Journal of Alzheimer's Disease - Volume 64, issue 2

Authors: Akhter, Hasina | Huang, Wen-Tan | van Groen, Thomas | Kuo, Hui-Chien | Miyata, Toshio | Liu, Rui-Ming

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is a major cause of dementia in the elderly with no effective treatment. Accumulation of amyloid-β peptide (Aβ) in the brain is a pathological hallmark of AD and is believed to be a central disease-causing and disease-promoting event. In a previous study, we showed that deletion of plasminogen activator inhibitor 1 (PAI-1), a primary inhibitor of tissue type and urokinase type plasminogen activators (tPA and uPA), significantly reduced brain Aβ load in APP/PS1 mice, an animal model of familial AD. In this study, we further show that oral administration of TM5275, a small molecule inhibitor of PAI-1, …for a period of 6 weeks, inhibits the activity of PAI-1 and increases the activities of tPA and uPA as well as plasmin, which is associated with a reduction of Aβ load in the hippocampus and cortex and improvement of learning/memory function in APP/PS1 mice. Protein abundance of low density lipoprotein related protein-1 (LRP-1), a multi ligand endocytotic receptor involved in transporting Aβ out of the brain, as well as plasma Aβ42 are increased, whereas the expression and processing of full-length amyloid-β protein precursor is not affected by TM5275 treatment in APP/PS1 mice. In vitro studies further show that PAI-1 increases, whereas TM5275 reduces, Aβ40 level in the culture medium of SHSY5Y-APP neuroblastoma cells. Collectively, our data suggest that TM5275 improves memory function of APP/PS1 mice, probably by reducing brain Aβ accumulation through increasing plasmin-mediated degradation and LRP-1-mediated efflux of Aβ in the brain. Show more

Keywords: Alzheimer’s disease, amyloid-β accumulation, memory, PAI-1 inhibitor

DOI: 10.3233/JAD-180241

Citation: Journal of Alzheimer's Disease, vol. 64, no. 2, pp. 447-457, 2018

Authors: Korthauer, Laura E. | Awe, Elizabeth | Frahmand, Marijam | Driscoll, Ira

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) is characterized by memory loss and executive dysfunction, which correspond to structural changes to the medial temporal lobes (MTL) and prefrontal cortex (PFC), respectively. Given the overlap in cognitive deficits between healthy aging and the earliest stages of AD, early detection of AD remains a challenge. The goal of the present study was to study MTL- and PFC-dependent cognitive functioning in middle-aged individuals at genetic risk for AD or cognitive impairment who do not currently manifest any clinical symptoms. Participants (N = 150; aged 40–60 years) underwent genotyping of 47 single nucleotide polymorphisms (SNPs) in six genes …previously associated with memory or executive functioning: APOE, SORL1, BDNF, TOMM40, KIBRA, and COMT. They completed two MTL-dependent tasks, the virtual Morris Water Task (vMWT) and transverse patterning discriminations task (TPDT), and the PFC-dependent reversal learning task. Although age was associated with poorer performance on the vMWT and TPDT within this middle-aged sample, there were no genotype-associated differences in cognitive performance. Although the vMWT and TPDT may be sensitive to age-related changes in cognition, carriers of APOE, SORL1, BDNF, TOMM40, KIBRA, and COMT risk alleles do not exhibit alteration in MTL- and PFC-dependent functioning in middle age compared to non-carriers. Show more

Keywords: Aging, Alzheimer’s disease, apolipoproteins E, brain-derived neurotrophic factor, cognition, hippocampus, prefrontal cortex, middle age

DOI: 10.3233/JAD-171043

Citation: Journal of Alzheimer's Disease, vol. 64, no. 2, pp. 459-471, 2018

Authors: Martínez-Sánchez, Francisco | Meilán, Juan José G. | Carro, Juan | Ivanova, Olga

Article Type: Research Article

Abstract: Background: Speech variations enable us to map the performance of cognitive processes of syntactic, semantic, phonological, and articulatory planning and execution. Speaking is one of the first functions to be affected by neurodegenerative complaints such as Alzheimer’s disease (AD), which makes the speech a highly promising biomarker for detecting the illness before the first preclinical symptoms appear. Objective: This paper has sought to develop and validate a technological prototype that adopts an automated approach to speech analysis among older people. Methods: It uses a mathematical algorithm based on certain discriminatory variables to estimate the probability of …developing AD. Results and Conclusion: This device may be used at a preclinical stage by non-expert health professionals to determine the likelihood of the onset of AD. Show more

Keywords: Alzheimer’s disease, diagnosis, prototype, voice

DOI: 10.3233/JAD-180037

Citation: Journal of Alzheimer's Disease, vol. 64, no. 2, pp. 473-481, 2018

Authors: Robinson, Andrew C. | Davidson, Yvonne S. | Horan, Michael A. | Pendleton, Neil | Mann, David M.A.

Article Type: Research Article

Abstract: The neuropathological changes responsible for cognitive impairment and dementia remain incompletely understood. Longitudinal studies with a brain donation end point allow the opportunity to examine relationships between cognitive status and neuropathology. We report on the first 97 participants coming to autopsy with sufficient clinical information from The University of Manchester Longitudinal Study of Cognition in Normal Healthy Old Age. This study began in 1983 and recruited 6,542 healthy individuals between 1983 and 1994, 312 of whom consented to brain donation. Alzheimer-type pathology was common throughout the cohort and generally correlated well with cognitive status. However, there was some overlap between …cognitive status and measures of Alzheimer pathology with 26% of cognitively intact participants reaching either CERAD B or C, 11% reaching Thal phase 4 or 5, and 29% reaching Braak stage III– VI. Cerebral amyloid angiopathy(CAA), α -synuclein, and TDP-43 pathology was less common, but when present correlated well with cognitive status. Possession of APOE ɛ 4 allele(s) was associated with more severe Alzheimer-type and CAA pathology and earlier death, whereas possession of APOE ɛ 2 allele(s) had no effect on pathology but was more common in cognitively intact individuals. The University of Manchester Longitudinal Study of Cognition in Normal Healthy Old Age cohort is pathologically representative when compared with similar studies. Cognitive impairment in life correlates strongly with all pathologies examined and the APOE status of an individual can affect pathology severity and longevity. Show more

Keywords: Alpha-synuclein, Alzheimer’s disease, APOE , cognitive dysfunction, cohort studies, dementia, longitudinal studies, neuropathology

DOI: 10.3233/JAD-180171

Citation: Journal of Alzheimer's Disease, vol. 64, no. 2, pp. 483-496, 2018

Authors: Bocchetta, Martina | Iglesias, Juan Eugenio | Scelsi, Marzia A. | Cash, David M. | Cardoso, M. Jorge | Modat, Marc | Altmann, Andre | Ourselin, Sebastien | Warren, Jason D. | Rohrer, Jonathan D.

Article Type: Research Article

Abstract: Background: Frontotemporal dementia (FTD) is a heterogeneous neurodegenerative disorder, with a strong genetic component. Previous research has shown that medial temporal lobe atrophy is a common feature of FTD. However, no study has so far investigated the differential vulnerability of the hippocampal subfields in FTD. Objectives: We aimed to investigate hippocampal subfield volumes in genetic FTD. Methods: We in6/2/2018vestigated hippocampal subfield volumes in a cohort of 75 patients with genetic FTD (age: mean (standard deviation) 59.3 (7.7) years; disease duration: 5.1 (3.4) years; 29 with MAPT , 28 with C9orf72 , and 18 with GRN …mutations) compared with 97 age-matched controls (age: 62.1 (11.1) years). We performed a segmentation of their volumetric T1-weighted MRI scans to extract hippocampal subfields volumes. Left and right volumes were summed and corrected for total intracranial volumes. Results: All three groups had smaller hippocampi than controls. The MAPT group had the most atrophic hippocampi, with the subfields showing the largest difference from controls being CA1-4 (24–27%, p < 0.0005). For C9orf72 , the CA4, CA1, and dentate gyrus regions (8–11%, p < 0.0005), and for GRN the presubiculum and subiculum (10–14%, p < 0.0005) showed the largest differences from controls. Conclusions: The hippocampus was affected in all mutation types but a different pattern of subfield involvement was found in the three genetic groups, consistent with differential cortical-subcortical network vulnerability. Show more

Keywords: Genetic frontotemporal dementia, hippocampal subfields, magnetic resonance imaging, volumetry

DOI: 10.3233/JAD-180195

Citation: Journal of Alzheimer's Disease, vol. 64, no. 2, pp. 497-504, 2018

Authors: Morenas-Rodríguez, Estrella | Sala, Isabel | Subirana, Andrea | Pascual-Goñi, Elba | Sánchez-Saudinós, Ma Belén | Alcolea, Daniel | Illán-Gala, Ignacio | Carmona-Iragui, María | Ribosa-Nogué, Roser | Camacho, Valle | Blesa, Rafael | Fortea, Juan | Lleó, Alberto

Article Type: Research Article

Abstract: Background: Dementia with Lewy bodies (DLB) is a heterogeneous disease in which clinical presentation, symptoms, and evolution widely varies between patients. Objective: To investigate the existence of clinical subtypes in DLB based on the initial clinical presentation. Methods: 81 patients with a clinical diagnosis of probable DLB were consecutively included. All patients underwent a neurological evaluation including a structured questionnaire about neuropsychiatric symptoms and sleep, an assessment of motor impairment (Unified Parkinson Disease Rating Scale subscale III), and a formal neuropsychological evaluation. Onset of core symptoms (hallucinations, parkinsonism, and fluctuations) and dementia were systematically reviewed from …medical records. We applied a K-means clustering method based on the initial clinical presentation. Results: Cluster analysis yielded three different groups. Patients in cluster I (cognitive-predominant, n = 46) presented more frequently with cognitive symptoms (95.7%, n = 44, p < 0.001), and showed a longer duration from onset to DLB diagnosis (p < 0.001) than the other clusters. Patients in cluster II (neuropsychiatric-predominant, n = 22) were older at disease onset (78.1±5 versus 73.6±6.1 and 73.6±4.2 in clusters I and III, respectively, both p < 0.01), presented more frequently with psychotic symptoms (77.3%, n = 17), and had a shorter duration until the onset of hallucinations (p < 0.001). Patients in cluster III (parkinsonism-predominant, n = 13) showed a shorter time from onset to presence of parkinsonism (p < 0.001) and dementia (0.008). Conclusions: Three clinical subtypes of DLB can be defined when considering the differential initial presentations. The proposed subtypes have distinct clinical profiles and progression patterns. Show more

Keywords: Clinical subtypes, cluster analyses, dementia with Lewy bodies, Lewy bodies

DOI: 10.3233/JAD-180167

Citation: Journal of Alzheimer's Disease, vol. 64, no. 2, pp. 505-513, 2018

Authors: Nakanishi, Miharu | Hirooka, Kayo | Imai, Yasuaki | Inoue, Shintaro | Yukari, Yukio | Katayama, Chie | Miyamoto, Yuki | Shindo, Yumi | Ueno, Hideki | Toya, Junichiro | Takano, Yosuke | Nishida, Atsushi

Article Type: Research Article

Abstract: Background: We developed a psychosocial dementia care program to help care managers and professional caregivers manage challenging behavior in home-dwelling persons with dementia in Japan. The program consists of a web-based tool for ongoing monitoring and assessment for challenging behavior, and multi-agency discussion meetings. Results of a cluster-randomized controlled trial indicate a reduction in challenging behavior through this program. Objectives: The present study aimed to identify a key component of the developed program that is associated with a reduction in challenging behavior. Methods: We used consecutive data of the intervention and examined the association between challenging …behavior in home-dwelling persons with dementia, professionals’ competence, and the frequency of revision of action plans. Challenging behavior was assessed using the total score of the Neuropsychiatric Inventory. A baseline and follow-up questionnaire was completed by care professionals using a Japanese version of the Sense of Competence in Dementia Care Staff scale. Results: A total of 86 care professionals completed a 6-month intervention with 219 persons with dementia. The 86 care professionals significantly improved in their dementia care competence. Challenging behavior was significantly reduced among the 219 persons with dementia at follow-up regardless of the level of professionals’ competence or the frequency of revision of action plans. Less pain was significantly related to the lower levels of challenging behavior. Conclusion: The ongoing multi-agency discussion meetings, with a focus on challenging behavior, may have been the key component in the psychosocial dementia care program. Pain management should be emphasized in action plans for challenging behavior. Show more

Keywords: Challenging behavior, dementia, home-dwelling, palliative care, professional competence

DOI: 10.3233/JAD-171077

Citation: Journal of Alzheimer's Disease, vol. 64, no. 2, pp. 515-523, 2018

Authors: Schirinzi, Tommaso | Di Lorenzo, Francesco | Sancesario, Giulia Maria | Di Lazzaro, Giulia | Ponzo, Viviana | Pisani, Antonio | Mercuri, Nicola Biagio | Koch, Giacomo | Martorana, Alessandro

Article Type: Research Article

Abstract: Background: Although motor disturbances parallel the course of dementia, worsening both quality of life and social costs, the pathogenesis remains still unclear. Objective: Through the combination of cerebrospinal fluid (CSF) biomarkers assessment and transcranial magnetic stimulation (TMS) protocols, here we provided a cross-sectional study to understand pathogenic mechanisms of Alzheimer’s disease (AD)-related early motor disturbances. Methods: The motor phenotype, as defined with Unified Parkinson’s Disease Rating Scale (UPDRS) part 2-3, Rating Scale for Gait Evaluation in Cognitive Deterioration (RSEGCD) and Tinetti scale, together with CSF profile of amyloid-β 42 (Aβ 42 ), total-tau, and phosphorylated-tau …were determined in 37 AD patients and compared to 18 patients with vascular dementia (VaD). A TMS protocol of short afferent inhibition (SAI) was further applied on a subset of AD patients. Clinical, biochemical, and neurophysiological data were then compared and correlated in order to find significant associations. Results: AD patients exhibited subtle locomotor impairment and slight extrapyramidal signs. Main motor features (UPDRS part 3, RSGECD, and Tinetti scale scores) correlate with Aβ 42 levels but not with t-tau and p-tau. AD patients also presented SAI impairment directly related to UPDRS part 3 score and Aβ 42 levels. Motor disturbances of VaD group did not differ statistically from AD and did not correlate with CSF biomarkers. Conclusions: The association of motor disturbances with low Aβ 42 CSF levels and individual SAI suggests that amyloid-mediated degeneration of cholinergic system may account for early AD-related motor impairment, providing interesting insights either for frailty stratification of patients or personalized therapies. Show more

Keywords: Alzheimer’s disease, amyloid, cholinergic, frailty, gait, locomotor, vascular dementia

DOI: 10.3233/JAD-171166

Citation: Journal of Alzheimer's Disease, vol. 64, no. 2, pp. 525-532, 2018

Authors: Payton, Nicola M. | Kalpouzos, Grégoria | Rizzuto, Debora | Fratiglioni, Laura | Kivipelto, Miia | Bäckman, Lars | Laukka, Erika J.

Article Type: Research Article

Abstract: Background: Cognitive and biological markers have shown varying degrees of success in identifying persons who will develop dementia. Objective: To evaluate different combinations of cognitive and biological markers and identify prediction models with the highest accuracy for identifying persons with increased dementia risk. Methods: Neuropsychological assessment, genetic testing (apolipoprotein E –APOE ), and structural magnetic resonance imaging (MRI) were performed for 418 older individuals without dementia (60–97 years) from a population-based study (SNAC-K). Participants were followed for six years. Results: Cognitive, genetic, and MRI markers were systematically combined to create prediction models for dementia at …six years. The most predictive individual markers were perceptual speed or carrying at least one APOE ɛ 4 allele (AUC = 0.875). The most predictive model (AUC = 0.924) included variables from all three modalities (category fluency, general knowledge, any ɛ 4 allele, hippocampal volume, white matter-hyperintensity volume). Conclusion: This study shows that combining markers within and between modalities leads to increased predictivity for future dementia. However, minor increases in predictive value should be weighed against the cost of additional tests in larger-scale screening. Show more

Keywords: Biomarkers, cognition, neuroimaging, preclinical dementia, prediction

DOI: 10.3233/JAD-180199

Citation: Journal of Alzheimer's Disease, vol. 64, no. 2, pp. 533-542, 2018

Authors: Ruiz, Maria | Arias, Alfonso | Sánchez-Llanos, Ernesto | Gil, Maria Pilar | López-Ortega, Ricard | Dakterzada, Faridé | Purroy, Francisco | Piñol-Ripoll, Gerard

Article Type: Research Article

Abstract: Background: Hallucinations may have a broad spectrum and include so-called minor hallucinations (MHs). MHs include passage hallucinations (PHs), visual illusions, and presence hallucinations (PrHs). Objective: To determine the prevalence and characteristics of MHs in Alzheimer’s disease (AD) and amnestic mild cognitive impairment (aMCI) patients, and to describe their potential relationship with cognition, behavioral symptoms, and use of psychoactive drugs. Methods: We have recruited prospectively and consecutively 268 subjects (90 AD mild-moderate drug-naïve patients, 78 aMCI, and 100 controls). All patients responded to a semi-structured questionnaire in order to rate psychotic phenomena. Clinical, neuropsychological, and demographic data …of patients with and without MH were compared with those of age, sex, and education-matched controls. Results: The prevalence of MHs was 21.1% (19) in AD, 12.8% (10) in aMCI, and 3% (3) in controls (p < 0.01). The most frequent MH was PrH (9.3%), followed by PH (4.9%) and illusion (0.7%). Eight (27.8%) patients had more than one MH. After adjusting for age and gender, there was a negative correlation between the presence of MHs and MMSE score (r = –0.261; p < 0.01) and a positive correlation between MHs and Neuropsychiatric Inventory score (r = 0.237; p < 0.01). We did not observe a significant relationship between presence of MHs and the consumption of psychoactive drugs (p > 0.05). Conclusion: We have shown that the presence of MHs in patients with newly diagnosed, untreated AD and aMCI is more than controls. MHs were correlated with other behavioral symptoms and a worse cognitive performance. We suggest the specific interrogation for MHs as a clinical feature for this population. Show more

Keywords: Alzheimer’s disease, dementia, drug-naïve, illusion, mild cognitive impairment, minor hallucination, passage hallucination, presence hallucination

DOI: 10.3233/JAD-180234

Citation: Journal of Alzheimer's Disease, vol. 64, no. 2, pp. 543-549, 2018