Journal of Alzheimer's Disease - Volume 68, issue 3

Authors: Cortés, Nicole | Guzmán-Martínez, Leonardo | Andrade, Víctor | González, Andrea | Maccioni, Ricardo B.

Article Type: Review Article

Abstract: The cyclin-dependent kinase 5 (CDK5) is known as an exceptional component of the CDK family, due to its characteristic regulatory pathways and its atypical roles in comparison to the classical cyclins. Despite its functional uniqueness, CDK5 shares a great part of its structural similarity with other members of the cyclin-dependent kinase family. After its discovery 26 years ago, a progressive set of cellular functions has been associated with this protein kinase, ranging from neuronal migration, axonal guidance, and synaptic plasticity in diverse stages of brain development, including specific and complex cognitive functions. More than 30 substrates for CDK5 have been …found in different cellular pathways. Together with its essential physiological roles, a major discovery was the finding twenty years ago that CDK5 participates in neurodegenerative diseases responsible for tau hyperphosphorylations, and, as a consequence, it becomes a neurotoxic factor. This review focuses on the wide roles of CDK5 in the central nervous system, its implications in neurodegeneration, and provides an integrative insight of its involvement in pain modulation, Alzheimer’s disease, and other contexts. Show more

Keywords: Alzheimer’s disease, CDK5, chemoreception, nervous system, tau

DOI: 10.3233/JAD-180792

Citation: Journal of Alzheimer's Disease, vol. 68, no. 3, pp. 843-855, 2019

Authors: Groussard, Mathilde | Chan, Tyler G. | Coppalle, Renaud | Platel, Hervé

Article Type: Review Article

Abstract: Through this review of 25 clinical and experimental works on long-term musical memories in Alzheimer’s disease (AD) patients, we attempt to clarify the conceptual understanding of musical memories, identify their evolution across the stages of the pathology, and propose possible explanations concerning the neural and cognitive mechanisms that underpin the preservation and impairment of certain musical memories. After clarifying the different kind of musical memories, we investigated their alterations throughout AD’s progression from mild to severe stages. Both procedural and retrograde semantic memory seem relatively spared in AD, while episodic memory appears to be impaired early. Moreover, partial preservation of …music encoding in AD can be revealed through paradigms that are especially designed for AD patients (relying on behavioral cues, using adapted settings, etc.). Although seldomly used, they would definitely help understanding the preserved capacities in every stage of AD. However, more research is needed to better understand this phenomenon and assess its specificity to music or other types of supports. These findings could lead to multiple applications in care settings and research designs, bringing more nuanced understanding of how long-term musical memory degrades throughout the course of AD, and should encourage us to prioritize patients’ preserved cognitive abilities in current AD recreational and care programs. Show more

Keywords: Alzheimer’s disease, care, memory, music, neuroimaging, preservation

DOI: 10.3233/JAD-180474

Citation: Journal of Alzheimer's Disease, vol. 68, no. 3, pp. 857-883, 2019

Authors: Smith, Carr J. | Ashford, J. Wesson | Perfetti, Thomas A.

Article Type: Review Article

Abstract: Inheritance of a single copy of the apolipoprotein E (APOE) ɛ 4 allele increases risk of Alzheimer’s disease (AD) by 3-4-fold, with homozygosity associated with a 12-16-fold increase in risk, relative to ɛ 3 allele homozygosity. There is a decreased risk associated with the APOE ɛ 2 allele. The pathological consequence of APOE genotype has led to intense efforts to understand the mechanistic basis of the interplay between APOE status and loss of synapses. Numerous ɛ 4 allele-related associations have been reported with the potential relevance of these associations to the pathogenesis of AD unknown at this time. In primarily …young subjects, we have reviewed a representative body of literature on ɛ 4 allele-associations related to the following: cardiovascular responses; impacts on reproduction and fetal development; co-morbidities; resistance to infectious disease; responses to head injury; biochemical differences possibly related to neural stress; and brain structure-function differences. In addition, the literature on the association between the ɛ 4 allele and cognitive performance has been reviewed comprehensively. The weight-of-the-evidence supports the hypothesis that possession of the ancestral ɛ 4 allele in youth is associated with improved fitness during fetal development, infancy, and youth relative to the more recently appearing ɛ 3 allele, at the expense of decreased fitness in old age, which is substantially improved by the ɛ 3 allele. However, possession of the ɛ 4 allele is also associated with higher levels of synaptic macromolecular turnover, which likely stresses basic cellular neuroplasticity mechanisms. Clinical trials of potential AD therapeutics should consider APOE status as an enrollment criterion. Show more

Keywords: Alzheimer’s disease, apolipoprotein E, ɛ4 allele, improved performance, youth

DOI: 10.3233/JAD-181089

Citation: Journal of Alzheimer's Disease, vol. 68, no. 3, pp. 885-923, 2019

Authors: Bohlken, Jens | Kostev, Karel

Article Type: Short Communication

Abstract: Little is known about the diagnostic methods currently used in routine care for patients with mild cognitive impairment (PwMCI). We estimated the frequency of diagnostic procedures in incident PwMCI compared to incident patients with dementia (PwD) in 2016-2017. The study is based on the Disease Analyzer database. After matching by age and sex, 4,700 PwMCI and 4,700 PwD were available. The diagnostic procedures were identified on the basis of the related medical fee schedule items. All diagnostic procedures were used more frequently in PwMCI than in PwD. The drafting of a practice-oriented MCI guideline is an important task for the future.

Keywords: Alzheimer’s disease, mild cognitive impairment, preclinical dementia, prevalence, real-world data

DOI: 10.3233/JAD-190012

Citation: Journal of Alzheimer's Disease, vol. 68, no. 3, pp. 925-930, 2019

Authors: Medoro, Alessandro | Bartollino, Silvia | Mignogna, Donatella | Marziliano, Nicola | Porcile, Carola | Nizzari, Mario | Florio, Tullio | Pagano, Aldo | Raimo, Gennaro | Intrieri, Mariano | Russo, Claudio

Article Type: Short Communication

Abstract: Certain proteases are involved in Alzheimer’s disease (AD) and their erroneous control may contribute to the pathology onset and progression. In this study we evaluated the cerebral expression of eight proteases, involved in both AβPP processing and extracellular matrix remodeling. Among these proteases, ADAM10, ADAMTS1, Cathepsin D, and Meprin β show a significantly higher mRNAs expression in sporadic AD subjects versus controls, while ADAMTS1, Cathepsin D, and Meprin β show an increment also at the protein level. These data indicate that transcriptional events affecting brain proteases are activated in AD patients, suggesting a link between proteolysis and AD.

Keywords: ADAMTS1, α-secretase, Alzheimer’s disease, cancer, Cathepsin D, Meprin β, RT-PCR, western blot

DOI: 10.3233/JAD-181284

Citation: Journal of Alzheimer's Disease, vol. 68, no. 3, pp. 931-938, 2019

Authors: Hollinger, Kristen R. | Alt, Jesse | Rais, Rana | Kaplin, Adam I. | Slusher, Barbara S.

Article Type: Short Communication

Abstract: Studies over the past two decades report significant reductions in brain N-acetylaspartyl glutamate (NAAG) levels in neurodegenerative diseases with associated cognitive impairment, including Alzheimer’s disease (AD). Because NAAG is cleaved by glutamate carboxypeptidase II (GCPII), restoration of brain NAAG levels via GCPII inhibition is a potential therapeutic strategy for AD. Herein, studies were conducted to identify an appropriate murine model of AD that recapitulates human brain NAAG changes in order to preclinically evaluate the therapeutic benefit of GCPII inhibition. Our opposing findings of brain NAAG changes in human and mouse AD highlights the limited predictive value of AD mouse models.

Keywords: Alzheimer’s disease, animal models, drug discovery, mass spectrometry

DOI: 10.3233/JAD-181251

Citation: Journal of Alzheimer's Disease, vol. 68, no. 3, pp. 939-945, 2019

Authors: Musaeus, Christian Sandøe | Nielsen, Malene Schjønning | Høgh, Peter

Article Type: Research Article

Abstract: Background: Mild cognitive impairment (MCI) is associated with clinical progression to Alzheimer’s disease (AD) but not all patients with MCI convert to AD. However, it is important to have methods that can differentiate between patients with MCI who progress (pMCI) and those who remain stable (sMCI), i.e., for timely administration of disease-modifying drugs. Objective: In the current study, we wanted to investigate whether quantitative EEG coherence and imaginary part of coherency (iCoh) could be used to differentiate between pMCI and sMCI. Methods: 17 patients with AD, 27 patients with MCI, and 38 older healthy controls were …recruited and followed for three years and 2nd year was used to determine progression. EEGs were recorded at baseline and coherence and iCoh were calculated after thorough preprocessing. Results: Between pMCI and sMCI, the largest difference in total coherence was found in the theta and delta bands. Here, the significant differences for coherence and iCoh were found in the lower frequency bands involving the temporal-frontal connections for coherence and parietal-frontal connections for iCoh. Furthermore, we found a significant negative correlation between theta coherence and the Addenbrooke’s Cognitive Examination (ACE) (p  = 0.0378; rho = –0.2388). Conclusion: These findings suggest that low frequency coherence and iCoh can be used to determine, which patients with MCI will progress to AD and is associated with the ACE score. Low-frequency coherence has previously been associated with increased hippocampal atrophy and degeneration of the cholinergic system and may be an early marker of AD pathology. Show more

Keywords: Coherence, dementia, EEG, mild cognitive impairment, progression

DOI: 10.3233/JAD-181081

Citation: Journal of Alzheimer's Disease, vol. 68, no. 3, pp. 947-960, 2019

Authors: Pentikäinen, Heikki | Savonen, Kai | Ngandu, Tiia | Solomon, Alina | Komulainen, Pirjo | Paajanen, Teemu | Antikainen, Riitta | Kivipelto, Miia | Soininen, Hilkka | Rauramaa, Rainer

Article Type: Research Article

Abstract: Background: Previous studies have found positive associations between cardiorespiratory fitness (CRF) and cognitive performance in older people but data are inconsistent and have methodological limitations. Objective: Our aim was to study the longitudinal associations of CRF with executive functions, processing speed and memory as well as with the overall cognitive function in older people at risk for cognitive impairment. Methods: Participants (n  = 421), mean age 69.0, were a sub-sample of The Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER). To be eligible, individuals were required to be 60–77 years old with a CAIDE …(Cardiovascular Risk Factors, Aging and Dementia) Dementia Risk Score of at least 6 points and cognition at mean level or slightly lower than expected for age. CRF was assessed as peak oxygen uptake (VO2peak , L/min) measured directly in a symptom-limited maximal exercise test on cycle ergometer at baseline and at 24 months. Cognitive performance was assessed using an extensive neuropsychological test battery (NTB) at baseline and at 24 months. NTB data were standardized to Z scores, and analyzed with the linear mixed model. Results: Over two years, VO2peak was associated with NTB total score (β= 0.12, p  = 0.01), executive functions (β= 0.16, p  = 0.01), and processing speed (β= 0.25, p  < 0.001), but not with memory (β= 0.11, p  = 0.12). Conclusion: Over two years follow-up, CRF was associated with executive functions and processing speed, and was related also to the overall cognitive function. Show more

Keywords: Aged, cardiorespiratory fitness, cognition, executive function, memory

DOI: 10.3233/JAD-180897

Citation: Journal of Alzheimer's Disease, vol. 68, no. 3, pp. 961-968, 2019

Authors: Brandt, Jason | Buchholz, Alison | Henry-Barron, Bobbie | Vizthum, Diane | Avramopoulos, Dimitrios | Cervenka, Mackenzie C.

Article Type: Research Article

Abstract: Ketone bodies, the products of fat metabolism, are a source of energy for the brain and are available even when glucose supplies are inadequate (such as with severe carbohydrate deprivation) or its metabolism is faulty (as it is in Alzheimer’s disease). This phase I/II randomized clinical trial examined the feasibility of using a modified Atkins diet (MAD) to induce ketogenesis in persons with mild cognitive impairment (MCI) or early AD, and the effect of this diet on memory and other clinical outcomes. In the first 2.5 years of active recruitment, only 27 eligible and willing patients enrolled. After extensive assessment …and education, they and their study partners were randomly assigned for 12 weeks to either the MAD or the National Institute on Aging (NIA) recommended diet for seniors. As of April 2018, 9 patients in the MAD arm and 5 in the NIA arm have completed the trial. In spite of extensive teaching, coaching, and monitoring, adherence to both diets was only fair. Among those in the MAD arm who generated at least trace amounts of urinary ketones, there was a large (effect size = 0.53) and statistically significant (p  = 0.03) increase in Memory Composite Score between the baseline and week-6 assessment. MAD participants also reported increased energy between baseline and week-6 assessment. Despite challenges to implementing this trial, resulting in a small sample, our preliminary data suggest that the generation of even trace ketones might enhance episodic memory and patient-reported vitality in very early AD. Show more

Keywords: Carbohydrates, clinical trial, cognitive function, diet, ketone bodies, memory, neuropsychological tests

DOI: 10.3233/JAD-180995

Citation: Journal of Alzheimer's Disease, vol. 68, no. 3, pp. 969-981, 2019

Authors: Lee, Sung | Parekh, Trusha | King, Sarah M. | Reed, Bruce | Chui, Helena C. | Krauss, Ronald M. | Yassine, Hussein N.

Article Type: Research Article

Abstract: Cerebral beta-amyloidosis (CA) is a condition in which amyloid-β (Aβ) proteins are deposited in the cerebral cortex and is a predictor of Alzheimer’s disease (AD). The Aging Brain Study (ABS) investigated risk factors for CA in persons with diabetes and dyslipidemia. In the ABS, we identified that greater levels of LDL cholesterol and lower levels of HDL cholesterol were associated with increased CA. LDL particles comprise multiple species of varying size, density, and protein composition. For example, within a lipoprotein profile characteristic for persons with obesity and diabetic dyslipidemia, larger LDL particles have a greater ApoE to ApoB ratio, enhancing …their binding affinity to LDL receptors. The goal of this study was to identify LDL particles that associate with CA in ABS. LDL particle size fractions were measured by ion mobility in plasma samples of 58 participants (40 women and 18 men). CA was assessed using Pittsburgh Compound B index-Positron Emission Tomography (PiB-PET) imaging. Among the LDL subfractions, greater plasma levels of large LDL particles were significantly associated with greater cerebral amyloidosis and lower hippocampal volumes independent of LDL cholesterol or triglyceride levels. Since Aβ is cleared by the LDL receptor family, such as lipoprotein-like receptor 1 (LRP1), one potential mechanism for our findings is competition between ApoE enriched larger LDL particles and brain-derived Aβ on hepatic Aβ clearance and degradation. We conclude that assessing larger LDL particles in persons with atherogenic dyslipidemia may provide a mechanistic biomarker for the extent of CA. Show more

Keywords: Alzheimer’s disease, apolipoproteins, lipids, lipoproteins, receptors

DOI: 10.3233/JAD-181252

Citation: Journal of Alzheimer's Disease, vol. 68, no. 3, pp. 983-990, 2019