Search

Purpose: Niemann-Pick type C (NPC) is a cholesterol storage disease characterized by disruption in the endosomal–lysosomal transport system that leads to the accumulation of cholesterol and glycolipids in lysosomes. Developmental cognitive delay and progressive motor and cognitive impairment are characteristic of the disease. Tau accumulation has been reported in some NPC patients. We investigated the presence of tau and Aβ-amyloid deposits in a group of NPC patients and for comparison in age-matched healthy controls (HC). Methods: Eight NPC patients and seven HC were included in the study. Participants underwent tau imaging with 18F-AV1451 and amyloid imaging with 11C-PiB. Both 18F-AV1451 and 11C-PiB standardized uptake value ratios were generated using the cerebellar cortex as the reference region. Associations between imaging results, and clinical and neurocognitive parameters were assessed through nonparametric analyses. Results: All participants were Aβ-negative. Four NPC patients presented with high tau burden in the brain. A 21-year-old female patient and a 40-year-old male patient showed high neocortical tau burden in a pattern different from that observed in patients with Alzheimer's disease, while the same 40-year-old male patient, a 40-year-old female patient and a 50-year-old female patient showed high regional tau burden in the mesial temporal cortex. Spearman's correlation analysis showed an association between tau burden in the mesial temporal lobe and age (p = 0.022), and age at symptom onset (p = 0.009), and between frontotemporal tau and duration of symptoms (p = 0.027). There were no correlations between global and regional tau and cognitive parameters. Conclusion: Four of eight NPC patients showed tau deposition in the brain. The results of our exploratory study suggest that while tau deposits do not affect cognitive performance, tau deposits are associated with measures of disease onset and progression. Further studies in a larger cohort of NPC patients are needed to confirm these initial findings. [ABSTRACT FROM AUTHOR]

Background and purpose Visualization of pathogenic protein aggregates is crucial to elucidate pathomechanisms and to make an accurate diagnosis in many neurodegenerative conditions. Aggregates of the microtubule-binding protein, tau, are one of the most important pathogenic molecules in neurodegenerative disorders. Progressive supranuclear palsy ( PSP) is characterized by the deposition of tau proteins in some specific area such as the basal ganglia and brainstem. We tried to detect tau lesions in the brains of living patients with PSP with a novel positron emission tomography (PET) tracer, [18F] THK-5351, which we have recently developed. Methods Paraffin-embedded brain sections of the patients with PSP were used for autoradiography with [3H] THK-5351 and immunohistochemistry. Nine healthy controls, 13 patients with Alzheimer's disease and three patients with PSP participated in this PET study with [18F] THK-5351. To detect amyloid-β deposition, PET imaging with Pittsburgh compound B was also performed. Results Autoradiography in the brain sections of patients with PSP demonstrated [3H] THK-5351 binding to tau deposits with a high selectivity. Although patients with PSP exhibited no remarkable [18F] THK-5351 retention in the temporal cortex, significantly higher tracer retention was observed in the globus pallidus and midbrain. In contrast, amyloid imaging with Pittsburgh compound B showed no remarkable accumulation in the cerebral cortex of PSP. Conclusions We conclude that [18F] THK-5351 PET can potentially be used to detect the regional brain distribution of tau lesions in PSP, thereby facilitating the differential diagnosis of neurodegenerative disorders associated with tau protein. [ABSTRACT FROM AUTHOR]

Accumulation of β-amyloid (Aβ) in the brain is associated with memory decline in healthy individuals as a prelude to Alzheimer's disease (AD). Genetic factors may moderate this decline. We examined the role of apolipoprotein E (ɛ4 carrier[ɛ4+], ɛ4 non-carrier[ɛ4−]) and brain-derived neurotrophic factor (BDNFVal/Val, BDNFMet) in the extent to which they moderate Aβ-related memory decline. Healthy adults (n=333, Mage=70 years) enrolled in the Australian Imaging, Biomarkers and Lifestyle study underwent Aβ neuroimaging. Neuropsychological assessments were conducted at baseline, 18-, 36- and 54-month follow-ups. Aβ positron emission tomography neuroimaging was used to classify participants as Aβ− or Aβ+. Relative to Aβ−ɛ4−, Aβ+ɛ4+ individuals showed significantly faster rates of cognitive decline over 54 months across all domains (d=0.40-1.22), while Aβ+ɛ4− individuals showed significantly faster decline only on verbal episodic memory (EM). There were no differences in rates of cognitive change between Aβ−ɛ4− and Aβ−ɛ4+ groups. Among Aβ+ individuals, ɛ4+/BDNFMet participants showed a significantly faster rate of decline on verbal and visual EM, and language over 54 months compared with ɛ4−/BDNFVal/Val participants (d=0.90-1.02). At least two genetic loci affect the rate of Aβ-related cognitive decline. Aβ+ɛ4+/BDNFMet individuals can expect to show clinically significant memory impairment after 3 years, whereas Aβ+ɛ4+/BDNFVal/Val individuals can expect a similar degree of impairment after 10 years. Little decline over 54 months was observed in the Aβ− and Aβ+ ɛ4− groups, irrespective of BDNF status. These data raise important prognostic issues in managing preclinical AD, and should be considered in designing secondary preventative clinical trials. [ABSTRACT FROM AUTHOR]

There is no consensus for a blood-based test for the early diagnosis of Alzheimer's disease (AD). Expression profiling of small non-coding RNA's, microRNA (miRNA), has revealed diagnostic potential in human diseases. Circulating miRNA are found in small vesicles known as exosomes within biological fluids such as human serum. The aim of this work was to determine a set of differential exosomal miRNA biomarkers between healthy and AD patients, which may aid in diagnosis. Using next-generation deep sequencing, we profiled exosomal miRNA from serum (N=49) collected from the Australian Imaging, Biomarkers and Lifestyle Flagship Study (AIBL). Sequencing results were validated using quantitative reverse transcription PCR (qRT-PCR; N=60), with predictions performed using the Random Forest method. Additional risk factors collected during the 4.5-year AIBL Study including clinical, medical and cognitive assessments, and amyloid neuroimaging with positron emission tomography were assessed. An AD-specific 16-miRNA signature was selected and adding established risk factors including age, sex and apolipoprotein ɛ4 (APOE ɛ4) allele status to the panel of deregulated miRNA resulted in a sensitivity and specificity of 87% and 77%, respectively, for predicting AD. Furthermore, amyloid neuroimaging information for those healthy control subjects incorrectly classified with AD-suggested progression in these participants towards AD. These data suggest that an exosomal miRNA signature may have potential to be developed as a suitable peripheral screening tool for AD. [ABSTRACT FROM AUTHOR]

The aim of this paper was to investigate the association of three well-recognised dietary patterns with cognitive change over a 3-year period. Five hundred and twenty-seven healthy participants from the Australian Imaging, Biomarkers and Lifestyle study of ageing completed the Cancer Council of Victoria food frequency questionnaire at baseline and underwent a comprehensive neuropsychological assessment at baseline, 18 and 36 months follow-up. Individual neuropsychological test scores were used to construct composite scores for six cognitive domains and a global cognitive score. Based on self-reported consumption, scores for three dietary patterns, (1) Australian-style Mediterranean diet (AusMeDi), (2) western diet and (3) prudent diet were generated for each individual. Linear mixed model analyses were conducted to examine the relationship between diet scores and cognitive change in each cognitive domain and for the global score. Higher baseline adherence to the AusMeDi was associated with better performance in the executive function cognitive domain after 36 months in apolipoprotein E (APOE) ɛ4 allele carriers (P<0.01). Higher baseline western diet adherence was associated with greater cognitive decline after 36 months in the visuospatial cognitive domain in APOE ɛ4 allele non-carriers (P<0.01). All other results were not significant. Our findings in this well-characterised Australian cohort indicate that adherence to a healthy diet is important to reduce risk for cognitive decline, with the converse being true for the western diet. Executive function and visuospatial functioning appear to be particularly susceptible to the influence of diet. [ABSTRACT FROM AUTHOR]

Dementia is a global epidemic with Alzheimer's disease (AD) being the leading cause. Early identification of patients at risk of developing AD is now becoming an international priority. Neocortical Aβ (extracellular β-amyloid) burden (NAB), as assessed by positron emission tomography (PET), represents one such marker for early identification. These scans are expensive and are not widely available, thus, there is a need for cheaper and more widely accessible alternatives. Addressing this need, a blood biomarker-based signature having efficacy for the prediction of NAB and which can be easily adapted for population screening is described. Blood data (176 analytes measured in plasma) and Pittsburgh Compound B (PiB)-PET measurements from 273 participants from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study were utilised. Univariate analysis was conducted to assess the difference of plasma measures between high and low NAB groups, and cross-validated machine-learning models were generated for predicting NAB. These models were applied to 817 non-imaged AIBL subjects and 82 subjects from the Alzheimer's Disease Neuroimaging Initiative (ADNI) for validation. Five analytes showed significant difference between subjects with high compared to low NAB. A machine-learning model (based on nine markers) achieved sensitivity and specificity of 80 and 82%, respectively, for predicting NAB. Validation using the ADNI cohort yielded similar results (sensitivity 79% and specificity 76%). These results show that a panel of blood-based biomarkers is able to accurately predict NAB, supporting the hypothesis for a relationship between a blood-based signature and Aβ accumulation, therefore, providing a platform for developing a population-based screen. [ABSTRACT FROM AUTHOR]

Testosterone and gonadotropins have been associated with cognitive decline in men and the modulation of β amyloid (Aβ) metabolism. The relatively few studies that have investigated whether changes in one or a combination of these hormones influence Aβ levels have focused primarily on plasma Aβ1-40 and not on the more pathogenic Aβ1-42. Currently, no study has investigated whether these hormones are associated with an increase in brain amyloid deposition, ante mortem. Through the highly characterised Australian imaging, biomarkers and lifestyle study, we have determined the impact of these hormones on plasma Aβ levels and brain amyloid burden (Pittsburgh compound B (PiB) retention). Spearman's rank correlation and linear regression analysis was carried out across the cohort and within subclassifications. Luteinizing hormone (LH) was the only variable shown, in the total cohort, to have a significant impact on plasma Aβ1-40 and Aβ1-42 levels (beta=0.163, P<0.001; beta=0.446, P<0.001). This held in subjective memory complainers (SMC) (Aβ1-40; beta=0.208, P=0.017; Aβ1-42; beta=0.215, P=0.017) but was absent in mild cognitive impairment (MCI) and Alzheimer's disease (AD) groups. In SMC, increased frequency of the APOE-ɛ4 allele (beta=0.536, P<0.001) and increasing serum LH levels (beta=0.421, P=0.004) had a significant impact on PiB retention. Whereas in MCI, PiB retention was associated with increased APOE-ɛ4 allele copy number (beta=0.674, P<0.001) and decreasing calculated free testosterone (beta=−0.303, P=0.043). These findings suggest a potential progressive involvement of LH and testosterone in the early preclinical stages of AD. Furthermore, these hormones should be considered while attempting to predict AD at these earliest stages of the disease. [ABSTRACT FROM AUTHOR]

Objective As large-scale medical imaging studies are becoming more common, there is an increasing reliance on automated software to extract quantitative information from these images. As the size of the cohorts keeps increasing with large studies, there is a also a need for tools that allow results from automated image processing and analysis to be presented in a way that enables fast and efficient quality checking, tagging and reporting on cases in which automatic processing failed or was problematic. Materials and methods MilxXplore is an open source visualization platform, which provides an interface to navigate and explore imaging data in a web browser, giving the end user the opportunity to perform quality control and reporting in a user friendly, collaborative and efficient way. Discussion Compared to existing software solutions that often provide an overview of the results at the subject's level, MilxXplore pools the results of individual subjects and time points together, allowing easy and efficient navigation and browsing through the different acquisitions of a subject over time, and comparing the results against the rest of the population. Conclusions MilxXplore is fast, flexible and allows remote quality checks of processed imaging data, facilitating data sharing and collaboration across multiple locations, and can be easily integrated into a cloud computing pipeline. With the growing trend of open data and open science, such a tool will become increasingly important to share and publish results of imaging analysis. [ABSTRACT FROM AUTHOR]

Previous studies suggest physical activity improves cognition and lowers Alzheimer's disease (AD) risk. However, key AD pathogenic factors that are thought to be influenced by physical activity, particularly plasma amyloid-β (Aβ) and Aβ brain load, have yet to be thoroughly investigated. The objective of this study was to determine if plasma Aβ and amyloid brain deposition are associated with physical activity levels, and whether these associations differed between carriers and non-carriers of the apolipoprotein E (APOE) ɛ4 allele. Five-hundred and forty six cognitively intact participants (aged 60-95 years) from the Australian Imaging, Biomarkers and Lifestyle Study of Ageing (AIBL) were included in these analyses. Habitual physical activity levels were measured using the International Physical Activity Questionnaire (IPAQ). Serum insulin, glucose, cholesterol and plasma Aβ levels were measured in fasting blood samples. A subgroup (n=116) underwent 11C-Pittsburgh compound B (PiB) positron emission tomography (PET) scanning to quantify brain amyloid load. Higher levels of physical activity were associated with higher high density lipoprotein (HDL) (P=0.037), and lower insulin (P<0.001), triglycerides (P=0.019) and Aβ1−42/1−40 ratio (P=0.001). After stratification of the cohort based on APOE ɛ4 allele carriage, it was evident that only non-carriers received the benefit of reduced plasma Aβ from physical activity. Conversely, lower levels of PiB SUVR (standardised uptake value ratio) were observed in higher exercising APOE ɛ4 carriers. Lower plasma Aβ1−42/1−40 and brain amyloid was observed in those reporting higher levels of physical activity, consistent with the hypothesis that physical activity may be involved in the modulation of pathogenic changes associated with AD. [ABSTRACT FROM AUTHOR]

Background:The prognostic value of subjective memory complaints (SMCs) in the diagnosis of dementia of the Alzheimer's type is unclear. While some studies have found an association between SMCs and cognitive decline, many have found a stronger association with depression, which raises questions about their diagnostic utility.Methods:We examined the cross-sectional association between SMC severity (as measured using the MAC-Q, a brief SMC questionnaire) and affect, memory, and Alzheimer's disease (AD) biomarkers (β-amyloid deposition and the apolipoprotein E ε4 (APOEε4) allele) in healthy elderly controls (HC; M = 78.74 years, SD = 6.7) and individuals with mild cognitive impairment (MCI; M = 72.74 years, SD = 8.8). We analyzed a subset of individuals drawn from the Australian Imaging Biomarkers and Lifestyle (AIBL) Study of Aging.Results:SMCs were more severe in MCI patients than in HCs. SMC severity was related to affective variables and the interaction between age and group membership (HC/MCI). Within the HC group, SMC severity was related to affective variables only, while severity correlated only with age in the MCI group. SMCs were not related to cognitive variables or AD biomarkers.Conclusion:SMCs were related to solely by poorer mood (greater depressive and anxious symptomatology) in the cognitively healthy elderly however mean levels were subclinical. This finding argues for the assessment of affective symptomatology in conjunction with cognitive assessment in elderly memory complainers. Future AIBL research will focus on assessing other AD biomarkers, such as brain atrophy and Aβ plasma markers, in relation to complaint severity. Once our 36-month follow-up data are collected, we propose to assess whether SMCs can predict future cognitive decline. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Brain amyloid imaging using positron emission tomography (PET) is of increasing importance in the premortem evaluation of dementias, particularly in relation to Alzheimer disease (AD). The purpose of this study was to explore the premortem diagnostic utility of 11C-PiB PET in sporadic Creutzfeldt–Jakob disease (CJD). METHODS: Two patients, 72 and 59 years old, underwent evaluation for rapidly progressive cognitive decline, dying after illness durations of 5 and 7 months, respectively. As part of their comprehensive assessment, 18F-FDG PET and 11C-PiB PET studies were performed approximately 2–4 weeks prior to death, and the brain regional distributions compared with those from cohorts of healthy controls (HC) and AD patients. RESULTS: Routine investigations, including brain MRI scans, revealed changes typical of sporadic CJD, with the diagnosis confirmed at autopsy in both patients. The 18F-FDG PET showed global hypometabolism in one patient and thalamic and frontal hypometabolism with unexpected hypermetabolism in the dentate nuclei of the cerebellum in the other. Neither patient displayed cerebral cortical 11C-PiB PET retention above the levels observed in HC. CONCLUSIONS: No grey-matter 11C-PiB retention was observed in two pathologically confirmed cases of typical sporadic CJD. We speculate that low PrP plaque density and small plaque size, as well as a relatively low affinity of the radioligand, explain the absence of 11C-PiB retention. More studies to validate this hypothesis are warranted. [ABSTRACT FROM AUTHOR]

Neuropathological studies have reported varying amounts of amyloid pathology in dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD). [11C]PIB positron emission tomography (PET) is a marker of brain amyloid deposition. The aim of this study was to quantify in vivo amyloid load in DLB and PDD compared with control subjects and subjects with Parkinson's disease (PD) without dementia. 13 DLB, 12 PDD, 10 PD subjects and 41 age matched controls (55-82 years) were recruited. Each subject underwent clinical evaluation, neuropsychological assessment, Ti and T2 MRI, and [1 1C]PIB PET. The amyloid load was estimated from 60-90' target region:cerebellar [11C]PIB uptake ratios. Object maps were created by segmenting individual MRIs and convolving them with a probabilistic atlas. Cortical [11C]PIB uptake was assessed by region of interest analysis. The DLB cohort showed a significant increase in mean brain [11C]PIB uptake and individuafly 11 of the 13 subjects with DLB had a significantly increased amyloid load. In contrast, mean [11C]PIB uptake was normal for the PDD group although two of 12 patients with PDD individually showed a raised amyloid load. Where significant increases in [11 C]PIB uptake were found, it was increased in cortical association areas, cingulate and striatum. None of the subjects with PD showed significantly raised cortical [11 C]PIB uptake. This study suggests that amyloid load is significantly raised in over 80% of subjects with DLB, while amyloid pathology is infrequent in PDD. These in vivo PET findings suggest that the presence of amyloid in DLB could contribute to the rapid progression of dementia in this condition and that anti-amyloid strategies may be relevant. [ABSTRACT FROM AUTHOR]

Explores the genetic causes of dementia. Explanation on the onset of familial Alzheimer's disease; Signs and symptoms of familial diffuse Lewy body dementia; Pathology underlying dementia in Parkinson's disease.

Several genetic disorders, though rare, are associated or present with dementia. Developments in the field of genetics are contributing to clarify and expand our knowledge of the complex physiopathological mechanisms leading to neurodegeneration and cognitive decline. Disorders associated with misfolded and aggregated proteins and lipid, metal or energy metabolism are examples of the multifarious disease processes converging in the clinical features of dementia, either as its predominant feature, as in cases of Alzheimer's disease (AD) or frontotemporal dementia (FTD), or as part of a cohort of accompanying or late-developing symptoms, as in Parkinson's disease (PD) or amyotrophic lateral sclerosis with dementia (ALS-D). Awareness of these disorders, allied with recent advances in genetic, biochemical and neuroimaging techniques, may lead to early diagnosis, successful treatment and better prognosis. [ABSTRACT FROM AUTHOR]

The yield of ictal, postictal, and interictal SPECT was compared in the localisation of seizure foci in 177 patients with partial epilepsy. In 119 patients with known unilateral temporal lobe epilepsy ictal SPECT (97% correct localisation) was superior to postictal SPECT (71% correct), which was better than interictal studies (48% correct). Similarly, in cases of known or suspected extratemporal epilepsy the yield of ictal SPECT studies was high (92%). By contrast, the yield of postictal studies was much lower (46%) and usually only very early postictal studies were diagnostic. Interictal SPECT was of little value. The accuracy of ictal SPECT in localising temporal lobe seizures is now well established. Extratemporal seizures are often brief and difficult to localise. This report shows that ictal SPECT also has a high diagnostic yield in a wide range of extratemporal epilepsies. The brevity of many extratemporal seizures means that true ictal SPECT examinations can be difficult to achieve, but the high diagnostic yield justifies the special organisational effort needed to obtain such studies. [ABSTRACT FROM AUTHOR]

The ictal increase of regional cerebral blood flow has yet to be fully utilised in the investigation of focal seizures. Although single photon emission tomography (SPECT) is being increasingly used in the localisation of epileptic foci, the evolution and time courses of the peri-ictal perfusion changes have yet to be clarified. We performed serial SPECT studies in the interictal, ictal and immediate postictal states in 12 patients with refractory temporal lobe epilepsy to define the patterns and duration of peri-ictal cerebral blood flow changes. Visual analysis showed a constant pattern of unilateral global increases in temporal lobe perfusion during seizures which suddenly switched to a pattern of relative mesial temporal (hippocampal) hyperperfusion and lateral temporal hypoperfusion in the immediate postictal period. Quantitative analysis confirmed the visual assessment. Lateral temporal cortex ictal/normal side to side ratios were increased by mean 35.1% (95% confidence interval 21.8% to 48.4%) more in the ictal studies than in the interictal studies and mesial temporal cortex ratios increased by mean 30.8% (22.4% to 39.2%). In the postictal state, however, lateral temporal ratios were reduced by mean 7.7% (-15.8% to 0.4%) compared with interictal values, whereas mesial temporal perfusion was maintained compared with the interictal studies. These observations provide critical information for interpreting scans which can be used in the localisation of epileptic foci. This postictal switch in blood flow patterns may reflect the underlying metabolic processes of neuronal activation and recovery and have implications for understanding the neurobiology of human epileptic seizures. [ABSTRACT FROM AUTHOR]