Journal of Alzheimer's Disease - Volume 51, issue 2

Authors: Pilotto, Andrea | Turrone, Rosanna | Liepelt-Scarfone, Inga | Bianchi, Marta | Poli, Loris | Borroni, Barbara | Alberici, Antonella | Premi, Enrico | Formenti, Anna | Bigni, Barbara | Cosseddu, Maura | Cottini, Elisabetta | Berg, Daniela | Padovani, Alessandro

Article Type: Research Article

Abstract: Vascular risk factors have been associated with cognitive deficits and incident dementia in the general population, but their role on cognitive dysfunction in Parkinson’s disease (PD) is still unclear. The present study addresses the single and cumulative effect of vascular risk factors on cognition in PD patients, taking clinical confounders into account. Standardized neuropsychological assessment was performed in 238 consecutive PD patients. We evaluated the association of single and cumulative vascular risk factors (smoking, diabetes, hypercholesterolemia, hypertension, and heart disease), with the diagnosis of PD normal cognition (PDNC, n  = 94), mild cognitive impairment (PD-MCI, n  = 111), and dementia (PDD, n … = 33). The association between single neuropsychological tests and vascular risk factors was evaluated with covariance analyses adjusted for age at onset, educational levels, gender, disease duration, and motor performance. Age, educational levels, disease duration, and motor function were significantly different between PDNC, PD-MCI, and PDD. Heart disease was the only vascular factor significantly more prevalent in PDD compared with PDNC in adjusted analyses. Performance of tests assessing executive and attention functions were significantly worse in patients with hypertension, heart disease, and/or diabetes (p  <  0.05). Heart disease is associated with dementia in PD, suggesting a potential window of intervention. Vascular risk factors act especially on attention and executive functions in PD. Vascular risk stratification may be useful in order to identify PD patients with a greater risk of developing dementia. These findings need to be verified in longitudinal studies. Show more

Keywords: Dementia, heart disease, hypertension, Parkinson disease, risk factors

DOI: 10.3233/JAD-150610

Citation: Journal of Alzheimer's Disease, vol. 51, no. 2, pp. 563-570, 2016

Authors: Fang, Du | Zhang, Zhihua | Li, Hang | Yu, Qing | Douglas, Justin T. | Bratasz, Anna | Kuppusamy, Periannan | Yan, Shirley ShiDu

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is a progressive neurodegenerative disease characterized clinically by cognitive decline and memory loss. The pathological features are amyloid-β peptide (Aβ) plaques and intracellular neurofibrillary tangles. Many studies have suggested that oxidative damage induced by reactive oxygen species (ROS) is an important mechanism for AD progression. Our recent study demonstrated that oxidative stress could further impair mitochondrial function. In the present study, we adopted a transgenic mouse model of AD (mAPP, overexpressing AβPP/Aβ in neurons) and performed redox measurements using in vivo electron paramagnetic resonance (EPR) imaging with methoxycarbamyl-proxyl (MCP) as a redox-sensitive probe for studying oxidative …stress in an early stage of pathology in a transgenic AD mouse model. Through assessing oxidative stress, mitochondrial function and cognitive behaviors of mAPP mice at the age of 8-9 months, we found that oxidative stress and mitochondrial dysfunction appeared in the early onset of AD. Increased ROS levels were associated with defects of mitochondrial and cognitive dysfunction. Notably, the in vivo EPR method offers a unique way of assessing tissue oxidative stress in living animals under noninvasive conditions, and thus holds a potential for early diagnosis and monitoring the progression of AD. Show more

Keywords: Aβ accumulation, cognitive function, mitochondrial dysfunction, oxidative stress

DOI: 10.3233/JAD-150917

Citation: Journal of Alzheimer's Disease, vol. 51, no. 2, pp. 571-580, 2016

Authors: Louwersheimer, Eva | Keulen, M. Antoinette | Steenwijk, Martijn D. | Wattjes, Mike P. | Jiskoot, Lize C. | Vrenken, Hugo | Teunissen, Charlotte E. | van Berckel, Bart N.M. | van der Flier, Wiesje M. | Scheltens, Philip | van Swieten, John C. | Pijnenburg, Yolande A.L.

Article Type: Research Article

Abstract: Background: The logopenic variant of Primary Progressive Aphasia (lvPPA) is associated with underlying Alzheimer’s disease (AD) pathology and characterized by impaired single word retrieval and repetition of phrases and sentences. Objective: We set out to study whether logopenic aphasia is indeed the prototypic language profile in PPA patients with biomarker evidence of underlying AD pathology and to correlate language profiles with cortical atrophy patterns on MRI. Methods: Inclusion criteria: (I) clinical diagnosis of PPA; (II) CSF profile and/or PiB-PET scan indicative for amyloid pathology; (III) availability of expert language evaluation. Based on language evaluation, patients were …classified as lvPPA (fulfilling lvPPA core criteria), lvPPA extended (fulfilling core criteria plus other language disturbances), or PPA unclassifiable (not fulfilling lvPPA core criteria). Cortical atrophy patterns on MRI were visually rated and quantitative measurements of cortical thickness were performed using FreeSurfer. Results: We included 22 patients (age 67±7 years, 50% female, MMSE 21±6). 41% were classified as lvPPA , 36% as lvPPA extended with additional deficits in language comprehension and/or confrontation naming, and 23% as PPA unclassifiable. By both qualitative and quantitative measurements, patients with lvPPA showed mild global cortical atrophy on MRI, whereas patients with lvPPA extended showed more focal cortical atrophy, predominantly at the left tempo-parietal side. For PPA unclassifiable, qualitative measurements revealed a heterogeneous atrophy pattern. Conclusion: Although most patients fulfilled the lvPPA criteria, we found that their language profiles were heterogeneous. The clinical and radiological spectrum of PPA due to underlying AD pathology is broader than pure lvPPA. Show more

Keywords: Atypical Alzheimer’s disease, cerebral atrophy, language disorders, logopenic aphasia, neurodegenerative disorder, primary progressive aphasia

DOI: 10.3233/JAD-150812

Citation: Journal of Alzheimer's Disease, vol. 51, no. 2, pp. 581-590, 2016

Authors: Song, Jung Min | Sung, You Me | Nam, Jin Han | Yoon, Hyejin | Chung, Andrew | Moffat, Emily | Jung, Mira | Pak, Daniel T.S. | Kim, Jungsu | Hoe, Hyang-Sook

Article Type: Research Article

Abstract: Background: The accumulation of amyloid-β (Aβ ) leads to the loss of dendritic spines and synapses, which is hypothesized to cause cognitive impairments in Alzheimer’s disease (AD) patients. In our previous study, we demonstrated that a novel mercaptoacetamide-based class II histone deacetylase inhibitor (HDACI), known as W2, decreased Aβ levels and improved learning and memory in mice. However, the underlying mechanism of this effect is unknown. Objective: Because dendritic spine formation is associated with cognitive performance, here we investigated whether HDACI W2 regulates dendritic spine density and its molecular mechanism of action. Methods: To examine …the effect of HDACI W2 on dendritic spine density, we conducted morphological analysis of dendritic spines using GFP transfection and Golgi staining. In addition, to determine the molecular mechanism of W2 effects on spines, we measured the levels of mRNAs and proteins involved in the Ras signaling pathway using quantitative real-time PCR, immunocytochemistry, and western analysis. Results: We found that HDACI W2 altered dendritic spine density and morphology in vitro and in vivo . Additionally, W2 increased the mRNA or protein levels of Ras GRF1 and phospho-ERK. Moreover, knockdown of RasGRF1 and inhibition of ERK activity prevented the W2-mediated spinogenesis in primary hippocampal neurons. Conclusion: Our Class II-selective HDACI W2 promotes the formation and growth of dendritic spines in a RasGRF1 and ERK dependent manner in primary hippocampal neurons. Show more

Keywords: Alzheimer’s disease, dendritic spine, HDAC inhibitor, ras signaling

DOI: 10.3233/JAD-150717

Citation: Journal of Alzheimer's Disease, vol. 51, no. 2, pp. 591-604, 2016

Authors: Hong, Xiao-Ping | Chen, Tao | Yin, Ni-Na | Han, Yong-Ming | Yuan, Fang | Duan, Yan-Jun | Shen, Feng | Zhang, Yan-Hong | Chen, Ze-Bin

Article Type: Research Article

Abstract: Enhanced neurogenesis has been reported in the hippocampus of patients with Alzheimer’s disease (AD), the most common neurodegenerative disorder characterized with amyloid-β (Aβ) aggregation, tau hyperphosphorylation, and progressive neuronal loss. Previously we reported that tau phosphorylation played an essential role in adult hippocampal neurogenesis, and activation of glycogen synthase kinase (GSK-3), a crucial tau kinase, could induce increased hippocampal neurogenesis. In the present study, we found that treatment of D-galactose rats with Puerarin could significantly improve behavioral performance and ameliorate the enhanced neurogenesis and microtubule-associated protein tau hyperphosphorylation in the hippocampus ofD-galactose rat brains. FGF-2/GSK-3 signaling pathway might be involved …in the effects of Puerarin on hippocampal neurogenesis and tau hyperphosphorylation. Our finding provides primary in vivo evidence that Puerarin can attenuate AD-like enhanced hippocampal neurogenesis and tau hyperphosphorylation. Our finding also suggests Puerarin can be served as a treatment for age-related neurodegenerative disorders, such as AD. Show more

Keywords: Alzheimer’s disease, glycogen synthase kinase, hippocampus, neurogenesis, Puerarin, spatial memory, tau hyperphosphorylation

DOI: 10.3233/JAD-150566

Citation: Journal of Alzheimer's Disease, vol. 51, no. 2, pp. 605-617, 2016

Authors: O’Caoimh, Rónán | Timmons, Suzanne | Molloy, D. William

Article Type: Research Article

Abstract: Background: Sensitive and specific instruments are required to screen for cognitive impairment (CI) in busy clinical practice. The Montreal Cognitive Assessment (MoCA) is widely validated but few studies compare it to tests designed specifically to detect mild cognitive impairment (MCI). Objective: Comparison of two “MCI specific” screens: the Quick Mild Cognitive Impairment screen (Qmci ) and MoCA. Methods: Patients with subjective memory complaints (SMC; n  = 73), MCI (n  = 103), or dementia (n  = 274), were referred to a university hospital memory clinic and underwent comprehensive assessment. Caregivers, without cognitive symptoms, were recruited as normal controls (n  = 101). …Results: The Qmci was more accurate than the MoCA in differentiating MCI from controls, area under the curve (AUC) of 0.90 versus 0.80, p  = 0.009. The Qmci had greater (AUC 0.81), albeit non-significant, accuracy than the MoCA (AUC 0.73) in separating MCI from SMC, p  = 0.09. At its recommended cut-off (<62/100), the Qmci had a sensitivity of 90% and specificity of 87% for CI (MCI/dementia). Raising the cut-off to <65 optimized sensitivity (94%), reducing specificity (80%). At <26/30 the MoCA had better sensitivity (96%) but poor specificity (58%). A MoCA cut-off of <24 provided the optimal balance. Median Qmci administration time was 4.5 (±1.3) minutes compared with 9.5 (±2.8) for the MoCA. Conclusions: Although both tests distinguish MCI from dementia, the Qmci is particularly accurate in separating MCI from normal cognition and has shorter administration times, suggesting it is more useful in busy hospital clinics. This study reaffirms the high sensitivity of the MoCA but suggests a lower cut-off (<24) in this setting. Show more

Keywords: Cognitive screening, dementia, mild cognitive impairment, Montreal Cognitive Assessment, Quick Mild Cognitive Impairment screen

DOI: 10.3233/JAD-150881

Citation: Journal of Alzheimer's Disease, vol. 51, no. 2, pp. 619-629, 2016

Article Type: Other

DOI: 10.3233/JAD-160060

Citation: Journal of Alzheimer's Disease, vol. 51, no. 2, pp. 631-635, 2016