Journal of Alzheimer's Disease - Volume 42, issue s3

Authors: Kristofikova, Zdena | Ricny, Jan | Kolarova, Michaela | Vyhnalek, Martin | Hort, Jakub | Laczo, Jan | Sirova, Jana | Ripova, Daniela

Article Type: Research Article

Abstract: Background: Despite the physiological sequestration of amyloid-β (Aβ) peptides by various carriers, interactions between peptides and protein tau appear to be pathological and involved in the development of Alzheimer’s disease (AD). A recent study reported increased Aβ-tau interactions in the neurons of AD patients. Objective: We investigated the possibility that levels of Aβ-tau complexes in cerebrospinal fluid could be a prospective biomarker of AD, with greater sensitivity and specificity than Aβ1-42 , tau, or phospho-tau individually. Methods: By means of ELISA, we estimated levels of the complexes in 161 people (non-demented controls, people with mild cognitive …impairment (MCI), probable AD or other types of dementia). Results: We found significant reductions in levels in people with MCI due to AD (down to 84.5%) or with AD (down to 80.5%) but not in other types of dementia. The sensitivity of the new biomarker to AD was 68.6%, the specificity 73.3% (compared to controls) or 59.1–66.1% (compared to other types of dementia). No significant correlations were observed between the complexes and the remaining biomarkers or between those and Mini-Mental State Examination score. Conclusion: We suppose that attenuated levels of complexes in cerebrospinal fluid reflect the accumulation of Aβ bound to tau in AD neurons and that changes start many years before symptom onset, analogously to those in Aβ1-42 , tau, or phospho-tau. Unfortunately, these complexes are not a significantly better biomarker of AD than current biomarkers. Show more

Keywords: Amyloid-β peptides, biomarker, cerebrospinal fluid, interactions, tau protein

DOI: 10.3233/JAD-132393

Citation: Journal of Alzheimer's Disease, vol. 42, no. s3, pp. S91-S98, 2014

Authors: Dörr, Jan | Ringelstein, Marius | Duning, Thomas | Kleffner, Ilka | for the European Susac Consortium (EUSAC)

Article Type: Review Article

Abstract: Susac syndrome (SuS) is a rare endotheliopathy of the brain, the retina, and the inner ear. The underlying pathophysiology is likely an autoimmune mediated occlusion of microvessels resulting in variable degrees of central nervous system (CNS) dysfunction, visual disturbances, and hearing loss. The disease manifests either with a monophasic or polycyclic course. Patients suffering from SuS are frequently misdiagnosed as having inflammatory demyelinating CNS disease, particularly multiple sclerosis because of some overlap in the clinical presentation and the paraclinical findings. Since appropriate treatment of SuS is crucial for the prognosis, a timely and sound establishment of the diagnosis is important. …Here, we summarize currently available information on the clinical presentation and diagnostic procedures in SuS. In particular, we discuss the added value of advanced techniques of brain and retinal imaging such as ultrahigh field magnetic resonance imaging and optical coherence tomography in SuS with respect to its differential diagnosis and pathophysiology. Since evidence-based treatment standards will not be available in the near future, we share some experiences in terms of treatment options. Finally, we briefly outline future areas of research in SuS. Show more

Keywords: Antiendothelial cell antibodies, branch retinal artery occlusion, encephalopathy, endotheliopathy, hearing loss, optical coherence tomography, Susac syndrome, treatment

DOI: 10.3233/JAD-132519

Citation: Journal of Alzheimer's Disease, vol. 42, no. s3, pp. S99-S108, 2014

Authors: Exalto, Lieza G. | Biessels, Geert Jan | Karter, Andrew J. | Huang, Elbert S. | Quesenberry Jr, Charles P. | Whitmer, Rachel A.

Article Type: Research Article

Abstract: Background: Persons with type 2 diabetes are at an increased risk of dementia compared to those without, but the etiology of this increased risk is unclear. Objective: Cerebral microvascular disease may mediate the link between diabetes and dementia. Given the anatomical and physiological similarities between cerebral and retinal microvessels, we examined the longitudinal association between diabetic retinal disease and dementia in patients with type 2 diabetes. Methods: Longitudinal cohort study of 29,961 patients with type 2 diabetes aged ≥60 years. Electronic medical records were used to collect diagnoses and treatment of severe diabetic retinal disease (i.e., …diabetic proliferative retinopathy and macular edema) between 1996–1998 and dementia diagnoses for the next ten years (1998–2008). The association between diabetic retinal disease and dementia was evaluated by Cox proportional hazard models adjusted for sociodemographics, as well as diabetes-specific (e.g., diabetes duration, pharmacotherapy, HbA1c, hypoglycemia, hyperglycemia) and vascular (e.g., vascular disease, smoking, body mass index) factors. Results: 2,008 (6.8%) patients had severe diabetic retinal disease at baseline and 5,173 (17.3%) participants were diagnosed with dementia during follow-up. Those with diabetic retinal disease had a 42% increased risk of incident dementia (demographics adjusted Hazards Ratio (HR) = 1.42, 95% Confidence Interval (CI) 1.27, 1.58); further adjustment for diabetes-specific (HR 1.29; 95% CI 1.14, 1.45) and vascular-related disease conditions (HR 1.35; 95% CI 1.21, 1.52) attenuated the relation slightly. Conclusion: Diabetic patients with severe diabetic retinal disease have an increased risk of dementia. This may reflect a causal link between microvascular disease and dementia. Show more

Keywords: Dementia, diabetes, macular edema, microvascular disease, retinal disease, retinopathy

DOI: 10.3233/JAD-132570

Citation: Journal of Alzheimer's Disease, vol. 42, no. s3, pp. S109-S117, 2014

Authors: Bartelet, Marjukka | Waterink, Wim | van Hooren, Susan

Article Type: Research Article

Abstract: In nursing homes, extreme sexual behavior is one of the most challenging behaviors in dementia. Despite this, however, there is no conformity in the literature regarding how to label and define this type of behavior. Examples of labels used include inappropriate sexual behavior, improper sexual behavior, sexually disinhibited behavior, or hyper sexuality. According to recent theoretical perspectives, extreme sexual behavior may be regarded as a part of disinhibited behavior or could be considered as an independent neuropsychiatric symptom. In this multicenter study, it was investigated whether there is a relationship between extreme sexual behavior and the typical neuropsychiatric symptoms seen …in dementia. In 179 residents diagnosed with dementia, extreme sexual behavior was measured using an observation scale. Twelve neuropsychiatric symptoms were measured by the Neuropsychiatric Inventory. Multivariate analysis of covariance with gender showed that residents with observed extreme sexual behavior (n = 43) only showed a higher score on neuropsychiatric symptom ‘disinhibition’, as compared to residents with non-observed sexual behavior (n = 136). In addition, the effect size was large. These findings indicate that among residents with dementia, extreme sexual behaviors should not be considered as an independent neuropsychiatric symptom. Instead, disinhibition may be an important underlying mechanism for extreme sexual behavior and thus validates the label ‘sexually disinhibited behavior’. Show more

Keywords: Dementia, disinhibition, elderly, sexual behavior

DOI: 10.3233/JAD-132378

Citation: Journal of Alzheimer's Disease, vol. 42, no. s3, pp. S119-S124, 2014

Authors: Radi, Elena | Formichi, Patrizia | Battisti, Carla | Federico, Antonio

Article Type: Review Article

Abstract: Neurodegenerative disorders affect almost 30 million individuals leading to disability and death. These disorders are characterized by pathological changes in disease-specific areas of the brain and degeneration of distinct neuron subsets. Despite the differences in clinical manifestations and neuronal vulnerability, the pathological processes appear similar, suggesting common neurodegenerative pathways. Apoptosis seems to play a key role in the progression of several neurologic disorders like Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis as demonstrated by studies on animal models and cell lines. On the other hand, research on human brains reported contradictory results. However, many dying neurons have …been detected in brains of patients with neurodegenerative diseases, and these conditions are often associated with significant cell loss accompanied by typical morphological features of apoptosis such as chromatin condensation, DNA fragmentation, and activation of cysteine-proteases, caspases. Cell death and neurodegenerative conditions have been linked to oxidative stress and imbalance between generation of free radicals and antioxidant defenses. Multiple sclerosis, stroke, and neurodegenerative diseases have been associated with reactive oxygen species and nitric oxide. Here we present an overview of the involvement of neuronal apoptosis and oxidative stress in the most important neurodegenerative diseases, mainly focusing the attention on several genetic disorders, discussing the interaction between primary genetic abnormalities and the apoptotic pathways. Show more

Keywords: Apoptosis, ATP13A2, CADASIL, caspases, neurodegeneration, Parkinson's disease, reactive oxygen species

DOI: 10.3233/JAD-132738

Citation: Journal of Alzheimer's Disease, vol. 42, no. s3, pp. S125-S152, 2014

Authors: Baloyannis, Stavros J.

Article Type: Research Article

Abstract: Alzheimer's disease (AD) is a progressive degeneration of the brain, inducing memory decline, inability in learning, and behavioral alterations, resulting progressively in a marked deterioration of all mental activities and eventually a vegetative state. The main causative factor, however, is still unclear. The implication of amyloid-β, AβPP, tau protein, the selective loss of neurons, the alteration of the synapses, the cytoskeletal changes, and the morphological alterations of the brain capillaries contribute substantially to the pathogenetic profile of the disease, without sufficiently enlightening the initial steps of the pathological procedures. The ultrastructure of the neuronal organelles as well as histochemical studies …revealed substantial alterations, primarily concerning mitochondria. In this study, the morphological and morphometric alterations of the Golgi apparatus (GA) are described in the Purkinje cells of the cerebellum in twenty AD brains, studied with electron microscopy. As it is well established, GA has a very important role to play in many procedures such as glycosylation, sulfation, and proteolysis of protein systems, which are synthesized in the endoplasmic reticulum of nerve cells and glia. GA may also play a crucial role in protein trafficking and in misfolding of protein aggregates. In addition, the hyperphosphorylation of tau protein is closely related with the pathology of GA. In AD cases, described in this study, an obvious fragmentation of the cisternae of GA was observed in the Purkinje cells of the vermis and the cerebellar hemispheres. This alteration of GA may be associated with alterations of microtubules, impaired protein trafficking, and dendritic, spinal, and synaptic pathology, since protein trafficking plays an essential role in the three dimensional organization of the dendritic arbor and in the integrity of the synaptic components. Show more

Keywords: Alzheimer's disease, electron microscopy, Golgi apparatus, proteins trafficking

DOI: 10.3233/JAD-132660

Citation: Journal of Alzheimer's Disease, vol. 42, no. s3, pp. S153-S162, 2014

Authors: Koutsouraki, Euphrosyni | Hatzifilippou, Eleni | Michmizos, Dimitrios | Banaki, Tania | Costa, Vassiliki | Baloyannis, Stavros

Article Type: Short Communication

Abstract: We examined the sera of 103 demented patients of a mean age of 75 years and 60 age-matched healthy individuals, using ELISA, to investigate the levels of IgM antibodies against GM1, GD1b, and GQ1b gangliosides and their possible correlation with clinical parameters (age, severity, and type of dementia). All the individuals that demonstrated positive titers of anti-ganglioside antibodies were demented patients whereas normal controls showed borderline or negative values. Significant correlation was revealed between IgM anti-GM1 and both the age of the patients and the severity of dementia. Most of the patients with increased IgM anti-GD1b titers suffered from AD.

Keywords: Alzheimer's disease, dementia, gangliosides, lipids

DOI: 10.3233/JAD-132633

Citation: Journal of Alzheimer's Disease, vol. 42, no. s3, pp. S163-S166, 2014

Authors: Ghiso, Jorge | Fossati, Silvia | Rostagno, Agueda

Article Type: Review Article

Abstract: Substantial genetic, biochemical, and in vivo data indicate that progressive accumulation of amyloid-β (Aβ) plays a central role in the pathogenesis of Alzheimer's disease (AD). Historically centered in the importance of parenchymal plaques, the role of cerebral amyloid angiopathy (CAA)—a frequently neglected amyloid deposit present in >80% of AD cases—for the mechanism of disease pathogenesis is now starting to emerge. CAA consistently associates with microvascular modifications, ischemic lesions, micro- and macro-hemorrhages, and dementia, progressively affecting cerebral blood flow, altering blood-brain barrier permeability, interfering with brain clearance mechanisms and triggering a cascade of deleterious pro-inflammatory and metabolic events that compromise the …integrity of the neurovascular unit. New evidence highlights the contribution of pre-fibrillar Aβ in the induction of cerebral endothelial cell dysfunction. The recently discovered interaction of oligomeric Aβ species with TRAIL DR4 and DR5 cell surface death receptors mediates the engagement of mitochondrial pathways and sequential activation of multiple caspases, eliciting a cascade of cell death mechanisms while unveiling an opportunity for exploring mechanistic-based therapeutic interventions to preserve the integrity of the neurovascular unit. Show more

Keywords: Amyloid-β genetic variants, amyloidosis, cerebral amyloid angiopathy, cerebral microvascular cells, death receptors, familial Alzheimer's disease, inflammation, mitochondrial dysfunction

DOI: 10.3233/JAD-140027

Citation: Journal of Alzheimer's Disease, vol. 42, no. s3, pp. S167-S176, 2014

Authors: Zádori, Dénes | Veres, Gábor | Szalárdy, Levente | Klivényi, Péter | Toldi, József | Vécsei, László

Article Type: Review Article

Abstract: The impairment of glutamatergic neurotransmission plays an important role in the development of Alzheimer's disease (AD). The pathological process, which involves the production of amyloid-β peptides and hyperphosphorylated tau proteins, spreads over well-delineated neuroanatomical circuits. The gradual deterioration of proper synaptic functioning (via GluN2A-containing N-methyl-D-aspartate receptors, NMDARs) and the development of excitotoxicity (via GluN2B-containing NMDARs) in these structures both accompany the disease pathogenesis. Although one of the most important therapeutic targets would be glutamate excitotoxicity, the application of conventional anti-glutamatergic agents could result in further deterioration of synaptic transmission and intolerable side-effects. With regard to NMDAR antagonists with tolerable side-effects, …ion channel blockers with low affinity, glycine site agents, and specific antagonists of polyamine site and GluN2B subunit may come into play. However, in the mirror of experimental data, only the application of ion channel blockers with pronounced voltage dependency, low affinity, and rapid unblocking kinetics (e.g., memantine) and specific antagonists of the GluN2B subunit (e.g., ifenprodil and certain kynurenic acid amides) resulted in desirable symptom amelioration. Therefore we propose that these kinds of chemical agents may have therapeutic potential for present and future drug development. Show more

Keywords: Alzheimer's disease, glutamate excitotoxicity, kynurenic acid amides, memantine, neurodegeneration, neuroprotection, therapy

DOI: 10.3233/JAD-132621

Citation: Journal of Alzheimer's Disease, vol. 42, no. s3, pp. S177-S187, 2014

Authors: Shaul, Merav E. | Hallacoglu, Bertan | Sassaroli, Angelo | Shukitt-Hale, Barbara | Fantini, Sergio | Rosenberg, Irwin H. | Troen, Aron M.

Article Type: Research Article

Abstract: Background: Senescent changes in brain microvascular circulation may cause or contribute to age-related cognitive decline. Such changes are promoted partly by aging, but also by chronic hypertension, a leading treatable cause of cognitive decline. Objectives: We aimed to non-invasively detect in vivo the senescent changes in brain microvascular circulation associated with age and hypertension, and inquired whether decrements driven by aging would be exacerbated by chronic hypertension. Methods: In this longitudinal study, absolute near infrared spectroscopy (NIRS) was used to quantify in vivo cerebral blood volume (CBV) and assess the hemodynamic response to a hypercapnic respiratory …challenge in normotensive Wistar-Kyoto (WKY) and spontaneous-hypertensive (SHR) rats. The impact of age and hypertension were evaluated by repeating these measurements on the same animals at 4- and 16-months of age. Results: CBV decreased markedly with age in both strains, from 4.5 ± 0.2 to 2.6 ± 0.1 ml/100g tissue, on average. Chronic hypertension, however, did not significantly exacerbate this age-related decrease in CBV (−48.1 ± 3.7% in WKYs versus −53.3 ± 5.4% in SHRs). In contrast, vasoreactivity was already impaired in the young hypertensive rats (ΔVMR 0.017 ± 0.014 in young SHRs versus 0.042 ± 0.005 in young WKYs) and further worsened by middle-age (ΔVMR 0.011 ± 0.017 middle-aged SHRs). Conclusion: Whereas a decrease in brain blood volume correlated with age but not hypertension, vasodilatory capacity was diminished due to hypertension but did not appear affected by age alone. The ability of absolute NIRS to distinguish between such senescent changes in brain (micro)vascular circulation in life may allow early detection and intervention to preserve cerebrovascular health with age. Show more

Keywords: Aging, cerebral blood volume, hypertension, near infrared spectroscopy, vasodilation

DOI: 10.3233/JAD-132504

Citation: Journal of Alzheimer's Disease, vol. 42, no. s3, pp. S189-S198, 2014