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

Authors: Molino, Ivana | Cavaliere, Carlo | Salvatore, Elena | Quarantelli, Mario | Colucci, Luisa | Fasanaro, Angiola Maria

Article Type: Research Article

Abstract: Anterior communicating artery (ACoA) syndrome, which may occur after rupture of ACoA aneurysms, consists of anterograde memory problems, executive dysfunctions, confabulations, and personality changes. Recently, the employment of diffusion tensor tractography (DTT) has related ACoA to microstructural lesions in the cingulum and the fornix, but an accurate characterization of these subjects should be provided. We report the clinical and neuropsychological findings of a patient who developed a severe and persistent amnesia together with significant behavioral changes, as well as her imaging results, where the sole evidence of brain damage was that of the fornix demonstrated by DTT. The four-year neuropsychological …follow-up of the subject allows exclusion of other causes. This case demonstrates that microstructural lesions of fornix may lead to persistent amnesia, executive impairments, and behavioral changes and contributes to the knowledge of its role in cognition. Show more

Keywords: Anterior communicating artery syndrome, cingulum, diffusion tensor tractography imaging, fornix

DOI: 10.3233/JAD-132648

Citation: Journal of Alzheimer's Disease, vol. 42, no. s3, pp. S199-S204, 2014

Authors: Schreiber, Stefanie | Drukarch, Benjamin | Garz, Cornelia | Niklass, Solveig | Stanaszek, Luiza | Kropf, Siegfried | Bueche, Celine | Held, Friederike | Vielhaber, Stefan | Attems, Johannes | Reymann, Klaus G. | Heinze, Hans-Jochen | Carare, Roxana O. | Wilhelmus, Micha M.M.

Article Type: Research Article

Abstract: Background: Accumulation of amyloid-β (Aβ) and hyperphosphorylated tau (ptau) accompany cerebral small vessel disease (CSVD) in the aging brain and in Alzheimer’s disease. CSVD is characterized by a heterogeneous spectrum of histopathological features possibly initiated by an endothelial dysfunction and blood-brain barrier (BBB) breakdown. Objective: We test the hypothesis that characteristic features of CSVD are associated with the accumulation of Aβ and ptau in non-transgenic spontaneously hypertensive stroke-prone rats (SHRSP). Methods: Amyloid-β protein precursor (AβPP) and tau were investigated by western blotting (n = 12 SHRSP, age 20 weeks). Lectin staining and plasma protein immunocytochemistry for …BBB examination were performed in 38 SHRSP (age 12–44 weeks) and Aβ (n = 29) and ptau (n = 17) immunocytochemistry in 20–44 week-old SHRSP. We assessed the correlation between extracellular amyloid deposits and features of CSVD (n = 135, 12–44 weeks). Results: In 20 week-old SHRSP, cortical AβPP expression was significantly increased compared to Wistar controls but tau levels were unchanged. At ages of 20–44 weeks, SHRSP exhibited an age-dependent increase in extracellular Aβ. Ptau was observed in 26–44 week-old SHRSP. Distinct features of CSVD pathology developed from the age of 12 weeks on. Conclusion: We demonstrate that in a hypertensive rat model that displays features of CSVD from 12 weeks, there is an age-dependent extracellular deposition of Aβ observed from 20 weeks onwards, increased AβPP expression at 20 weeks and ptau accumulation from 26 weeks on. This study suggests that CSVD associated with hypertension results in an age-related failure of Aβ clearance, increase in AβPP expression, and intraneuronal tau hyperphosphorylation. Show more

Keywords: Amyloid-β, amyloid-β protein precursor, cerebral small vessel disease, hyperphosphorylated tau, spontaneously hypertensive stroke-prone rats

DOI: 10.3233/JAD-132618

Citation: Journal of Alzheimer's Disease, vol. 42, no. s3, pp. S205-S215, 2014

Authors: Rektorova, Irena | Krajcovicova, Lenka | Marecek, Radek | Novakova, Marie | Mikl, Michal

Article Type: Research Article

Abstract: Background: The default mode network (DMN) decreases its activity when switching from a resting state to a cognitive task condition, while activity of the network engaged in the given task increases. Visual processing is typically disturbed in Parkinson’s disease dementia (PDD). Objective: Using functional MRI, we studied the DMN effective connectivity patterns in PDD as compared with cognitively normal patients with Parkinson’s disease (PD) and healthy controls (HC) when switching from baseline to a visual cognitive task condition. Methods: In all, 14 PDD, 18 PD, and 18 age-matched healthy controls participated in this functional MRI study. …We used a psychophysiological interaction analysis with the precuneus (PCu) as a seed. The threshold was set at p(FWE) <0.05. Results: The healthy controls showed greater PCu connectivity with the bilateral middle temporal/middle occipital gyri at baseline than during the task condition. The correlation direction changed from positive to negative. Both PD and PDD showed disturbed DMN connectivity with the brain regions that are involved in bottom-up visual processing. In PD, we also found impaired integration of the areas engaged in the ventral attentional network, which might reflect specific attentional deficits observed during the early course of PD. In mild PDD, we detected increased engagement of areas involved in the dorsal attentional network, which corresponds to increased top-down control in this patient group as compared to the healthy controls. Conclusion: Our results show impaired dynamic interplay between large scale brain networks in PD that spread far beyond the motor system. Show more

Keywords: Default mode network, dementia, functional MRI, Parkinson's disease, precuneus, visual processing

DOI: 10.3233/JAD-132684

Citation: Journal of Alzheimer's Disease, vol. 42, no. s3, pp. S217-S228, 2014

Authors: Seiler, Stephan | Ropele, Stefan | Schmidt, Reinhold

Article Type: Review Article

Abstract: Magnetization-transfer imaging (MTI), a magnetic resonance imaging acquisition protocol, can detect microstructural brain tissue changes by assessing the magnetization exchange between tissue water and protons bound to macromolecules. This short literature review summarizes results of previous MTI studies in normal aging, cerebral small vessel disease, and Alzheimer's disease (AD). During normal aging, the magnetization transfer ratio (MTR), a measure for the magnitude of magnetization transfer between macromolecular and water protons, declines in normal appearing brain tissue and associations between lower MTR and executive dysfunction have been described. In AD, MTR changes follow a disease-specific temporo-parietal pattern, independent of cortical atrophy. …The differential diagnostic contribution beyond atrophy seems to be modest and the independent effect of MTR alterations as predictors of conversion from mild cognitive impairment to AD needs to be explored. MTR correlates well with global cognitive measures like the Mini-Mental State Examination, and MTR decreases rapidly over time in AD. Longitudinal studies are needed to determine the clinical relevance of global and regional MTI measures in normal aging and neurodegenerative disease. Moreover, correlative MTI-histopathologic postmortem studies are warranted to determine the full spectrum of tissue destruction underlying MTR lowering apart from demyelination. Show more

Keywords: Aging, Alzheimer's disease, dementia, magnetic resonance imaging, magnetization transfer contrast imaging, mild cognitive impairment, vascular dementia

DOI: 10.3233/JAD-132750

Citation: Journal of Alzheimer's Disease, vol. 42, no. s3, pp. S229-S237, 2014

Authors: de Bruijn, Renée F.A.G. | Akoudad, Saloua | Cremers, Lotte G.M. | Hofman, Albert | Niessen, Wiro J. | van der Lugt, Aad | Koudstaal, Peter J. | Vernooij, Meike W. | Ikram, M. Arfan

Article Type: Research Article

Abstract: Mild cognitive impairment (MCI) marks a transitional stage between healthy aging and dementia, but the understanding of MCI in the general population remains limited. We investigated determinants, MRI-correlates, and prognosis of MCI within the population-based Rotterdam Study. Firstly, we studied age, APOE-ε4 carriership, waist circumference, hypertension, diabetes mellitus, total and HDL-cholesterol levels, smoking, and stroke as potential determinants of MCI. Determinants were assessed cross-sectionally at baseline (2002–2005) and up to 7 years prior to baseline (1997–2001). Secondly, we compared volumetric, microstructural, and focal MRI-correlates in persons with and without MCI. Thirdly, we followed participants for incident dementia and mortality until …2012. Out of 4,198 participants, 417 had MCI, of whom 163 amnestic and 254 non-amnestic MCI. At baseline, older age, APOE-ε4 carriership, lower total cholesterol levels, and stroke were associated with MCI. Additionally, lower HDL-cholesterol levels and smoking were related to MCI when assessed 7 years prior to baseline. Persons with MCI, particularly those with non-amnestic MCI, had larger white matter lesion volumes, worse microstructural integrity of normal-appearing white matter, and a higher prevalence of lacunes, compared to cognitively healthy participants. MCI was associated with an increased risk of dementia (hazard ratio (HR) 3.98, 95% confidence interval (CI) 2.97;5.33), Alzheimer's disease (HR 4.03, 95% CI 2.92;5.56), and mortality (HR 1.54, 95% CI 1.28;1.85). In conclusion, we found that several vascular risk factors and MRI-correlates of cerebrovascular disease were related to MCI in the general population. Participants with MCI had an increased risk of dementia, including Alzheimer's disease, and mortality. Show more

Keywords: Dementia, determinants, epidemiology, magnetic resonance imaging, mild cognitive impairment, mortality, population-based, prognosis

DOI: 10.3233/JAD-132558

Citation: Journal of Alzheimer's Disease, vol. 42, no. s3, pp. S239-S249, 2014

Authors: Tsivgoulis, Georgios | Katsanos, Aristeidis H. | Papageorgiou, Sokratis G. | Dardiotis, Efthimios | Voumvourakis, Konstantinos | Giannopoulos, Sotirios

Article Type: Research Article

Abstract: Although transcranial sonography is not yet an established diagnostic modality for dementia screening or differential diagnosis of Alzheimer's disease (AD) from vascular dementia (VaD), intracranial hemodynamic assessment may provide crucial information about the association between cognitive deterioration and vascular risk factors. We conducted a systematic narrative review of available literature through MEDLINE and EMBASE search to identify all available data about the evaluation of VaD patients with transcranial Doppler, and to discuss further the vascular disorders of the cerebral circulation in patients with vascular cognitive impairment. According to the available literature data to date, VaD patients were found to have …lower mean flow velocity values in four studies (indicating cerebral hypoperfusion), higher pulsatility indices in three studies (indicating increased downstream vascular resistance), and more severe impairment of cerebrovascular reactivity in five studies (indicating exhausted vasodilatory reserve) compared to AD patients and controls. Microembolic signals were also found to be significantly more common in patients with VaD or AD compared to their age- and gender-matched controls, suggesting that asymptomatic microembolism, apart for being only marker of VaD, could presumably be involved in the genesis of dementia, and in the overlap between VaD and AD. Further studies with larger and carefully selected groups are required to eliminate potential confounders and to set specific cut-off values for the aforementioned hemodynamic parameters in demented patients and dementia subtypes. Show more

Keywords: Cerebral hemodynamics, multi-infarct dementia, transcranial Doppler, transcranial ultrasound, vascular dementia

DOI: 10.3233/JAD-132441

Citation: Journal of Alzheimer's Disease, vol. 42, no. s3, pp. S251-S257, 2014

Authors: Demarin, Vida | Morovic, Sandra

Article Type: Review Article

Abstract: Aging is often associated with some cognitive impairment. Greater population life expectancy is one explanation for increased incidence of cognitive impairment cases. Large numbers of people with cognitive impairment and dementia is becoming one of the most important medical and social problems worldwide. Therefore, prevention of cognitive impairment is an imperative. Dementia includes a heterogeneous group of disorders, the most common being Alzheimer's disease and vascular dementia. Most cardiovascular risk factors, such as hypertension, diabetes mellitus, hypercholesterolemia, atrial fibrillation, and smoking, are not exclusively risk factors for vascular dementia, but also for Alzheimer's disease. Early changes in the blood vessel …wall can be detected by early ultrasound screening methods which allow us to detect changes before the disease becomes clinically evident. Intracranial hemodynamics can be assessed by transcranial Doppler sonography (TCD), functional TCD with various functional tests, and TCD detection of cerebral emboli. Extracranial circulation (carotid and vertebral arteries) can be assessed by means of color Doppler flow imaging. Novel ultrasound technology enables non-invasive, portable, bedside detection of early vascular changes such as arterial stiffness, measurement of the intima-media thickness, pulse-wave velocity, flow-mediated dilation, or endothelial dysfunction in order to obtain information necessary to determine more closely the relation between vascular status and disease development, so that the evolution of cardiovascular disease can be prevented or at least postponed. Early disease detection enables in-time management, and studies have shown that careful control of vascular risk factors can postpone or even reverse disease progression. Show more

Keywords: Alzheimer's disease, cognitive impairment, subclinical ultrasound markers, vascular dementia, vascular risk factors

DOI: 10.3233/JAD-132507

Citation: Journal of Alzheimer's Disease, vol. 42, no. s3, pp. S259-S266, 2014

Authors: Baskys, Andrius

Article Type: Review Article

Abstract: Treatment of hypertension reduces vascular dementia (VaD) risk but not all anti-hypertensive drugs (AHDs) are equally effective, suggesting drug-gene interactions. To understand this relationship, publicly accessible databases were searched for genes deregulated in VaD and their interactions with AHDs. Genes that were downregulated in association with VaD were MTHFR, SYK, AGT, and RPGRIP1L. Genes that were upregulated in VaD were MMP9 and VEGFA. TNFSF14, AR, and PHLDB2 were also associated with VaD, however, transcription or protein level changes could not be ascertained. Analysis of gene expression data suggests that AHDs differentially regulate VaD-associated genes. Information about AHD up- or downregulation …of VaD-associated genes could be used as an empirical basis for the optimal selection of AHDs in clinical trials and, ultimately, for VaD prevention and treatment. Show more

Keywords: Androgen receptor, angiotensinogen, matrix metalloproteinase 9, methylenetetrahydrofolate reductase (NAD(P)H), pleckstrin homology-like domain family B member 2, retinitis pigmentosa gtpase regulator interacting protein 1-like, spleen tyrosine kinase, tumor necrosis factor (ligand) superfamily member 14, vascular endothelial growth factor A

DOI: 10.3233/JAD-140003

Citation: Journal of Alzheimer's Disease, vol. 42, no. s3, pp. S267-S276, 2014

Authors: Goldsmith, Harry S.

Article Type: Review Article

Abstract: It has been commonly believed that a decrease in cerebral blood flow (CBF), which routinely occurs in Alzheimer's disease (AD), results from the death of critical intracerebral neurons that no longer require the maintenance of an adequate blood supply. This belief is presently being challenged by the idea that it is not neuronal death that causes a decrease in CBF, but actually a decrease in the CBF which leads to the death of neurons seen in AD. In association with dead neurons located within the AD brain are varying numbers of deteriorating neurons. Increasing the CBF to still viable but …deteriorating neurons in AD is believed to delay and even improve the clinical manifestations of AD. This increase in CBF has proven effective in treating a group of patients with AD. The increase in CBF was accomplished surgically by placing an intact pedicled omentum directly on the AD brain. While surgery is not a long-term answer in the treatment of AD, the surgical procedure should be evaluated by a carefully controlled study while awaiting the future development of a pharmaceutical method to control the disease. Show more

Keywords: Alzheimer's disease, cerebral blood flow, omental transposition, omentum

DOI: 10.3233/JAD-132405

Citation: Journal of Alzheimer's Disease, vol. 42, no. s3, pp. S277-S280, 2014

Authors: Amenta, Francesco | Carotenuto, Anna | Fasanaro, Angiola Maria | Rea, Raffaele | Traini, Enea

Article Type: Research Article

Abstract: Cholinesterase inhibitors (ChE-Is) are used for symptomatic treatment of mild-to-moderate Alzheimer's disease (AD), but long-term effects of these compounds are mild and not always obvious. Preclinical studies have shown that combination of ChE-Is and the cholinergic precursor choline alphoscerate increases brain acetylcholine levels more effectively than single compounds alone. ASCOMALVA (Effect of association between a ChE-I and choline alphoscerate on cognitive deficits in AD associated with cerebrovascular injury) is a double-blind trial investigating if the ChE-I donepezil and choline alphoscerate in combination are more effective that donepezil alone. The trial has recruited AD patients suffering from ischemic brain damage documented …by neuroimaging and has completed 2 years of observation in 113 patients of the 210 planned. Patients were randomly allotted to an active treatment group (donepezil + choline alphoscerate) or to a reference group (donepezil + placebo). Cognitive functions were assessed by the Mini-Mental State Evaluation and Alzheimer's Disease Assessment Scale Cognitive subscale. Daily activity was evaluated by the basic and instrumental activities of daily living tests. Behavioral symptoms were assessed by the Neuropsychiatric Inventory. Over the 24-month observation period, patients of the reference group showed a moderate time-dependent worsening in all the parameters investigated. Treatment with donepezil plus choline alphoscerate significantly slowed changes of the different items analyzed. These findings suggest that the combination of choline alphoscerate with a ChE-I may prolong/increase the effectiveness of cholinergic therapies in AD with concomitant ischemic cerebrovascular injury. Show more

Keywords: Alzheimer's disease, association, cerebrovascular injury, choline alphoscerate, donepezil

DOI: 10.3233/JAD-140150

Citation: Journal of Alzheimer's Disease, vol. 42, no. s3, pp. S281-S288, 2014