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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.
PMCID: PMC3580394  PMID: 23014271
2.  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.
PMCID: PMC3707047  PMID: 23680123
3.  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.
PMCID: PMC3580458  PMID: 23269019
4.  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.
PMCID: PMC3506933  PMID: 22643124
7.  BACE1 inhibitor drugs in clinical trials for Alzheimer’s disease 
β-site amyloid precursor protein cleaving enzyme 1 (BACE1) is the β-secretase enzyme required for the production of the neurotoxic β-amyloid (Aβ) peptide that is widely considered to have a crucial early role in the etiology of Alzheimer’s disease (AD). As a result, BACE1 has emerged as a prime drug target for reducing the levels of Aβ in the AD brain, and the development of BACE1 inhibitors as therapeutic agents is being vigorously pursued. It has proven difficult for the pharmaceutical industry to design BACE1 inhibitor drugs that pass the blood–brain barrier, however this challenge has recently been met and BACE1 inhibitors are now in human clinical trials to test for safety and efficacy in AD patients and individuals with pre-symptomatic AD. Initial results suggest that some of these BACE1 inhibitor drugs are well tolerated, although others have dropped out because of toxicity and it is still too early to know whether any will be effective for the prevention or treatment of AD. Additionally, based on newly identified BACE1 substrates and phenotypes of mice that lack BACE1, concerns have emerged about potential mechanism-based side effects of BACE1 inhibitor drugs with chronic administration. It is hoped that a therapeutic window can be achieved that balances safety and efficacy. This review summarizes the current state of progress in the development of BACE1 inhibitor drugs and the evaluation of their therapeutic potential for AD.
PMCID: PMC4304279  PMID: 25621019
8.  Imaging endpoints for clinical trials in Alzheimer’s disease 
As the need to develop a successful disease-modifying treatment for Alzheimer’s disease (AD) becomes more urgent, imaging is increasingly used in therapeutic trials. We provide an overview of how the different imaging modalities are used in AD studies and the current regulatory guidelines for their use in clinical trials as endpoints. We review the current literature for results of imaging endpoints of efficacy and safety in published clinical trials. We start with trials in mild to moderate AD, where imaging (largely magnetic resonance imaging (MRI)) has long played a role in inclusion and exclusion criteria; more recently, MRI has been used to identify adverse events and to measure rates of brain atrophy. The advent of amyloid imaging using positron emission tomography has led to trials incorporating amyloid measurements as endpoints and incidentally to the recognition of the high proportion of amyloid-negative individuals that may be recruited into these trials. Ongoing and planned trials now commonly include multimodality imaging: amyloid positron emission tomography, MRI and other modalities. At the same time, the failure of recent large profile trials in mild to moderate AD together with the realisation that there is a long prodromal period to AD has driven a push to move studies to earlier in the disease. Imaging has particularly important roles, alongside other biomarkers, in assessing efficacy because conventional clinical outcomes may have limited ability to detect treatment effects in these early stages.
Electronic supplementary material
The online version of this article (doi:10.1186/s13195-014-0087-9) contains supplementary material, which is available to authorized users.
PMCID: PMC4304258  PMID: 25621018
9.  Eyes-closed task-free electroencephalography in clinical trials for Alzheimer’s disease: an emerging method based upon brain dynamics 
Electroencephalography (EEG) is a longstanding technique to measure electrical brain activity and thereby an indirect measure of synaptic activity. Synaptic dysfunction accompanies Alzheimer’s disease (AD) and EEG can be regarded as a potentially useful biomarker in this disease. Lately, emerging analysis techniques of time series have become available for EEG, such as functional connectivity and network analysis, which have increased the possibilities for use in AD clinical trials. In this review, we report the EEG changes in the course of AD, including slowing of the EEG oscillations, decreased functional connectivity in the higher-frequency bands, and decline in optimal functional network organization. We discuss the use of EEG in clinical trials and provide directions for future research.
PMCID: PMC4304266  PMID: 25621017
10.  Expression of one important chaperone protein, heat shock protein 27, in neurodegenerative diseases 
Many neurodegenerative diseases are characterised by accumulations of misfolded proteins that can colocalise with chaperone proteins (for example, heat shock protein 27 (HSP27)), which might act as modulators of protein aggregation.
The role of HSP27 in the pathogenesis of neurodegenerative disorders such as frontotemporal lobar degeneration (FTLD), Alzheimer’s disease (AD) and motor neuron disease (MND) was investigated. We used immunohistochemical and Western blot analysis to determine the distribution and amount of this protein in the frontal and temporal cortices of diseased and control subjects.
HSP27 immunostaining presented as accumulations of granules within neuronal and glial cell perikarya. Patients with AD and FTLD were affected more often, and showed greater immunostaining for HSP27, than patients with MND and controls. In FTLD, there was no association between HSP27 and histological type. The neuropathological changes of FTLD, AD and MND were not immunoreactive to HSP27. Western blot analysis revealed higher HSP27 expression in FTLD than in controls, but without qualitative differences in banding patterns.
The pattern of HSP27 immunostaining observed may reflect the extent of ongoing neurodegeneration in affected brain areas and is not specific to FTLD, AD or MND. It may represent an accumulation of misfolded, damaged or unwanted proteins, awaiting or undergoing degradation.
PMCID: PMC4304251  PMID: 25621016
11.  Abnormal daytime sleepiness in dementia with Lewy bodies compared to Alzheimer’s disease using the Multiple Sleep Latency Test 
Excessive daytime sleepiness is a commonly reported problem in dementia with Lewy bodies (DLB). We examined the relationship between nighttime sleep continuity and the propensity to fall asleep during the day in clinically probable DLB compared to Alzheimer’s disease (AD) dementia.
A full-night polysomnography was carried out in 61 participants with DLB and 26 with AD dementia. Among this group, 32 participants with DLB and 18 with AD dementia underwent a daytime Multiple Sleep Latency Test (MSLT). Neuropathologic examinations of 20 participants with DLB were carried out.
Although nighttime sleep efficiency did not differentiate diagnostic groups, the mean MSLT initial sleep latency was significantly shorter in participants with DLB than in those with AD dementia (mean 6.4 ± 5 minutes vs 11 ± 5 minutes, P <0.01). In the DLB group, 81% fell asleep within 10 minutes compared to 39% of the AD dementia group (P <0.01), and 56% in the DLB group fell asleep within 5 minutes compared to 17% in the AD dementia group (P <0.01). Daytime sleepiness in AD dementia was associated with greater dementia severity, but mean MSLT latency in DLB was not related to dementia severity, sleep efficiency the night before, or to visual hallucinations, fluctuations, parkinsonism or rapid eye movement sleep behavior disorder. These data suggest that abnormal daytime sleepiness is a unique feature of DLB that does not depend on nighttime sleep fragmentation or the presence of the four cardinal DLB features. Of the 20 DLB participants who underwent autopsy, those with transitional Lewy body disease (brainstem and limbic) did not differ from those with added cortical pathology (diffuse Lewy body disease) in dementia severity, DLB core features or sleep variables.
Daytime sleepiness is more likely to occur in persons with DLB than in those with AD dementia. Daytime sleepiness in DLB may be attributed to disrupted brainstem and limbic sleep–wake physiology, and further work is needed to better understand the underlying mechanisms.
PMCID: PMC4266572  PMID: 25512763
12.  Differentiating between visual hallucination-free dementia with Lewy bodies and corticobasal syndrome on the basis of neuropsychology and perfusion single-photon emission computed tomography 
Dementia with Lewy bodies (DLB) and Corticobasal Syndrome (CBS) are atypical parkinsonian disorders with fronto-subcortical and posterior cognitive dysfunction as common features. While visual hallucinations are a good predictor of Lewy body pathology and are rare in CBS, they are not exhibited in all cases of DLB. Given the clinical overlap between these disorders, neuropsychological and imaging markers may aid in distinguishing these entities.
Prospectively recruited case–control cohorts of CBS (n =31) and visual hallucination-free DLB (n =30), completed neuropsychological and neuropsychiatric measures as well as brain perfusion single-photon emission computed tomography and structural magnetic resonance imaging (MRI). Perfusion data were available for forty-two controls. Behavioural, perfusion, and cortical volume and thickness measures were compared between the groups to identify features that serve to differentiate them.
The Lewy body with no hallucinations group performed more poorly on measures of episodic memory compared to the corticobasal group, including the delayed and cued recall portions of the California Verbal Learning Test (F (1, 42) =23.1, P <0.001 and F (1, 42) =14.0, P =0.001 respectively) and the delayed visual reproduction of the Wechsler Memory Scale-Revised (F (1, 36) =9.7, P =0.004). The Lewy body group also demonstrated reduced perfusion in the left occipital pole compared to the corticobasal group (F (1,57) =7.4, P =0.009). At autopsy, the Lewy body cases all demonstrated mixed dementia with Lewy bodies, Alzheimer’s disease and small vessel arteriosclerosis, while the corticobasal cases demonstrated classical corticobasal degeneration in five, dementia with agyrophilic grains + corticobasal degeneration + cerebral amyloid angiopathy in one, Progressive Supranuclear Palsy in two, and Frontotemporal Lobar Degeneration-Ubiquitin/TAR DNA-binding protein 43 proteinopathy in one. MRI measures were not significantly different between the patient groups.
Reduced perfusion in the left occipital region and worse episodic memory performance may help to distinguish between DLB cases who have never manifested with visual hallucinations and CBS at earlier stages of the disease. Development of reliable neuropsychological and imaging markers that improve diagnostic accuracy will become increasingly important as disease modifying therapies become available.
PMCID: PMC4256921  PMID: 25484929
13.  Evaluating the relationship between amyloid-β and α-synuclein phosphorylated at Ser129 in dementia with Lewy bodies and Parkinson’s disease 
Lewy body and Alzheimer-type pathologies often co-exist. Several studies suggest a synergistic relationship between amyloid-β (Aβ) and α-synuclein (α-syn) accumulation. We have explored the relationship between Aβ accumulation and the phosphorylation of α-syn at serine-129 (pSer129 α-syn), in post-mortem human brain tissue and in SH-SY5Y neuroblastoma cells transfected to overexpress human α-syn.
We measured levels of Aβ40, Aβ42, α-syn and pSer129 α-syn by sandwich enzyme-linked immunosorbent assay, in soluble and insoluble fractions of midfrontal, cingulate and parahippocampal cortex and thalamus, from cases of Parkinson’s disease (PD) with (PDD; n = 12) and without dementia (PDND; n = 23), dementia with Lewy bodies (DLB; n = 10) and age-matched controls (n = 17). We also examined the relationship of these measurements to cognitive decline, as measured by time-to-dementia and the mini-mental state examination (MMSE) score in the PD patients, and to Braak tangle stage.
In most brain regions, the concentration of insoluble pSer129 α-syn correlated positively, and soluble pSer129 α-syn negatively, with the levels of soluble and insoluble Aβ. Insoluble pSer129 α-syn also correlated positively with Braak stage. In most regions, the levels of insoluble and soluble Aβ and the proportion of insoluble α-syn that was phosphorylated at Ser129 were significantly higher in the PD and DLB groups than the controls, and higher in the PDD and DLB groups than the PDND brains. In PD, the MMSE score correlated negatively with the level of insoluble pSer129 α-syn. Exposure of SH-SY5Y cells to aggregated Aβ42 significantly increased the proportion of α-syn that was phosphorylated at Ser129 (aggregated Aβ40 exposure had a smaller, non-significant effect).
Together, these data show that the concentration of pSer129 α-syn in brain tissue homogenates is directly related to the level of Aβ and Braak tangle stage, and predicts cognitive status in Lewy body diseases.
Electronic supplementary material
The online version of this article (doi:10.1186/s13195-014-0077-y) contains supplementary material, which is available to authorized users.
PMCID: PMC4248436  PMID: 25452767
14.  Quantitative neuropathological assessment to investigate cerebral multi-morbidity 
The aging brain is characterized by the simultaneous presence of multiple pathologies, and the prevalence of cerebral multi-morbidity increases with age. To understand the impact of each subtype of pathology and the combined effects of cerebral multi-morbidity on clinical signs and symptoms, large clinico-pathological correlative studies have been performed. However, such studies are often based on semi-quantitative assessment of neuropathological hallmark lesions. Here, we discuss some of the new methods for high-throughput quantitative neuropathological assessment. These methods combine increased quantitative rigor with the added technical capacity of computers and networked analyses. There are abundant new opportunities - with specific techniques that include slide scanners, automated microscopes, and tissue microarrays - and also potential pitfalls. We conclude that quantitative and digital neuropathologic approaches will be key resources to further elucidate cerebral multi-morbidity in the aged brain and also hold the potential for changing routine neuropathologic diagnoses.
PMCID: PMC4247208  PMID: 25435922
15.  Applying a cumulative deficit model of frailty to dementia: progress and future challenges 
The article by Song and colleagues presents findings from the Canadian Study of Health and Aging showing that the accumulation of health deficits, defined dichotomously and unqualified by severity or domain, predicted late-life dementia independent of chronological age. We identify strengths of this model, and also areas for future research. Importantly, this article broadens the perspective of research into measuring risk of dementia from focusing on specific neuropathological markers of dementia subtypes, to mechanisms underlying more general bodily vitality and health, as well as dysfunctions in repair. This work places late-life dementia in a new context, influenced more broadly by health maintenance, and less by specific neurological disease. While useful at a global level, the lack of specificity of this approach may ultimately limit its application to individual patients because without linking risk to etiology, assessment does not indicate an intervention. Ultimately, the article has value for stimulating debate about approaches to risk identification and risk reduction, suggesting that the current focus on cardiometabolic risk factors may be too limited.
PMCID: PMC4244050  PMID: 25426173
16.  BrainCheck – a very brief tool to detect incipient cognitive decline: optimized case-finding combining patient- and informant-based data 
Optimal identification of subtle cognitive impairment in the primary care setting requires a very brief tool combining (a) patients’ subjective impairments, (b) cognitive testing, and (c) information from informants. The present study developed a new, very quick and easily administered case-finding tool combining these assessments (‘BrainCheck’) and tested the feasibility and validity of this instrument in two independent studies.
We developed a case-finding tool comprised of patient-directed (a) questions about memory and depression and (b) clock drawing, and (c) the informant-directed 7-item version of the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE). Feasibility study: 52 general practitioners rated the feasibility and acceptance of the patient-directed tool. Validation study: An independent group of 288 Memory Clinic patients (mean ± SD age = 76.6 ± 7.9, education = 12.0 ± 2.6; 53.8% female) with diagnoses of mild cognitive impairment (n = 80), probable Alzheimer's disease (n = 185), or major depression (n = 23) and 126 demographically matched, cognitively healthy volunteer participants (age = 75.2 ± 8.8, education = 12.5 ± 2.7; 40% female) partook. All patient and healthy control participants were administered the patient-directed tool, and informants of 113 patient and 70 healthy control participants completed the very short IQCODE.
Feasibility study: General practitioners rated the patient-directed tool as highly feasible and acceptable. Validation study: A Classification and Regression Tree analysis generated an algorithm to categorize patient-directed data which resulted in a correct classification rate (CCR) of 81.2% (sensitivity = 83.0%, specificity = 79.4%). Critically, the CCR of the combined patient- and informant-directed instruments (BrainCheck) reached nearly 90% (that is 89.4%; sensitivity = 97.4%, specificity = 81.6%).
A new and very brief instrument for general practitioners, ‘BrainCheck’, combined three sources of information deemed critical for effective case-finding (that is, patients’ subject impairments, cognitive testing, informant information) and resulted in a nearly 90% CCR. Thus, it provides a very efficient and valid tool to aid general practitioners in deciding whether patients with suspected cognitive impairments should be further evaluated or not (‘watchful waiting’).
PMCID: PMC4241397  PMID: 25422675
17.  Prevalence of mixed pathologies in the aging brain 
The spectrum of mixed brain pathologies expands beyond accompanying vascular pathology in brains with Alzheimer’s disease-related pathology. Co-occurrence of neurodegenerative non-Alzheimer’s disease-type proteinopathies is increasingly recognized to be a frequent event in the brains of symptomatic and asymptomatic patients, particularly in older people. Owing to the evolving concept of neurodegenerative diseases, clinical and neuropathological diagnostic criteria have changed during the last decades. Autopsy-based studies differ in the selection criteria and also in the applied staining methods used. The present review summarizes the prevalence of mixed brain pathologies reported in recent community-based studies. In these cohorts, irrespective of the clinical symptoms, the frequency of Alzheimer’s disease-related pathology is between 19 and 67%, of Lewy body pathology is between 6 and 39%, of vascular pathologies is between 28 and 70%, of TDP-43 proteinopathy is between 13 and 46%, of hippocampal sclerosis is between 3 and 13% and, finally, of mixed pathologies is between 10 and 74%. Some studies also mention tauopathies. White-matter pathologies are not discussed specifically in all studies, although these lesions may be present in more than 80% of the aging brains. In summary, community-based neuropathology studies have shown that complex constellations of underlying pathologies may lead to cognitive decline, and that the number of possible combinations increases in the aging brain. These observations have implications for the prediction of the prognosis, for the development of biomarkers or therapy targets, or for the stratification of patient cohorts for genome-wide studies or, eventually, for therapy trials.
PMCID: PMC4239398  PMID: 25419243
18.  β-site amyloid precursor protein-cleaving enzyme 1(BACE1) inhibitor treatment induces Aβ5-X peptides through alternative amyloid precursor protein cleavage 
The β-secretase enzyme, β-site amyloid precursor protein-cleaving enzyme 1 (BACE1), cleaves amyloid precursor protein (APP) in the first step in β-amyloid (Aβ) peptide production. Thus, BACE1 is a key target for candidate disease-modifying treatment of Alzheimer’s disease. In a previous exploratory Aβ biomarker study, we found that BACE1 inhibitor treatment resulted in decreased levels of Aβ1-34 together with increased Aβ5-40, suggesting that these Aβ species may be novel pharmacodynamic biomarkers in clinical trials. We have now examined whether the same holds true in humans.
In an investigator-blind, placebo-controlled and randomized study, healthy subjects (n =18) were randomly assigned to receive a single dose of 30 mg of LY2811376 (n =6), 90 mg of LY2811376 (n =6), or placebo (n =6). We used hybrid immunoaffinity-mass spectrometry (HI-MS) and enzyme-linked immunosorbent assays to monitor a variety of Aβ peptides.
Here, we demonstrate dose-dependent changes in cerebrospinal fluid (CSF) Aβ1-34, Aβ5-40 and Aβ5-X after treatment with the BACE1-inhibitor LY2811376. Aβ5-40 and Aβ5-X increased dose-dependently, as reflected by two independent methods, while Aβ1-34 dose-dependently decreased.
Using HI-MS for the first time in a study where subjects have been treated with a BACE inhibitor, we confirm that CSF Aβ1-34 may be useful in clinical trials on BACE1 inhibitors to monitor target engagement. Since it is less hydrophobic than longer Aβ species, it is less susceptible to preanalytical confounding factors and may thus be a more stable marker. By independent measurement techniques, we also show that BACE1 inhibition in humans is associated with APP-processing into N-terminally truncated Aβ peptides via a BACE1-independent pathway.
Trial registration NCT00838084. Registered: First received: January 23, 2009, Last updated: July 14, 2009, Last verified: July 2009.
PMCID: PMC4233234  PMID: 25404952
19.  Transcranial magnetic stimulation and transcranial direct current stimulation: treatments for cognitive and neuropsychiatric symptoms in the neurodegenerative dementias? 
Two methods of non-invasive brain stimulation, transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS), have demonstrable positive effects on cognition and can ameliorate neuropsychiatric symptoms such as depression. Less is known about the efficacy of these approaches in common neurodegenerative diseases. In this review, we evaluate the effects of TMS and tDCS upon cognitive and neuropsychiatric symptoms in the major dementias, including Alzheimer’s disease (AD), vascular dementia (VaD), dementia with Lewy bodies (DLB), Parkinson’s disease with dementia (PDD), and frontotemporal dementia (FTD), as well as the potential pre-dementia states of Mild Cognitive Impairment (MCI) and Parkinson’s disease (PD).
PubMed (until 7 February 2014) and PsycINFO (from 1967 to January Week 3 2014) databases were searched in a semi-systematic manner in order to identify relevant treatment studies. A total of 762 studies were identified and 32 studies (18 in the dementias and 14 in PD populations) were included.
No studies were identified in patients with PDD, FTD or VaD. Of the dementias, 13 studies were conducted in patients with AD, one in DLB, and four in MCI. A total of 16 of the 18 studies showed improvements in at least one cognitive or neuropsychiatric outcome measure. Cognitive or neuropsychiatric improvements were observed in 12 of the 14 studies conducted in patients with PD.
Both TMS and tDCS may have potential as interventions for the treatment of symptoms associated with dementia and PD. These results are promising; however, available data were limited, particularly within VaD, PDD and FTD, and major challenges exist in order to maximise the efficacy and clinical utility of both techniques. In particular, stimulation parameters vary considerably between studies and are likely to subsequently impact upon treatment efficacy.
PMCID: PMC4255638  PMID: 25478032
20.  When the dust settles: what did we learn from the bexarotene discussion? 
With 27 million people affected by Alzheimer’s disease (AD), any proposal of a novel avenue for drug development is hot news. When Cramer and colleagues proposed last year that they could tackle AD pathology in an AD mouse model with bexarotene, a drug already in use in the clinic for other diseases, the news was covered worldwide by the popular press. Apolipoprotein E4 is the strongest genetic risk factor for AD and bexarotene appeared to exert spectacular effects on AD pathology when tested in APP/PS1 transgenic mice. One year later the slumbering discussion on the use of bexarotene in AD exploded in a flurry of papers. Four papers question the initial optimistic claims, while two others can only partially support the original work. We summarize here the available data and try to make sense out of the controversy. The major question is what we can learn from the experiments and what these studies imply for the further development of bexarotene in the clinic.
PMCID: PMC3979032  PMID: 24229456
21.  PLD3 is accumulated on neuritic plaques in Alzheimer’s disease brains 
Recently, a whole-exome sequencing (WES) study showed that a rare variant rs145999145 composed of p.Val232Met located in exon 7 of the phospholipase D3 (PLD3) gene confers a doubled risk for late-onset Alzheimer’s disease (AD). Knockdown of PLD3 elevates the levels of extracellular amyloid-beta (Aβ), suggesting that PLD3 acts as a negative regulator of Aβ precursor protein (APP) processing. However, the precise cellular location and distribution of PLD3 in AD brains remain largely unknown.
By quantitative RT-PCR (qPCR), western blot, immunohistochemistry, and bioinformatics analysis, we studied PLD3 expression patterns and levels in a series of AD and control brains, including amyotrophic lateral sclerosis, Parkinson’s disease, multiple system atrophy, and non-neurological cases.
The levels of PLD3 mRNA and protein expression were reduced modestly in AD brains, compared with those in non-AD brains. In all brains, PLD3 was expressed constitutively in cortical neurons, hippocampal pyramidal and granular neurons but not in glial cells. Notably, PLD3 immunoreactivity was accumulated on neuritic plaques in AD brains. We identified the human granulin (GRN) gene encoding progranulin (PRGN) as one of most significant genes coexpressed with PLD3 by bioinformatics database search. PLD3 was actually coexpressed and interacted with PGRN both in cultured cells in vitro and in AD brains in vivo.
We identified an intense accumulation of PLD3 on neuritic plaques coexpressed with PGRN in AD brains, suggesting that PLD3 plays a key role in the pathological processes of AD.
PMCID: PMC4255636  PMID: 25478031
22.  Study protocol: Randomised controlled trial to evaluate the impact of an educational programme on Alzheimer’s disease patients’ quality of life 
Therapeutic education is expanding in the management of Alzheimer’s disease (AD) patients. Several studies have revealed a positive impact of therapeutic educational programmes on the caregiver’s burden and/or quality of life. However, to date, no study has evaluated its impact on the quality of life of the AD patient.
The THERAD study (THerapeutic Education in Alzheimer’s Disease) is a 12-month randomised controlled trial that started in January 2013. This paper describes the study protocol. THERAD plans to enroll 170 dyads (AD patient and caregiver) on the basis of the following criteria: patient at a mild to moderately severe stage of AD, living at home, receiving support from a family caregiver. The main outcome is the patient’s quality of life assessed by the Logsdon QoL-AD scale at 2 months, reported by the caregiver. The study is being led by geriatricians trained in therapeutic education at Toulouse University Hospital in France. To date, 107 caregiver/patient dyads have been recruited.
This is the first trial designed to assess the specific impact of a therapeutic educational programme on the AD patient’s quality of life. The final results will be available in 2015.
Trial registration
[ NCT01796314] Registered 19 February 2013
PMCID: PMC4255540  PMID: 25478028
23.  Association between cell-bound blood amyloid-β(1–40) levels and hippocampus volume 
The identification of early, preferably presymptomatic, biomarkers and true etiologic factors for Alzheimer’s disease (AD) is the first step toward establishing effective primary and secondary prevention programs. Consequently, the search for a relatively inexpensive and harmless biomarker for AD continues. Despite intensive research worldwide, to date there is no definitive plasma or blood biomarker indicating high or low risk of conversion to AD.
Magnetic resonance imaging and β-amyloid (Aβ) levels in three blood compartments (diluted in plasma, undiluted in plasma and cell-bound) were measured in 96 subjects (33 with mild cognitive impairment, 14 with AD and 49 healthy controls). Pearson correlations were completed between 113 regions of interest (ROIs) (45 subcortical and 68 cortical) and Aβ levels. Pearson correlation analyses adjusted for the covariates age, sex, apolipoprotein E (ApoE), education and creatinine levels showed neuroimaging ROIs were associated with Aβ levels. Two statistical methods were applied to study the major relationships identified: (1) Pearson correlation with phenotype added as a covariate and (2) a meta-analysis stratified by phenotype. Neuroimaging data and plasma Aβ measurements were taken from 630 Alzheimer’s Disease Neuroimaging Initiative (ADNI) subjects to be compared with our results.
The left hippocampus was the brain region most correlated with Aβ(1–40) bound to blood cell pellets (partial correlation (pcor) = −0.37, P = 0.0007) after adjustment for the covariates age, gender and education, ApoE and creatinine levels. The correlation remained almost the same (pcor = −0.35, P = 0.002) if phenotype is also added as a covariate. The association between both measurements was independent of cognitive status. The left hemisphere entorhinal cortex also correlated with Aβ(1–40) cell-bound fraction. AB128 and ADNI plasma Aβ measurements were not related to any brain morphometric measurement.
Association of cell-bound Aβ(1–40) in blood with left hippocampal volume was much stronger than previously observed in Aβ plasma fractions. If confirmed, this observation will require careful interpretation and must be taken into account for blood amyloid-based biomarker development.
PMCID: PMC4255526  PMID: 25484928
24.  Association between Hoehn and Yahr, Mini-Mental State Examination, age, and clinical syndrome predominance and diagnostic effectiveness of ioflupane I 123 injection (DaTSCAN™) in subjects with clinically uncertain parkinsonian syndromes 
Diagnostic effectiveness of Ioflupane I 123 injection (DaTSCAN™, DaTscan™, or [123I]FP-CIT or ioflupane [123I]) SPECT imaging, was assessed in patients with clinically uncertain parkinsonian syndrome (CUPS).
We investigated the association between subject’s Hoehn & Yahr (H&Y) stage, Mini-Mental State Examination (MMSE), age, and motor symptom subgroups and diagnostic performance of ioflupane [123I] imaging. Phase 4 study data were used to calculate sensitivity, specificity, positive and negative predictive value, and accuracy in 92 CUPS subjects, using 1-year clinical diagnosis after ioflupane [123I] imaging as reference standard.
Diagnostic effectiveness of ioflupane [123I] imaging was high in all subgroups: 91% to 100% for H&Y low (<2) and high (≥2) stage subjects; 93% to 96% for MMSE low (<29) or high (≥29) scores; 91% to100% in both age subgroups (younger [<68] and older [≥68]); and 92% to 100% in subjects with both tremor dominant and balanced motor signs. Specificity of ioflupane [123I] imaging for bradykinetic rigid or posturally (BRP) unstable motor subtype was lower, but better than for baseline clinical diagnosis.
Strongest diagnostic performance of ioflupane [123I] imaging for clinical diagnosis of Parkinson’s syndrome (PS) or non-PS was associated with tremor and balanced motor dominance rather than with BRP dominance. High diagnostic effectiveness of ioflupane [123I] imaging and favourable performance relative to final clinical diagnosis at 1 year post-scan in subjects with CUPS was demonstrated. This study suggests that the diagnostic performance of ioflupane [123I] imaging in CUPS remains high at all stages of disease, including early stage, and across both age groups and cognitive state (MMSE).
PMCID: PMC4255542  PMID: 25478029
25.  Comorbidity profile in dementia with Lewy bodies versus Alzheimer’s disease: a linkage study between the Swedish Dementia Registry and the Swedish National Patient Registry 
Compared to Alzheimer’s disease (AD), dementia with Lewy bodies (DLB) is usually associated with a more complex clinical picture and higher burden of care. Yet, few investigations have been performed on comorbidities and risk factors of DLB. Therefore, we aimed to compare clinical risk factors and comorbidity profile in DLB and AD patients using two nationwide registries.
This is a linkage study between the Swedish dementia registry (SveDem) and the Swedish National Patient Registry conducted on 634 subjects with DLB and 9161 individuals with AD registered during the years 2007–2012. Comorbidity profile has been coded according to the International Classification of Diseases version 10 (ICD 10) in addition to the date of each event. The main chapters of the ICD-10, the Charlson score of comorbidities and a selected number of neuropsychiatric diseases were compared between the DLB and AD groups. Comorbidity was registered before and after the dementia diagnosis.
“Mental and behavioral disorders”, “diseases of the nervous system”, “diseases of the eye and adnexa”, diseases of the “circulatory”, “respiratory”, and “genitourinary” systems, “diseases of the skin and subcutaneous tissue” and “diseases of the musculoskeletal system and connective tissue” occurred more frequently in the DLB group after multivariate adjustment. Depression [adjusted OR = 2.12 (95%CI 1.49 to 3.03)] and migraine [adjusted OR = 3.65 (95%CI 1.48 to 9.0)] were more commonly recorded before the diagnosis of dementia in the DLB group. Following dementia diagnosis, ischemic stroke [adjusted OR = 1.89 (95%CI 1.21 to 2.96)] was more likely to happen among the DLB patients compared to the AD population.
Our study indicated a worse comorbidity profile in DLB patients with higher occurrence of depression, stroke and migraine compared with the AD group. Deeper knowledge about the underlying mechanisms of these associations is needed to explore possible reasons for the different pattern of comorbidity profile in DLB compared to AD and their prognostic significance.
PMCID: PMC4255539  PMID: 25478027

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