Journal of Alzheimer's Disease - Volume 50, issue 1

Authors: Avondino, Emilie | Antoine, Pascal

Article Type: Research Article

Abstract: Currently, the lack of awareness of deficits, i.e., anosognosia, is a major obstacle in the healthcare circuit that delays the diagnosis of Alzheimer’s disease (AD). However, a clear framework is lacking in the literature related to this phenomenon in terms of its definition, mechanisms, and objects. The aim of this study is to assess the different levels of cognitive anosognosia using a prediction-performance procedure and to identify the potential correlates of these levels. A sample of patients with probable AD was divided into three groups according to the severity of dementia (mild (MiD), moderate (MoD), and moderately severe (MSD) dementia), ranked …according to the results of the Mini-Mental State Examination. We observed the following three scores: the real score, the prediction score, and the anosognosia score. These scores were calculated based on the prediction-performance task MISAwareness from the Dementia Rating Scale for cognitive processes (i.e., Attention, Initiation, Conceptualization, Construction, and Memory). We obtained a strong plateau effect between the MiD and MoD groups for anosognosia scores for actual performance or prediction for both the level of overall functioning and for specific processes. The sole exception was the result for memory processes. Moreover, the profiles of the patients’ responses on the Memory subscale were substantially different and, indeed, opposite from those for the other processes. The main results confirm the multidimensionality of anosognosia and its variability with the stage of dementia and specifically implicate memory processes that indicate a cleavage between memory and other cognitive functions. Show more

Keywords: Alzheimer’s disease, anosognosia, awareness, cognition, dementia, executive functions, memory, self-assessment

DOI: 10.3233/JAD-150496

Citation: Journal of Alzheimer's Disease, vol. 50, no. 1, pp. 89-99, 2016

Authors: Vallortigara, Julie | Whitfield, David | Quelch, William | Alghamdi, Amani | Howlett, David | Hortobágyi, Tibor | Johnson, Mary | Attems, Johannes | O’Brien, John T. | Thomas, Alan | Ballard, Clive G. | Aarsland, Dag | Francis, Paul T.

Article Type: Research Article

Abstract: Alpha-synuclein (α -syn) aggregations are the key pathological hallmark of dementia with Lewy bodies (DLB) and Parkinson’s disease dementia (PDD), but are also frequently present in Alzheimer’s disease (AD). Much remains unknown about the role of α -syn in the synapse and the wider role of synaptic dysfunction in these dementias. Changes in concentrations of key ‘SNAP (Soluble N-ethylmaleimide Sensitive Factor Attachment Protein) Receptor’ (SNARE) proteins as a consequence of alterations in the aggregation state of α -syn may contribute to synaptic dysfunction in patients with DLB, PDD, and AD and result in impaired cognition. We have studied a large …cohort (n  = 130) of autopsy confirmed DLB, PDD, AD, and control brains. Using semi-quantitative western blotting, we have demonstrated significant changes across the diagnostic groups of DLB, PDD, and AD in the SNARE and vesicle proteins syntaxin, Munc18, VAMP2, and monomeric α -syn in the prefrontal cortex, with a significant reduction of Munc18 in AD patients (p  <  0.001). This correlated to the final MMSE score before death (p  = 0.016). We also identified a significant negative correlation between the duration of dementia and the levels of the binding partners VAMP2 (p  = 0.0004) and monomeric α -syn (p  = 0.0002). Our findings may indicate that an upregulation of SNARE complex related proteins occurs in the early stages of disease as an attempt at compensating for failing synapses, prior to widespread deposition of pathological α -syn. Show more

Keywords: Alpha-synuclein, Alzheimer’s disease, dementia with lewy bodies, munc18, Parkinson’s disease dementia, SNARE process, synaptic dysfunction, VAMP2

DOI: 10.3233/JAD-150707

Citation: Journal of Alzheimer's Disease, vol. 50, no. 1, pp. 101-110, 2016

Authors: Kleinschmidt, Martin | Schoenfeld, Robby | Göttlich, Claudia | Bittner, Daniel | Metzner, Jürgen Erich | Leplow, Bernd | Demuth, Hans-Ulrich

Article Type: Research Article

Abstract: Background: Current treatment in Alzheimer’s disease (AD) is initiated at a stage where the brain already has irreversible structural deteriorations. Therefore, the concept of treatment prior to obvious cognitive deficits has become widely accepted, and simple biochemical tests to discriminate normal aging from prodromal or demented stages are now common practice. Objective: The objective of the study was the differentiation of controls, mild cognitive impairment (MCI) and AD patients by novel blood-based assays in combination with neuropsychological tests. Methods: In a cross-sectional study, 143 subjects aged 18 to 85 years were recruited. All participants were classified …by a comprehensive neuropsychological assessment. Blood samples were analyzed for several amyloid-β (Aβ) species, pro-inflammatory markers, anti-Aβ autoantibodies, and ApoE allele status, respectively. Results: Plasma Aβ1-42 was significantly decreased in MCI and AD compared to age-matched controls, whereas Aβ1-40 did not differ, but increases with age in healthy controls. The Aβ1-42 to Aβ1-40 ratio was stepwise decreased from age-matched controls via MCI to AD, and shows a clear correlation with memory scores. Reduced Aβ1-42 and Aβ1-42 to Aβ1-40 ratio have strongly correlated with carrying ApoE ɛ 4 allele. Autoantibodies against pyroglutamate-modified Aβ, but only a certain subclass, were significantly decreased in AD compared to MCI and age-matched controls, whereas autoantibodies against the unmodified N-terminus of Aβ did not differ. Conclusion: Comprehensive sample preparation and assay standardization enable reliable usage of plasma Aβ for diagnosis of MCI and AD. Anti-pGlu-Aβ autoantibodies correlate with cognition, but not with ApoE, supporting the associated plasma Aβ analysis with additional and independent information. Show more

Keywords: Aging, Alzheimer’s disease, amyloid-β, ApoE, autoantibodies, blood, mild cognitive impairment, neuropsychology

DOI: 10.3233/JAD-143189

Citation: Journal of Alzheimer's Disease, vol. 50, no. 1, pp. 111-126, 2016

Authors: Santos, Cláudia Yang | Lim, Yen Ying | Wu, Wen-Chih | Machan, Jason Timothy | Polynice, Shahena | Schindler, Rachel | Maruff, Paul | Snyder, Peter Jeffrey

Article Type: Research Article

Abstract: We sought to determine whether there is any association between a cardiac workload marker, rate pressure product (RPP), working memory, and cortical amyloid-β (Aβ) burden in 63 cognitively normal midlife adults (Mage  = 62.8 years; range = 55 to 75 years) at risk for Alzheimer’s disease (AD). The results show a small-to-moderate relationship between increasing cardiac workload (at rest) and neocortical amyloidosis in individuals at the preclinical stage of AD. Moreover, increasing RPP was linearly related to increasing relative impairments on a spatial working memory task (R2  = 0.30), but only for those individuals with neuroimaging evidence suggestive of preclinical AD. These results support …a relationship between the aggregation of Aβ protein plaques in the neocortex, increased cognitive impairment, and more inefficient myocardial oxygen use in the absence of significant metabolic demands. Show more

Keywords: Alzheimer’s disease, amyloid beta-peptides, blood pressure, cardiovascular diseases, cerebrovascular disorders, comorbidity, memory, mild cognitive impairment, risk factors, short-term, workload

DOI: 10.3233/JAD-150576

Citation: Journal of Alzheimer's Disease, vol. 50, no. 1, pp. 127-131, 2016

Authors: Yu, Rosa | Deochand, Chetram | Krotow, Alexander | Leão, Raiane | Tong, Ming | Agarwal, Amit R. | Cadenas, Enrique | de la Monte, Suzanne M.

Article Type: Research Article

Abstract: Background: Meta-analysis studies showed that smokers have increased risk for developing Alzheimer’s disease (AD) compared with non-smokers, and neuroimaging studies revealed that smoking damages white matter structural integrity. Objective: The present study characterizes the effects of side-stream (second hand) cigarette smoke (CS) exposures on the expression of genes that regulate oligodendrocyte myelin-synthesis, maturation, and maintenance and neuroglial functions. Methods: Adult male A/J mice were exposed to air (8 weeks; A8), CS (4 or 8 weeks; CS4, CS8), or CS8 followed by 2 weeks recovery (CS8 + R). The frontal lobes were used for histology and qRT-PCR analysis. …Results: Luxol fast blue, Hematoxylin and Eosin stained histological sections revealed CS-associated reductions in myelin staining intensity and narrowing of the corpus callosum. CS exposures broadly decreased mRNA levels of immature and mature oligodendrocyte myelin-associated, neuroglial, and oligodendrocyte-related transcription factors. These effects were more prominent in the CS8 compared with CS4 group, suggesting that molecular abnormalities linked to white matter atrophy and myelin loss worsen with duration of CS exposure. Recovery normalized or upregulated less than 25% of the suppressed genes; in most cases, inhibition of gene expression was either sustained or exacerbated. Conclusion: CS exposures broadly inhibit expression of genes needed for myelin synthesis and maintenance. These adverse effects often were not reversed by short-term CS withdrawal. The results support the hypothesis that smoking contributes to white matter degeneration, and therefore could be a key risk factor for a number of neurodegenerative diseases, including AD. Show more

Keywords: Alzheimer’s disease, cigarette smoke, mouse model, myelin genes, neurodegeneration, tobacco, white matter

DOI: 10.3233/JAD-150751

Citation: Journal of Alzheimer's Disease, vol. 50, no. 1, pp. 133-148, 2016

Authors: Hisatsune, Tatsuhiro | Kaneko, Jun | Kurashige, Hiroki | Cao, Yuan | Satsu, Hideo | Totsuka, Mamoru | Katakura, Yoshinori | Imabayashi, Etsuko | Matsuda, Hiroshi

Article Type: Research Article

Abstract: Our goal in this study was to determine whether or not anserine/carnosine supplementation (ACS) is capable of preserving cognitive function of elderly people. In a double-blind randomized controlled trial, volunteers were randomly assigned to an ACS or placebo group at a 1:1 ratio. The ACS group took 1.0 g of an anserine/carnosine (3:1) formula daily for 3 months. Participants were evaluated by psychological tests before and after the 3-month supplementation period. Thirty-nine healthy elderly volunteers (60–78 years old) completed the follow-up tests. Among the tests, delayed recall verbal memory assessed by the Wechsler Memory Scale-Logical Memory showed significant preservation in the …ACS group, compared to the placebo group (p  = 0.0128). Blood analysis revealed a decreased secretion of inflammatory cytokines, including CCL-2 and IL-8, in the ACS group. MRI analysis using arterial spin labeling showed a suppression in the age-related decline in brain blood flow in the posterior cingulate cortex area in the ACS group, compared to the placebo group (p  = 0.0248). In another randomized controlled trial, delayed recall verbal memory showed significant preservation in the ACS group, compared to the placebo group (p  = 0.0202). These results collectively suggest that ACS may preserve verbal episodic memory and brain perfusion in elderly people, although further study is needed. Show more

Keywords: Alzheimer’s disease, anserine and carnosine, cognitive function, dementia, elderly people, inflammatory cytokine, perfusion MRI, randomized controlled trial, verbal memory

DOI: 10.3233/JAD-150767

Citation: Journal of Alzheimer's Disease, vol. 50, no. 1, pp. 149-159, 2016

Authors: Mishima, Aki | Nihashi, Takashi | Ando, Yoshio | Kawai, Hisashi | Kato, Takashi | Ito, Kengo | Terasawa, Teruhiko

Article Type: Research Article

Abstract: Background: Several nuclear imaging and cerebrospinal fluid (CSF) biomarkers are under investigation, aimed at facilitating the differential diagnosis of dementias. Objective: To quantitatively synthesize data on test performance in differentiating dementia with Lewy bodies (DLB) from other dementias. Methods: We searched PubMed (January 2000– March 2015) for English-language publications that assessed a selected set of five imaging and three CSF biomarkers for this purpose. We meta-analyzed measures of agreement between biomarker results and clinical diagnosis. Results: Forty-five publications were eligible. The majority of evidence was based on studies that enrolled representative disease populations. For …differentiating between DLB and Alzheimer’s disease (AD) or other dementias, metaiodobenzylguanidine scintigraphy and dopamine transporter (DAT) single photon emission computed tomography (SPECT) showed, respectively, excellent (summary kappa  = 0.85; 95% confidence interval [95% CI], 0.74–0.96) and good (summary kappa  = 0.71; 95% CI, 0.43–0.99) agreement. Metaiodobenzylguanidine scintigraphy appeared superior to fluorodeoxyglucose– positron emission tomography (summary kappa  = 0.53; 95% CI, 0.36–0.69) and cerebral blood flow SPECT (summary kappa  = 0.40; 95% CI, 0.33–0.47). For differentiating DLB from AD, CSF t-tau levels (summary kappa  = 0.68; 95% CI, 0.55–0.82) performed comparably to metaiodobenzylguanidine scintigraphy and DAT SPECT. Sparse direct comparative evidence failed to corroborate these indirect comparisons. Conclusion: Metaiodobenzylguanidine scintigraphy and DAT SPECT are highly concordant with clinical diagnosis in differentiating DLB from other dementias. However, given the limitations in the study design, the applicability of these results to real-world differential diagnosis remains unclear. Prospective studies targeting patients with atypical presentations that adopt gold standard tests would reliably estimate the true test performance of these promising biomarkers. Show more

Keywords: Alzheimer’s disease, dementia, dementia with Lewy bodies, diagnosis, meta-analysis

DOI: 10.3233/JAD-150675

Citation: Journal of Alzheimer's Disease, vol. 50, no. 1, pp. 161-174, 2016

Authors: Ezra, Assaf | Rabinovich-Nikitin, Inna | Rabinovich-Toidman, Polina | Solomon, Beka

Article Type: Research Article

Abstract: Alzheimer’s disease (AD), the prevalent dementia in the elderly, involves many related and interdependent pathologies that manifests simultaneously, eventually leading to cognitive impairment and death. No treatment is currently available; however, an agent addressing several key pathologies simultaneously has a better therapeutic potential. Human serum albumin (HSA) is a highly versatile protein, harboring multifunctional properties that are relevant to key pathologies underlying AD. This study provides insight into the mechanism for HSA’s therapeutic effect. In vivo , a myriad of beneficial effects were observed by pumps infusing HSA intracerebroventricularly, for the first time in an AD 3xTg mice model. A …significant effect on amyloid-β (Aβ) pathology was observed. Aβ1-42 , soluble oligomers, and total plaque area were reduced. Neuroblastoma SHSY5Y cell line confirmed that the reduction in Aβ1-42 toxicity was due to direct binding rather than other properties of HSA. Total and hyperphosphorylated tau were reduced along with an increase in tubulin, suggesting increased microtubule stability. HSA treatment also reduced brain inflammation, affecting both astrocytes and microglia markers. Finally, evidence for blood-brain barrier and myelin integrity repair was observed. These multidimensional beneficial effects of intracranial administrated HSA, together or individually, contributed to an improvement in cognitive tests, suggesting a non-immune or Aβ efflux dependent means for treating AD. Show more

Keywords: Albumin, Alzheimer’s disease, blood-brain barrier, cognitive impairment, inflammation, myelin, therapy

DOI: 10.3233/JAD-150694

Citation: Journal of Alzheimer's Disease, vol. 50, no. 1, pp. 175-188, 2016

Authors: Lim, Soonmin | Choi, Jin Gyu | Moon, Minho | Kim, Hyo Geun | Lee, Wonil | Bak, Hyoung-rok | Sung, Hachang | Park, Chi Hye | Kim, Sun Yeou | Oh, Myung Sook

Article Type: Research Article

Abstract: The progressive aggregation of amyloid-β protein (Aβ) into senile plaques is a major pathological factor of Alzheimer’s disease (AD) and is believed to result in memory impairment. We aimed to investigate the effect of an optimized combination of ginger and peony root (OCGP), a standardized herbal mixture of ginger and peony root, on Aβ accumulation and memory impairment in amyloid-β protein precursor (AβPP)/presenilin 1 (PS1) double-transgenic mice. In an in vitro thioflavin T fluorescence assay, 100 μg/ml OCGP inhibited Aβ accumulation to the same extent as did 10 μM curcumin. Furthermore, AβPP/PS1 double-transgenic mice treated with OCGP (50 or …100 mg/kg/day given orally for 14 weeks) exhibited reduced Aβ plaque accumulation in the hippocampus and lower levels of glial fibrillary acid protein and cyclooxygease-2 expression compared with vehicle-treated controls. These results suggest that OCGP may prevent memory impairment in AD by inhibiting Aβ accumulation and inflammation in the brain. Show more

Keywords: Aβ accumulation, AβPP/PS1 double-transgenic mice, neuroinflammation, optimized combination of ginger and peony root

DOI: 10.3233/JAD-150839

Citation: Journal of Alzheimer's Disease, vol. 50, no. 1, pp. 189-200, 2016

Authors: Stockburger, Carola | Miano, Davide | Baeumlisberger, Marion | Pallas, Thea | Arrey, Tabiwang N. | Karas, Michael | Friedland, Kristina | Müller, Walter E.

Article Type: Research Article

Abstract: Aberrant neuronal network activity associated with neuronal hyperexcitability seems to be an important cause of cognitive decline in aging and Alzheimer’s disease (AD). Out of many antiepileptics, only levetiracetam improved cognitive dysfunction in AD patients and AD animal models by reducing hyperexcitability. As impaired inhibitory interneuronal function, rather than overactive neurons, seems to be the underlying cause, improving impaired neuronal function rather than quieting overactive neurons might be relevant in explaining the lack of activity of the other antiepileptics. Interestingly, improvement of cognitive deficits by levetiracetam caused by small levels of soluble Aβ was accompanied by improvement of synaptic function …and plasticity. As the negative effects of Aβ on synaptic plasticity strongly correlate with mitochondrial dysfunction, wehypothesized that the effect of levetiracetam on synaptic activity might be raised by an improved mitochondrial function. Accordingly, we investigated possible effects of levetiracetam on neuronal deficits associated with mitochondrial dysfunction linked to aging and AD. Levetiracetam improved several aspects of mitochondrial dysfunction including alterations of fission and fusion balance in a cell model for aging and early late-onset AD. We demonstrate for the first time, using immunohistochemistry and proteomics, that the synaptic vesicle protein 2A (SV2a), the molecular target of levetiracetam, is expressed in mitochondria. In addition, levetiracetam shows significant effect on the opening of the mitochondrial permeability transition pore. Importantly, the effects of levetiracetam were significantly abolished when SV2a was knockdown using siRNA. In conclusion, interfering with the SV2a protein at the mitochondrial level and thereby improving mitochondrial function might represent an additional therapeutic effect of levetiracetam to improve symptoms of late-onset AD. Show more

Keywords: Aging, Alzheimer’s disease, amyloid-β, levetiracetam, mitochondrial dynamics, mitochondrial function, mitochondrial permeability transition, synaptic vesicle protein 2A (SV2a)

DOI: 10.3233/JAD-150687

Citation: Journal of Alzheimer's Disease, vol. 50, no. 1, pp. 201-215, 2016