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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
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.
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.
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.
PMCID: PMC3506933  PMID: 22643124
8.  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.
PMCID: PMC3978417  PMID: 24495408
9.  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.
PMCID: PMC4056619  PMID: 25031629
10.  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.
PMCID: PMC3979082  PMID: 24423082
11.  Open questions for Alzheimer’s disease immunotherapy 
Perhaps more definitively than any other class of novel Alzheimer’s disease (AD) therapy, pre-clinical studies in mouse models of amyloid β (Aβ) deposition have established the disease-modifying potential of anti-Aβ immunotherapy. Despite disappointing results to date from anti-Aβ immunotherapy therapeutic trials, there is continued hope that such immunotherapies, especially if used in the preclinical stages, could prove to be the first disease-modifying therapies available for AD. The general optimism that Aβ-targeting and emerging tau-targeting immunotherapies may prove to be disease modifying is tempered by many unanswered questions regarding these therapeutic approaches, including but not limited to i) lack of precise understanding of mechanisms of action, ii) the factors that regulate antibody exposure in the brain, iii) the optimal target epitope, and iv) the mechanisms underlying side effects. In this review I discuss how answering these and other questions could increase the likelihood of therapeutic success. As passive immunotherapies are also likely to be extremely expensive, I also raise questions relating to cost-benefit of biologic-based therapies for AD that could limit future impact of these therapies by limiting access due to economic constraints.
PMCID: PMC4056616  PMID: 24393284
12.  Clinicopathologic assessment and imaging of tauopathies in neurodegenerative dementias 
Microtubule-associated protein tau encoded by the MAPT gene binds to microtubules and is important for maintaining neuronal morphology and function. Alternative splicing of MAPT pre-mRNA generates six major tau isoforms in the adult central nervous system resulting in tau proteins with three or four microtubule-binding repeat domains. In a group of neurodegenerative disorders called tauopathies, tau becomes aberrantly hyperphosphorylated and dissociates from microtubules, resulting in a progressive accumulation of intracellular tau aggregates. The spectrum of sporadic frontotemporal lobar degeneration associated with tau pathology includes progressive supranuclear palsy, corticobasal degeneration, and Pick’s disease. Alzheimer’s disease is considered the most prevalent tauopathy. This review is divided into two broad sections. In the first section we discuss the molecular classification of sporadic tauopathies, with a focus on describing clinicopathologic relationships. In the second section we discuss the neuroimaging methodologies that are available for measuring tau pathology (directly using tau positron emission tomography ligands) and tau-mediated neuronal injury (magnetic resonance imaging and fluorodeoxyglucose positron emission tomography). Both sections have detailed descriptions of the following neurodegenerative dementias – Alzheimer’s disease, progressive supranuclear palsy, corticobasal degeneration and Pick’s disease.
PMCID: PMC3978456  PMID: 24382028
13.  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
14.  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
15.  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
16.  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
17.  Should interventions to treat or prevent Alzheimer’s disease be tested in a population or as targeted treatment of highly selected study participants? 
Symptomatic treatments for Alzheimer’s disease should retain a place in the advanced stages of disease since their actions on these symptoms, even if not modifying the course of disease, are critical for improving patients’ comfort and reducing the burden felt by caregivers, especially those facing behavioral disorders. In mild or prodromal stages, the opportunity to act on specific pathophysiological targets should be considered. These targeted and tailored therapies have the greatest chance to be active in the early stages of disease, in the context of heterogeneous pathological mechanisms to be specified by reliable and accessible biomarkers. Finally, interventional approaches in large populations seem particularly appropriate for prevention strategies.
PMCID: PMC3979024  PMID: 24325910
18.  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
19.  Protein quality control by Rer1p in the early secretory pathway: from mechanism to implication in Alzheimer’s disease 
γ-Secretase-mediated production of amyloid β from the amyloid precursor protein is recognized as a central player in the neuropathogenesis of Alzheimer’s disease (AD). One of the most peculiar features of this enzymatic activity is the fact that it targets transmembrane domains of mostly type I integral membrane proteins and thus manages to proteolyse peptide bonds within the hydrophobic lipid bilayers. In addition, γ-secretase does not exert its activity solely towards amyloid precursor protein, but to an increasing number of membrane proteins, including Notch, cadherins, syndecans, and so on. Because of the requirement of intramembrane proteolysis for a plethora of signaling pathways and cellular processes during embryonic development and organ physiology, this enzyme has drawn a lot of attention in the past 20 years. γ-Secretase is a multimeric transmembrane complex consisting of the catalytic presenilin, nicastrin, presenilin enhancer 2 (PEN2) and anterior-pharynx defective-1 (APH1) subunits. Proper assembly into functional complexes requires quality control mechanisms associated with the early biosynthetic compartments and allows mature complexes to transit to distal compartments where its activity is required. We previously identified Retrieval to ER protein 1 (Rer1p) as the first negative regulator of the stepwise assembly of γ-secretase during endoplasmic reticulum-to-Golgi transport. We review here the state of the art on how Rer1p regulates complex assembly, particularly γ-secretase, and evaluate the therapeutic potential of such regulatory processes in the context of AD.
PMCID: PMC3978424  PMID: 24314151
20.  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
21.  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
22.  Amyloid β-protein oligomers and Alzheimer’s disease 
The oligomer cascade hypothesis, which states that oligomers are the initiating pathologic agents in Alzheimer’s disease, has all but supplanted the amyloid cascade hypothesis, which suggested that fibers were the key etiologic agents in Alzheimer’s disease. We review here the results of in vivo, in vitro and in silico studies of amyloid β-protein oligomers, and discuss important caveats that should be considered in the evaluation of these results. This article is divided into four sections that mirror the main approaches used in the field to better understand oligomers: (1) attempts to locate and examine oligomers in vivo in situ; that is, without removing these species from their environment; (2) studies involving oligomers extracted from human or animal tissues and the subsequent characterization of their properties ex vivo; (3) studies of oligomers that have been produced synthetically and studied using a reductionist approach in relatively simple in vitro biophysical systems; and (4) computational studies of oligomers in silico. These multiple orthogonal approaches have revealed much about the molecular and cell biology of amyloid β-protein. However, as informative as these approaches have been, the amyloid β-protein oligomer system remains enigmatic.
PMCID: PMC3978746  PMID: 24289820
23.  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
24.  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
25.  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

Résultats 1-25 (263)