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1.  Adjusting the compass: new insights into the role of angiogenesis in Alzheimer’s disease 
Growing evidence suggests that vascular perturbation plays a critical role in the pathogenesis of Alzheimer’s disease (AD). It appears to be a common feature in addition to the classic pathological hallmarks of amyloid beta (Aβ) plaques and neurofibrillary. Moreover, the accumulation of Aβ in the cerebral vasculature is closely associated with cognitive decline, and disruption of the blood–brain barrier (BBB) has been shown to coincide with the onset of cognitive impairment. Although it was originally hypothesized that the accumulation of Aβ and the subsequent disruption of the BBB were due to the impaired clearance of Aβ from the brain, a body of data now suggests an alternative hypothesis for vascular dysfunction in AD that amyloidogenesis promotes extensive neoangiogenesis leading to increased vascular permeability and subsequent hypervascularization. In this review, we discuss the role Aβ plays in angiogenesis of the neurovasculature and BBB and how it may contribute to the pathogenesis of AD. These studies suggest that interventions that directly or indirectly affect angiogenesis could have beneficial effects on amyloid and other pathways in AD.
doi:10.1186/alzrt230
PMCID: PMC4056615  PMID: 24351529
2.  Cerebral microbleeds: overview and implications in cognitive impairment 
Cerebral microbleeds (MBs) are small chronic brain hemorrhages which are likely caused by structural abnormalities of the small vessels of the brain. Owing to the paramagnetic properties of blood degradation products, MBs can be detected in vivo by using specific magnetic resonance imaging (MRI) sequences. Over the last decades, the implementation of these MRI sequences in both epidemiological and clinical studies has revealed MBs as a common finding in many different populations, including healthy individuals. Also, the topographic distribution of these MBs has been shown to be potentially associated with specific underlying vasculopathies. However, the clinical and prognostic significance of these small hemorrhages is still a matter of debate as well as a focus of extensive research. In this article, we aim to review the current knowledge on the pathophysiology and clinical implications of MBs, with special emphasis on the links between lobar MBs, cerebral amyloid angiopathy, and Alzheimer’s disease.
doi:10.1186/alzrt263
PMCID: PMC4075149  PMID: 24987468
3.  β-amyloid deposition is shifted to the vasculature and memory impairment is exacerbated when hyperhomocysteinemia is induced in APP/PS1 transgenic mice 
Introduction
Vascular dementia is the second most common cause of dementia after Alzheimer’s disease (AD). In addition, it is estimated that almost half of all AD patients have significant cerebrovascular disease comorbid with their AD pathology. We hypothesized that cerebrovascular disease significantly impacts AD pathological progression.
Methods
We used a dietary model of cerebrovascular disease that relies on the induction of hyperhomocysteinemia (HHcy). HHcy is a significant clinical risk factor for stroke, cardiovascular disease and type 2 diabetes. In the present study, we induced HHcy in APP/PS1 transgenic mice.
Results
While total β-amyloid (Aβ) load is unchanged across groups, Congophilic amyloid deposition was decreased in the parenchyma and significantly increased in the vasculature as cerebral amyloid angiopathy (CAA; vascular amyloid deposition) in HHcy APP/PS1 mice. We also found that HHcy induced more microhemorrhages in the APP/PS1 mice than in the wild-type mice and that it switched the neuroinflammatory phenotype from an M2a biased state to an M1 biased state. Associated with these changes was an induction of the matrix metalloproteinase protein 2 (MMP2) and MMP9 systems. Interestingly, after 6 months of HHcy, the APP/PS1 mice were cognitively worse than wild-type HHcy mice or APP/PS1 mice, indicative of an additive effect of the cerebrovascular pathology and amyloid deposition.
Conclusions
These data show that cerebrovascular disease can significantly impact Aβ distribution in the brain, favoring vascular deposition. We predict that the presence of cerebrovascular disease with AD will have a significant impact on AD progression and the efficacy of therapeutics.
doi:10.1186/alzrt262
PMCID: PMC4078260  PMID: 24991237
4.  Fluid biomarkers for diagnosing dementia: rationale and the Canadian Consensus on Diagnosis and Treatment of Dementia recommendations for Canadian physicians 
Alzheimer's Research & Therapy  2013;5(Suppl 1):S8.
Fluid biomarkers improve the diagnostic accuracy in dementia and provide an objective measure potentially useful as a therapeutic response in clinical trials. The role of fluid biomarkers in patient care is a rapidly evolving field. Here, we provide a review and recommendations regarding the use of fluid biomarkers in clinical practice as discussed at the Fourth Canadian Consensus Conference on the Diagnosis and Treatment of Dementia (CCCDTD4) convened in Montreal, 4 to 5 May 2012. At present, there is no consensus regarding the optimal methodology for conducting quantification of plasma amyloid-beta (Aβ) peptides. In addition, since there is insufficient evidence supporting clinical applications for plasma Aβ-peptide measures, the CCCDTD4 does not recommended plasma biomarkers either for primary care or for specialists. Evidence for CSF Aβ1-42, total tau and phosphorylated tau in the diagnosis of Alzheimer pathology is much stronger, and can be considered at the tertiary care level for selected cases to improve diagnostic certainty, particularly in those cases presenting atypical clinical features.
doi:10.1186/alzrt223
PMCID: PMC3980280  PMID: 24565514
5.  The association of angiotensin-converting enzyme with biomarkers for Alzheimer’s disease 
Introduction
Lower angiotensin-converting enzyme (ACE) activity could increase the risk of Alzheimer’s disease (AD) as ACE functions to degrade amyloid-β (Aβ). Therefore, we investigated whether ACE protein and activity levels in cerebrospinal fluid (CSF) and serum were associated with CSF Aβ, total tau (tau) and tau phosphorylated at threonine 181 (ptau).
Methods
We included 118 subjects from our memory clinic-based Amsterdam Dementia Cohort (mean age 66 ± 8 years) with subjective memory complaints (n = 40) or AD (n = 78), who did not use antihypertensive drugs. We measured ACE protein levels (ng/ml) and activity (RFU) in CSF and serum, and amyloid β1–42, tau and ptau (pg/ml) in CSF.
Results
Cross-sectional regression analyses showed that ACE protein level and activity in CSF and serum were lower in patients with AD compared to controls. Lower CSF ACE protein level, and to a lesser extent serum ACE protein level and CSF ACE activity, were associated with lower CSF Aβ, indicating more brain Aβ pathology; adjusted regression coefficients (B) (95% CI) per SD increase were 0.09 (0.04; 0.15), 0.06 (0.00; 0.12) and 0.05 (0.00; 0.11), respectively. Further, lower CSF ACE protein level was associated with lower CSF tau and ptau levels; adjusted B’s (95% CI) per SD increase were 0.15 (0.06; 0.25) and 0.17 (0.10; 0.25), respectively.
Conclusions
These results strengthen the hypothesis that ACE degrades Aβ. This could suggest that lowering ACE levels by for example ACE-inhibitors might have adverse consequences for patients with, or at risk for AD.
doi:10.1186/alzrt257
PMCID: PMC4075229  PMID: 24987467
6.  A coimmunization vaccine of Aβ42 ameliorates cognitive deficits without brain inflammation in an Alzheimer’s disease model 
Introduction
Vaccination against amyloid-β protein (Aβ42) induces high levels of antibody, making it a promising strategy for treating Alzheimer’s disease (AD). One drawback in the past was that clinical trial approval was withheld because of speculation that the Aβ42 vaccine induces CD4+ T cell infiltrations into the central nervous system. To reduce T-cell activation while concomitantly maintaining high anti-Aβ42 titers is a great challenge in immunology.
Methods
We aimed to demonstrate that coimmunization with Aβ42 protein and expression plasmid can be beneficial in a mouse AD model and can prevent inflammation. We immunized the AD mice with the coimmunization vaccine and assessed behavior change and Aβ42 deposition. Furthermore, to determine the safety of the coimmunization vaccine, we used an induced Aβ42-EAE model to mimic the meningoencephalitis that happened in the AN-1792 vaccine clinical phase II trial and tested whether the coimmunization vaccine could ameliorate T-cell-mediated brain inflammation.
Results
The coimmunization vaccination reduced Aβ plaques and significantly ameliorated cognitive deficit while inhibiting T-cell-mediated brain inflammation and infiltration. These studies demonstrate that the coimmunization strategy that we describe in this article can ameliorate AD pathology without notable adverse effects in mice.
Conclusions
A coimmunization strategy leading to the development of a safe immunotherapeutic/preventive protocol against AD in humans is warranted.
doi:10.1186/alzrt256
PMCID: PMC4075150  PMID: 24987466
7.  Levels of cerebrospinal fluid α-synuclein oligomers are increased in Parkinson’s disease with dementia and dementia with Lewy bodies compared to Alzheimer’s disease 
Introduction
The objective was to study whether α-synuclein oligomers are altered in the cerebrospinal fluid (CSF) of patients with dementia, including Parkinson disease with dementia (PDD), dementia with Lewy bodies (DLB), and Alzheimer disease (AD), compared with age-matched controls.
Methods
In total, 247 CSF samples were assessed in this study, including 71 patients with DLB, 30 patients with PDD, 48 patients with AD, and 98 healthy age-matched controls. Both total and oligomeric α-synuclein levels were evaluated by using well-established immunoassays.
Results
The levels of α-synuclein oligomers in the CSF were increased in patients with PDD compared with the controls (P < 0.05), but not in patients with DLB compared with controls. Interestingly, the levels of α-synuclein oligomers in the CSF were also significantly higher in patients with PDD (P < 0.01) and DLB (P < 0.05) compared with patients with AD. The levels of CSF α-synuclein oligomers and the ratio of oligomeric/total-α-synuclein could distinguish DLB or PDD patients from AD patients, with areas under the curves (AUCs) of 0.64 and 0.75, respectively. In addition, total-α-synuclein alone could distinguish DLB or PDD patients from AD patients, with an AUC of 0.80.
Conclusions
The levels of α-synuclein oligomers were increased in the CSF from α-synucleinopathy patients with dementia compared with AD cases.
doi:10.1186/alzrt255
PMCID: PMC4075410  PMID: 24987465
8.  Performance on a pattern separation task by Alzheimer’s patients shows possible links between disrupted dentate gyrus activity and apolipoprotein E ∈4 status and cerebrospinal fluid amyloid-β42 levels 
Introduction
Emerging evidence suggests that decreased adult hippocampal neurogenesis represents an early critical event in the course of Alzheimer’s disease (AD). In mice, adult neurogenesis is reduced by knock-in alleles for human apolipoprotein E (ApoE) ∈4. Decreased dentate gyrus (DG) neural progenitor cells proliferation has been observed in the triple-transgenic mouse model of AD (3xTg-AD); this reduction being directly associated with the presence of amyloid-β (Aβ) plaques and an increase in the number of Aβ-containing neurons in the hippocampus. Cognitive tasks involving difficult pattern separations have been shown to reflect DG activity and thus potentially neurogenesis in both animals and man. This study involved the administration of a pattern separation paradigm to Alzheimer’s patients to investigate relationships between task performance and both ApoE status and cerebrospinal fluid (CSF) Aβ42 levels.
Methods
The CDR System pattern separation task involves the presentation of pictures that must later be discriminated from closely similar pictures. This paper presents pattern separation data from 66 mild to moderate AD patients, of which 50 were genotyped and 65 in whom CSF Aβ42 was measured.
Results
ApoE ∈4 homozygotes were not compromised on the easy pattern separations compared with the other patients, but they were statistically significantly poorer at the difficult separations. In all patients CSF Aβ42 correlated significantly with the ability to make the difficult discriminations, but not easier discriminations. Pattern separation speed correlated negatively with CSF Aβ42, and thus the association was not due to increased impulsivity.
Conclusions
These are, to our knowledge, the first human pattern separation data to suggest a possible genetic link to poor hippocampal neurogenesis in AD, as well as a relationship to Aβ42. Therapies which target neurogenesis may thus be useful in preventing the early stages of AD, notably in ApoE ∈4 homocygotes.
doi:10.1186/alzrt250
PMCID: PMC4054957  PMID: 24735568
9.  Modulation of β-amyloid by a single dose of GSK933776 in patients with mild Alzheimer’s disease: a phase I study 
Introduction
In this study, we evaluated the safety and pharmacodynamic effects of the Fc-inactivated anti-β-amyloid (anti-Aβ) monoclonal antibody GSK933776 in patients with mild Alzheimer’s disease and mild cognitive impairment. Aβ and tau levels were investigated in cerebrospinal fluid (CSF), and the relationship between Aβ levels and Aβ modulation in plasma was explored. The feasibility of a continuous sampling method using a lumbar catheter was assessed.
Methods
This trial was a phase I, open-label, uncontrolled, single-dose, exploratory experimental medicine study of intravenous GSK933776 at doses of 1 mg/kg, 3 mg/kg or 6 mg/kg (n = 6/group). The time course of plasma and CSF concentrations of GSK933776 and Aβ was assessed. Sample size was based on feasibility, and no formal statistical analyses were performed.
Results
Following administration of GSK933776 at doses of 1 mg/kg, 3 mg/kg and 6 mg/kg, there were decreases from baseline in CSF Aβ1–42 (from 0 to 12 hours) by 22.8 pg/ml (6.2%), 43.5 pg/ml (9.2%) and 60.5 pg/ml (12.5%), respectively. Plasma concentrations of total Aβ18–35 and Aβ4228–42 increased immediately after infusion and CSF tau concentration increased slightly, but did not significantly change, following administration of all doses of GSK933776. Pharmacokinetics confirmed the presence of GSK933776 in the CSF, which exhibited a dose–response relationship. One patient underwent minor surgery without sequelae following a ruptured lumbar catheter.
Conclusion
GSK933776 demonstrated pharmacological activity and target engagement in CSF and plasma, and the continuous sampling method via a catheter successfully assessed the Aβ changes following single-dose administration of GSK933776.
Trial registration
ClinicalTrials.gov Identifier: NCT01424436. Registered 4 August 2011
doi:10.1186/alzrt249
PMCID: PMC4055052  PMID: 24716469
10.  TMEM106B expression is reduced in Alzheimer’s disease brains 
Introduction
TMEM106B is a transmembrane glycoprotein of unknown function located within endosome/lysosome compartments expressed ubiquitously in various cell types. Previously, the genome-wide association study (GWAS) identified a significant association of TMEM106B single nucleotide polymorphisms (SNPs) with development of frontotemporal lobar degeneration with ubiquitinated TAR DNA-binding protein-43 (TDP-43)-positive inclusions (FTLD-TDP), particularly in the patients exhibiting the progranulin (PGRN) gene (GRN) mutations. Recent studies indicate that TMEM106B plays a pathological role in various neurodegenerative diseases, including Alzheimer’s disease (AD). However, at present, the precise levels of TMEM106B expression in AD brains remain unknown.
Methods
By quantitative reverse transcription (RT)-PCR (qPCR), western blot and immunohistochemistry, we studied TMEM106B and PGRN expression levels in a series of AD and control brains, including amyotrophic lateral sclerosis, Parkinson’s disease, multiple system atrophy and non-neurological cases.
Results
In AD brains, TMEM106B mRNA and protein levels were significantly reduced, whereas PGRN mRNA levels were elevated, compared with the levels in non-AD brains. In all brains, TMEM106B was expressed in the majority of cortical neurons, hippocampal neurons, and some populations of oligodendrocytes, reactive astrocytes and microglia with the location in the cytoplasm. In AD brains, surviving neurons expressed intense TMEM106B immunoreactivity, while senile plaques, neurofibrillary tangles and the perivascular neuropil, almost devoid of TMEM106B, intensely expressed PGRN.
Conclusions
We found an inverse relationship between TMEM106B (downregulation) and PGRN (upregulation) expression levels in AD brains, suggesting a key role of TMEM106B in the pathological processes of AD.
doi:10.1186/alzrt247
PMCID: PMC4055042  PMID: 24684749
11.  Platelet-activating factor antagonists enhance intracellular degradation of amyloid-β42 in neurons via regulation of cholesterol ester hydrolases 
Introduction
The progressive dementia that is characteristic of Alzheimer’s disease is associated with the accumulation of amyloid-beta (Aβ) peptides in extracellular plaques and within neurons. Aβ peptides are targeted to cholesterol-rich membrane micro-domains called lipid rafts. Observations that many raft proteins undertake recycling pathways that avoid the lysosomes suggest that the accumulation of Aβ in neurons may be related to Aβ targeting lipid rafts. Here we tested the hypothesis that the degradation of Aβ by neurons could be increased by drugs affecting raft formation.
Methods
Primary neurons were incubated with soluble Aβ preparations. The amounts of Aβ42 in neurons or specific cellular compartments were measured by enzyme-linked immunosorbent assay. The effects of drugs on the degradation of Aβ42 were studied.
Results
Aβ42 was targeted to detergent-resistant, low-density membranes (lipid rafts), trafficked via a pathway that avoided the lysosomes, and was slowly degraded by neurons (half-life was greater than 5 days). The metabolism of Aβ42 was sensitive to pharmacological manipulation. In neurons treated with the cholesterol synthesis inhibitor squalestatin, less Aβ42 was found within rafts, greater amounts of Aβ42 were found in lysosomes, and the half-life of Aβ42 was reduced to less than 24 hours. Treatment with phospholipase A2 inhibitors or platelet-activating factor (PAF) antagonists had the same effects on Aβ42 metabolism in neurons as squalestatin. PAF receptors were concentrated in the endoplasmic reticulum (ER) along with enzymes that constitute the cholesterol ester cycle. The addition of PAF to ER membranes triggered activation of cholesterol ester hydrolases and the release of cholesterol from stores of cholesterol esters. An inhibitor of cholesterol ester hydrolases (diethylumbelliferyl phosphate) also increased the degradation of Aβ42 in neurons.
Conclusions
We conclude that the targeting of Aβ42 to rafts in normal cells is a factor that affects its degradation. Critically, pharmacological manipulation of neurons can significantly increase Aβ42 degradation. These results are consistent with the hypothesis that the Aβ-induced production of PAF controls a cholesterol-sensitive pathway that affects the cellular localization and hence the fate of Aβ42 in neurons.
doi:10.1186/alzrt245
PMCID: PMC4055000  PMID: 24625058
12.  A controlled trial of Partners in Dementia Care: veteran outcomes after six and twelve months 
Introduction
“Partners in Dementia Care” (PDC) tested the effectiveness of a care-coordination program integrating healthcare and community services and supporting veterans with dementia and their caregivers. Delivered via partnerships between Veterans Affairs medical centers and Alzheimer’s Association chapters, PDC targeted both patients and caregivers, distinguishing it from many non-pharmacological interventions. Hypotheses posited PDC would improve five veteran self-reported outcomes: 1) unmet need, 2) embarrassment about memory problems, 3) isolation, 4) relationship strain and 5) depression. Greater impact was expected for more impaired veterans. A unique feature was self-reported research data collected from veterans with dementia.
Methods and Findings
Five matched communities were study sites. Two randomly selected sites received PDC for 12 months; comparison sites received usual care. Three structured telephone interviews were completed every 6 months with veterans who could participate.
Results
Of 508 consenting veterans, 333 (65.6%) completed baseline interviews. Among those who completed baseline interviews, 263 (79.0%) completed 6-month follow-ups and 194 (58.3%) completed 12-month follow-ups. Regression analyses showed PDC veterans had significantly less adverse outcomes than those receiving usual care, particularly for more impaired veterans after 6 months, including reduced relationship strain (B = −0.09; p = 0.05), depression (B = −0.10; p = 0.03), and unmet need (B = −0.28; p = 0.02; and B = −0.52; p = 0.08). PDC veterans also had less embarrassment about memory problems (B = −0.24; p = 0.08). At 12 months, more impaired veterans had further reductions in unmet need (B = −0.96; p < 0.01) and embarrassment (B = −0.05; p = 0.02). Limitations included use of matched comparison sites rather than within-site randomization and lack of consideration for variation within the PDC group in amounts and types of assistance provided.
Conclusions
Partnerships between community and health organizations have the potential to meet the dementia-related needs and improve the psychosocial functioning of persons with dementia.
Trial Registry
NCT00291161
doi:10.1186/alzrt242
PMCID: PMC3978714  PMID: 24764496
13.  Histone deacetylase 6 inhibition improves memory and reduces total tau levels in a mouse model of tau deposition 
Introduction
Tau pathology is associated with a number of age-related neurodegenerative disorders. Few treatments have been demonstrated to diminish the impact of tau pathology in mouse models and none are yet effective in humans. Histone deacetylase 6 (HDAC6) is an enzyme that removes acetyl groups from cytoplasmic proteins, rather than nuclear histones. Its substrates include tubulin, heat shock protein 90 and cortactin. Tubastatin A is a selective inhibitor of HDAC6. Modification of tau pathology by specific inhibition of HDAC6 presents a potential therapeutic approach in tauopathy.
Methods
We treated rTg4510 mouse models of tau deposition and non-transgenic mice with tubastatin (25 mg/kg) or saline (0.9%) from 5 to 7 months of age. Cognitive behavior analysis, histology and biochemical analysis were applied to access the effect of tubastatin on memory, tau pathology and neurodegeneration (hippocampal volume).
Results
We present data showing that tubastatin restored memory function in rTg4510 mice and reversed a hyperactivity phenotype. We further found that tubastatin reduced the levels of total tau, both histologically and by western analysis. Reduction in total tau levels was positively correlated with memory improvement in these mice. However, there was no impact on phosphorylated forms of tau, either by histology or western analysis, nor was there an impact on silver positive inclusions histologically.
Conclusion
Potential mechanisms by which HDAC6 inhibitors might benefit the rTg4510 mouse include stabilization of microtubules secondary to increased tubulin acetylation, increased degradation of tau secondary to increased acetylation of HSP90 or both. These data support the use of HDAC6 inhibitors as potential therapeutic agents against tau pathology.
doi:10.1186/alzrt241
PMCID: PMC3978441  PMID: 24576665
14.  Assessing THK523 selectivity for tau deposits in Alzheimer’s disease and non–Alzheimer’s disease tauopathies 
Introduction
The introduction of tau imaging agents such as 18F-THK523 offers new hope for the in vivo assessment of tau deposition in tauopathies such as Alzheimer’s disease (AD), where preliminary 18F-THK523-PET studies have demonstrated significantly higher cortical retention of 18F-THK523 in AD compared to age-matched healthy individuals. In addition to AD, tau imaging with PET may also be of value in assessing non-AD tauopathies, such as corticobasal degeneration (CBD), progressive supranuclear palsy (PSP) and Pick’s disease (PiD).
Methods
To further investigate the ability of THK523 to recognize tau lesions, we undertook immunohistochemical and fluorescence studies in serial brain sections taken from individuals with AD (n = 3), CBD (n = 2), PSP (n = 1), PiD (n = 2) and Parkinson’s disease (PD; n = 2). In addition to the neuropathological analysis, one PSP patient had undergone a 18F-THK523 PET scan 5 months before death.
Results
Although THK523 labelled tau-containing lesions such as neurofibrillary tangles and neuropil threads in the hippocampus and frontal regions of AD brains, it failed to label tau-containing lesions in non-AD tauopathies. Furthermore, though THK523 faintly labelled dense-cored amyloid-β plaques in the AD frontal cortex, it failed to label α-synuclein-containing Lewy bodies in PD brain sections.
Conclusion
The results of this study suggest that 18F-THK523 selectively binds to paired helical filament tau in AD brains but does not bind to tau lesions in non-AD tauopathies, or to α-synuclein in PD brains.
doi:10.1186/alzrt240
PMCID: PMC3979096  PMID: 24572336
15.  Cognitive training and cognitive rehabilitation for persons with mild to moderate dementia of the Alzheimer's or vascular type: a review 
Cognitive impairments, and particularly memory deficits, are a defining feature of the early stages of Alzheimer's disease and vascular dementia. Interventions that target these cognitive deficits and the associated difficulties with activities of daily living are the subject of ever-growing interest. Cognitive training and cognitive rehabilitation are specific forms of non-pharmacological intervention to address cognitive and non-cognitive outcomes. The present review is an abridged version of a Cochrane Review and aims to systematically evaluate the evidence for these forms of intervention in people with mild Alzheimer's disease or vascular dementia. Randomized controlled trials (RCTs), published in English, comparing cognitive rehabilitation or cognitive training interventions with control conditions and reporting relevant outcomes for the person with dementia or the family caregiver (or both), were considered for inclusion. Eleven RCTs reporting cognitive training interventions were included in the review. A large number of measures were used in the different studies, and meta-analysis could be conducted for several primary and secondary outcomes of interest. Several outcomes were not measured in any of the studies. Overall estimates of the treatment effect were calculated by using a fixed-effects model, and statistical heterogeneity was measured by using a standard chi-squared statistic. One RCT of cognitive rehabilitation was identified, allowing the examination of effect sizes, but no meta-analysis could be conducted. Cognitive training was not associated with positive or negative effects in relation to any of the reported outcomes. The overall quality of the trials was low to moderate. The single RCT of cognitive rehabilitation found promising results in relation to some patient and caregiver outcomes and was generally of high quality. The available evidence regarding cognitive training remains limited, and the quality of the evidence needs to improve. However, there is still no indication of any significant benefits from cognitive training. Trial reports indicate that some gains resulting from intervention may not be captured adequately by available standardized outcome measures. The results of the single RCT of cognitive rehabilitation show promise but are preliminary in nature. Further well-designed studies of cognitive training and cognitive rehabilitation are required to provide more definitive evidence. Researchers should describe and classify their interventions appropriately by using the available terminology.
doi:10.1186/alzrt189
PMCID: PMC3979126  PMID: 23924584
16.  Early-onset dementias: diagnostic and etiological considerations 
Alzheimer's Research & Therapy  2013;5(Suppl 1):S7.
This paper summarizes the body of literature about early-onset dementia (EOD) that led to recommendations from the Fourth Canadian Consensus Conference on the Diagnosis and Treatment of Dementia. A broader differential diagnosis is required for EOD compared with late-onset dementia. Delays in diagnosis are common, and the social impact of EOD requires special care teams. The etiologies underlying EOD syndromes should take into account family history and comorbid diseases, such as cerebrovascular risk factors, that may influence the clinical presentation and age at onset. For example, although many EODs are more likely to have Mendelian genetic and/or metabolic causes, the presence of comorbidities may drive the individual at risk for late-onset dementia to manifest the symptoms at an earlier age, which contributes further to the observed heterogeneity and may confound diagnostic investigation. A personalized medicine approach to diagnosis should therefore be considered depending on the age at onset, clinical presentation, and comorbidities. Genetic counseling and testing as well as specialized biochemical screening are often required, especially in those under the age of 40 and in those with a family history of autosomal dominant or recessive disease. Novel treatments in the drug development pipeline for EOD, such as genetic forms of Alzheimer's disease, should target the specific pathogenic cascade implicated by the mutation or biochemical defect.
doi:10.1186/alzrt197
PMCID: PMC3936399  PMID: 24565469
17.  Amyloid-beta 42 adsorption following serial tube transfer 
Introduction
Cerebrospinal fluid (CSF) amyloid-beta 38 (Aβ38), 40 (Aβ40), 42 (Aβ42) and total tau (T-tau) are finding increasing utility as biomarkers of Alzheimer’s disease (AD). The purpose of this study was to determine whether measured CSF biomarker concentrations were affected by transfer of CSF between tubes, and whether addition of a non-ionic surfactant mitigates any observed effects.
Methods
AD and control CSF was transferred consecutively between polypropylene tubes. Aβ peptides and T-tau were measured with and without addition of Tween 20 (0.05%).
Results
Measured concentrations of Aβ42 decreased by approximately 25% with each consecutive transfer. Measured concentrations of Aβ38 and Aβ40 were also observed to decrease significantly with each consecutive transfer (approximately 16% loss per transfer). Measured concentrations of T-tau also decreased significantly, but at much smaller magnitude than the Aβ peptides (approximately 4% loss per transfer). The addition of Tween 20 mitigated this effect in all samples.
Conclusions
Consecutive CSF transfer between tubes has a significant impact on the measured concentration of all Aβ peptides, and significant effect of lesser magnitude on T-tau. This would be sufficient to alter biomarker ratios enough to mislead diagnosis. The introduction of Tween 20 at the initial aliquoting stage was observed to significantly mitigate this effect.
doi:10.1186/alzrt236
PMCID: PMC4059346  PMID: 24472496
18.  Epidemiology of neurodegeneration in American-style professional football players 
The purpose of this article is to review the history of head injuries in relation to American-style football play, summarize recent research that has linked football head injuries to neurodegeneration, and provide a discussion of the next steps for refining the examination of neurodegeneration in football players. For most of the history of football, the focus of media reports and scientific studies on football-related head injuries was on the acute or short-term effects of serious, traumatic head injuries. Beginning about 10 years ago, a growing concern developed among neurologists and researchers about the long-term effects that playing professional football has on the neurologic health of the players. Autopsy-based studies identified a pathologically distinct neurodegenerative disorder, chronic traumatic encephalopathy, among athletes who were known to have experienced concussive and subconcussive blows to the head during their playing careers. Football players have been well represented in these autopsy findings. A mortality study of a large cohort of retired professional football players found a significantly increased risk of death from neurodegeneration. Further analysis found that non-line players were at higher risk than line players, possibly because of an increased risk of concussion. Although the results of the studies reviewed do not establish a cause effect relationship between football-related head injury and neurodegenerative disorders, a growing body of research supports the hypothesis that professional football players are at an increased risk of neurodegeneration. Significant progress has been made in the last few years on detecting and defining the pathology of neurodegenerative diseases. However, less progress has been made on other factors related to the progression of those diseases in football players. This review identifies three areas for further research: (a) quantification of exposure - a consensus is needed on the use of clinically practical measurements of blows to the head among football players; (b) genetic susceptibility factors - a more rigorous set of unbiased epidemiological and clinical studies is needed before any causal relationships can be drawn between suspected genetic factors, head injury, and neurodegeneration; and (c) earlier detection and prevention of neurodegenerative diseases.
doi:10.1186/alzrt188
PMCID: PMC3978683  PMID: 23876143
19.  Evidence for impaired amyloid β clearance in Alzheimer's disease 
Alzheimer's disease (AD) is a common neurodegenerative disease characterized by the accumulation of extracellular plaques and intracellular tangles. Recent studies support the hypothesis that the accumulation of amyloid beta (Aβ) peptide within the brain arises from an imbalance of the production and clearance of Aβ. In rare genetic forms of AD, this imbalance is often caused by increased production of Aβ. However, recent evidence indicates that, in the majority of cases of AD, Aβ clearance is impaired. Apolipoprotein E (ApoE), the dominant cholesterol and lipid carrier in the brain, is critical for Aβ catabolism. The isoform of ApoE and its degree of lipidation critically regulate the efficiency of Aβ clearance. Studies in preclinical models of AD have demonstrated that coordinately increasing levels of ApoE and its lipid transporter, ABCA1, increases the clearance of Aβ, suggesting that this pathway may be a potential therapeutic target for AD.
doi:10.1186/alzrt187
PMCID: PMC3978761  PMID: 23849219
21.  Knowledge translation: an overview and recommendations in relation to the Fourth Canadian Consensus Conference on the Diagnosis and Treatment of Dementia 
Alzheimer's Research & Therapy  2013;5(Suppl 1):S6.
The growing population of persons with dementia in Canada and the provision of quality care for this population is an issue that no healthcare authority will escape. Physicians often view dementia as a difficult and time-consuming condition to diagnose and manage. Current evidence must be effectively transformed into usable recommendations for physicians; however, we know that use of evidence-based practice recommendations is a challenge in all realms of medical care, and failure to utilize these leads to less than optimal care for patients. Despite this expanding need for readily available resources, knowledge translation (KT) is often seen as a daunting, if not confusing, undertaking for researchers. Here we offer a brief introduction to the processes around KT, including terms and definitions, and outline some common KT frameworks including the knowledge to action cycle, the Promoting Action on Research Implementation in Health Services framework and the Consolidated Framework for Implementation Research. We also outline practical steps for planning and executing a KT strategy particularly around the implementation of recommendations for practice, and offer recommendations for KT planning in relation to the Fourth Canadian Consensus Conference on the Diagnosis and Treatment of Dementia.
doi:10.1186/alzrt202
PMCID: PMC3980259  PMID: 24565407
22.  Clinical applications of neuroimaging in patients with Alzheimer's disease: a review from the Fourth Canadian Consensus Conference on the Diagnosis and Treatment of Dementia 2012 
Alzheimer's Research & Therapy  2013;5(Suppl 1):S3.
In May 2012, the Fourth Canadian Consensus Conference on the Diagnosis and Treatment of Dementia brought together in Montreal experts from around Canada to update Canadian recommendations for the diagnosis and management of patients with neurodegenerative conditions associated with deterioration of cognition. Multiple topics were discussed. The present paper is a highly condensed version of those recommendations that were produced to support discussions in the field of neuroimaging for clinical diagnosis of those conditions.
doi:10.1186/alzrt199
PMCID: PMC3980588  PMID: 24565260
23.  Pharmacological recommendations for the symptomatic treatment of dementia: the Canadian Consensus Conference on the Diagnosis and Treatment of Dementia 2012 
Alzheimer's Research & Therapy  2013;5(Suppl 1):S5.
Background
While there have been no new medications approved for the treatment of Alzheimer's disease (AD) or other dementias in Canada since 2004, the Canadian Consensus Conference on the Diagnosis and Treatment of Dementia (CCCDTD) reviewed and updated the clinical practice guidelines on the pharmacological management of dementia that were published previously.
Methods
This review focused on the literature for the pharmacological treatment of dementia based on studies published since the third CCCDTD in 2006. A literature search of English-language medical databases was preformed for studies pertaining to the pharmacological treatment of AD and other dementias that examined the management of cognitive and functional impairment, as well as neuropsychiatric symptoms. All previous recommendations were reviewed, and only those that required updating based on new published studies were revised. Several new recommendations were also added. Recommendations were rated for quality of evidence and were approved by consensus.
Results
There were 15 revised or new recommendations approved by consensus. The revised recommendations included acknowledging that cholinesterase inhibitors (ChEIs) possess a class effect and any of the agents can be used for AD across the spectrum of severity and with co-existing cerebrovascular disease. There was insufficient evidence to recommend for or against the use of ChEIs in combination with memantine for the primary indication of treating neuropsychiatric symptoms, or for the treatment of vascular dementia. Recommendations for the discontinuation of cognitive enhancers were revised and clarified, as well as the risks associated with discontinuing these drugs. ChEIs were recommended as a treatment option for dementia with Parkinson's disease. Risks associated with use of antipsychotics for neuropsychiatric symptoms were strengthened, and guidelines regarding the use of antidepressants for affective disturbances in dementia were weakened, and are now considered an option but not a firm recommendation. Valproate was recommended not to be used, and there was insufficient evidence to recommend for or against the use of selective serotonin reuptake inhibitors or trazodone for the treatment of agitation and aggression.
Conclusion
In spite of the lack of new therapeutic agents for the treatment of dementia, recent studies have helped to clarify and strengthen recommendations to optimize the pharmacological management of these illnesses.
doi:10.1186/alzrt201
PMCID: PMC3980908  PMID: 24565367
24.  Definitions of dementia and predementia states in Alzheimer's disease and vascular cognitive impairment: consensus from the Canadian conference on diagnosis of dementia 
Alzheimer's Research & Therapy  2013;5(Suppl 1):S2.
There have been several newly proposed sets of diagnostic criteria for Alzheimer's disease/mild cognitive impairment, advanced by the National Institute of Aging/Alzheimer's Association working groups in 2011 and by the International Working Group in 2007 and 2010. These sets each aim to provide broader disease stage coverage with incorporation of disease biomarkers into the diagnostic process. They have focused particular attention on the earlier identification of disease with focus on the preclinical and predementia stages. This paper reviews these diagnostic criteria and provides 2012 consensus recommendations from the Canadian Consensus Conference on the Diagnosis and Treatment of Dementia on their applications in both clinical and research settings.
doi:10.1186/alzrt198
PMCID: PMC3981054  PMID: 24565215
25.  Role of emerging neuroimaging modalities in patients with cognitive impairment: a review from the Canadian Consensus Conference on the Diagnosis and Treatment of Dementia 2012 
Alzheimer's Research & Therapy  2013;5(Suppl 1):S4.
The Fourth Canadian Consensus Conference on the Diagnosis and Treatment of Dementia (CCCDTD4) was held 3 to 4 May 2012 in Montreal, Quebec, Canada. A group of neuroimaging experts were assigned the task of reviewing and summarizing the literature on clinical and research applications of different neuroimaging modalities in cognitive disorders. This paper summarizes the literature and recommendations made to the conference regarding the role of several emerging neuroimaging modalities in cognitive disorders. Functional magnetic resonance imaging (MRI), magnetic resonance spectroscopy, and diffusion tensor imaging are discussed in detail within this paper. Other emergent neuroimaging modalities such as positron emission tomography with novel ligands, high-field MRI, arterial spin labeling MRI and noncerebral blood flow single-photon emission computerized tomography are only discussed briefly. Neuroimaging modalities that were recommended at the CCCDTD4 for both clinical and research applications such as amyloid and flurodeoxyglucose positron emission tomography, computerized tomography and structural MRI are discussed in a separate paper by the same authors. A literature search was conducted using the PubMed database including articles in English that involved human subjects and covered the period from the last CCCDTD publication (CCCDTD3; January 2006) until April 2012. Search terms included the name of the specific modality, dementia, Alzheimer's disease, and mild cognitive impairment. A separate search used the same parameters but was restricted to review articles to identify recent evidence-based reviews. Case studies and small case series were not included. Papers representing current evidence were selected, reviewed, and summarized, and the results were presented at the CCCDTD4 meeting with recommendations regarding the utility of various neuroimaging modalities in cognitive disorders. The evidence was graded according to the Oxford Centre for Evidence Based Medicine guidelines. Due to the limitations of current evidence, the neuroimaging modalities discussed in this paper were not recommended for clinical investigation of patients presenting with cognitive impairment. However, in the research setting, each modality provides a unique contribution to the understanding of basic mechanisms and neuropathological markers of cognitive disorders, to the identification of markers for early detection and for the risk of conversion to dementia in the at-risk populations, to the differentiation between different types of cognitive disorders, and to the identification of treatment targets and indicators of treatment response. In conclusion, for all of the neuroimaging modalities discussed in this paper, further studies are needed to establish diagnostic utility such as validity, reliability, and predictive and prognostic value. More multicenter studies are therefore needed with standardized image acquisition, experimental protocols, definition of the clinical population studied, larger numbers of participants, and longer duration of follow-up to allow generalizability of the results to the individual patient.
doi:10.1186/alzrt200
PMCID: PMC3981649  PMID: 24565285

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