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1.  C9orf72 immunohistochemistry in Alzheimer's disease 
Mutation in chromosome 9 open reading frame 72 (C9orf72) is a major genetic cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), referred to as C9FTD/ALS. The function of the protein is currently unknown, and the pathomechanism of C9FTD/ALS remains to be elucidated. The study by Satoh and colleagues in the previous issue of Alzheimer's Research & Therapy presents important new findings on C9orf72 protein expression in neurodegenerative disorders along with characterization of C9orf72 antibodies.
doi:10.1186/alzrt140
PMCID: PMC3580394  PMID: 23014271
3.  Separation of cognitive domains to improve prediction of progression from mild cognitive impairment to Alzheimer's disease 
Addressing causes of heterogeneity in cognitive outcomes is becoming more critical as Alzheimer's disease (AD) research focuses on earlier disease. One of the causes of this heterogeneity may be that individuals with deficiencies in different cognitive domains may perform similarly on a neuropsychological (NP) test for very different reasons. Tatsuoka and colleagues have applied a Bayesian model in order to integrate knowledge about cognitive domains relevant to each NP test with the observed outcomes from the Alzheimer's Disease Neuroimaging Initiative (ADNI) mild cognitive impairment data. This approach resulted in better prediction of AD diagnosis than more traditional approaches.
doi:10.1186/alzrt176
PMCID: PMC3707047  PMID: 23680123
4.  Assessment of psychiatric changes in C9ORF72 frontotemporal dementia 
Recent neuroimaging evidence highlights cerebellar atrophy as one feature of frontotemporal dementia (FTD) with C9ORF72 mutation. Interestingly, C9ORF72 patients do not present with classic cerebellar symptoms, such as ataxia, but have instead a higher incidence of psychiatric changes compared to sporadic FTD. To date there exists no objective tool to assess such psychiatric changes due to cerebellar dysfunction. In the previous edition of Alzheimer's Research & Therapy, Downey and colleagues present a novel task, including a new apparatus, that targets such psychiatric disturbances. In the task participants are required to make self-other attributions, which have been shown to be dependent on the cerebellum in functional neuroimaging in healthy subjects. The data Downey and colleagues present on a case of C9ORF72 compared to four age-matched controls reveal that the patient shows impaired judgement only for other induced actions. These findings highlight the sensitivity of such a simple task to tap into potential cerebellar dysfunction in C9ORF72. Future studies are needed to now to determine whether this task is mediated solely via the cerebellum and is disease specific to C9ORF72. Nevertheless, this study is an important first step in the development of cerebellar-specific tasks tapping into psychiatric dysfunction, which will inform future diagnosis and disease management of patients with cerebellar dysfunction, and in particular C9ORF72.
doi:10.1186/alzrt152
PMCID: PMC3580458  PMID: 23269019
5.  Resistant to amyloid-β or just waiting for disease to happen? 
The post-mortem finding of abundant intracerebral accumulation of amyloid-β (Aβ) in the cerebral cortex of some people who develop minimal neurofibrillary pathology and remain cognitively intact until death (so-called pathological aging, or PA) challenges the orthodox view of the pathogenesis of Alzheimer's disease (AD). This issue of Alzheimer's Research & Therapy reports a study by Moore and colleagues, of the McKnight Brain Institute (Gainesville, FL, USA) and the Mayo Clinic College of Medicine (Jacksonville, FL, USA), who have performed the most detailed analysis to date of the levels and types of Aβ that accumulate in such cases. Although the levels of the different forms of Aβ in prefrontal cortex from patients with AD tended to be higher than those from patients with PA, the authors found extensive overlap between the two groups and suggest that PA is likely to represent a prodromal stage of AD. It is also possible that the quantity of Aβ is less important than the extent to which it accumulates intraneuronally or that some people are resistant to its effects - perhaps because of genetically determined differences in the inflammatory and astrocytic reactions to Aβ. The study emphasizes the continuing importance of careful human clinical and post-mortem studies in elucidating the pathogenesis of this disease.
doi:10.1186/alzrt122
PMCID: PMC3506933  PMID: 22643124
8.  Imaging as a biomarker in drug discovery for Alzheimer’s disease: is MRI a suitable technology? 
This review provides perspectives on the utility of magnetic resonance imaging (MRI) as a neuroimaging approach in the development of novel treatments for Alzheimer’s disease. These considerations were generated in a roundtable at a recent Wellcome Trust meeting that included experts from academia and industry. It was agreed that MRI, either structural or functional, could be used as a diagnostic, for assessing worsening of disease status, for monitoring vascular pathology, and for stratifying clinical trial populations. It was agreed also that MRI implementation is in its infancy, requiring more evidence of association with the disease states, test-retest data, better standardization across multiple clinical sites, and application in multimodal approaches which include other imaging technologies, such as positron emission tomography, electroencephalography, and magnetoencephalography.
doi:10.1186/alzrt276
PMCID: PMC4255417  PMID: 25484927
9.  An integrated multi-study analysis of intra-subject variability in cerebrospinal fluid amyloid-β concentrations collected by lumbar puncture and indwelling lumbar catheter 
Introduction
Amyloid-β (Aβ) has been investigated as a diagnostic biomarker and therapeutic drug target. Recent studies found that cerebrospinal fluid (CSF) Aβ fluctuates over time, including as a diurnal pattern, and increases in absolute concentration with serial collection. It is currently unknown what effect differences in CSF collection methodology have on Aβ variability. In this study, we sought to determine the effect of different collection methodologies on the stability of CSF Aβ concentrations over time.
Methods
Grouped analysis of CSF Aβ levels from multiple industry and academic groups collected by either lumbar puncture (n=83) or indwelling lumbar catheter (n=178). Participants were either placebo or untreated subjects from clinical drug trials or observational studies. Participants had CSF collected by lumbar puncture or lumbar catheter for quantitation of Aβ concentration by enzyme linked immunosorbent assay. Data from all sponsors was converted to percent of the mean for Aβ40 and Aβ42 for comparison. Repeated measures analysis of variance was performed to assess for factors affecting the linear rise of Aβ concentrations over time.
Results
Analysis of studies collecting CSF via lumbar catheter revealed tremendous inter-subject variability of Aβ40 and Aβ42 as well as an Aβ diurnal pattern in all of the sponsors’ studies. In contrast, Aβ concentrations from CSF samples collected at two time points by lumbar puncture showed no significant differences. Repeated measures analysis of variance found that only time and draw frequency were significantly associated with the slope of linear rise in Aβ40 and Aβ42 concentrations during the first 6 hours of collection.
Conclusions
Based on our findings, we recommend minimizing the frequency of CSF draws in studies measuring Aβ levels and keeping the frequency standardized between experimental groups. The Aβ diurnal pattern was noted in all sponsors’ studies and was not an artifact of study design. Averaging Aβ concentrations at each time point is recommended to minimize the effect of individual variability. Indwelling lumbar catheters are an invaluable research tool for following changes in CSF Aβ over 24-48 hours, but factors affecting Aβ concentration such as linear rise and diurnal variation need to be accounted for in planning study designs.
Electronic supplementary material
The online version of this article (doi:10.1186/s13195-015-0136-z) contains supplementary material, which is available to authorized users.
doi:10.1186/s13195-015-0136-z
PMCID: PMC4518529
10.  Report from the Alzheimer’s Research UK Conference 2015 
On 10–11 March 2015 University College London hosted the annual Alzheimer’s Research UK Conference. This report provides an overview of the presentations and discussions that took place.
doi:10.1186/s13195-015-0138-x
PMCID: PMC4517508
11.  Effects of Souvenaid on plasma micronutrient levels and fatty acid profiles in mild and mild-to-moderate Alzheimer’s disease 
Introduction
Circulating levels of uridine, selenium, vitamins B12, E and C, folate, docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) have been shown to be lower in patients with Alzheimer’s disease (AD) than in healthy individuals. These low levels may affect disease pathways involved in synapse formation and neural functioning. Here, we investigated whether, and to what extent, circulating levels of micronutrients and fatty acids can be affected by oral supplementation with Souvenaid (containing a specific nutrient combination), using data derived from three randomized clinical trials (RCT) and an open-label extension (OLE) study with follow-up data from 12 to 48 weeks.
Methods
Subjects with mild (RCT1, RCT2) or mild-to-moderate AD (RCT3) received active or control product once daily for 12–24 weeks or active product during the 24-week OLE following RCT2 (n = 212–527). Measurements included plasma levels of B vitamins, choline, vitamin E, selenium, uridine and homocysteine and proportions of DHA, EPA and total n-3 long-chain polyunsaturated fatty acids in plasma and erythrocytes. Between-group comparisons were made using t tests or non-parametric alternatives.
Results
We found that 12–24-week active product intake increased plasma and/or erythrocyte micronutrients: uridine; choline; selenium; folate; vitamins B6, B12 and E; and fatty acid levels of DHA and EPA (all p < 0.001). In the OLE study, similar levels were reached in former control product/initial active product users, whereas 24-week continued active product intake showed no suggestion of a further increase in nutrient levels.
Conclusions
These data show that circulating levels of nutrients known to be decreased in the AD population can be increased in patients with mild and mild-tomoderate AD by 24–48-week oral supplementation with Souvenaid. In addition, to our knowledge, this is the first report of the effects of sustained dietary intake of uridine monophosphate on plasma uridine levels in humans. Uptake of nutrients is observed within 6 weeks, and a plateau phase is reached for most nutrients during prolonged intake, thus increasing the availability of precursors and cofactors in the circulation that may be used for the formation and function of neuronal membranes and synapses in the brain.
Electronic supplementary material
The online version of this article (doi:10.1186/s13195-015-0134-1) contains supplementary material, which is available to authorized users.
doi:10.1186/s13195-015-0134-1
PMCID: PMC4513634  PMID: 26213579
12.  A survey of attitudes toward clinical trials and genetic disclosure in autosomal dominant Alzheimer’s disease 
Introduction
Because of its genetic underpinnings and consistent age of onset within families, autosomal dominant Alzheimer’s disease (ADAD) provides a unique opportunity to conduct clinical trials of investigational agents as preventative or symptom-delaying treatments. The design of such trials may be complicated by low rates of genetic testing and disclosure among persons at risk of inheriting disease-causing mutations.
Methods
To better understand the attitudes toward genetic testing and clinical trials of persons at risk for ADAD, we surveyed participants in the Dominantly Inherited Alzheimer’s Network (DIAN), a multisite longitudinal study of clinical and biomarker outcomes in ADAD that does not require learning genetic status to participate.
Results
Eighty participants completed a brief anonymous survey by mail or on-line; 40 % reported knowing if they carried a gene mutation, 15 % did not know but expressed a desire to learn their genetic status, and 45 % did not know and did not desire to know their genetic status. Among participants who knew or wished to know their genetic status, 86 % were interested in participating in a clinical trial. Seventy-two percent of participants who did not wish to learn their genetic status reported that they would change their mind, if learning that they carried a mutation gave them the opportunity to participate in a clinical trial. Nearly all participants responded that they would be interested if an open-label extension were offered.
Conclusions
These results suggest that the availability of clinical trials to prevent ADAD can affect persons’ desire to undergo genetic testing and that consideration can be given to performing studies in which such testing is required.
doi:10.1186/s13195-015-0135-0
PMCID: PMC4511231  PMID: 26203303
13.  The clinical characteristics of dementia with Lewy bodies and a consideration of prodromal diagnosis 
Dementia with Lewy bodies (DLB) is the second most common type of degenerative dementia following Alzheimer’s disease (AD). DLB is clinically and pathologically related to Parkinson's disease (PD) and PD dementia, and the three disorders can be viewed as existing on a spectrum of Lewy body disease. In recent years there has been a concerted effort to establish the phenotypes of AD and PD in the prodromal phase (before the respective syndromes of cognitive and motor impairment are expressed). Evidence for the prodromal presentation of DLB is also emerging. This paper briefly reviews what is known about the clinical presentation of prodromal DLB before discussing the pathology of Lewy body disease and how this relates to potential biomarkers of prodromal DLB. The presenting features of DLB can be broadly placed in three categories: cognitive impairment (particularly nonamnestic cognitive impairments), behavioural/psychiatric phenomena (for example, hallucinations, rapid eye movement sleep behaviour disorder (RBD)) and physical symptoms (for example, parkinsonism, decreased sense of smell, autonomic dysfunction). Some noncognitive symptoms such as constipation, RBD, hyposmia and postural dizziness can predate the onset of memory impairment by several years in DLB. Pathological studies of Lewy body disease have found that the earliest sites of involvement are the olfactory bulb, the dorsal motor nucleus of the vagal nerve, the peripheral autonomic nervous system, including the enteric nervous system, and the brainstem. Some of the most promising early markers for DLB include the presence of RBD, autonomic dysfunction or hyposmia, 123I-metaiodobenzylguanidine cardiac scintigraphy, measures of substantia nigra pathology and skin biopsy for α-synuclein in peripheral autonomic nerves. In the absence of disease-modifying therapies, the diagnosis of prodromal DLB is of limited use in the clinic. That said, knowledge of the prodromal development of DLB could help clinicians identify cases of DLB where the diagnosis is uncertain. Prodromal diagnosis is of great importance in research, where identifying Lewy body disease at an earlier stage may allow researchers to investigate the initial phases of dementia pathophysiology, develop treatments designed to interrupt the development of the dementia syndrome and accurately identify the patients most likely to benefit from these treatments.
doi:10.1186/alzrt274
PMCID: PMC4255387  PMID: 25484925
14.  Association of cognitive function with glucose tolerance and trajectories of glucose tolerance over 12 years in the AusDiab study 
Introduction
We investigated the association between glucose tolerance status and trajectories of change in blood glucose, and cognitive function in adults aged 25 to 85.
Methods
The sample (n = 4547) was drawn from a national, population-based cohort study in Australia (AusDiab). Fasting plasma glucose (FPG), glycated haemoglobin (HbA1c) and general health were assessed at 0, 5 and 12 years. Covariates included age, education, body mass index, blood pressure and physical activity. At 12 years, participants completed assessments of memory, processing speed and verbal ability.
Results
Known diabetes at baseline was associated with slower processing speed at 12 years in both younger (25–59 years) and older (>60 years) age-groups. After 12 years of follow-up, adults aged < 60 with diabetes at baseline had a mean speed score of 49.17 (SE = 1.09) compared with 52.39 (SE = 0.20) in normals. Among younger males without diagnosed diabetes, reduced memory at 12 years was associated with higher HbA1c at 5 years (β = −0.91, SE = 0.26, p < 0.001). No effects were apparent for females or older males. Adjusting for insulin sensitivity (HOMA-%S) and hs-C reactive protein attenuated these associations, but depression and CVD risk did not. Latent class analysis was used to analyse the associations between trajectories of HbA1C and glucose over 12 years, and cognition. Identified classes were described as 1) normal and stable blood glucose over time (reference), 2) high intercept but stable blood glucose over time, and 3) increasing blood glucose over time. In both young males and females, high stable glucose measures were associated with poorer cognitive function after 12 years.
Conclusion
Those with type 2 diabetes, younger males with high non-diabetic HbA1c, and adults with high stable blood glucose are at increased risk of poorer cognition. The findings reinforce the need for management of diabetes risk factors in midlife.
Electronic supplementary material
The online version of this article (doi:10.1186/s13195-015-0131-4) contains supplementary material, which is available to authorized users.
doi:10.1186/s13195-015-0131-4
PMCID: PMC4499451  PMID: 26167206
15.  Unraveling the potential co-contributions of cerebral small vessel vasculopathy to the pathogenesis of Alzheimer’s dementia 
Emerging evidence for the potential co-contributions of small vessel vasculopathy to dementia has resulted in a more nuanced view of Alzheimer’s disease (AD) pathogenesis. Although cerebral small vessel disease, visualized on magnetic resonance imaging as hyperintense signal abnormalities, independently predicts the incidence and clinical progression of dementia, the relationships between AD pathology, white matter hyperintensity volume, genotype, and cognitive decline in AD remain unclear. The study by Morgen and colleagues, recently published in Alzheimer’s Research & Therapy, presents important new findings on the associations between apolipoprotien E ε4 genotype, white matter hyperintensities, and cognition, independent of vascular risk, in a cohort of AD patients.
doi:10.1186/s13195-015-0133-2
PMCID: PMC4496891  PMID: 26161148
16.  Targeting the proper amyloid-beta neuronal toxins: a path forward for Alzheimer’s disease immunotherapeutics 
Levels of amyloid-beta monomer and deposited amyloid-beta in the Alzheimer’s disease brain are orders of magnitude greater than soluble amyloid-beta oligomer levels. Monomeric amyloid-beta has no known direct toxicity. Insoluble fibrillar amyloid-beta has been proposed to be an in vivo mechanism for removal of soluble amyloid-beta and exhibits relatively low toxicity. In contrast, soluble amyloid-beta oligomers are widely reported to be the most toxic amyloid-beta form, both causing acute synaptotoxicity and inducing neurodegenerative processes. None of the amyloid-beta immunotherapies currently in clinical development selectively target soluble amyloid-beta oligomers, and their lack of efficacy is not unexpected considering their selectivity for monomeric or fibrillar amyloid-beta (or both) rather than soluble amyloid-beta oligomers. Because they exhibit acute, memory-compromising synaptic toxicity and induce chronic neurodegenerative toxicity and because they exist at very low in vivo levels in the Alzheimer’s disease brain, soluble amyloid-beta oligomers constitute an optimal immunotherapeutic target that should be pursued more aggressively.
doi:10.1186/alzrt272
PMCID: PMC4100318  PMID: 25045405
17.  Basic to translational research in dementia: meeting report from the Alzheimer’s Research UK Conference 2014 
This report summarizes the findings presented at the Alzheimer’s Research UK Conference, which was held in Oxford on 25 and 26 March 2014 and which provided an overview of current dementia research from fundamental disease mechanisms to clinical studies.
doi:10.1186/alzrt270
PMCID: PMC4095573
18.  Diffusion imaging changes in grey matter in Alzheimer’s disease: a potential marker of early neurodegeneration 
Alzheimer’s disease (AD) is recognized to have a long presymptomatic period, during which there is progressive accumulation of molecular pathology, followed by inexorable neuronal damage. The ability to identify presymptomatic individuals with evidence of neurodegenerative change, to stage their disease, and to track progressive changes will be important for early diagnosis and for prevention trials. Despite recent advances, particularly in magnetic resonance imaging, our ability to identify early neurodegenerative changes reliably is limited. The development of diffusion-weighted magnetic resonance imaging, which is sensitive to microstructural changes not visible with conventional volumetric techniques, has led to a number of diffusion imaging studies in AD; these have largely focused on white matter changes. However, in AD cerebral grey matter is affected very early, with pathological studies suggesting that grey matter changes predate those in white matter. In this article we review the growing number of studies that assess grey matter diffusivity changes in AD. Although use of the technique is still at a relatively early stage, results so far have been promising. Initial studies identified changes in diffusion measures in the hippocampi of patients with mild cognitive impairment, which predated macroscopic volume loss, with positive predictive value for progression to AD dementia. More recent studies have identified abnormalities in multiple neocortical areas (particularly the posterior cingulate) at various stages of disease progression. Studies of patients who carry genetic mutations predisposing to autosomal dominant familial AD have shown cortical and subcortical grey matter diffusivity changes several years before the expected onset of the first clinical symptoms. The technique is not without potential methodological difficulties, especially relating to partial volume effects, although recent advances appear to be reducing such issues. Going forward, further utilization of grey matter diffusion measurements in AD may improve our understanding with regards to the timing and nature of the earliest presymptomatic neurodegenerative changes. This imaging technique may also be useful in comparing and contrasting subtle variations in different disease subgroups, and as a sensitive outcome measure for presymptomatic clinical trials in AD and other neurodegenerative diseases.
doi:10.1186/s13195-015-0132-3
PMCID: PMC4487800  PMID: 26136857
19.  Characterization of the postsynaptic protein neurogranin in paired cerebrospinal fluid and plasma samples from Alzheimer’s disease patients and healthy controls 
Introduction
Synaptic dysfunction and degeneration are central events in Alzheimer’s disease (AD) pathophysiology that are thought to occur early in disease progression. Synaptic pathology may be studied by examining protein biomarkers specific for different synaptic elements. We recently showed that the dendritic protein neurogranin (Ng), including the endogenous Ng peptide 48 to 76 (Ng48–76), is markedly increased in cerebrospinal fluid (CSF) in AD and that Ng48–76 is the dominant peptide in human brain tissue. The aim of this study was to characterize Ng in plasma and CSF using mass spectrometry and to investigate the performance of plasma Ng as an AD biomarker.
Methods
Paired plasma and CSF samples from patients with AD (n = 25) and healthy controls (n = 20) were analyzed in parallel using an immunoassay developed in-house on the Meso Scale Discovery platform and hybrid immunoaffinity-mass spectrometry (HI-MS). A second plasma material from patients with AD (n = 13) and healthy controls (n = 17) was also analyzed with HI-MS. High-resolution mass spectrometry was used for identification of endogenous plasma Ng peptides.
Results
Ng in human plasma is present as several endogenous peptides. Of the 16 endogenous Ng peptides identified, seven were unique for plasma and not detectable in CSF. However, Ng48–76 was not present in plasma. CSF Ng was significantly increased in AD compared with controls (P < 0.0001), whereas the plasma Ng levels were similar between the groups in both studies. Plasma and CSF Ng levels showed no correlation. CSF Ng was stable during storage at −20°C for up to 2 days, and no de novo generation of peptides were detected.
Conclusions
For the first time, to our knowledge, we have identified several endogenous Ng peptides in human plasma. In agreement with previous studies, we show that CSF Ng is significantly increased in AD as compared with healthy controls. The origin of Ng in plasma and its possible use as a biomarker need to be further investigated. The results suggest that CSF Ng, in particular Ng48–76, might reflect the neurodegenerative processes within the brain, indicating a role for Ng as a potential novel clinical biomarker for synaptic function in AD.
Electronic supplementary material
The online version of this article (doi:10.1186/s13195-015-0124-3) contains supplementary material, which is available to authorized users.
doi:10.1186/s13195-015-0124-3
PMCID: PMC4487851  PMID: 26136856
20.  Comparing recruitment, retention, and safety reporting among geographic regions in multinational Alzheimer’s disease clinical trials 
Introduction
Most Alzheimer’s disease (AD) clinical trials enroll participants multinationally. Yet, few data exist to guide investigators and sponsors regarding the types of patients enrolled in these studies and whether participant characteristics vary by region.
Methods
We used data derived from four multinational phase III trials in mild to moderate AD to examine whether regional differences exist with regard to participant demographics, safety reporting, and baseline scores on the Mini Mental State Examination (MMSE), the 11-item Alzheimer’s Disease Assessment Scale–Cognitive subscale (ADAS-cog11), the Clinical Dementia Rating scale Sum of Boxes (CDR-SB), the Alzheimer’s Disease Cooperative Study–Activities of Daily Living Inventory (ADCS-ADL), and the Neuropsychiatric Inventory (NPI). We assigned 31 participating nations to 7 geographic regions: North America, South America/Mexico, Western Europe/Israel, Eastern Europe/Russia, Australia/South Africa, Asia, and Japan.
Results
North America, Western Europe/Israel, and Australia/South Africa enrolled similar proportions of men, apolipoprotein E ε4 carriers, and participants with spouse study partners, whereas Asia, Eastern Europe/Russia, and South America/Mexico had lower proportions for these variables. North America and South America/Mexico enrolled older subjects, whereas Asia and South America/Mexico enrolled less-educated participants than the remaining regions. Approved AD therapy use differed among regions (range: 73% to 92%) and was highest in North America, Western Europe/Israel, and Japan. Dual therapy was most frequent in North America (48%). On the MMSE, North America, Western Europe/Israel, Japan, and Australia/South Africa had higher (better) scores, and Asia, South America/Mexico, and Eastern Europe/Russia had lower scores. Eastern Europe/Russia had more impaired ADAS-cog11 scores than all other regions. Eastern Europe/Russia and South America/Mexico had more impaired scores for the ADCS-ADL and the CDR-SB. Mean scores for the CDR-SB in Asia were milder than all regions except Japan. NPI scores were lower in Asia and Japan than in all other regions. Participants in North America and Western Europe/Israel reported more adverse events than those in Eastern Europe/Russia and Japan.
Conclusions
These findings suggest that trial populations differ across geographic regions on most baseline characteristics and that multinational enrollment is associated with sample heterogeneity. The data provide initial guidance with regard to the regional differences that contribute to this heterogeneity and are important to consider when planning global trials.
doi:10.1186/s13195-015-0122-5
PMCID: PMC4481112  PMID: 26120368
21.  Alzheimer’s disease progression by geographical region in a clinical trial setting 
Introduction
To facilitate enrollment and meet local registration requirements, sponsors have increasingly implemented multi-national Alzheimer’s disease (AD) studies. Geographic regions vary on many dimensions that may affect disease progression or its measurement. To aid researchers designing and implementing Phase 3 AD trials, we assessed disease progression across geographic regions using placebo data from four large, multi-national clinical trials of investigational compounds developed to target AD pathophysiology.
Methods
Four similarly-designed 76 to 80 week, randomized, double-blind placebo-controlled trials with nearly identical entry criteria enrolled patients aged ≥55 years with mild or moderate NINCDS/ADRDA probable AD. Descriptive analyses were performed for observed mean score and observed mean change in score from baseline at each scheduled visit. Data included in the analyses were pooled from the intent-to-treat placebo-assigned overall (mild and moderate) AD dementia populations from all four studies. Disease progression was assessed as change from baseline for each of 5 scales - the AD Assessment Scale-cognitive subscale (ADAS-cog11), the AD Cooperative Study- Activities of Daily Living Scale (ADCS-ADL), Mini-Mental State Examination (MMSE), the Clinical Dementia Rating scored by the sum of boxes method (CDR-SB), and the Neuropsychiatric Inventory (NPI).
Results
Regions were heterogeneous at baseline. At baseline, disease severity as measured by ADAS-cog11, ADCS-ADL, and CDR-SB was numerically worse for Eastern Europe/Russia compared with other regions. Of all regional populations, Eastern Europe/Russia showed the greatest cognitive and functional decline from baseline; Japan, Asia and/or S. America/Mexico showed the least cognitive and functional decline.
Conclusions
These data suggest that in multi-national clinical trials, AD progression or its measurement may differ across geographic regions; this may be in part due to heterogeneity across populations at baseline. The observed differences in AD progression between outcome measures across geographic regions may generalize to 'real-world' clinic populations, where heterogeneity is the norm.
Trial registrations
ClinicalTrials.gov NCT00594568 – IDENTITY. Registered 11 January 2008.
ClinicalTrials.gov NCT00762411 – IDENTITY2. Registered 26 September 2008
ClinicalTrials.gov NCT00905372 – EXPEDITION. Registered 18 May 2009
ClinicalTrials.gov NCT00904683 – EXPEDITION2. Registered 18 May 2009
doi:10.1186/s13195-015-0127-0
PMCID: PMC4481070  PMID: 26120369
22.  Dietary regulation of PI3K/AKT/GSK-3β pathway in Alzheimer’s disease 
Alzheimer’s disease (AD) is characterized by the formation of senile plaques and neurofibrillary tangles composed of phosphorylated Tau. Several findings suggest that correcting signal dysregulation for Tau phosphorylation in AD may offer a potential therapeutic approach. The PI3K/AKT/GSK-3β pathway has been shown to play a pivotal role in neuroprotection, enhancing cell survival by stimulating cell proliferation and inhibiting apoptosis. This pathway appears to be crucial in AD because it promotes protein hyper-phosphorylation in Tau. Understanding those regulations may provide a better efficacy of new therapeutic approaches. In this review, we summarize advances in the involvement of the PI3K/AKT/GSK-3β pathways in cell signaling of neuronal cells. We also review recent studies on the features of several diets and the signaling pathway involved in AD.
doi:10.1186/alzrt265
PMCID: PMC4075129  PMID: 25031641
23.  The impact of diabetes on cognitive decline: potential vascular, metabolic, and psychosocial risk factors 
Older people with type 2 diabetes are at increased risk of developing cognitive impairment, for which several potential risk factors have been proposed. The present article reviews evidence in people with type 2 diabetes for associations of cognitive impairment with a range of vascular, metabolic, and psychosocial risk factors, many of which have a higher prevalence in people with type 2 diabetes than in non-diabetic adults of a similar age. Definitive research studies in this field are few in number. The risk factors may be involved in causal pathways or may act as useful markers of cerebrovascular damage (or both), and for which relatively consistent evidence is available, include poor glycemic control, hypoglycemia, microvascular disease, inflammation, and depression. For macrovascular disease, the strength of the association with cognitive impairment appears to depend on which vascular system has been examined. A role for pre-morbid ability in young adulthood as influencing the risk of both diabetes and cognitive impairment has also been suggested. The importance of considering inter-relationships between risk factors when investigating their potential contribution to cognitive impairment in future investigations is discussed.
Electronic supplementary material
The online version of this article (doi:10.1186/s13195-015-0130-5) contains supplementary material, which is available to authorized users.
doi:10.1186/s13195-015-0130-5
PMCID: PMC4460635  PMID: 26060511
24.  Peripheral and central effects of γ-secretase inhibition by semagacestat in Alzheimer’s disease 
Introduction
The negative efficacy study examining the γ-secretase inhibitor semagacestat in mild to moderate Alzheimer’s disease (AD) included a number of biomarkers of the disease as well as safety outcomes. We analyzed these data to explore relationships between drug exposure and pharmacodynamic effects and to examine the correlations among outcome measures.
Methods
The study was a multicenter, randomized, placebo-controlled trial of two dose regimens of semagacestat and a placebo administered for 18 months to individuals with mild to moderate AD. Changes in measures of central and peripheral drug activity were compared between the three treatment groups using one-way analysis of variance. The relationship between changes in each of the outcome measures and measures of drug exposure and peripheral pharmacodynamic effect were assessed using Spearman’s correlation coefficient.
Results
Assignment to the active treatment arms was associated with reduction in plasma amyloid-β (Aβ) peptides, increase in ventricular volume, decrease in cerebrospinal fluid phosphorylated tau (p-tau) and several other laboratory measures and adverse event categories. Within the active arms, exposure to drug, as indicated by area under the concentration curve (AUC) of blood concentration, was associated with reduction in plasma Aβ peptides and a subset of laboratory changes and adverse event rates. Ventricular volume increase, right hippocampal volume loss and gastrointestinal symptoms were related to change in plasma Aβ peptide but not AUC, supporting a link to inhibition of γ-secretase cleavage of the amyloid precursor protein. Cognitive decline correlated with ventricular expansion and reduction in p-tau.
Conclusion
These findings may inform future studies of drugs targeting secretases involved in Aβ generation.
Trial registration
ClinicalTrials.gov Identifier: NCT00594568. Registered 11 January 2008.
Electronic supplementary material
The online version of this article (doi:10.1186/s13195-015-0121-6) contains supplementary material, which is available to authorized users.
doi:10.1186/s13195-015-0121-6
PMCID: PMC4461930  PMID: 26064192
25.  Cumulative impact of health deficits, social vulnerabilities, and protective factors on cognitive dynamics in late life: a multistate modeling approach 
Introduction
Many factors influence late-life cognitive changes, and evaluating their joint impact is challenging. Typical approaches focus on average decline and a small number of factors. We used multistate transition models and index variables to look at changes in cognition in relation to frailty (accumulation of health deficits), social vulnerability, and protective factors in the Honolulu-Asia Aging Study (HAAS).
Methods
The HAAS is a prospective cohort study of 3,845 men of Japanese descent, aged 71 to 93 years at baseline. Cognitive function was measured using the Cognitive Abilities Screening Instrument (CASI). Baseline index variables were constructed of health deficits (frailty), social vulnerabilities, and protective factors. The chances of improvement/stability/decline in cognitive function and death were simultaneously estimated using multistate transition modeling for 3- and 6-year transitions from baseline.
Results
On average, CASI scores declined by 5.3 points (standard deviation (SD) = 10.0) over 3 years and 9.5 points (SD = 13.9) over 6 years. After adjusting for education and age, baseline frailty was associated with an increased risk of cognitive decline at 3 years (β = 0.18, 95% confidence interval (CI), 0.08 to 0.29) and 6 years (β = 0.40, 95% CI, 0.27 to 0.54). The social vulnerability index was associated with 3-year changes (β = 0.16, 95% CI, 0.09 to 0.23) and 6-year changes (β = 0.14, 95% CI, 0.05 to 0.24) in CASI scores. The protective index was associated with reductions in cognitive decline over the two intervals (3-year: β = −0.16, 95% CI, −0.24 to −0.09; 6-year: β = −0.21, 95% CI, −0.31 to –0.11,).
Conclusions
Research on cognition in late life needs to consider overall health, the accumulation of protective factors, and the dynamics of cognitive change. Index variables and multistate transition models can enhance understanding of the multifactorial nature of late-life changes in cognition.
Electronic supplementary material
The online version of this article (doi:10.1186/s13195-015-0120-7) contains supplementary material, which is available to authorized users.
doi:10.1186/s13195-015-0120-7
PMCID: PMC4457088  PMID: 26052349

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