Journal of Alzheimer's Disease - Volume 43, issue 1

Authors: Ambrose, Charles T.

Article Type: Review Article

Abstract: Alzheimer's disease (AD) and related senile dementias (SDs) represent a growing medical and economic crisis in this country. Apart from cautioning persons about risk factors, no practical, effective therapy is currently available. Much of the recent research in AD has been based on the amyloid cascade theory. Another approach assumes a vascular basis for SDs. This paper presents evidence from a score of studies that cerebral capillary density (CCD) declines during old age in animals and people as well as in AD. Neuroangiogenic (NAG) factors initiate and maintain capillaries in the brain. Thus a waning level of these factors and …the ensuing declining CCD would lead to local areas of reduced oxygen and glucose and result in impaired synaptic and neuronal function. The NAG hypothesis developed here proposes that the age-linked decline in CCD is a terminal condition in SDs, including many cases of AD. This age-linked decline is independent of any other of the various pathologies proposed as causing AD and listed in Table 1. Waning NAG factors would render the SDs a deficiency condition, somewhat like falling androgen levels in aging males. A logical corollary of this hypothesis is that chronic replacement therapy with recombinant forms of NAG factors may arrest the age-linked decline in CCD and prevent further loss of memory and mental deterioration. A transnasal route of therapy seems the most practical one for general use in the large aging populations. Show more

Keywords: Alzheimer's disease, cerebral capillary density, cognitive impairment, neuroangiogenesis, senile dementia

DOI: 10.3233/JAD-140498

Citation: Journal of Alzheimer's Disease, vol. 43, no. 1, pp. 1-17, 2015

Authors: Oren, Noga | Yogev-Seligmann, Galit | Ash, Elissa | Hendler, Talma | Giladi, Nir | Lerner, Yulia

Article Type: Short Communication

Abstract: The Montreal Cognitive Assessment (MoCA) is a widely used screening test for evaluation of mild cognitive impairment (MCI), with a single cutoff for all ages. We examined whether it is associated with age in a sample of cognitively-intact elderly (CIE). The average MoCA score was negatively correlated with age and was significantly higher for younger than older CIE. Additionally, 42% of the older elderly fell below the proposed MCI cutoff score, although all subjects were CIE. Thus, cognitive abilities captured by the MoCA test decrease with age, even in CIE. Therefore, cutoff scores by age for the MoCA are needed.

Keywords: Aging, cognition, MOCA, screening, MCI

DOI: 10.3233/JAD-140774

Citation: Journal of Alzheimer's Disease, vol. 43, no. 1, pp. 19-22, 2015

Authors: Safouris, Apostolos | Hambye, Anne-Sophie | Sculier, Claudine | Papageorgiou, Sokratis G. | Vasdekis, Spyros N. | Gazagnes, Marie-Dominique | Tsivgoulis, Georgios

Article Type: Short Communication

Abstract: A 62-year-old patient presented with persistent cognitive deficits 3 months after a right temporal ischemic stroke due to ipsilateral carotid occlusion. Work-up disclosed hemodynamically significant contralateral carotid artery stenosis and left subclavian steal phenomenon. Brain SPECT imaging revealed bihemispheric chronic brain hypoperfusion that substantially improved on repeat imaging when the subclavian steal was temporarily diminished by inflating a cuff around the left arm. Carotid endarterectomy of the asymptomatic carotid stenosis substantially ameliorated bihemispheric brain perfusion and reversed cognitive impairment. This case highlights that multi-vessel, extracranial atherosclerotic disease may cause chronic diffuse brain hypoperfusion that can be associated with cognitive impairment.

Keywords: Asymptomatic carotid stenosis, carotid endarterectomy, chronic brain hypoperfusion, SPECT, subclavian steal, transcranial Doppler

DOI: 10.3233/JAD-141203

Citation: Journal of Alzheimer's Disease, vol. 43, no. 1, pp. 23-27, 2015

Authors: Li, Jian-Guo | Praticò, Domenico

Article Type: Research Article

Abstract: High levels of homocysteine is a risk factor for developing Alzheimer's disease (AD), and the effect that this amino acid has on amyloid-β (Aβ) protein precursor metabolism is considered one of the potential mechanism(s) involved in this effect. However, despite consistent literature indicating that this condition results in brain parenchyma amyloidosis, no data are available on whether it may also influence the amount of Aβ deposited in the vasculature. To test this hypothesis, we implemented a model of diet-inducing high homocysteinemia in AD transgenic mice, 3xTg, and assessed them for the development of cerebral amyloid angiopathy (CAA). Compared with controls, …mice with high homocysteine showed a significant increase in the amount of Aβ deposited in the brain vasculature, which was not associated with histological evidence of microhemorrhage occurrence. Mice with high homocysteine had a significant reduction in steady state level of the apolipoprotein E, which is a main Aβ chaperon protein, but no changes in its receptor, the low-density-lipoprotein-receptor-1. Our data demonstrate that a diet-induced high homocysteine level favors the development of CAA via a reduction of Aβ clearance and transport within the brain. Therapeutic approaches aimed at restoring brain apolipoprotein E levels should be considered in individuals carrying this environmental risk factor in order to reduce the incidence of homocysteine-dependent CAA. Show more

Keywords: Alzheimer's disease, amyloid-β, homocysteine, transgenic mouse model

DOI: 10.3233/JAD-141101

Citation: Journal of Alzheimer's Disease, vol. 43, no. 1, pp. 29-35, 2015

Authors: Bishnoi, Ram J. | Palmer, Raymond F. | Royall, Donald R.

Article Type: Research Article

Abstract: Vitamin D binding protein (VDBP), a multifunctional protein, has been found to be elevated in the cerebrospinal fluid (CSF) of neurodegenerative disorder cases, implicating it in the pathogenesis of Alzheimer's disease (AD). However, the contribution of VDBP to AD has not been fully explored. We used a Multiple Indicators Multiple Causes (MIMIC) approach to examine the relationship between serum VDBP levels and cognitive performance in a well characterized AD cohort, the Texas Alzheimer's Research and Care Consortium (TARCC). Instead of categorical diagnoses, we used a latent dementia phenotype (d), which has been validated in several prior studies using this dataset. …We found that serum VDBP levels are significantly positively associated with d scores, which in turn are inversely related to cognitive performance. This suggests that d mediates the adverse effects of serum VDB on cognition and therefore that its effects are specifically dementing. d scores are also specifically related to default mode network (DMN) structure. VDBP acts as an amyloid-β (Aβ) scavenger, and Aβ deposition in the DMN is seen in the pre-clinical stages of AD. We speculate then that serum effects of VDBP are mediated through changes in DMN structure or function, most probably via Aβ. Aβ affects the DMN early in the course of AD. Therefore, raised serum VDBP levels may be a useful indicator of future dementia and/or dementia conversion. This might be confirmed through longitudinal analysis of TARCC data. Show more

Keywords: Dementia, serum biomarker, vitamin D binding protein

DOI: 10.3233/JAD-140042

Citation: Journal of Alzheimer's Disease, vol. 43, no. 1, pp. 37-45, 2015

Authors: Pérez-Grijalba, Virginia | Pesini, Pedro | Allué, José Antonio | Sarasa, Leticia | Montañés, María | Lacosta, Ana-María | Casabona, Diego | San-José, Itziar | Boada, Mercè | Tárraga, Lluis | Ruiz, Agustín | Sarasa, Manuel

Article Type: Research Article

Abstract: This work was prompted by the finding that Aβ1-17 (Aβ17 ) appeared to be the second-most abundant cerebrospinal fluid (CSF) Aβ fragment, after Aβ40 . We developed an ELISA to quantify levels of Aβ17 directly accessible in plasma (DA17), recovered from the proteomic plasma matrix (RP17) and associated with the cellular pellet (CP17) that remained after plasma collection. Then, we used a sample of 19 healthy control (HC), 27 mild cognitive impairment (MCI), and 17 mild Alzheimer's disease (AD) patients to explore the association of the diagnostic groups with those direct markers, their ratios or the ratios with …their Aβ40 or Aβ42 counterparts. After dichotomization (d) for the median of the sample population, logistic regression analysis showed that in the AD versus HC subgroup, subjects with a dDA/CP17 higher than the median had a significantly greater risk of being AD than those with marker levels equal to or below the median (odds ratio OR; 95% confidence interval; 17.21; 1.42–208.81). Subjects with dRP17/42 below the median had an increased likelihood of being MCI (20.00; 1.17–333.33) or AD (40.00; 1.87–1000) versus being HC, than those with dRP17/42 higher than the median. Although the confidence intervals are wide, these findings suggest that assessment of Aβ17 may increase the diagnostic performance of blood-based Aβ tests which might be developed into minimally invasive first-step screening tests for people with increased risk for AD. Show more

Keywords: Amyloid-β, biomarkers, cerebrospinal fluid, ELISA, mass spectrometry

DOI: 10.3233/JAD-140156

Citation: Journal of Alzheimer's Disease, vol. 43, no. 1, pp. 47-56, 2015

Authors: Hradek, Alex C. | Lee, Hyun-Pil | Siedlak, Sandra L. | Torres, Sandy L. | Jung, Wooyoung | Han, Ashley H. | Lee, Hyoung-gon

Article Type: Research Article

Abstract: Cell cycle re-entry in Alzheimer's disease (AD) has emerged as an important pathological mechanism in the progression of the disease. This appearance of cell cycle related proteins has been linked to tau pathology in AD, but the causal and temporal relationship between the two is not completely clear. In this study, we found that hyperphosphorylated retinoblastoma protein (ppRb), a key regulator for G1/S transition, is correlated with a late marker for hyperphosphorylation of tau but not with other early markers for tau alteration in the 3xTg-AD mouse model. However, in AD brains, ppRb can colocalize with both early and later …markers for tau alterations, and can often be found singly in many degenerating neurons, indicating the distinct development of pathology between the 3xTg-AD mouse model and human AD patients. The conclusions of this study are two-fold. First, our findings clearly demonstrate the pathological link between the aberrant cell cycle re-entry and tau pathology. Second, the chronological pattern of cell cycle re-entry with tau pathology in the 3xTg-AD mouse is different compared to AD patients suggesting the distinct pathogenic mechanism between the animal AD model and human AD patients. Show more

Keywords: Alzheimer's disease, animal model, cell cycle, retinoblastoma protein (Rb), tau, transgenic mouse

DOI: 10.3233/JAD-141083

Citation: Journal of Alzheimer's Disease, vol. 43, no. 1, pp. 57-65, 2015

Authors: Poole, Sophie | Singhrao, Sim K. | Chukkapalli, Sasanka | Rivera, Mercedes | Velsko, Irina | Kesavalu, Lakshmyya | Crean, StJohn

Article Type: Research Article

Abstract: Periodontal disease is a polymicrobial inflammatory disease that leads to chronic systemic inflammation and direct infiltration of bacteria/bacterial components, which may contribute to the development of Alzheimer's disease. ApoE-/- mice were orally infected (n = 12) with Porphyromonas gingivalis , Treponema denticola , Tannerella forsythia , and Fusobacterium nucleatum as mono- and polymicrobial infections. ApoE-/- mice were sacrificed following 12 and 24 weeks of chronic infection. Bacterial genomic DNA was isolated from all brain tissues except for the F. nucleatum mono-infected group. Polymerase chain reaction was performed using universal 16 s rDNA primers and species-specific primer …sets for each organism to determine whether the infecting pathogens accessed the brain. Sequencing amplification products confirmed the invasion of bacteria into the brain during infection. The innate immune responses were detected using antibodies against complement activation products of C3 convertase stage and the membrane attack complex. Molecular methods demonstrated that 6 out of 12 ApoE-/- mice brains contained P. gingivalis genomic DNA at 12 weeks (p = 0.006), and 9 out of 12 at 24 weeks of infection (p = 0.0001). Microglia in both infected and control groups demonstrated strong intracellular labeling with C3 and C9, due to on-going biosynthesis. The pyramidal neurons of the hippocampus in 4 out of 12 infected mice brains demonstrated characteristic opsonization with C3 activation fragments (p = 0.032). These results show that the oral pathogen P. gingivalis was able to access the ApoE-/- mice brain and thereby contributed to complement activation with bystander neuronal injury. Show more

Keywords: Alzheimer's disease, chronic periodontitis, inflammation, periodontal bacteria

DOI: 10.3233/JAD-140315

Citation: Journal of Alzheimer's Disease, vol. 43, no. 1, pp. 67-80, 2015

Authors: Nascimento, Carla Manuela Crispim | Pereira, Jessica Rodrigues | Pires de Andrade, Larissa | Garuffi, Marcelo | Ayan, Carlos | Kerr, Daniel Shikanai | Talib, Leda Leme | Cominetti, Márcia Regina | Stella, Florindo

Article Type: Research Article

Abstract: The benefits of physical exercise on improvements in brain-derived neurotrophic factor (BDNF) levels and cognitive functioning have been reported in the literature. However, the variability of individual responses may be linked to genetic differences. BDNF is considered one of the most plausible factors involved in the cognitive benefits associated with physical activity practice. A single nucleotide polymorphism localized in the gene that codes BDNF results in a missense mutation that promotes an amino acid substitution (Val66Met) in the protein. This process has been associated with decreased levels of BDNF secretion, with corresponding impairments in specific cognitive functions. Therefore, the objective …of this study was to analyze the effects of a multimodal physical exercise program on peripheral BDNF levels and cognitive functions in elderly individuals with mild cognitive impairment (MCI). The participants were genotyped for the BDNF Val66Met polymorphism. Cognitive functions were assessed by the Montreal Cognitive Assessment (MoCA) prior to and after the intervention. Forty-five participants were assigned to the control and trained groups. The trained group participated in a multimodal physical training for a 16-week period. The results showed a significant between-subjects interaction (p < 0.05), which indicates the beneficial contribution of training on cognitive functions independent of the BDNF genotype. However, only participants with BDNF-Met genotypes exhibited significant improvements in peripheral BDNF levels. The BDNF genotype appears to modulate the effects of physical exercise on BDNF secretion, but it does not influence cognition. This is the first study that evaluated the influence of a BDNF polymorphism on physical activity and cognition performance in elderly MCI individuals. Show more

Keywords: Brain-derived neurotrophic factor, cognition, genetic polymorphism, mild cognitive impairment, physical exercises

DOI: 10.3233/JAD-140576

Citation: Journal of Alzheimer's Disease, vol. 43, no. 1, pp. 81-91, 2015

Authors: Naughton, Bartholomew J. | Duncan, F. Jason | Murrey, Darren A. | Meadows, Aaron S. | Newsom, David E. | Stoicea, Nicoleta | White, Peter | Scharre, Douglas W. | Mccarty, Douglas M. | Fu, Haiyan

Article Type: Research Article

Abstract: To date, little is known regarding the etiology and disease mechanisms of Alzheimer's disease (AD). There is a general urgency for novel approaches to advance AD research. In this study, we analyzed blood RNA from female patients with advanced AD and matched healthy controls using genome-wide gene expression microarrays. Our data showed significant alterations in 3,944 genes (≥2-fold, FDR ≤1%) in AD whole blood, including 2,932 genes that are involved in broad biological functions. Importantly, we observed abnormal transcripts of numerous tissue-specific genes in AD blood involving virtually all tissues, especially the brain. Of altered genes, 157 are known to …be essential in neurological functions, such as neuronal plasticity, synaptic transmission and neurogenesis. More importantly, 205 dysregulated genes in AD blood have been linked to neurological disease, including AD/dementia and Parkinson's disease, and 43 are known to be the causative genes of 42 inherited mental retardation and neurodegenerative diseases. The detected transcriptional abnormalities also support robust inflammation, profound extracellular matrix impairments, broad metabolic dysfunction, aberrant oxidative stress, DNA damage, and cell death. While the mechanisms are currently unclear, this study demonstrates strong blood-brain correlations in AD. The blood transcriptional profiles reflect the complex neuropathological status in AD, including neuropathological changes and broad somatic impairments. The majority of genes altered in AD blood have not previously been linked to AD. We believe that blood genome-wide transcriptional profiling may provide a powerful and minimally invasive tool for the identification of novel targets beyond Aβ and tauopathy for AD research. Show more

Keywords: Alzheimer's disease, blood-brain transcriptional association, genome-wide expression arrays, neuropathology

DOI: 10.3233/JAD-140606

Citation: Journal of Alzheimer's Disease, vol. 43, no. 1, pp. 93-108, 2015