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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.  Dementia trials and dementia tribulations: methodological and analytical challenges in dementia research 
Dementia is a substantial and increasing public health concern. Despite decades of research, a cure or effective preventative treatment for dementia remains elusive. We offer critical review of contemporary dementia research and discuss potential reasons why progress in the field has not been as rapid as in other disciplines. We adopt a broad approach in keeping with the broad nature of the topic. We cover the difficulties inherent in studying dementia from 'bench' to 'bedside' to 'population'. We make particular reference to issues of operationalisation of the dementia syndrome and our evolving understanding of dementia as a research 'outcome'. We discuss contemporary 'hot topics' in dementia research methodology focussing on dementia models, pre-dementia states and biomarkers. Recognising the importance of prospective epidemiological cohorts and large-scale clinical trials we pay particular attention to these approaches and the challenges of generating results that have 'real world' external validity. Based on our thoughts we end with suggestions for future dementia research. Our review is designed to be critical but not unnecessarily negative. There is reason for cautious optimism in dementia research. The recent G8 summit on dementia and subsequent establishment of the World Dementia Council are examples of initiatives that reflect societal and political will to increase research efforts in dementia.
doi:10.1186/s13195-015-0113-6
PMCID: PMC4364079  PMID: 25788988
9.  Kidney disease as a determinant of cognitive decline and dementia 
Chronic kidney disease (CKD) has evolved as a possible new determinant of cognitive decline and dementia. This review outlines the presumed pathophysiology of cognitive decline in CKD, which consists of traditional and new vascular risk factors as well as nonvascular risk factors and metabolic and biochemical abnormalities within the central nervous system caused by CKD. The recent major cross-sectional studies and longitudinal studies – including one meta-analysis – that mostly suggest an association of cognitive decline and CKD are discussed. Finally, potential therapeutic strategies are presented.
doi:10.1186/s13195-015-0115-4
PMCID: PMC4360943  PMID: 25780391
10.  Changes in the neurochemistry of athletes with repetitive brain trauma: preliminary results using localized correlated spectroscopy 
Introduction
The goal was to identify which neurochemicals differ in professional athletes with repetitive brain trauma (RBT) when compared to healthy controls using a relatively new technology, in vivo Localized COrrelated SpectroscopY (L-COSY).
Methods
To achieve this, L-COSY was used to examine five former professional male athletes with 11 to 28 years of exposure to contact sports. Each athlete who had had multiple symptomatic concussions and repetitive sub concussive trauma during their career was assessed by an experienced neuropsychologist. All athletes had clinical symptoms including headaches, memory loss, confusion, impaired judgment, impulse control problems, aggression, and depression. Five healthy men, age and weight matched to the athlete cohort and with no history of brain trauma, were recruited as controls. Data were collected from the posterior cingulate gyrus using a 3 T clinical magnetic resonance scanner equipped with a 32 channel head coil.
Results
The variation of the method was calculated by repeated examination of a healthy control and phantom and found to be 10% and 5%, respectively, or less. The L-COSY measured large and statistically significant differences (P ≤0.05), between healthy controls and those athletes with RBT. Men with RBT showed higher levels of glutamine/glutamate (31%), choline (65%), fucosylated molecules (60%) and phenylalanine (46%). The results were evaluated and the sample size of five found to achieve a significance level P = 0.05 and a power of 90%. Differences in N-acetyl aspartate and myo-inositol between RBT and controls were small and were not statistically significance.
Conclusions
A study of a small cohort of professional athletes, with a history of RBT and symptoms of chronic traumatic encephalopathy when compared with healthy controls using 2D L-COSY, showed elevations in brain glutamate/glutamine and choline as recorded previously for early traumatic brain injury. For the first time increases in phenylalanine and fucose are recorded in the brains of athletes with RBT. Larger studies utilizing the L-COSY method may offer an in-life method of diagnosis and personalized approach for monitoring the acute effects of mild traumatic brain injury and the chronic effects of RBT.
doi:10.1186/s13195-015-0094-5
PMCID: PMC4361214  PMID: 25780390
11.  Interpreting Alzheimer’s disease clinical trials in light of the effects on amyloid-β 
The failure of several potential Alzheimer’s disease therapeutics in mid- to late-stage clinical development has provoked significant discussion regarding the validity of the amyloid hypothesis. In this review, we propose a minimum criterion of 25% for amyloid-β (Aβ) lowering to achieve clinically meaningful slowing of disease progression. This criterion is based on genetic, risk factor, clinical and preclinical studies. We then compare this minimum criterion with the degree of Aβ lowering produced by the potential therapies that have failed in clinical trials. If the proposed minimum Aβ lowering criterion is used, then the amyloid hypothesis has yet to be adequately tested in the clinic. Therefore, we believe that the amyloid hypothesis remains valid and remains to be confirmed or refuted in future clinical trials.
doi:10.1186/alzrt244
PMCID: PMC4014014  PMID: 25031632
12.  Responder analysis of a randomized comparison of the 13.3 mg/24 h and 9.5 mg/24 h rivastigmine patch 
Introduction
OPtimizing Transdermal Exelon In Mild-to-moderate Alzheimer’s disease (OPTIMA) was a randomized, double-blind comparison of 13.3 mg/24 h versus 9.5 mg/24 h rivastigmine patch in patients with mild-to-moderate Alzheimer’s disease who declined despite open-label treatment with 9.5 mg/24 h patch. Over 48 weeks of double-blind treatment, high-dose patch produced greater functional and cognitive benefits compared with 9.5 mg/24 h patch.
Methods
Using OPTIMA data, a post-hoc responder analysis was performed to firstly, compare the proportion of patients demonstrating improvement or absence of decline with 13.3 mg/24 h versus 9.5 mg/24 h patch; and secondly, identify predictors of improvement or absence of decline. ‘Improvers’ were patients who improved on the Alzheimer’s Disease Assessment Scale–cognitive subscale (ADAS-cog) by ≥4 points from baseline, and did not decline on the instrumental domain of the Alzheimer’s Disease Cooperative Study–Activities of Daily Living scale (ADCS-IADL). ‘Non-decliners’ were patients who did not decline on either scale.
Results
Overall, 265 patients randomized to 13.3 mg/24 h and 271 to 9.5 mg/24 h patch met the criteria for inclusion in the intention-to-treat population and were included in the analyses. Significantly more patients were ‘improvers’ with 13.3 mg/24 h compared with 9.5 mg/24 h patch at Weeks 24 (44 (16.6%) versus 19 (7.0%); P < 0.001) and 48 (21 (7.9%) versus 10 (3.7%); P = 0.023). A significantly greater proportion of patients were ‘non-decliners’ with 13.3 mg/24 h compared with 9.5 mg/24 h patch at Week 24 (71 (26.8%) versus 44 (16.2%); P = 0.002). At Week 48, there was a trend in favor of 13.3 mg/24 h patch. Functional and cognitive assessment scores at double-blind baseline did not consistently predict effects at Weeks 24 or 48.
Conclusion
More patients with mild-to-moderate Alzheimer’s disease who are titrated to 13.3 mg/24 h rivastigmine patch at time of decline are ‘improvers’ or ‘non-decliners’ i.e. show responses on cognition and activities of daily living compared with patients remaining on 9.5 mg/24 h patch.
Trial registration
Clinicaltrials.gov identifier: NCT00506415; registered July 20, 2007.
Electronic supplementary material
The online version of this article (doi:10.1186/s13195-014-0088-8) contains supplementary material, which is available to authorized users.
doi:10.1186/s13195-014-0088-8
PMCID: PMC4353453  PMID: 25755685
13.  Protein recycling pathways in neurodegenerative diseases 
Many progressive neurodegenerative diseases, including Alzheimer disease, Parkinson disease, Huntington disease, amyotrophic lateral sclerosis, and frontotemporal lobe dementia, are associated with the formation of insoluble intracellular proteinaceous inclusions. It is therefore imperative to understand the factors that regulate normal, as well as abnormal, protein recycling in neurons. Dysfunction of the ubiquitin-proteasome or autophagy pathways might contribute to the pathology of various neurodegenerative diseases. Induction of these pathways may offer a rational therapeutic strategy for a number of these diseases.
doi:10.1186/alzrt243
PMCID: PMC4055009  PMID: 25031631
14.  Predicting amyloid status in corticobasal syndrome using modified clinical criteria, magnetic resonance imaging and fluorodeoxyglucose positron emission tomography 
Introduction
Group comparisons demonstrate greater visuospatial and memory deficits and temporoparietal-predominant degeneration on neuroimaging in patients with corticobasal syndrome (CBS) found to have Alzheimer’s disease (AD) pathology versus those with underlying frontotemporal lobar degeneration (FTLD). The value of these features in predicting underlying AD pathology in individual patients is unknown. The goal of this study is to evaluate the utility of modified clinical criteria and visual interpretations of magnetic resonance imaging (MRI) and fluorodeoxyglucose positron emission tomography (FDG-PET) for predicting amyloid deposition (as a surrogate of Alzheimer’s disease neuropathology) in patients presenting with CBS.
Methods
In total, 25 patients meeting CBS core criteria underwent amyloid (Pittsburgh compound B; PIB) PET scans. Clinical records, MRI, and FDG scans were reviewed blinded to PIB results. Modified clinical criteria were used to classify CBS patients as temporoparietal variant CBS (tpvCBS) or frontal variant CBS (fvCBS). MRI and FDG-PET were classified based on the predominant atrophy/hypometabolism pattern (frontal or temporoparietal).
Results
A total of 9 out of 13 patients classified as tpvCBS were PIB+, compared to 2out of 12 patients classified as fvCBS (P < 0.01, sensitivity 82%, specificity 71% for PIB+ status). Visual MRI reads had 73% sensitivity and 46% specificity for PIB+ status with moderate intra-rater reliability (Cohen’s kappa = 0.42). Visual FDG reads had higher sensitivity (91%) for PIB+ status with perfect intra-rater reliability (kappa = 1.00), though specificity was low (50%). PIB results were confirmed in all 8 patients with available histopathology (3 PIB+ with confirmed AD, 5 PIB- with FTLD).
Conclusions
Splitting CBS patients into frontal or temporoparietal clinical variants can help predict the likelihood of underlying AD, but criteria require further refinement. Temporoparietal-predominant neuroimaging patterns are sensitive but not specific for AD.
Electronic supplementary material
The online version of this article (doi:10.1186/s13195-014-0093-y) contains supplementary material, which is available to authorized users.
doi:10.1186/s13195-014-0093-y
PMCID: PMC4346122  PMID: 25733984
15.  Clinical and imaging features of mixed Alzheimer and vascular pathologies 
The co-occurrence of both Alzheimer disease (AD) pathology and vascular brain injury (VBI) is very common, especially amongst the oldest of old. In neuropathologic studies, the prevalence of AD, VBI, and mixed AD/VBI lesions ranks ahead of Lewy bodies and hippocampal sclerosis. In the modern era of structural magnetic resonance imaging (MRI) and amyloid positron emission tomography (PET) imaging, this review examines 1) the prevalence of mixed AD and VBI pathology, 2) the significance of these pathologies for cognitive impairment (AD and vascular cognitive impairment (VCI)), and 3) the diagnosis and treatment of mixed AD/VCI. Although epidemiologic studies report that vascular risk factors for arteriosclerosis increase the risk of incident AD, both autopsy and amyloid PET studies indicate that AD and VBI contribute additively, but independently, to the risk of dementia. The literature confirms the malignancy of AD and highlights the adverse effects of microinfarcts on cognitive function. For the clinical diagnosis of mixed AD/VCI, the presence of AD can be recognized by neuropsychological profile, structural imaging, cerebrospinal fluid biomarkers, and glucose PET and amyloid PET imaging. The diagnosis of VBI, however, still hinges predominantly on the structural MRI findings. Severe amnesia and atrophy of the hippocampus are characteristic of early AD, whereas the cognitive profile for VCI is highly variable and dependent on size and location of VBI. The cognitive profile of mixed AD/VBI is dominated by AD. With the notable exception of microinfarcts (which elude in vivo detection), infarcts, hemorrhages, and white matter hyperintensities on structural MRI currently represent the best markers for the presence VBI. Better markers that reflect the health and reactivity of intracerebral blood vessels are needed. For prevention and treatment, the type of underlying cerebrovascular disease (for example, arteriosclerosis or cerebral amyloid angiopathy) should be considered. It is likely that reduction of vascular risk factors for arteriosclerosis can significantly reduce vascular contributions to mixed dementia.
doi:10.1186/s13195-015-0104-7
PMCID: PMC4342006  PMID: 25722748
16.  ‘Hearts and minds’: association, causation and implication of cognitive impairment in heart failure 
The clinical syndrome of heart failure is one of the leading causes of hospitalisation and mortality in older adults. An association between cognitive impairment and heart failure is well described but our understanding of the relationship between the two conditions remains limited. In this review we provide a synthesis of available evidence, focussing on epidemiology, the potential pathogenesis, and treatment implications of cognitive decline in heart failure. Most evidence available relates to heart failure with reduced ejection fraction and the syndromes of chronic cognitive decline or dementia. These conditions are only part of a complex heart failure-cognition paradigm. Associations between cognition and heart failure with preserved ejection fraction and between acute delirium and heart failure also seem evident and where data are available we will discuss these syndromes. Many questions remain unanswered regarding heart failure and cognition. Much of the observational evidence on the association is confounded by study design, comorbidity and insensitive cognitive assessment tools. If a causal link exists, there are several potential pathophysiological explanations. Plausible underlying mechanisms relating to cerebral hypoperfusion or occult cerebrovascular disease have been described and it seems likely that these may coexist and exert synergistic effects. Despite the prevalence of the two conditions, when cognitive impairment coexists with heart failure there is no specific guidance on treatment. Institution of evidence-based heart failure therapies that reduce mortality and hospitalisations seems intuitive and there is no signal that these interventions have an adverse effect on cognition. However, cognitive impairment will present a further barrier to the often complex medication self-management that is required in contemporary heart failure treatment.
doi:10.1186/s13195-015-0106-5
PMCID: PMC4342092  PMID: 25722749
17.  Neuroimaging in repetitive brain trauma 
Sports-related concussions are one of the major causes of mild traumatic brain injury. Although most patients recover completely within days to weeks, those who experience repetitive brain trauma (RBT) may be at risk for developing a condition known as chronic traumatic encephalopathy (CTE). While this condition is most commonly observed in athletes who experience repetitive concussive and/or subconcussive blows to the head, such as boxers, football players, or hockey players, CTE may also affect soldiers on active duty. Currently, the only means by which to diagnose CTE is by the presence of phosphorylated tau aggregations post-mortem. Non-invasive neuroimaging, however, may allow early diagnosis as well as improve our understanding of the underlying pathophysiology of RBT. The purpose of this article is to review advanced neuroimaging methods used to investigate RBT, including diffusion tensor imaging, magnetic resonance spectroscopy, functional magnetic resonance imaging, susceptibility weighted imaging, and positron emission tomography. While there is a considerable literature using these methods in brain injury in general, the focus of this review is on RBT and those subject populations currently known to be susceptible to RBT, namely athletes and soldiers. Further, while direct detection of CTE in vivo has not yet been achieved, all of the methods described in this review provide insight into RBT and will likely lead to a better characterization (diagnosis), in vivo, of CTE than measures of self-report.
doi:10.1186/alzrt239
PMCID: PMC3978843  PMID: 25031630
18.  Neural correlates of visual hallucinations in dementia with Lewy bodies 
Introduction
The aim of this study was to investigate the association between visual hallucinations in dementia with Lewy bodies (DLB) and brain perfusion using single-photon emission computed tomography.
Methods
We retrospectively included 66 patients with DLB, 36 of whom were having visual hallucinations (DLB-hallu) and 30 of whom were not (DLB-c). We assessed visual hallucination severity on a 3-point scale of increasing severity: illusions, simple visual hallucinations and complex visual hallucinations. We performed voxel-level comparisons between the two groups and assessed correlations between perfusion and visual hallucinations severity.
Results
We found a significant decrease in perfusion in the left anterior cingulate cortex, the left orbitofrontal cortex and the left cuneus in the DLB-hallu group compared with the DLB-c group. We also found a significant correlation between decreased bilateral anterior cingulate cortex, left orbitofrontal cortex, right parahippocampal gyrus, right inferior temporal cortex and left cuneus perfusion with the severity of hallucinations.
Conclusions
Visual hallucinations seem to be associated with the impairment of anterior and posterior regions (secondary visual areas, orbitofrontal cortex and anterior cingulate cortex) involved in a top-down and bottom-up mechanism, respectively. Furthermore, involvement of the bilateral anterior cingulate cortex and right parahippocampal gyrus seems to lead to more complex hallucinations.
doi:10.1186/s13195-014-0091-0
PMCID: PMC4339752  PMID: 25717349
19.  The monoaminergic footprint of depression and psychosis in dementia with Lewy bodies compared to Alzheimer’s disease 
Introduction
Depression and psychosis are two of the most severe neuropsychiatric symptoms (NPS) in dementia with Lewy bodies (DLB) and Alzheimer’s disease (AD). Both NPS have negative effects on cognitive performance and life expectancy. The current study aimed to investigate and compare monoaminergic etiologies between both neurodegenerative conditions, given the lack of an efficient pharmacological treatment until present.
Methods
Eleven behaviorally relevant brain regions of the left frozen hemisphere of 10 neuropathologically confirmed AD patients with/without depression (AD + D/-D; 5 were psychotic within AD + D), 10 confirmed DLB patients, all of whom were depressed (DLB + D; 5 psychotic patients), and, finally, 10 confirmed control subjects were regionally dissected. All patients were retrospectively assessed before death using the Behavioral Pathology in Alzheimer’s Disease Rating Scale (Behave-AD) and Cornell Scale for Depression in Dementia amongst others. The concentrations of dopamine (DA), serotonin (5-HT), (nor)adrenaline and respective metabolites, i.e. 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), 5-hydroxy-3-indoleacetic acid (5-HIAA), and, 3-methoxy-4-hydroxyphenylglycol (MHPG), were determined using reversed-phase high-performance liquid chromatography with electrochemical detection.
Results
DLB subjects had the overall lowest monoamine and metabolite concentrations regarding 33 out of 41 significant monoaminergic group alterations. Moreover, MHPG levels were significantly decreased in almost 8 out of 11 brain regions of DLB- compared to AD patients. We also observed the lowest 5-HT and 5-HIAA levels, and 5-HIAA/5-HT turnover ratios in DLB + D compared to AD + D subjects. Additionally, a 4- and 7-fold increase of DOPAC/DA and HVA/DA turnover ratios, and, a 10-fold decrease of thalamic DA levels in DLB + D compared to AD + D patients and control subjects was noticed. Regarding psychosis, hippocampal DA levels in the overall DLB group significantly correlated with Behave-AD AB scores. In the total AD group, DA levels and HVA/DA ratios in the amygdala significantly correlated with Behave-AD AB scores instead.
Conclusions
Monoaminergic neurotransmitter alterations contribute differently to the pathophysiology of depression and psychosis in DLB as opposed to AD, with a severely decreased serotonergic neurotransmission as the main monoaminergic etiology of depression in DLB. Similarly, psychosis in DLB might, in part, be etiologically explained by dopaminergic alterations in the hippocampus, whereas in AD, the amygdala might be involved.
doi:10.1186/s13195-014-0090-1
PMCID: PMC4339739  PMID: 25717350
20.  Fyn kinase inhibition as a novel therapy for Alzheimer’s disease 
Alzheimer’s disease (AD) is a devastating neurodegenerative disorder, afflicting more than one-third of people over the age of 85. While many therapies for AD are in late-stage clinical testing, rational drug design based on distinct signaling pathways in this disorder is only now emerging. Here we review the putative signaling pathway of amyloid-beta (Aβ), by which the tyrosine kinase Fyn is activated via cell surface binding of Aβ oligomers to cellular prion protein. Several lines of evidence implicate Fyn in the pathogenesis of AD, and its interaction with both Aβ and Tau renders Fyn a unique therapeutic target that addresses both of the major pathologic hallmarks of AD. We are currently enrolling patients in a phase Ib study of saracatinib (AZD0530), a small molecule inhibitor with high potency for Src and Fyn, for the treatment of AD. The results of this trial and a planned phase IIa multisite study will provide important data regarding the potential for this therapeutic strategy in AD.
doi:10.1186/alzrt238
PMCID: PMC3978417  PMID: 24495408
21.  Long-term donepezil use for dementia with Lewy bodies: results from an open-label extension of Phase III trial 
Introduction
The long-term efficacy and safety of donepezil 10 mg in patients with dementia with Lewy bodies (DLB) were investigated in a 52-week Phase 3 trial.
Methods
This 52-week study consisted of 16-week randomized placebo-controlled (RCT) and 36-week open-label extension phases. Of 142 DLB patients enrolled in the RCT phase (three arms: placebo, 5 mg, and 10 mg), 110 entered the extension phase. The placebo group of the RCT phase initiated active treatment at week 16, and the active groups maintained allocated treatment and dosages until week 24. After week 24, all patients received 10 mg. Dose reduction to 5 mg for safety concerns was allowed. Efficacy measures included Mini-Mental State Examination (MMSE) for cognitive function and Neuropsychiatric Inventory (NPI) for behavioral symptoms. Safety evaluations included adverse events (AEs) and the unified Parkinson disease rating scale.
Results
In total, 100 subjects completed the study. Cognitive function improvement was sustained for 52 weeks (MMSE at week 52 in 10 mg: 2.8 ± 3.5 (mean ± standard deviation); P <0.001, Student paired t test)). Those who received placebo in the RCT phase showed an improvement after starting active treatment. NPI improved in all the groups throughout the study, including the placebo period. In the subgroup of the 5 mg group without remarkable cognitive or behavioral improvement at week 24, further improvement was observed after a dose increase to 10 mg. After week 24, 21 patients experienced dose reduction. The incidence of any AEs did not increase over time.
Conclusions
The long-term administration of donepezil at 10 mg/day improved cognitive function for up to 52 weeks in patients with DLB without increasing the risk of clinically significant safety events.
Trial registration
NCT01278407. Trial registration date: January 14, 2011.
Electronic supplementary material
The online version of this article (doi:10.1186/s13195-014-0081-2) contains supplementary material, which is available to authorized users.
doi:10.1186/s13195-014-0081-2
PMCID: PMC4338564  PMID: 25713600
22.  Donepezil for dementia with Lewy bodies: a randomized, placebo-controlled, confirmatory phase III trial 
Introduction
The efficacy of a cholinesterase inhibitor, donepezil, in patients with dementia with Lewy bodies (DLB) was investigated to confirm the superiority over placebo in the 12-week, double-blind phase of this phase III study.
Methods
Patients with probable DLB (n = 142) were randomly assigned to placebo or to 5 mg or 10 mg of donepezil administered once daily for 12 weeks. The co–primary endpoints were changes in cognitive function assessed using the Mini-Mental State Examination (MMSE) and behavioral and neuropsychiatric symptoms using the Neuropsychiatric Inventory (NPI-2: hallucinations and fluctuations). The superiority of each active group over placebo was determined with simultaneous statistical significance in both endpoints. Safety evaluations included adverse events (AEs) and the unified Parkinson's disease rating scale (UPDRS) part III.
Results
The predefined superiority of donepezil to the placebo was not confirmed in either active group in the primary analysis. MMSE score significantly improved compared to placebo in the 10 mg group (10 mg: 2.2 ± 0.4, placebo: 0.6 ± 0.5 (mean ± standard error); P = 0.016). The change in MMSE score in the 5 mg group was not significant (1.4 ± 0.5 (mean ± standard error); P = 0.232). Although NPI-2 improved compared to baseline in the active groups, the differences from placebo were not significant. Most AEs were mild or moderate. Although the incidence of parkinsonism was slightly higher in the 10 mg group, the change in the UPDRS score was minimal and without a significant difference from the placebo group.
Conclusions
The co–primary endpoints were not achieved in this trial. However, significant improvement in MMSE score was demonstrated with 10 mg, but not 5 mg, of donepezil. The evaluation of psychiatric symptoms might be affected by advanced education and instructions given to caregivers. Overall, donepezil was well tolerated in patients with DLB. With careful attention on gastrointestinal or parkinsonian symptoms, patients with DLB can safely benefit from treatment with donepezil.
Trial registration
ClinicalTrials.gov Identifier: NCT01278407 (trial registration date: 14 January 2011)
Electronic supplementary material
The online version of this article (doi:10.1186/s13195-014-0083-0) contains supplementary material, which is available to authorized users.
doi:10.1186/s13195-014-0083-0
PMCID: PMC4338565  PMID: 25713599
23.  Circulating biomarkers that predict incident dementia 
Dementia is currently diagnosed based on clinical symptoms and signs, but significant brain damage has already occurred by the time a clinical diagnosis of dementia is made, and it is increasingly recognized that this may be too late for any effective intervention. It would therefore be of great public health and preventive value to define a variety of biomarkers that could permit early detection of persons at a higher risk for developing dementia, and specifically dementia due to Alzheimer’s disease. Nevertheless, for the purpose of large-scale screening, circulating biomarkers are more appropriate because they are less invasive than lumbar puncture, less costly than brain amyloid imaging and can be easily assessed repeatedly in a primary care clinic setting. In this brief review we will review a number of candidate molecules implicated as possible predictors of dementia risk. These candidates include markers of vascular injury, metabolic and inflammatory states, amyloid and tau pathway markers, measures of neural degeneration and repair efforts, and other molecules that might contribute to anatomical and functional changes characteristic of dementia and Alzheimer’s disease.
doi:10.1186/alzrt235
PMCID: PMC4056619  PMID: 25031629
24.  Chronic traumatic encephalopathy: a spectrum of neuropathological changes following repetitive brain trauma in athletes and military personnel 
Chronic traumatic encephalopathy (CTE) is a progressive neurodegenerative disease that occurs in association with repetitive traumatic brain injury experienced in sport and military service. In most instances, the clinical symptoms of the disease begin after a long period of latency ranging from several years to several decades. The initial symptoms are typically insidious, consisting of irritability, impulsivity, aggression, depression, short-term memory loss and heightened suicidality. The symptoms progress slowly over decades to include cognitive deficits and dementia. The pathology of CTE is characterized by the accumulation of phosphorylated tau protein in neurons and astrocytes in a pattern that is unique from other tauopathies, including Alzheimer’s disease. The hyperphosphorylated tau abnormalities begin focally, as perivascular neurofibrillary tangles and neurites at the depths of the cerebral sulci, and then spread to involve superficial layers of adjacent cortex before becoming a widespread degeneration affecting medial temporal lobe structures, diencephalon and brainstem. Most instances of CTE (>85% of cases) show abnormal accumulations of phosphorylated 43 kDa TAR DNA binding protein that are partially colocalized with phosphorylated tau protein. As CTE is characterized pathologically by frontal and temporal lobe atrophy, by abnormal deposits of phosphorylated tau and by 43 kDa TAR DNA binding protein and is associated clinically with behavioral and personality changes, as well as cognitive impairments, CTE is increasingly categorized as an acquired frontotemporal lobar degeneration. Currently, some of the greatest challenges are that CTE cannot be diagnosed during life and the incidence and prevalence of the disorder remain uncertain. Furthermore, the contribution of age, gender, genetics, stress, alcohol and substance abuse to the development of CTE remains to be determined.
doi:10.1186/alzrt234
PMCID: PMC3979082  PMID: 24423082
25.  Fitting the epidemiology and neuropathology of the early stages of Alzheimer’s disease to prevent dementia 
Introduction
Recent research on biomarkers has made possible the diagnosis of pre-dementia and even preclinical Alzheimer’s disease (AD), thus providing the ideal context for prevention. The aim of this study was to investigate the epidemiology of the early stages of AD by fitting neuropathologic and epidemiological data to assess the feasibility of prevention programs.
Methods
The study addressed primarily the construction of a discrete event simulation model of the stages of dementia. Age was included in the mathematical functions to combine the two competitive risks that determine the epidemiology of AD, that is, time to onset of dementia and time until death by other causes. Subsequently, this model was calibrated to reproduce the prevalence of pathological findings associated with AD. The beginning of the preclinical stage was taken to coincide with Thal phase 1 deposition of amyloid-beta. The duration of the prodromal stage, marked by mild cognitive impairment, was based on a 10% annual conversion rate from this level of impairment to dementia. The validation of prevalence figures also permitted estimation of the incidence and duration of preclinical and prodromal stages.
Results
In Spain, half of the nearly 10 million people aged more than 60 years are in the early stages of AD; 35.9% are in a preclinical stage, and up to 14.2% are in a prodromal stage. However, dementia will develop in only 38% of this population. The weighted mean time to dementia was 22.0 years from the start of Thal phase 1 and 9.0 years from the start of phase 2. Results of simulation models showed a lack of correlation between clinical and pathological classifications.
Conclusions
These findings raise questions about the feasibility of drug-based prevention strategies. Currently, screening programs with biomarkers in the early stages of AD cannot be applied to the half of the general population older than 60 years. Hence, intensive research is needed regarding risk factors, so that more affordable strategies may be planned. More efficient criteria are also needed to select those subjects with mild cognitive impairment who have an increased probability of positive screening for biomarkers (prodromal stage).
Electronic supplementary material
The online version of this article (doi:10.1186/s13195-014-0079-9) contains supplementary material, which is available to authorized users.
doi:10.1186/s13195-014-0079-9
PMCID: PMC4338563  PMID: 25713598

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