Jane Hecker - Academia.edu (original) (raw)

Papers by Jane Hecker

Metabolites

The metabolomic and proteomic basis of mild cognitive impairment (MCI) and Alzheimer’s disease (A... more The metabolomic and proteomic basis of mild cognitive impairment (MCI) and Alzheimer’s disease (AD) is poorly understood, and the relationships between systemic abnormalities in metabolism and AD/MCI pathogenesis is unclear. This study compared the metabolomic and proteomic signature of plasma from cognitively normal (CN) and dementia patients diagnosed with MCI or AD, to identify specific cellular pathways and new biomarkers altered with the progression of the disease. We analysed 80 plasma samples from individuals with MCI or AD, as well as age- and gender-matched CN individuals, by utilising mass spectrometry methods and data analyses that included combined pathway analysis and model predictions. Several proteins clearly identified AD from the MCI and CN groups and included plasma actins, mannan-binding lectin serine protease 1, serum amyloid A2, fibronectin and extracellular matrix protein 1 and Keratin 9. The integrated pathway analysis showed various metabolic pathways were af...

Frontotemporal dementia–amyotrophic lateral sclerosis syndrome locus on chromosome 16p12.1–q12.2:... more Frontotemporal dementia–amyotrophic lateral sclerosis syndrome locus on chromosome 16p12.1–q12.2: genetic, clinical and neuropathological analysis

Southern Medical Journal, 2001

Brain, 2020

Frontotemporal dementia and amyotrophic lateral sclerosis are clinically and pathologically overl... more Frontotemporal dementia and amyotrophic lateral sclerosis are clinically and pathologically overlapping disorders with shared genetic causes. We previously identified a disease locus on chromosome 16p12.1-q12.2 with genome-wide significant linkage in a large European Australian family with autosomal dominant inheritance of frontotemporal dementia and amyotrophic lateral sclerosis and no mutation in known amyotrophic lateral sclerosis or dementia genes. Here we demonstrate the segregation of a novel missense variant in CYLD (c.2155A>G, p.M719V) within the linkage region as the genetic cause of disease in this family. Immunohistochemical analysis of brain tissue from two CYLD p.M719V mutation carriers showed widespread glial CYLD immunoreactivity. Primary mouse neurons transfected with CYLDM719V exhibited increased cytoplasmic localization of TDP-43 and shortened axons. CYLD encodes a lysine 63 deubiquitinase and CYLD cutaneous syndrome, a skin tumour disorder, is caused by mutatio...

Journal of Alzheimer's Disease, 2021

Background: The metabolomic and proteomic basis of mild cognitive impairment (MCI) and Alzheimer’... more Background: The metabolomic and proteomic basis of mild cognitive impairment (MCI) and Alzheimer’s disease (AD) is poorly understood and the relationships between systemic abnormalities in metabolism and AD/AMCI pathogenesis are unclear. Objective: The aim of the study was to compare the metabolomic and proteomic signature of saliva from cognitively normal and patients diagnosed with MCI or AD, to identify specific cellular pathways altered with the progression of the disease. Methods: We analyzed 80 saliva samples from individuals with MCI or AD as well as age- and gender-matched healthy controls. Saliva proteomic and metabolomic analyses were conducted utilizing mass spectrometry methods and data combined using pathway analysis. Results: We found significant alterations in multiple cellular pathways, demonstrating that at the omics level, disease progression impacts numerous cellular processes. Multivariate statistics using SIMCA showed that partial least squares-data analysis cou...

Mutation research

An early cellular response to DNA double-strand breaks is the phosphorylation of histone H2AX to ... more An early cellular response to DNA double-strand breaks is the phosphorylation of histone H2AX to form γH2AX. Although increased levels of γH2AX have been reported in neuronal nuclei of Alzheimer's disease (AD) patients, γH2AX responses in the lymphocytes of individuals with mild cognitive impairment (MCI) and AD remain unexplored. In this study, the endogenous γH2AX level was measured, using laser scanning cytometry (LSC) and visual scoring, in lymphocyte nuclei from MCI (n = 18), or AD (n = 20) patients and healthy controls (n = 40). Levels were significantly elevated in nuclei of the AD group compared to the MCI and control groups, and there was a concomitant increase, with a significant trend, from the control group through MCI to the AD group. A significant negative correlation was seen between γH2AX and the mini mental state examination (MMSE) score, when the analysis included all subjects. Receiver Operation Characteristic curves were carried out for different γH2AX parame...

DNA Repair, 2016

Guanine-quadruplexes (G4) are highly stable DNA secondary structures known to mediate gene regula... more Guanine-quadruplexes (G4) are highly stable DNA secondary structures known to mediate gene regulation and to trigger genomic instability events during replication. G4 are known to be associated with DNA damage and we propose that G4 are involved in the ageing disorder mild cognitive impairment (MCI). Lymphocytes were obtained from healthy controls and individuals with MCI. The intensity and frequency of G4 foci as well as γH2AX (a marker of DNA damage) intensity were measured by quantitative immunofluorescence and were correlated with cognitive function and cytokinesis-block micronucleus cytome markers of DNA damage. γH2AX intensity as well as G4 frequency and intensity were significantly elevated in MCI lymphocytes compared to controls. The combined biomarker panel was tested in a predictive statistical model, which improved the demarcation of MCI from controls with 80.3% accuracy. The results obtained from this pilot study showed for the first time that G4 levels are increased with cognitive impairment and thus, may be involved in the early development of Alzheimer&amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s disease possibly via an association with chromosomal DNA damage and DNA double strand breaks.

Www Informahealthcare Com Cmo, Aug 26, 2008

To investigate the efficacy and safety of donepezil in a subgroup of patients with Alzheimer&... more To investigate the efficacy and safety of donepezil in a subgroup of patients with Alzheimer&amp;#39;s disease (AD) of moderate severity from a previous trial. Two hundred and seven patients with moderate AD (standardized Mini-Mental State Examination [sMMSE] score 10-17) were randomized to treatment in this 24-week, double-blind, placebo-controlled trial. Patents received either donepezil, 5 mg/day for the first 28 days and 10 mg/day thereafter according to the clinician&amp;#39;s judgement (n = 102), or placebo (n = 105). The primary outcome measure was the Clinician&amp;#39;s Interview-Based Impression of Change with caregiver input (CIBIC-plus) at week 24 using a last observation carried forward (LOCF) analysis. Baseline patient demographics were similar between treatment groups. Mean age was 74.3 years (range 48-92). Least-squares (LS) mean sMMSE scores at baseline were 13.6 +/- 0.3 for the donepezil group and 13.9 +/- 0.3 for the placebo group. LS mean CIBIC-plus scores for donepezil-treated patients were improved from, or close to, baseline severity at all visits, and were significantly different from placebo at weeks 8, 12, 18, and 24 (week 24 LOCF mean difference = 0.53, p = 0.0003). LS mean change from baseline scores on the sMMSE and Severe Impairment Battery (SIB) for the donepezil group improved throughout the study, and were significantly different from placebo at each visit for the sMMSE (week 24 LOCF mean difference = 2.06, p = 0.0002) and from week 8 for the SIB (week 24 LOCF mean difference = -4.44, p = 0.0026). LS mean change scores on the Disability Assessment for Dementia remained at or above baseline levels throughout the study for the donepezil group, while the placebo group showed a steady decline; treatment differences were significant at each visit (week 24 LOCF mean difference = -9.25, p &amp;lt; 0.0001). LS mean change scores on the Neuropsychiatric Inventory 12-item total improved throughout the study for the donepezil group and were significantly different from placebo at weeks 4 and 24 (week 24 LOCF mean difference = 5.92, p = 0.0022). Eighty-one per cent of donepezil-treated and 89% of placebo-treated patients completed the trial, with 9% and 5%, respectively, discontinuing due to adverse events (AEs). Eighty-two per cent of donepezil-treated and 80% of placebo-treated patients experienced AEs, the majority of which were rated mild in severity and, in general, were similar between treatment groups. The significant treatment responses observed with donepezil in these patients reinforce the findings from earlier studies that show donepezil to have important benefits, compared wih placebo, across functional, cognitive, and behavioral symptoms, with good tolerability, in patients with AD of moderate severity.

Aust N Z J Psychiat, 2000

Australian and New Zealand journal of medicine, 1998

The Medical journal of Australia, Jan 18, 2002

Clinical trials and independent reviews support the use of cholinesterase inhibitors for treating... more Clinical trials and independent reviews support the use of cholinesterase inhibitors for treating the symptoms of patients with mild to moderate Alzheimer's disease (AD). Before initiating cholinesterase inhibitor therapy, patients should be thoroughly assessed, and the diagnosis confirmed, preferably by a specialist. Compliance with cholinesterase inhibitor therapy should be monitored and the response (in global, cognitive, functional and behavioural domains) reassessed after 2-3 months of treatment. Vitamin E may be protective against AD, and therapy with 1000 IU twice daily may be considered. There is insufficient evidence to support the use of other antioxidant agents, anti-inflammatory agents, monoamine oxidase B inhibitors, folate/homocysteine or antihypertensive drugs in patients with AD, or hormone replacement therapy in affected women.

Article abstract—Objective: To investigate the efficacy and safety of donepezil in patients with ... more Article abstract—Objective: To investigate the efficacy and safety of donepezil in patients with moderate to severe AD (standardized Mini-Mental State Examination (sMMSE) scores of 5 to 17; Functional Assessment Staging score 6a t baseline). Methods: Two-hundred ninety patients were randomized to treatment in this 24-week, double-blind, placebo- controlled trial. Patients received either donepezil 5 mg/day for the first 28 days

Environmental and Molecular Mutagenesis, 2014

Loss of genome integrity may be associated with increased risk for neurodegenerative disease. The... more Loss of genome integrity may be associated with increased risk for neurodegenerative disease. The aim of this study was to investigate whether mild cognitive impairment (MCI) or Alzheimer's disease (AD) individuals have increased DNA damage relative to age-and gender-matched controls using the cytokinesisblock micronucleus cytome (CBMN-Cyt) assay. DNA damage was measured as micronuclei (MN), nucleoplasmic bridges (NPB), and nuclear buds (NBUD) in binucleated cells. The assay was performed on blood samples from 80 participants consisting of (i) MCI cases (N 5 20) and age-and gender-matched controls (N 5 20), and (ii) AD cases (N 5 20) and age-and gender-matched controls (N 5 20). There was a significant increase in MCI NBUD frequency (P 5 0.006) relative to controls, which was also observed in male (P 5 0.03) and female (P 5 0.04) subgroups. For AD cases, there were no significant differences in assay biomarkers relative to controls. There was a significant negative correlation between Mini Mental State Examination (MMSE) and (i) MN in all controls, (R 5 20.3, P 5 0.04), and AD cases (R 5 20.4, P 5 0.03), (ii) NPB in all controls, (R 5 20.4, P 5 0.006) and AD cases (R 5 20.5, P 5 0.01), and (iii) NBUD in MCI cases (R 5 20.5, P 5 0.007) and AD cases (R 5 20.7, P 5 0.0002). The results suggest that an increase in lymphocyte CBMN-Cyt DNA damage biomarkers may be associated with cognitive decline. Environ. Mol. Mutagen.

Alzheimer's & Dementia, 2014

Progress in Neurology and Psychiatry, 2010

With the ageing of the population, Alzheimer's disease (AD) represents an individual and public h... more With the ageing of the population, Alzheimer's disease (AD) represents an individual and public health problem of enormous significance. Research is ongoing worldwide in the search for more effective treatments, including drugs to slow or prevent progression in AD. Three cholinesterase inhibitor drugs (donepezil, rivastigmine and galantamine) are currently subsidised in Australia for the management of core cognitive symptoms in mild to moderate AD. Other drugs are available for the secondary management of behavioural and psychological symptoms associated with AD. This article reviews the pharmacological management of AD, treatment efficacy, side effects, and practical issues in drug use.

Neurobiology of Aging, 2000

Cytometry Part A, 2014

Altered cytological parameters in buccal cells from individuals with mild cognitive impairment an... more Altered cytological parameters in buccal cells from individuals with mild cognitive impairment and Alzheimer's disease. Cytometry Part A, 85(8), 698-708], which has been published in final form here. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving.