed
%A Mackenzie, Ian R A
%A Neumann, Manuela
%A Bigio, Eileen H
%A Cairns, Nigel J
%A Alafuzoff, Irina
%A Kril, Jillian
%A Kovacs, Gabor G
%A Ghetti, Bernardino
%A Halliday, Glenda
%A Holm, Ida E
%A Ince, Paul G
%A Kamphorst, Wouter
%A Revesz, Tamas
%A Rozemuller, Annemieke J M
%A Kumar-Singh, Samir
%A Akiyama, Haruhiko
%A Baborie, Atik
%A Spina, Salvatore
%A Dickson, Dennis W
%A Trojanowski, John Q
%A Mann, David M A
%T Nomenclature and nosology for neuropathologic subtypes of frontotemporal lobar degeneration: an update.
%B Acta Neuropathologica
%D 2010
%C Germany, United King
%I Springer
%V 119
%N 1
%P 1-4
%@ 1432-0533
%X 
%Z FOR Codes: 110903 110316


%0 Journal Article
%~ PubMed
%A van Eersel, Janet
%A Ke, Yazi D
%A Liu, Xin
%A Delerue, Fabien
%A Kril, Jillian J
%A Götz, Jürgen
%A Ittner, Lars M
%T Sodium selenate mitigates tau pathology, neurodegeneration, and functional deficits in Alzheimer's disease models.
%B Proceedings of the National Academy of Sciences of the United States of America
%D 2010
%C United States
%I National Academy of Sciences
%V 107
%N 31
%P 13888-13893
%@ 0027-8424
%X Alzheimer''s disease (AD) brains are characterized by amyloid-beta-containing plaques and hyperphosphorylated tau-containing neurofibrillary tangles (NFTs); however, in frontotemporal dementia, the tau pathology manifests in the absence of overt amyloid-beta plaques. Therapeutic strategies so far have primarily been targeting amyloid-beta, although those targeting tau are only slowly beginning to emerge. Here, we identify sodium selenate as a compound that reduces tau phosphorylation both in vitro and in vivo. Importantly, chronic oral treatment of two independent tau transgenic mouse strains with NFT pathology, P301L mutant pR5 and K369I mutant K3 mice, reduces tau hyperphosphorylation and completely abrogates NFT formation. Furthermore, treatment improves contextual memory and motor performance, and prevents neurodegeneration. As hyperphosphorylation of tau precedes NFT formation, the effect of selenate on tau phosphorylation was assessed in more detail, a process regulated by both kinases and phosphatases. A major phosphatase implicated in tau dephosphorylation is the serine/threonine-specific protein phosphatase 2A (PP2A) that is reduced in both levels and activity in the AD brain. We found that selenate stabilizes PP2A-tau complexes. Moreover, there was an absence of therapeutic effects in sodium selenate-treated tau transgenic mice that coexpress a dominant-negative mutant form of PP2A, suggesting a mediating role for PP2A. Taken together, sodium selenate mitigates tau pathology in several AD models, making it a promising lead compound for tau-targeted treatments of AD and related dementias.
%Z FOR Codes: 110903 30406 110316


%0 Journal Article
%~ PubMed
%A Loy, Clement T
%A Kril, Jillian J
%A Trollor, Julian N
%A Kiernan, Matthew C
%A Kwok, John B J
%A Vucic, Steve
%A Halliday, Glenda M
%A Hodges, John R
%A , Medscape
%T The case of a 48 year-old woman with bizarre and complex delusions.
%B Nature Reviews Neurology
%D 2010
%C United Kingdom
%I Nature Publishing Group
%V 6
%N 3
%P 175-179
%@ 1759-4766
%X BACKGROUND: A 48 year-old woman presented with an 18 month history of bizarre and complex delusions on a background of social, behavioral and cognitive decline over several years. Her psychosis progressed despite receiving high doses of antipsychotics. The patient''s father also had a psychotic episode in his 40s. He subsequently developed motor neuron disease, which caused his death at 68 years of age. INVESTIGATIONS: Physical examination, neuropsychological testing, nerve conduction studies, brain MRI and transcranial magnetic stimulation. DIAGNOSIS: On the basis of the patient''s age at onset of the delusions, imaging findings and family history, a diagnosis of frontotemporal dementia (FTD) was favored over a primary psychotic disorder. The ubiquitin-positive and TAR DNA binding protein 43-positive inclusions that were found at autopsy confirmed the diagnosis of FTD. MANAGEMENT: The patient was treated with various antipsychotics at high doses; however, her delusions continued to progress. No disease-specific treatments for FTD currently exist.
%Z FOR Codes: 110903 110308 110319


%0 Journal Article
%~ PubMed
%A Loy, Clement T
%A McCusker, Elizabeth
%A Kril, Jillian J
%A Kwok, John B
%A Brooks, William S
%A McCann, Heather
%A Isaacs, Adrian M
%A Halliday, Glenda M
%T Very early-onset frontotemporal dementia with no family history predicts underlying fused in sarcoma pathology.
%B Brain : a journal of neurology
%D 2010
%C United Kingdom
%I Oxford University Press
%V 133
%N 12
%P e158; author reply e159
%@ 1460-2156
%X 
%Z FOR Codes: 110999 110999


%0 Journal Article
%~ PubMed
%A Kril, Jillian J
%T Alzheimer disease: Alzheimer disease neuropathology in the oldest old.
%B Nature Reviews. Neurology
%D 2009
%C United Kingdom
%I Nature Publishing Group
%V 5
%N 8
%P 411-412
%@ 1759-4766
%X 
%Z FOR Codes: 110308 110316


%0 Journal Article
%~ PubMed
%A Piguet, Olivier
%A Halliday, Glenda M
%A Creasey, Helen
%A Broe, G Anthony
%A Kril, Jillian J
%T Frontotemporal dementia and dementia with Lewy bodies in a case-control study of Alzheimer's disease.
%B International Psychogeriatrics
%D 2009
%C United Kingdom, Unit
%I Cambridge University Press
%V 21
%N 4
%P 688-695
%@ 1041-6102
%X ABSTRACTBackground: The clinical presentations in dementia with Lewy bodies (DLB) and frontotemporal dementia (FTD) overlap considerably with that of Alzheimer''s disease (AD) despite different pathological processes. Autopsy studies have also shown that multiple brain pathology occurs frequently, even in cases with a single clinical diagnosis. We aimed to determine the frequency of clinical diagnosis of FTD and DLB and the underlying pathology in a well-characterized cohort of patients with a clinical diagnosis of probable or possible AD.Methods: We conducted a retrospective analysis of 170 AD patients (probable AD = 83; possible AD = 87) originally enrolled in a case-control study, 27 with postmortem examination, to establish the number of cases meeting probable diagnosis for FTD and DLB, using a checklist of features compiled from their consensus criteria.Results: 23/83 probable AD cases and 32/87 possible AD cases met probable criteria for another dementia, more commonly DLB than FTD. AD pathology was present in 8/15 probable AD and 8/12 possible AD cases coming to autopsy. DLB pathology was seen in four cases and FTD pathology in eight cases. In the AD cases reaching clinical diagnosis for a second dementia syndrome and coming to autopsy, a minority showed non-AD pathology only.Conclusions: Presence of core clinical features of non-AD dementia syndromes is common in AD. Concordance between clinical and pathological diagnoses of dementia remains variable. We propose that repeat clinical examinations and structural neuroimaging will improve diagnostic accuracy. In addition, clinical diagnostic criteria for the main dementia syndromes require refinement.
%Z FOR Codes: 110903 110308


%0 Journal Article
%~ PubMed
%A Mackenzie, Ian R A
%A Neumann, Manuela
%A Bigio, Eileen H
%A Cairns, Nigel J
%A Alafuzoff, Irina
%A Kril, Jillian
%A Kovacs, Gabor G
%A Ghetti, Bernardino
%A Halliday, Glenda
%A Holm, Ida E
%A Ince, Paul G
%A Kamphorst, Wouter
%A Revesz, Tamas
%A Rozemuller, Annemieke J M
%A Kumar-Singh, Samir
%A Akiyama, Haruhiko
%A Baborie, Atik
%A Spina, Salvatore
%A Dickson, Dennis W
%A Trojanowski, John Q
%A Mann, David M A
%T Nomenclature for neuropathologic subtypes of frontotemporal lobar degeneration: consensus recommendations.
%B Acta Neuropathologica
%D 2009
%C Germany, United King
%I Springer
%V 117
%N 1
%P 15-18
%@ 1432-0533
%X 
%Z FOR Codes: 110316


%0 Journal Article
%~ PubMed
%A van Eersel, Janet
%A Bi, Mian
%A Ke, Yazi
%A Hodges, John
%A Xuereb, John
%A Gregory, Gillian
%A Halliday, Glenda
%A Götz, Jürgen
%A Kril, Jillian
%A Ittner, Lars
%T Phosphorylation of soluble tau differs in Pick's disease and Alzheimer's disease brains.
%B Journal of Neural Transmission
%D 2009
%C Austria
%I Springer Wien
%V 116
%N 10
%P 1243-1251
%@ 1435-1463
%X Frontotemporal lobar degeneration (FTLD) is a common cause of presenile dementia characterised by behavioural and language disturbances. Pick''s disease (PiD) is a subtype of FTLD, which presents with intraneuronal inclusions consisting of hyperphosphorylated tau protein aggregates. Although Alzheimer''s disease (AD) is also characterised by tau lesions, these are both histologically and biochemically distinct from the tau aggregates found in PiD. What determines the distinct characteristics of these tau lesions is unknown. As phosphorylated, soluble tau has been suggested to be the precursor of tau aggregates, we compared both the level and phosphorylation profile of tau in tissue extracts of AD and PiD brains to determine whether the differences in the tau lesions are reflected by differences in soluble tau. Levels of soluble tau were decreased in AD but not PiD. In addition, soluble tau was phosphorylated to a greater extent in AD than in PiD and displayed a different phosphorylation profile in the two disorders. Consistently, tau kinases were activated to different degrees in AD compared with PiD. Such differences in solubility and phosphorylation may contribute, at least in part, to the formation of distinct tau deposits, but may also have implications for the clinical differences between AD and PiD.
%Z FOR Codes: 110308 60105 110316


%0 Journal Article
%~ Isi
%A Davies, R. R.
%A Halliday, G. M.
%A Xuereb, J. H.
%A Kril, J. J.
%A Hodges, J. R.
%T The neural basis of semantic memory: Evidence from semantic dementia
%B Neurobiology of Aging
%D 2009
%C United States
%I Elsevier Inc.
%V 30
%N 12
%P 2043-2052
%@ 0197-4580
%X 
%Z FOR Codes: 110904


%0 Journal Article
%~ PubMed
%A Monoranu, C M
%A Apfelbacher, M
%A Grünblatt, E
%A Puppe, B
%A Alafuzoff, I
%A Ferrer, I
%A Al-Saraj, S
%A Keyvani, K
%A Schmitt, A
%A Falkai, P
%A Schittenhelm, J
%A Halliday, G
%A Kril, J
%A Harper, C
%A McLean, C
%A Riederer, P
%A Roggendorf, W
%T pH measurement as quality control on human post mortem brain tissue: a study of the BrainNet Europe consortium.
%B Neuropathology and Applied Neurobiology
%D 2009
%C United Kingdom
%I Wiley-Blackwell Publishing Ltd.
%V 35
%N 3
%P 329-337
%@ 1365-2990
%X AIMS: Most brain diseases are complex entities. Although animal models or cell culture experiments mimic some disease aspects, human post mortem brain tissue remains essential to advance our understanding of brain diseases using biochemical and molecular techniques. Post mortem artefacts must be properly understood, standardized, and either eliminated or factored into such experiments. Here we examine the influence of several premortem and post mortem factors on pH, and discuss the role of pH as a biochemical marker for brain tissue quality. METHODS: We assessed brain tissue pH in 339 samples from 116 brains provided by 8 different European and 2 Australian brain bank centres. We correlated brain pH with tissue source, post mortem delay, age, gender, freezing method, storage duration, agonal state and brain ischaemia. RESULTS: Our results revealed that only prolonged agonal state and ischaemic brain damage influenced brain tissue pH next to repeated freeze/thaw cycles. CONCLUSIONS: pH measurement in brain tissue is a good indicator of premortem events in brain tissue and it signals limitations for post mortem investigations.
%Z FOR Codes: 110316 60199


%0 Journal Article
%~ PubMed
%A Young, Vanessa G
%A Halliday, Glenda M
%A Kril, Jillian J
%T Neuropathologic correlates of white matter hyperintensities.
%B Neurology
%D 2008
%C United States
%I Lippincott Williams & Wilkins
%V 71
%N 11
%P 804-11
%@ 0028-3878
%X White matter hyperintensities (WMH) are commonly seen on neuroimaging scans, but their underlying histopathologic substrate is unclear. The aim of this work was to establish the pathologic correlates of WMH in unselected elderly cases using two study designs. To avoid potential bias from comparisons of different anatomic regions, study 1 compared, region-by-region, the severity of WMH determined in vivo with measures of each of the major white matter (WM) components. Study 2 compared the histopathology of WMH with normal WM.
%Z FOR Codes: 110903


%0 Book Section
%A Harris, John
%A Chimelli, Leila
%A Kril, Jillian
%A Ray, David
%T Nutritional deficiencies, metabolic disorders and toxins affecting the nervous system
%B Greenfield's Neuropathology
%D 2008
%C United Kingdom
%I Hodder Arnold
%V 
%N 
%P 675-731
%@ 9780340906811
%E Love, Seth
%E Louis, David N
%E Ellison, David W
%X 
%Z FOR Codes: 110903 111103


%0 Journal Article
%~ PubMed
%A Kipps, Christopher M
%A Davies, R Rhys
%A Mitchell, Joanna
%A Kril, Jillian J
%A Halliday, Glenda M
%A Hodges, John R
%T Clinical significance of lobar atrophy in frontotemporal dementia: application of an MRI visual rating scale.
%B Dementia and geriatric cognitive disorders
%D 2007
%C Germany
%I S. Karger AG
%V 23
%N 5
%P 334-342
%@ 1420-8008
%X BACKGROUND/AIMS: The status of imaging findings in the clinical diagnosis of frontotemporal dementia (FTD) remains uncertain; while they may be supportive of a diagnosis of frontotemporal dementia, they are not mandatory. Our aim was to assess patterns of lobar atrophy in a large sample of clinically defined, prospectively studied, patients using a magnetic resonance image (MRI) rating scale, to (1) determine whether imaging findings warrant a more prominent position in FTD diagnosis and (2) correlate the extent of lobar atrophy with clinical data. METHODS: We adapted a recently devised post mortem rating scale for FTD to rate lobar atrophy on MRI scans. The areas rated included the frontal cortex and both anterior and posterior temporal regions bilaterally. All available brain scans from all patients seen in the Cambridge Dementia Clinic (n = 258) diagnosed as having FTD, together with controls (n = 20), were used to assess the reliability of the method. A subset of these (n = 121) were used for clinico-anatomic analysis. RESULTS: The scale proved quick and reliable (intra-, inter-rater k = 0.80, 0.67). MRI scans were abnormal in the majority of patients (75%), with focal atrophy present in 100% of semantic dementia (SD) patients. By contrast, nearly half (47%) of the patients with clinical behavioural variant FTD had scans within the normal range. Behavioural cases with normal scans generally had fewer cognitive deficits and milder functional impairment than those with abnormal scans, yet displayed a clinically indistinguishable behavioural syndrome. They were not, however, simply at an earlier stage of the disease. CONCLUSIONS: MRI findings should form part of the diagnostic criteria for SD; the absence of atrophy on MRI in many behavioural cases raises the prospect that the behavioural syndrome of FTD is not specific for patients with a neurodegenerative disease.
%Z FOR Codes: 110903


%0 Journal Article
%~ PubMed
%A Peisah, Carmelle
%A Snowdon, John
%A Kril, Jillian
%A Rodriguez, Michael
%T Clinicopathological findings of suicide in the elderly: three cases.
%B Suicide & life-threatening behavior
%D 2007
%C United States
%I Guilford Publications, Inc.
%V 37
%N 6
%P 648-658
%@ 0363-0234
%X The neuropathological correlates of suicide in older persons have received little research attention. Our recent study of elderly suicide victims from an Australian forensic medicine department (n = 143), unlike a previous case-control study, did not find an increased prevalence of Alzheimer''s disease (AD) in older persons who committed suicide despite a history of dementia in 6.3%. Both studies were limited to the examination of AD-related pathology by the availability of tissue. We present clinicopathological data on three cases from our study for whom autopsy findings were available. These cases included: a community-dwelling male in his early eighties with dementia who was found to have multiple cortical and striatal lacunes and glial scars, small vessel cerebrovascular disease (SVD) and AD-related pathology; a community-dwelling male in his mid-seventies with depression and loss of concentration, with brainstem predominant Lewy body disease (LBD) and AD-related pathology; and a female nursing home resident in her nineties with a history of stroke and prior suicide attempts who was found to have infarcts and SVD in frontal regions. Neuropathological findings in elderly suicide victims may include multiple neurodegenerative pathologies. The burden and distribution of neurodegenerative diseases apart from AD, including SVD and LBD, should be assessed as possible pathophysiological factors contributing to late life suicide.
%Z FOR Codes:


%0 Journal Article
%~ PubMed
%A Sutherland, Greg T
%A Nowak, Greg
%A Halliday, Glenda M
%A Kril, Jillian J
%T Tau isoform expression in frontotemporal dementia without tau deposition.
%B Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia
%D 2007
%C UK
%I Churchill Livingstone
%V 14
%N 12
%P 1182-5
%@ 0967-5868
%X In many cases of sporadic frontotemporal dementia (FTD) and in FTD caused by tau mutations (FTDP-17) there is disruption of the normal splicing of tau leading to the aberrant expression of tau isoforms and neurodegeneration. This suggests a central role for tau in the pathogenesis of FTD. However, more than half the cases of sporadic FTD show no tau deposition. We question whether altered expression is also involved in the pathogenesis of tau-negative FTD. Real-time polymerase chain reaction was used to investigate tau isoform expression in tau-negative FTD and age-matched controls. There were no differences in total tau mRNA or 4R versus 3R isoform expression. Our study suggests that perturbed tau mRNA expression is unlikely to be involved in the pathogenesis of tau-negative FTD.
%Z FOR Codes: 110903


%0 Journal Article
%~ PubMed
%A Karlstrom, Helena
%A Brooks, William S
%A Kwok, John B J
%A Broe, G Anthony
%A Kril, Jillian J
%A McCann, Heather
%A Halliday, Glenda M
%A Schofield, Peter R
%T Variable phenotype of Alzheimer's disease with spastic paraparesis.
%B Journal of neurochemistry
%D 2007
%C UK
%I Blackwell Publishing Ltd
%V 104
%N 3
%P 573-83
%@ 1471-4159
%X Pedigrees with familial Alzheimer''s disease (AD) show considerable phenotypic variability. Spastic paraparesis (SP), or progressive spasticity of the lower limbs is frequently hereditary and exists either as uncomplicated (paraparesis alone) or complicated (paraparesis and other neurological features) disease subtypes. In some AD families, with presenilin-1 (PSEN1) mutations, affected individuals also have SP. These PSEN1 AD pedigrees frequently have a distinctive and variant neuropathology, namely large, non-cored plaques without neuritic dystrophy called cotton wool plaques (CWP). The PSEN1 AD mutations giving rise to CWP produce unusually high levels of the amyloid beta peptide (Abeta) ending at position 42 or 43, and the main component of CWP is amino-terminally truncated forms of amyloid beta peptide starting after the alternative beta-secretase cleavage site at position 11. This suggests a molecular basis for the formation of CWP and an association with both SP and AD. The SP phenotype in some PSEN1 AD pedigrees also appears to be associated with a delayed onset of dementia compared with affected individuals who present with dementia only, suggesting the existence of a protective factor in some individuals with SP. Variations in neuropathology and neurological symptoms in PSEN1 AD raise the prospect that modifier genes may underlie this phenotypic heterogeneity.
%Z FOR Codes: 110903


%0 Journal Article
%~ PubMed
%A Piguet, O
%A Double, K L
%A Kril, J J
%A Harasty, J
%A Macdonald, V
%A McRitchie, D A
%A Halliday, G M
%T White matter loss in healthy ageing: A postmortem analysis.
%B Neurobiology of aging
%D 2007
%C United Kingdom
%I Elsevier
%V 30
%N 0
%P 1288-95
%@ 1558-1497
%X Age-related brain changes are widely documented. Because of differences in measurement methods and case selection, the reported effects of age on regional grey and white matter brain volumes, however, are much more pronounced and widespread in neuroimaging than in postmortem studies. Consequently, the magnitude of the effect that is specific to chronological age remains unresolved. We present postmortem volume measurements for 26 cortical, subcortical and white matter regions, in 24 human brains aged 46-92 years, free of neuropathological abnormalities. Significant age-related loss was observed in anterior and posterior white matter but not in total grey matter volumes. Further analyses on five cortical subregions previously reported to exhibit large age-related loss on MRI yielded negative results. These analyses demonstrate smaller changes with age than those reported in imaging studies. Although this discrepancy between postmortem and imaging studies may partly be explained by the increase in noise of the neuroimaging data with age, our results suggest that healthy brain ageing is a process affecting predominantly white matter not grey matter.
%Z FOR Codes: 110903


%0 Journal Article
%~ PubMed
%A Piguet, Olivier
%A Cramsie, Jane
%A Bennett, Hayley
%A Kril, Jillian
%A Lye, Tanya
%A Corbett, Alastair
%A Hayes, Michael
%A Creasey, Helen
%A Broe, G
%T Contributions of age and alcohol consumption to cerebellar integrity, gait and cognition in non-demented very old individuals.
%B European archives of psychiatry and clinical neuroscience
%D 2006
%C Gernmany
%I Dr. Dietrich Steinkopff Verlag
%V 256
%N 8
%P 504-11
%@ 0940-1334
%X Gait disturbance and cognitive changes are common with ageing. The cerebellum contributes to motor coordination and participates in various aspects of cognition. However, no research has investigated the possible cerebellar contribution to gait and cognition in non-demented very old individuals. The current study aimed to determine the associations between indices of cerebellar size (vermal area and total volume) and measures of motor and cognitive integrity, as well as the role of variables known to impact on cerebellar size (alcohol consumption and chronological age) in a sample of 111 community dwellers (mean age: 85 years; range: 81-97 years). A marginally significant association was present between age and total vermal area. Significant correlations between current daily alcohol intake and some vermal areas were observed. These associations were more pronounced in men, particularly after controlling for cerebrum size. Multiple linear regression models revealed limited unique contributions of cerebellar predictors to neurological and cognitive measures. In summary, the results indicate that the cerebellum may be susceptible to alcohol-related shrinkage in non-demented very old individuals, more so in men, even at low dose. It also appears that the observed changes in cerebellum size in this population contribute little to neurological and cognitive changes.
%Z FOR Codes: 110903


%0 Journal Article
%~ PubMed
%A Gregory, Gillian C
%A Macdonald, Virginia
%A Schofield, Peter R
%A Kril, Jillian J
%A Halliday, Glenda M
%T Differences in regional brain atrophy in genetic forms of Alzheimer's disease.
%B Neurobiology of aging
%D 2006
%C USA
%I Elsevier Inc.
%V 27
%N 3
%P 387-93
%@ 0197-4580
%X Multiple degenerative hallmarks characterize Alzheimer''s disease: insoluble protein deposition, neuronal loss and cortical atrophy. Atrophy begins in the medial temporal lobe and becomes global by end stage. In a small proportion of cases, these tissue changes are caused by mutations in three known genes. These cases are affected earlier in life and have more abundant protein deposition, which may indicate greater tissue atrophy and degeneration. This issue remains unresolved. Grey matter atrophy in different cortical regions was determined in genetic cases of Alzheimer''s disease (N = 13) and compared to sporadic cases (N = 13) and non-diseased controls (N = 23). Genetic mutations were found to influence the degree and regional pattern of atrophy. The majority of cases had greater medial temporal atrophy than sporadic disease, suggesting that abnormalities affecting Abeta metabolism selectively increase hippocampal degeneration. Cases with mutations in presenilin-1 demonstrated additional increased frontotemporal atrophy. This effect may be due to the influence of presenilin-1 on tau phosphorylation and metabolism. These differences may explain the earlier onset ages in these different forms of Alzheimer''s disease.
%Z FOR Codes: 110903


%0 Journal Article
%~ PubMed
%A Peisah, C
%A Snowdon, J
%A Gorrie, C
%A Kril, J
%A Rodriguez, M
%T Investigation of Alzheimer's disease-related pathology in community dwelling older subjects who committed suicide.
%B Journal of affective disorders
%D 2006
%C Netherlands
%I Elsevier BV
%V 99
%N 1-3
%P 127-32
%@ 0165-0327
%X Older people have a higher risk of completed suicide than any other age group worldwide. The contribution of neurodegenerative disease to this risk remains controversial.
%Z FOR Codes: 110903


%0 Journal Article
%~ PubMed
%A Pickering-Brown, Stuart M
%A Baker, Matt
%A Gass, Jenny
%A Boeve, Bradley F
%A Loy, Clement T
%A Brooks, William S
%A Mackenzie, Ian R A
%A Martins, Ralph N
%A Kwok, John B J
%A Halliday, Glenda M
%A Kril, Jillian
%A Schofield, Peter R
%A Mann, David M A
%A Hutton, Mike
%T Mutations in progranulin explain atypical phenotypes with variants in MAPT.
%B Brain
%D 2006
%C UK
%I Oxford University Press
%V 129
%N Pt 11
%P 3124-31246
%@ 1460-2156
%X Mutations in presenilin-1 (PSEN1) cause autosomal dominant Alzheimer''s disease and mutations in MAPT cause the familial tauopathy Frontotemporal dementia linked to chromosome 17 (FTDP-17). However, there have been reports of mutations in PSEN1 and MAPT associated with cases of FTD with ubiquitin-positive tau-negative inclusion pathology. Here, we demonstrate that the MAPT variants are almost certainly rare benign polymorphisms as all of these cases harbour mutations in Progranulin (PGRN). Mutations in PGRN were recently shown to cause ubiquitin-positive FTDP-17.
%Z FOR Codes: 110903


%0 Journal Article
%~ Isi
%A Halliday, G. M.
%A Song, Y. J. C.
%A Creasey, H.
%A Morris, J. G.
%A Brooks, W. S.
%A Kril, J. J.
%T Neuropathology in the S305S tau gene mutation.
%B Brain
%D 2006
%C UK
%I Oxford University Press
%V 129
%N 3
%P e40
%@ 
%X 
%Z FOR Codes:


%0 Journal Article
%~ Isi
%A Kril, J. J.
%T Neuropathology of alcohol abuse: A comparison with ageing and Alzheimer's disease.
%B Alcoholism-Clinical and Experimental Research
%D 2006
%C United States
%I Blackwell Publishing, Inc.
%V 30
%N 9
%P 51A-51A
%@ 0145-6008
%X 
%Z FOR Codes: 110903


%0 Journal Article
%~ PubMed
%A Lye, T C
%A Grayson, D A
%A Creasey, H
%A Piguet, O
%A Bennett, H P
%A Ridley, L J
%A Kril, J J
%A Broe, G A
%T Predicting memory performance in normal ageing using different measures of hippocampal size.
%B Neuroradiology
%D 2006
%C Germany
%I Springer-Verlag
%V 48
%N 2
%P 90-9
%@ 0028-3940
%X A number of different methods have been employed to correct hippocampal volumes for individual variation in head size. Researchers have previously used qualitative visual inspection to gauge hippocampal atrophy. The purpose of this study was to determine the best measure(s) of hippocampal size for predicting memory functioning in 102 community-dwelling individuals over 80 years of age. Hippocampal size was estimated using magnetic resonance imaging (MRI) volumetry and qualitative visual assessment. Right and left hippocampal volumes were adjusted by three different estimates of head size: total intracranial volume (TICV), whole-brain volume including ventricles (WB+V) and a more refined measure of whole-brain volume with ventricles extracted (WB). We compared the relative efficacy of these three volumetric adjustment methods and visual ratings of hippocampal size in predicting memory performance using linear regression. All four measures of hippocampal size were significant predictors of memory performance. TICV-adjusted volumes performed most poorly in accounting for variance in memory scores. Hippocampal volumes adjusted by either measure of whole-brain volume performed equally well, although qualitative visual ratings of the hippocampus were at least as effective as the volumetric measures in predicting memory performance in community-dwelling individuals in the ninth or tenth decade of life.
%Z FOR Codes: 110903


%0 Journal Article
%~ PubMed
%A Piguet, Olivier
%A Bennett, Hayley P
%A Waite, Louise M
%A Kril, Jillian J
%A Creasey, Helen
%A Anthony Broe, G
%A Halliday, Glenda M
%T Preserved cognition and functional independence after a large right posterior cerebral artery infarct: longitudinal clinical and neuropathological findings.
%B Neurocase : case studies in neuropsychology, neuropsychiatry, and behavioural neurology
%D 2006
%C United Kingdom
%I Psychology Press
%V 12
%N 2
%P 81-90
%@ 1355-4794
%X BVR was 77 years old when he sustained a large posterior cerebral artery territory infarct. Medical, cognitive and functional data collected on four occasions over 10 years initially revealed circumscribed neurological signs, no functional or cognitive deficits. BVR became significantly impaired only after two other strokes, 3 years before death. On brain MRI, the lesions involved large portions of the right occipital and temporal cortices, the right thalamus, and the left cerebellum, as well as thinning of the corpus callosum. Postmortem investigations revealed additional recent vascular lesions in the occipital region. This case study underscores the importance of comprehensive assessment methods combining neurological, neuroimaging and cognitive tools.
%Z FOR Codes: 110903


%0 Journal Article
%~ PubMed
%A Davies, Rhys R
%A Kipps, Christopher M
%A Mitchell, Joanna
%A Kril, Jillian J
%A Halliday, Glenda M
%A Hodges, John R
%T Progression in Frontotemporal Dementia: Identifying a Benign Behavioral Variant by Magnetic Resonance Imaging.
%B Archives of neurology
%D 2006
%C USA
%I American Medical Association
%V 63
%N 11
%P 1627-1631
%@ 0003-9942
%X OBJECTIVE: To assess the clinical course and prognosis in patients with behavioral-variant frontotemporal dementia (FTD) lacking evidence of brain atrophy on magnetic resonance imaging (MRI). DESIGN: Patients were enrolled into this prospective cohort study over a period of 15 years; cognitive status, duration of symptoms, and behavioral indexes were recorded. Brain MRIs were rated using a standardized scale. SETTING: Regional early-onset dementia clinic. PARTICIPANTS: Thirty-one participants diagnosed clinically with behavioral-variant FTD. Intervention Rating of MRIs. MAIN OUTCOME MEASURES: Death or institutionalization after a minimum of 3 years'' follow-up indicated poor prognosis, while the ability to live independently was regarded as a good prognosis for the purpose of survival (Kaplan-Meier) and discriminant function analysis. RESULTS: Patients with normal or borderline MRI findings (n = 15) showed significantly longer survival to institutionalization or death than those (n = 16) with definite frontotemporal atrophy (mean +/- SE, 9.3 +/- 1.7 years vs 3.0 +/- 0.7 years; P<.01). Using groups defined by 3-year outcome (good or bad prognosis), cerebral atrophy predicted poor outcome while age, symptom duration, cognitive performance, behavioral impairment, and overall disability at baseline did not. CONCLUSIONS: Patients with FTD with normal MRI results follow a more benign course than cases with atrophy at presentation. The substrate of the behavioral symptoms in such cases may differ from the neurodegenerative pathological features typically associated with FTD.
%Z FOR Codes: 110903


%0 Journal Article
%~ Isi
%A Kersaitis, C.
%A Halliday, G.
%A Xuereb, J.
%A Pamphlett, R.
%A Bak, T.
%A Hodges, J.
%A Kril, J.
%T Ubiquitin positive inclusions and early pathology in frontotemporal lobar degeneration and motor neuron disease.
%B Brain Pathology
%D 2006
%C USA
%I Blackwell Publishing, Inc.
%V 16
%N 
%P S43-S43
%@ 
%X 
%Z FOR Codes: 110903


%0 Journal Article
%~ PubMed
%A Kersaitis, C
%A Halliday, G M
%A Xuereb, J H
%A Pamphlett, R
%A Bak, T H
%A Hodges, J R
%A Kril, J J
%T Ubiquitin-positive inclusions and progression of pathology in frontotemporal dementia and motor neurone disease identifies a group with mainly early pathology.
%B Neuropathology and applied neurobiology
%D 2006
%C United Kingdom
%I Blackwell Publishing Ltd.
%V 32
%N 1
%P 83-91
%@ 0305-1846
%X Frontotemporal lobar degeneration (FTLD) with tau-negative, ubiquitin-positive inclusions has been a topic of major interest in recent years, with this group now accounting for the majority of tau-negative cases of frontotemporal degeneration. The severity of neurodegeneration in FTLD is dependent on the stage of disease and is substantial even in the earliest stages. Elucidating the pathogenesis of FTLD requires evaluation of changes during the earliest possible stage of disease. However, the long survival of most frontotemporal dementia cases means that cases with early neuropathology are not frequently encountered. Cases of FTLD with the shortest survival are those with coexisting motor neurone disease (FTLD + MND), making these the ideal group for studying early FTLD pathology. It is not clear, however, what the pathological contribution of MND is in these cases. This study evaluates the pathology of 20 cases of FTLD (11 with no clinical signs of MND and nine with FTLD + MND) as well as 10 cases of MND without dementia. Our findings indicate that the deposition of ubiquitin does not play a key role in the neurodegenerative process in FTLD, and that the severity of neurodegeneration in FTLD is similar in cases with and without clinical MND.
%Z FOR Codes: 110903