Tau Positron Emission Tomography Binding Is Not Elevated in HIV-Infected Individuals.

Regional standardized uptake value ratios (SUVRs) for tau positron emission tomography (PET) were compared among 19 cognitively normal human immunodeficiency virus (HIV)-negative control individuals, 20 HIV-negative patients with symptomatic Alzheimer disease, 15 cognitively normal HIV-positive individuals, and 17 cognitively impaired HIV-positive individuals. Among the HIV-positive participants, the correlation between tau PET SUVRs and both HIV loads and CD4+ T-cell counts (recent and nadir). Tau PET SUVRs were similar for HIV-positive individuals and HIV-negative control individuals. Individuals with symptomatic Alzheimer disease had elevated tau PET SUVRs. Tau PET SUVRs did not correlate with impairment or clinical markers in HIV-positive participants. Older HIV-positive individuals are not at increased risk of tau-mediated neurodegeneration.

Homocysteine as a predictor of cognitive decline in Alzheimer's disease.

OBJECTIVE: Moderately elevated levels of plasma total homocysteine are associated with an increased risk of developing Alzheimer's disease. We have tested whether baseline concentrations of homocysteine relate to the subsequent rate of cognitive decline in patients with established Alzheimer's disease (AD). METHODS: In 97 patients with AD, 73 pathologically-confirmed, we analysed the decline of global cognitive test scores (CAMCOG) over time from the first assessment for at least three 6-monthly visits up to a maximum of 9.5 years (in total 689 assessments). Non-linear mixed-effects statistical models were used. RESULTS: Baseline homocysteine levels showed a concentration-response relationship with the subsequent rate of decline in CAMCOG scores: the higher the homocysteine, the faster the decline. The relationship was significant in patients aged < 75 years who had not suffered a prior stroke. For example, in patients aged 65 years with a baseline homocysteine of 14 micromol/L, the decline from a CAMCOG score of 88 to a score of 44 occurred 19.2 (95% CI 6.8, 31.6) months earlier than in patients with a baseline homocysteine of 10 micromol/L. CONCLUSIONS: Raised homocysteine concentrations within the normal range among the elderly strongly relate to the rate of global cognitive decline in patients with Alzheimer disease. Plasma homocysteine can readily be lowered by B-vitamin treatment and trials should be carried out to see if such treatments can slow the rate of cognitive decline in relatively young patients with Alzheimer disease.

Imaging biomarkers in neurodegeneration: current and future practices.

There is an increasing role for biological markers (biomarkers) in the understanding and diagnosis of neurodegenerative disorders. The application of imaging biomarkers specifically for the in vivo investigation of neurodegenerative disorders has increased substantially over the past decades and continues to provide further benefits both to the diagnosis and understanding of these diseases. This review forms part of a series of articles which stem from the University College London/University of Gothenburg course "Biomarkers in neurodegenerative diseases". In this review, we focus on neuroimaging, specifically positron emission tomography (PET) and magnetic resonance imaging (MRI), giving an overview of the current established practices clinically and in research as well as new techniques being developed. We will also discuss the use of machine learning (ML) techniques within these fields to provide additional insights to early diagnosis and multimodal analysis.

Loss of white matter integrity reflects tau accumulation in Alzheimer disease defined regions.

OBJECTIVE: White matter (WM) projections were assessed from Alzheimer disease (AD) gray matter regions associated with ß-amyloid (Aß), tau, or neurodegeneration to ascertain relationship between WM structural integrity with Aß and/or tau deposition. METHODS: Participants underwent diffusion tensor imaging (DTI), PET Aß ([18F]AV-45 [florbetapir]), and PET tau ([18F]AV-1451 [flortaucipir]) imaging. Probabilistic WM summary and individual tracts were created from either a composite or individual gray matter seed regions derived from Aß, tau, and neurodegeneration. Linear regressions were performed for Aß, age, tau and WM hyperintensities (WMH) to predict mean diffusivity (MD) or fractional anisotropy (FA) from the corresponding WM summaries or tracts. RESULTS: Our cohort was composed of 59 cognitively normal participants and 10 cognitively impaired individuals. Aß was not associated with DTI metrics in WM summary or individual tracts. Age and WMH strongly predicted MD and FA in several WM regions, with tau a significant predictor of MD only in the anterior temporal WM. CONCLUSION: Tau, not Aß, was associated with changes in anterior temporal WM integrity. WMH, a proxy for vascular damage, was strongly associated with axonal damage, but tau independently contributed to the model, suggesting an additional degenerative mechanism within tracts projecting from regions vulnerable to AD pathology. WM decline was associated with early tau accumulation, and further decline may reflect tau propagation in more advanced stages of AD.

In vivo [18F]-AV-1451 tau-PET imaging in sporadic Creutzfeldt-Jakob disease.

OBJECTIVE: To determine whether specific patterns of [18F]-AV-1451 tau-PET retention are observed in patients with autopsy-proven sporadic Creutzfeldt-Jakob disease (CJD). METHODS: In vivo [18F]-AV-1451 PET neuroimaging was performed in 5 patients with sporadic CJD (median age, 66 years [63-74]), and results were compared to cognitively normal (CN) persons (n = 44; median age, 68 years [63-74]) and to participants with very mild Alzheimer disease (AD) dementia (n = 8; median age, 77 years [63-90]). Autopsy was completed in all patients with CJD, confirming the clinical diagnosis and permitting characterization of AD neuropathologic change (ADNC). RESULTS: All patients with CJD presented with rapidly progressive dementia, typical magnetic resonance brain imaging changes, and elevated CSF total tau (median = 6,519; range = 1,528-13,240 pg/mL). Death occurred within 9 months of symptom onset, with a median 1 month (0.2-3.3) interval from [18F]-AV-1451 PET to autopsy. No unique pattern of [18F]-AV-1451 retention was observed on visual inspection. Summary standardized uptake value ratios in patients with CJD (1.17, 1.08-1.36) were indistinguishable from CN persons (1.14, 0.84-1.54; p = 0.6), and well below those of participants with AD (2.23, 1.60-3.04; p ≤ 0.01). [18F]-AV-1451 retention in patients with CJD and CN persons was similar in brain areas frequently affected in AD and CJD. Neuropathologic analysis confirmed the clinical diagnosis in all patients with CJD. Four patients with CJD also had low-level ADNC (A1B1C0); one patient had intermediate-level ADNC (A2B2C1/2). CONCLUSION: Increased [18F]-AV-1451 retention was not observed in patients with rapidly progressive dementia due to sporadic CJD. The [18F]-AV-1451 PET tracer maintains good specificity for paired helical tau filaments associated with AD dementia.

Susceptibility groups for Alzheimer's disease (OPTIMA cohort): integration of gene variants and biochemical factors.

Information on gene variants and blood levels (APOE, BCHE-K, TF-C2, HFE-D, HFE-Y, ACE I/D, AR1; homocysteine, folate and vitamin B(12)) is available for participants in the Oxford Project to Investigate Memory and Ageing (OPTIMA) cohort (n=575). This information identified four risk sets for Alzheimer's disease (AD) using grade of membership analysis (GoM). Graded membership scores that relate individuals to each set are automatically generated. Sets I and III had low intrinsic risk. Set II had high intrinsic risk associated with multiple gene variants, e.g., APOE44/34. Set IV also had high intrinsic risk demonstrating low folate and B(12) levels. Membership in the high intrinsic risk sets was summed, coded as either close versus not close (>or=0.80 versus <0.80) and input into logistic models to predict relative risk: close resemblance multiplied risk 80-fold for possible AD before age 65 and 55-fold for probable or definite AD at ages 65-74. These findings implicate both biochemical and genetic factors in the risk for AD and further support dietary supplementation with folate and vitamin B(12) as a potential means to delay the onset of AD and/or its rate of progression.

Arterial spin labelling shows functional depression of non-lesion tissue in chronic Wernicke's aphasia.

Behavioural impairment post-stroke is a consequence of structural damage and altered functional network dynamics. Hypoperfusion of intact neural tissue is frequently observed in acute stroke, indicating reduced functional capacity of regions outside the lesion. However, cerebral blood flow (CBF) is rarely investigated in chronic stroke. This study investigated CBF in individuals with chronic Wernicke's aphasia (WA) and examined the relationship between lesion, CBF and neuropsychological impairment. Arterial spin labelling CBF imaging and structural MRIs were collected in 12 individuals with chronic WA and 13 age-matched control participants. Joint independent component analysis (jICA) investigated the relationship between structural lesion and hypoperfusion. Partial correlations explored the relationship between lesion, hypoperfusion and language measures. Joint ICA revealed significant differences between the control and WA groups reflecting a large area of structural lesion in the left posterior hemisphere and an associated area of hypoperfusion extending into grey matter surrounding the lesion. Small regions of remote cortical hypoperfusion were observed, ipsilateral and contralateral to the lesion. Significant correlations were observed between the neuropsychological measures (naming, repetition, reading and semantic association) and the jICA component of interest in the WA group. Additional ROI analyses found a relationship between perfusion surrounding the core lesion and the same neuropsychological measures. This study found that core language impairments in chronic WA are associated with a combination of structural lesion and abnormal perfusion in non-lesioned tissue. This indicates that post-stroke impairments are due to a wider disruption of neural function than observable on structural T1w MRI.

Frontotemporal lobar degeneration and social behaviour: Dissociation between the knowledge of its consequences and its conceptual meaning.

Inappropriate social behaviour is an early symptom of frontotemporal lobar degeneration (FTLD) in both behavioural variant frontotemporal dementia (bvFTD) and semantic dementia (SD) subtypes. Knowledge of social behaviour is essential for appropriate social conduct. The superior anterior temporal lobe (ATL) has been identified as one key neural component for the conceptual knowledge of social behaviour, but it is unknown whether this is dissociable from knowledge of the consequences of social behaviour. Here, we used a newly-developed test of knowledge about long-term and short-term consequences of social behaviour to investigate its impairment in patients with FTLD relative to a previously-developed test of social conceptual knowledge. We included 19 healthy elderly control participants and 19 consecutive patients with features of bvFTD or SD and defined dissociations as performance differences between tasks for each patient (Bonferroni-corrected p < .05). Knowledge of long-term consequences was selectively impaired relative to short-term consequences in five patients and the reverse dissociation occurred in one patient. Six patients showed a selective impairment of social concepts relative to long-term consequences with the reverse dissociation occurring in one patient. These results corroborate the hypothesis that knowledge of long-term consequences of social behaviour is dissociable from knowledge of short-term consequences, as well as of social conceptual knowledge. Confirming our hypothesis, we found that patients with more marked grey matter (GM) volume loss in frontopolar relative to right superior ATL regions of interest exhibited poorer knowledge of the long-term consequences of social behaviour relative to the knowledge of its conceptual meaning and vice versa (n = 15). These findings support the hypothesis that frontopolar and ATL regions represent distinct aspects of social knowledge. This suggests that rather than being unable to suppress urges to behave inappropriately, FTLD patients often lose the knowledge of what appropriate social behaviour is and can therefore not be expected to behave accordingly.

Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer's disease.

We sought to identify new susceptibility loci for Alzheimer's disease through a staged association study (GERAD+) and by testing suggestive loci reported by the Alzheimer's Disease Genetic Consortium (ADGC) in a companion paper. We undertook a combined analysis of four genome-wide association datasets (stage 1) and identified ten newly associated variants with P ≤ 1 × 10(-5). We tested these variants for association in an independent sample (stage 2). Three SNPs at two loci replicated and showed evidence for association in a further sample (stage 3). Meta-analyses of all data provided compelling evidence that ABCA7 (rs3764650, meta P = 4.5 × 10(-17); including ADGC data, meta P = 5.0 × 10(-21)) and the MS4A gene cluster (rs610932, meta P = 1.8 × 10(-14); including ADGC data, meta P = 1.2 × 10(-16)) are new Alzheimer's disease susceptibility loci. We also found independent evidence for association for three loci reported by the ADGC, which, when combined, showed genome-wide significance: CD2AP (GERAD+, P = 8.0 × 10(-4); including ADGC data, meta P = 8.6 × 10(-9)), CD33 (GERAD+, P = 2.2 × 10(-4); including ADGC data, meta P = 1.6 × 10(-9)) and EPHA1 (GERAD+, P = 3.4 × 10(-4); including ADGC data, meta P = 6.0 × 10(-10)).

Concordant association of insulin degrading enzyme gene (IDE) variants with IDE mRNA, Abeta, and Alzheimer's disease.

BACKGROUND: The insulin-degrading enzyme gene (IDE) is a strong functional and positional candidate for late onset Alzheimer's disease (LOAD). METHODOLOGY/PRINCIPAL FINDINGS: We examined conserved regions of IDE and its 10 kb flanks in 269 AD cases and 252 controls thereby identifying 17 putative functional polymorphisms. These variants formed eleven haplotypes that were tagged with ten variants. Four of these showed significant association with IDE transcript levels in samples from 194 LOAD cerebella. The strongest, rs6583817, which has not previously been reported, showed unequivocal association (p = 1.5x10(-8), fold-increase = 2.12,); the eleven haplotypes were also significantly associated with transcript levels (global p = 0.003). Using an in vitro dual luciferase reporter assay, we found that rs6583817 increases reporter gene expression in Be(2)-C (p = 0.006) and HepG2 (p = 0.02) cell lines. Furthermore, using data from a recent genome-wide association study of two Croatian isolated populations (n = 1,879), we identified a proxy for rs6583817 that associated significantly with decreased plasma Abeta40 levels (ss = -0.124, p = 0.011) and total measured plasma Abeta levels (b = -0.130, p = 0.009). Finally, rs6583817 was associated with decreased risk of LOAD in 3,891 AD cases and 3,605 controls. (OR = 0.87, p = 0.03), and the eleven IDE haplotypes (global p = 0.02) also showed significant association. CONCLUSIONS: Thus, a previously unreported variant unequivocally associated with increased IDE expression was also associated with reduced plasma Abeta40 and decreased LOAD susceptibility. Genetic association between LOAD and IDE has been difficult to replicate. Our findings suggest that targeted testing of expression SNPs (eSNPs) strongly associated with altered transcript levels in autopsy brain samples may be a powerful way to identify genetic associations with LOAD that would otherwise be difficult to detect.

PSEN1 polymorphisms alter the rate of cognitive decline in sporadic Alzheimer's disease patients.

Mutations in amyloid precursor protein (APP) and presenilin (PSEN) genes are known to cause familial early-onset Alzheimer's disease (AD), which account for around 5% of AD cases. Genetic associations for the remaining "sporadic" cases, other than the risks associated with the apolipoprotein (APOE) epsilon4 allele are currently not fully established. The aim of this study was to investigate whether single nucleotide polymorphisms (SNPs) in PSEN1 are associated with a modified risk for sporadic AD or a modified disease phenotype. Eight tag SNPs were identified using linkage disequilibrium (LD) data from the International HapMap project providing coverage of the entire PSEN1 gene. These SNPs were investigated for AD susceptibility in a case-control haplotype association study (N=714) and for genotype-specific effects on cognitive performance in AD patients (N=169) using non-linear mixed effects modelling. Replication of a mild associated-risk of an intronic PSEN1 polymorphism with AD was achieved (P=0.03). No other single SNPs or haplotypes were associated with AD risk. However, 3 SNPs were associated with an altered rate of cognitive decline underlining their role as genetic modifiers of disease.

Regulatory region single nucleotide polymorphisms of the apolipoprotein E gene and the rate of cognitive decline in Alzheimer's disease.

The aim of this study was to investigate whether single nucleotide polymorphisms (SNPs) in the regulatory regions of the apolipoprotein E (APOE) gene modify the well-established epsilon4-associated risk for Alzheimer's disease (AD). Sequencing of the APOE gene regulatory regions revealed four previously reported promoter SNPs and one novel SNP in the previously described macrophage enhancer (ME.1). In addition, we also studied the two classic allelic missense SNPs that define epsilon2/epsilon3/epsilon4 status in a case-control association study. Analysis of pair-wise linkage disequilibrium (LD) of the five regulatory region SNPs with classic APOE SNPs revealed a previously unreported 7 kb LD block covering the entire APOE gene, part of the promoter and 3' enhancer region. We report here that in a case-control association study (N=719) of the seven SNPs, the genotype at codon 112 captures all the information required to assess disease risk. To explore correlations with quantitative traits, 169 patients were studied in whom rates of cognitive decline were available. In addition to the epsilon4 allele, two regulatory region SNPs were associated with the rate of cognitive decline in AD patients. This study highlights the effect of APOE gene variation on risk of AD and rate of cognitive decline and demonstrates that a single SNP, which confers epsilon4 status, captures all of the risk of developing AD but two SNPs in the regulatory region may affect the rate of cognitive decline in AD patients.