Journal of Alzheimer's Disease - Volume 62, issue 3

Authors: Dubois, Bruno

Article Type: Review Article

Abstract: The New Criteria for the diagnosis of Alzheimer’s disease (AD), published by a group of experts in 2007, have resulted in a revolution in the comprehension of the disease. Before 2007, the diagnosis of AD dementia was done through a process of exclusion: it was considered in the case of patients with a dementia syndrome without identified etiologies. This traditional algorithm had three major limitations that penalize the disease: 1) a low accuracy of the performance which may share responsibility for negative results in clinical trials; 2) a late identification of the patients only when they reach the threshold of …dementia which may delay the activation of optimal care; and last but not least, 3) an absence of clear recognition of AD as a disease because of the lack of specific arguments for its identification. Since 2007, the disease has gained a clear definition based on positive evidence: a specific clinical phenotype (the amnestic syndrome of the hippocampal type) and the presence of biomarkers, considered as a biological signature of the disease. Thanks to these positive arguments, AD is a clinically and biologically well-delineated disease, no longer defined as “probable”. It is now possible to certify that a given patient has or does not have the disease. Like diabetes, cancer, hyperthyroidism or any other disorder, AD has now a clear definition with well-defined borders. The disease has entered the world of medicine with identified diseases with a biological fingerprint. This is the story of this adventure that we will present now. Show more

Keywords: Alzheimer’s disease, biomarkers, criteria, diagnosis, preclinical stage, prodromal stage

DOI: 10.3233/JAD-170536

Citation: Journal of Alzheimer's Disease, vol. 62, no. 3, pp. 1059-1066, 2018

Authors: Molinuevo, José Luis | Minguillon, Carolina | Rami, Lorena | Gispert, Juan Domingo

Article Type: Review Article

Abstract: In the last decades, progress in neuroimaging techniques and cerebrospinal fluid assays has enabled the characterization of several Alzheimer’s disease (AD) biomarkers. This knowledge has shifted the conceptualization of AD from a clinical-pathological construct, where its diagnosis required the presence of dementia with distinct pathologic features, toward a clinical-biological one that recognizes AD as a pathological continuum with a clinical picture that ranges from normal cognition to a dementia stage. Specifically, AD is now divided into three stages: preclinical (abnormal biomarkers and no or only subtle cognitive impairment), mild cognitive impairment or prodromal AD (abnormal pathophysiological biomarkers and episodic memory …impairment), and dementia (abnormal biomarkers and clear cognitive and functional impairment). The possibility of assessing AD pathophysiology in vivo before the onset of clinical symptoms in the preclinical stage provides the unprecedented opportunity to intervene at earlier stages of the continuum in secondary prevention trials. Currently, large cohort studies of cognitively healthy participants are undergoing with the main aim of disentangling the natural history of AD to identify individuals with an increased risk of developing AD in the near future to be recruited in these clinical trials. In this paper, we review how the concept of AD has changed over the years as well as discuss the implications of this conceptual change. Show more

Keywords: Alzheimer’s disease, biomarkers, continuum, ethical challenges, preclinical, prevention

DOI: 10.3233/JAD-170698

Citation: Journal of Alzheimer's Disease, vol. 62, no. 3, pp. 1067-1077, 2018

Authors: Boada, Mercè | Santos-Santos, Miguel A. | Rodríguez-Gómez, Octavio | Alegret, Montserrat | Cañabate, Pilar | Lafuente, Asunción | Abdelnour, Carla | Buendía, Mar | de Dios, Maria José | Morera, América | Sanabria, Ángela | Campo, Laura | Ruiz, Agustín | Tárraga, Lluís

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) research is at a critical time. The global society is increasingly aware of the frightening rate of growth of the human and financial burden caused by this condition and of the urgent need to halt its progression. Consequently, the scientific community holds great responsibility to quickly put in place and optimize the machinery necessary for testing new treatments or interventions. In this context demand for participants for AD research is at an all-time high. In this review, we will focus on a methodological factor that is increasingly recognized as a key factor that shapes trial populations and …affects validity of results in clinical trials: patient engagement, recruitment, and retention. We outline specific problems relevant to patient engagement in AD including recruiting enough participants, difficulties in participant retention, ensuring the recruited sample is representative of the general AD population, the burden of screening failures, and new challenges related to recruiting in preclinical disease. To address the urgent need for more research studying the applicability and cost-effectiveness of different recruitment strategies across different settings and nationalities, we describe the Models of Patient Engagement for Alzheimer’s Disease (MOPEAD) project, a public-private partnership promoted by the Innovative Medicine Initiative (IMI), which will provide a large multinational quantitative analysis comparing different innovative recruitment models. We also discuss strategies that address each problem and draw on the experience of Fundació ACE to argue that focusing resources on comprehensive AD centers that offer coordinated clinical and social care and participate in basic and clinical research, is an effective and efficient way of implementing many of the discussed strategies. Show more

Keywords: Alzheimer’s disease, clinical trials, community outreach, Fundació ACE, MOPEAD, patient engagement, recruitment, retention

DOI: 10.3233/JAD-170866

Citation: Journal of Alzheimer's Disease, vol. 62, no. 3, pp. 1079-1090, 2018

Authors: van der Flier, Wiesje M. | Scheltens, Philip

Article Type: Review Article

Abstract: The Alzheimer center of the VU University Medical Center opened in 2000 and was initiated to combine both patient care and research. Together, to date, all patients forming the Amsterdam Dementia Cohort number almost 6,000 individuals. In this cohort profile, we provide an overview of the results produced based on the Amsterdam Dementia Cohort. We describe the main results over the years in each of these research lines: 1) early diagnosis, 2) heterogeneity, and 3) vascular factors. Among the most important research efforts that have also impacted patients’ lives and/or the research field, we count the development of novel, easy …to use diagnostic measures such as visual rating scales for MRI and the Amsterdam IADL Questionnaire, insight in different subgroups of AD, and findings on incidence and clinical sequelae of microbleeds. Finally, we describe in the outlook how our research endeavors have improved the lives of our patients. Show more

Keywords: Alzheimer’s disease, Amsterdam Dementia Cohort, dementia, diagnosis, heterogeneity, mild cognitive impairment, prognosis, vascular factors

DOI: 10.3233/JAD-170850

Citation: Journal of Alzheimer's Disease, vol. 62, no. 3, pp. 1091-1111, 2018

Authors: Borroni, Barbara | Benussi, Alberto | Premi, Enrico | Alberici, Antonella | Marcello, Elena | Gardoni, Fabrizio | Di Luca, Monica | Padovani, Alessandro

Article Type: Review Article

Abstract:  Frontotemporal dementia (FTD) is a heterogeneous clinical, genetic, and neuropathological disorder. Clinical diagnosis and prediction of neuropathological substrates are hampered by heterogeneous pictures. Diagnostic markers are key in clinical trials to differentiate FTD from other neurodegenerative dementias. In the same view, identifying the neuropathological hallmarks of the disease is key in light of future disease-modifying treatments. The aim of the present review is to unravel the progress in biomarker discovery, discussing the potential applications of available biological, imaging, and neurophysiological markers.

Keywords: Biomarkers, cerebrospinal fluid, frontotemporal lobar degeneration, neuroimaging, transcranial magneticstimulation

DOI: 10.3233/JAD-170584

Citation: Journal of Alzheimer's Disease, vol. 62, no. 3, pp. 1113-1123, 2018

Authors: Blennow, Kaj | Zetterberg, Henrik

Article Type: Review Article

Abstract: Following the development of the first methods to measure the core Alzheimer’s disease (AD) cerebrospinal fluid (CSF) biomarkers total-tau (T-tau), phosphorylated tau (P-tau) and the 42 amino acid form of amyloid-β (Aβ42 ), there has been an enormous expansion of this scientific research area. Today, it is generally acknowledged that these biochemical tests reflect several central pathophysiological features of AD and contribute diagnostically relevant information, also for prodromal AD. In this article in the 20th anniversary issue of the Journal of Alzheimer ’s Disease , we review the AD biomarkers, from early assay development to their entrance into diagnostic criteria. …We also summarize the long journey of standardization and the development of assays on fully automated instruments, where we now have high precision and stable assays that will serve as the basis for common cut-off levels and a more general introduction of these diagnostic tests in clinical routine practice. We also discuss the latest expansion of the AD CSF biomarker toolbox that now also contains synaptic proteins such as neurogranin, which seemingly is specific for AD and predicts rate of future cognitive deterioration. Last, we are at the brink of having blood biomarkers that may be implemented as screening tools in the early clinical management of patients with cognitive problems and suspected AD. Whether this will become true, and whether it will be plasma Aβ42 , the Aβ42/40 ratio, or neurofilament light, or a combination of these, remains to be established in future clinical neurochemical studies. Show more

Keywords: Alzheimer’s disease, amyloid, biomarkers, cerebrospinal fluid, neurogranin, plasma, tau

DOI: 10.3233/JAD-170773

Citation: Journal of Alzheimer's Disease, vol. 62, no. 3, pp. 1125-1140, 2018

Authors: Jellinger, Kurt A.

Article Type: Review Article

Abstract: Multiple system atrophy (MSA) is an orphan, fatal, adult-onset neurodegenerative disorder of uncertain etiology that is clinically characterized by various combinations of parkinsonism, cerebellar, autonomic, and motor dysfunction. MSA is an α-synucleinopathy with specific glioneuronal degeneration involving striatonigral, olivopontocerebellar, and autonomic nervous systems but also other parts of the central and peripheral nervous systems. The major clinical variants correlate with the morphologic phenotypes of striatonigral degeneration (MSA-P) and olivopontocerebellar atrophy (MSA-C). While our knowledge of the molecular pathogenesis of this devastating disease is still incomplete, updated consensus criteria and combined fluid and imaging biomarkers have increased its diagnostic accuracy. The …neuropathologic hallmark of this unique proteinopathy is the deposition of aberrant α-synuclein in both glia (mainly oligodendroglia) and neurons forming glial and neuronal cytoplasmic inclusions that cause cell dysfunction and demise. In addition, there is widespread demyelination, the pathogenesis of which is not fully understood. The pathogenesis of MSA is characterized by propagation of misfolded α-synuclein from neurons to oligodendroglia and cell-to-cell spreading in a “prion-like” manner, oxidative stress, proteasomal and mitochondrial dysfunction, dysregulation of myelin lipids, decreased neurotrophic factors, neuroinflammation, and energy failure. The combination of these mechanisms finally results in a system-specific pattern of neurodegeneration and a multisystem involvement that are specific for MSA. Despite several pharmacological approaches in MSA models, addressing these pathogenic mechanisms, no effective neuroprotective nor disease-modifying therapeutic strategies are currently available. Multidisciplinary research to elucidate the genetic and molecular background of the deleterious cycle of noxious processes, to develop reliable biomarkers and targets for effective treatment of this hitherto incurable disorder is urgently needed. Show more

Keywords: α-synuclein, diagnostic criteria, glio-neuronal degeneration, multiple system atrophy, oligodendroglial proteinopathy, pathogenesis, prion-like seeding

DOI: 10.3233/JAD-170397

Citation: Journal of Alzheimer's Disease, vol. 62, no. 3, pp. 1141-1179, 2018

Authors: Shi, Liu | Baird, Alison L. | Westwood, Sarah | Hye, Abdul | Dobson, Richard | Thambisetty, Madhav | Lovestone, Simon

Article Type: Review Article

Abstract: Blood-based biomarkers represent a less invasive and potentially cheaper approach for aiding Alzheimer’s disease (AD) detection compared with cerebrospinal fluid and some neuroimaging biomarkers. Acknowledging that many in the field have made great progress, here we review some of the work that our group has pursued to identify and validate blood-based proteomic biomarkers through both case control and AD pathology endophenotype-based approaches. Our focus is primarily to identify a minimally invasive and hopefully cost-effective blood-based biomarker to reduce screen failure in clinical trials where participants have prodromal or even pre-clinical disease. We summarize some of the key findings and approaches …taken in these biomarker studies, while addressing the main challenges, including that of limited replication in the field, and discuss opportunities for biomarker development. Show more

Keywords: Alzheimer’s disease, blood proteomic biomarkers, endophenotype, replication, validation

DOI: 10.3233/JAD-170531

Citation: Journal of Alzheimer's Disease, vol. 62, no. 3, pp. 1181-1198, 2018

Authors: Bjerke, Maria | Engelborghs, Sebastiaan

Article Type: Review Article

Abstract: An accurate and early diagnosis of Alzheimer’s disease (AD) is important to select optimal patient care and is critical in current clinical trials targeting core AD neuropathological features. The past decades, much progress has been made in the development and validation of cerebrospinal fluid (CSF) biomarkers for the biochemical diagnosis of AD, including standardization and harmonization of (pre-) analytical procedures. This has resulted in three core CSF biomarkers for AD diagnostics, namely the 42 amino acid long amyloid-beta peptide (Aβ1-42 ), total tau protein (T-tau), and tau phosphorylated at threonine 181 (P-tau181 ). These biomarkers have been incorporated into research …diagnostic criteria for AD and have an added value in the (differential) diagnosis of AD and related disorders, including mixed pathologies, atypical presentations, and in case of ambiguous clinical dementia diagnoses. The implementation of the CSF Aβ1-42 /Aβ1-40 ratio in the core biomarker panel will improve the biomarker analytical variability, and will also improve early and differential AD diagnosis through a more accurate reflection of pathology. Numerous biomarkers are being investigated for their added value to the core AD biomarkers, aiming at the AD core pathological features like the amyloid mismetabolism, tau pathology, or synaptic or neuronal degeneration. Others aim at non-AD neurodegenerative, vascular or inflammatory hallmarks. Biomarkers are essential for an accurate identification of preclinical AD in the context of clinical trials with potentially disease-modifying drugs. Therefore, a biomarker-based early diagnosis of AD offers great opportunities for preventive treatment development in the near future. Show more

Keywords: Alzheimer’s disease, amyloid, biomarkers, cerebrospinal fluid, dementia, diagnosis, mild cognitive impairment, neuropathology, tau

DOI: 10.3233/JAD-170680

Citation: Journal of Alzheimer's Disease, vol. 62, no. 3, pp. 1199-1209, 2018

Authors: Baazaoui, Narjes | Iqbal, Khalid

Article Type: Review Article

Abstract: Alzheimer’s disease (AD), at present, is considered an incurable disease and a major dilemma with no drug to stop or slow down its progression. Drugs that are currently available in the market are able to only transiently improve the clinical symptoms. The repeated failures in developing an effective drug has led to the suggestion that the medical intervention was probably too late to be effective since the pathology starts many years before the appearance of the clinical symptoms. Probably, at the time of the appearance of clinical symptoms the brain has undergone major neuronal and synaptic loss. Because of the …uncertainty on when to use a prevention therapy, especially targeting amyloid-β (Aβ) and tau pathologies, interventions that rely on the regenerative capacity of the brain such as the modulation of the inherent neurogenesis and neuronal plasticity represent a promising therapeutic strategy. Such an approach can act both at early as well as late stages of the disease and remove the barrier of the time of intervention. In this article, we review studies mainly from our laboratory that show the merit of early intervention during the synaptic and neuronal compensation period where the brain still has the capacity to self-repair by offering neurotrophic support in reversing cognitive impairment, neuronal and synaptic deficits, Aβ, and tau pathologies and decreasing mortality in a transgenic mouse model of AD. Show more

Keywords: 3xTg-AD mice, Alzheimer’s disease, amyloid-β, ciliary neurotrophic factor, neurodegeneration, neuronal connectivity, neurotrophic factors, prevention, synaptic plasticity, tau, therapeutics

DOI: 10.3233/JAD-170839

Citation: Journal of Alzheimer's Disease, vol. 62, no. 3, pp. 1211-1218, 2018