Journal of Alzheimer's Disease - Volume 52, issue 4

Authors: Tang, Shan-Shan | Li, Jun | Tan, Lan | Yu, Jin-Tai

Article Type: Review Article

Abstract: Frontotemporal lobar degeneration (FTLD) is a clinically heterogeneous neurodegenerative disease with a strong genetic component. In this review, we summarize most common mutations in MAPT, GRN, and C90RF72, as well as less common mutations in VCP, CHMP2B, TARDBP, FUS gene and so on. Several guidelines have been developed to help gene testing based on genotype–phenotype correlation, the underlying histopathological subtypes, and the neuroanatomic associations. Furthermore, we also summarize molecular pathways implicated by genes and novel targets for FTLD prevention and management in recent years.

Keywords: Frontotemporal lobar degeneration, genes, genetic testing, mechanisms, neuroimaging, therapeutics

DOI: 10.3233/JAD-160236

Citation: Journal of Alzheimer's Disease, vol. 52, no. 4, pp. 1157-1176, 2016

Authors: Otto, Grant P. | Sharma, Devdutt | Williams, Robin S.B.

Article Type: Review Article

Abstract: Research into Alzheimer’s disease pathology and treatment has often focused on presenilin proteins. These proteins provide the key catalytic activity of the γ-secretase complex in the cleavage of amyloid-β precursor protein and resultant amyloid tangle deposition. Over the last 25 years, screening novel drugs to control this aberrant proteolytic activity has yet to identify effective treatments for the disease. In the search for other mechanisms of presenilin pathology, several studies have demonstrated that mammalian presenilin proteins also act in a non-proteolytic role as a scaffold to co-localize key signaling proteins. This role is likely to represent an ancestral presenilin function, …as it has been described in genetically distant species including non-mammalian animals, plants, and a simple eukaryotic amoeba Dictyostelium that diverged from the human lineage over a billion years ago. Here, we review the non-catalytic scaffold role of presenilin, from mammalian models to other biomedical models, and include recent insights using Dictyostelium, to suggest that this role may provide an early evolutionary function of presenilin proteins. Show more

Keywords: Alzheimer’s disease, β-catenin, development, glycogen synthase kinase 3β, non-proteolytic mechanism, presenilin, 3Rs

DOI: 10.3233/JAD-150940

Citation: Journal of Alzheimer's Disease, vol. 52, no. 4, pp. 1177-1187, 2016

Authors: Rego, Ângela | Viana, Sofia D. | Ribeiro, Carlos A. Fontes | Rodrigues-Santos, Paulo | Pereira, Frederico C.

Article Type: Review Article

Abstract: Neuroinflammation is a two-edged sword in Alzheimer’s disease (AD). A certain degree of neuroinflammation is instrumental in the clearance of amyloid-β (Aβ) peptides by activated microglia, although a sustained neuroinflammation might accelerate Aβ deposition, thus fostering the neurodegenerative process and functional decline in AD. There is an increasing body of evidence suggesting that the innate immune system via Toll-like receptor 4 (TLR4) finely orchestrates the highly regulated inflammatory cascade that takes place in AD pathology. Herein we critically review pre-clinical (in vitro and in vivo approaches) and clinical studies showing that monophosphoryl lipid A (MPL), a partial TLR4 …agonist, may have beneficial effect on AD physiopathology. The in vivo data elegantly showed that MPL enhanced Aβ plaque phagocytosis thus decreasing the number and the size of Aβ deposits and soluble Aβ in brain from APPswe/PS1 mice. Furthermore, MPL also improved their cognition. The mechanism underlying this MPL effect was proposed to be microglial activation by recruiting TLR4. Additionally, it was demonstrated that MPL increased the Aβ antibody titer and showed a safe profile in mice and primates, when used as a vaccine adjuvant. Clinical studies using MPL as an adjuvant in Aβ immunotherapy are currently ongoing. Overall, we argue that the TLR4 partial agonist MPL is a potentially safe and effective new pharmacological tool in AD. Show more

Keywords: Alzheimer’s disease, monophosphoryl lipid A, neuroinflammation, toll-like receptor

DOI: 10.3233/JAD-151183

Citation: Journal of Alzheimer's Disease, vol. 52, no. 4, pp. 1189-1202, 2016

Authors: Clarelli, Ferdinando | Mascia, Elisabetta | Santangelo, Roberto | Mazzeo, Salvatore | Giacalone, Giacomo | Galimberti, Daniela | Fusco, Federica | Zuffi, Marta | Fenoglio, Chiara | Franceschi, Massimo | Scarpini, Elio | Forloni, Gianluigi | Magnani, Giuseppe | Comi, Giancarlo | Albani, Diego | Martinelli Boneschi, Filippo

Article Type: Short Communication

Abstract: Previous studies suggest that genetic variants in CHRNA7, which encodes for the major subunit of the acetylcholine receptor (α 7-nAChR), are associated with the clinical response to cholinesterase inhibitors (ChEI) in Alzheimer’s disease (AD) patients. We sought to replicate the association of two SNPs in the CHRNA7 gene, rs6494223 and rs8024987, with response to ChEI treatment in an Italian cohort of 169 AD patients, further extending the study to gene-level analysis. None of the tested variants was associated with clinical response. However, rs6494223 showed a consistent effect direction (OR = 1.4; p  = 0.17), which after meta-analysis with previous study yielded …a significant result (OR = 1.57, p  = 0.02, I2 = 0%). Show more

Keywords: Alpha7 nicotinic acetylcholine receptor, Alzheimer’s disease, biomarkers, cholinesterase inhibitors, pharmacogenetics

DOI: 10.3233/JAD-160074

Citation: Journal of Alzheimer's Disease, vol. 52, no. 4, pp. 1203-1208, 2016

Authors: Pliássova, Anna | Canas, Paula M. | Xavier, Ana Carolina | da Silva, Beatriz S. | Cunha, Rodrigo A. | Agostinho, Paula

Article Type: Short Communication

Abstract: Amyloid-β protein precursor (AβPP) is involved in synaptic formation and function. In the human cingulate cortex, AβPP was preferentially located in the presynaptic active zone as in rodents, indicating a preserved subsynaptic AβPP distribution across species and brain regions. Synaptic AβPP immunoreactivity was decreased with aging in cortical samples collected from autopsies of males (20-80 years), whereas the synaptic levels of α -secretase (ADAM10) and β-secretase (BACE1) did not significantly change. Decreased AβPP levels may be related to lower allostasis of synapses in the aged brain and their greater susceptibility to dysfunction characteristic of the onset of neurodegenerative disorders.

Keywords: Aging, amyloid-β protein, human brain, α-secretase, β-secretase, sub-synaptic fractions, synapse

DOI: 10.3233/JAD-160213

Citation: Journal of Alzheimer's Disease, vol. 52, no. 4, pp. 1209-1214, 2016

Authors: Müller, Stephan | Mychajliw, Christian | Reichert, Carolin | Melcher, Tobias | Leyhe, Thomas

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is characterized by memory disturbances primarily caused by pathogenic mechanisms affecting medial temporal lobe structures. As proposed by current theories of memory formation, this decrease is mediated by the age of the acquired knowledge. However, they cannot fully explain specific patterns of retrograde amnesia in AD. In the current study we examined an alternative approach and investigated whether the extent and severity of retrograde amnesia in AD is mediated by the frequency of memory retrieval or whether it depends on the mere age of knowledge. We compared recall of autobiographical incidents from three life periods in patients …with amnestic mild cognitive impairment (aMCI), patients with early dementia of Alzheimer type (eDAT), and healthy control (HC) individuals using the Autobiographical Memory Interview. Retrieval frequency was operationalized by a paired comparison analysis. In contrast to HC individuals, recall of autobiographical incidents was impaired in patients with aMCI and eDAT following Ribot’s gradient, with a reduced memory loss for remote compared to more recent life events. However, there was a strong effect of retrieval frequency on memory performance with frequently retrieved incidents memorized in more detail than less frequently retrieved episodes. Remote memories were recalled more often than recent ones. These findings suggest that more frequently retrieved autobiographical memories generally become more independent of the hippocampal complex and might thus be better protected against early hippocampal damage related to AD. Hence, the extent of retrograde amnesia in AD appears mainly mediated by the frequency of memory retrieval, which could plausibly explain why cognitive activity can effectively delay the onset of memory decline in AD. Show more

Keywords: Alzheimer’s disease, autobiographical memory, cognitive impairment, multiple trace theory, retrieval frequency, Ribot’s Law, standard model of memory consolidation

DOI: 10.3233/JAD-151071

Citation: Journal of Alzheimer's Disease, vol. 52, no. 4, pp. 1215-1225, 2016

Authors: Premi, Enrico | Gualeni, Vera | Costa, Paolo | Cosseddu, Maura | Gasparotti, Roberto | Padovani, Alessandro | Borroni, Barbara

Article Type: Research Article

Abstract: Frontotemporal dementia (FTD) is characterized by executive dysfunctions, behavioral disturbances, language deficits and extrapyramidal symptoms. Frontotemporal lobar degeneration-modified Clinical Dementia Rating Scale (FTLD modified-CDR) has been proposed to measure disease severity in behavioral variant FTD (bvFTD). No tools of global disease severity are available in the other FTLD phenotypes [primary progressive aphasias (PPAs), progressive supranuclear palsy (PSP), and corticobasal syndrome (CBS)]. This would be strategic as outcome measures in clinical trials. To this aim, we evaluated the association between brain volume (voxel based morphometry) and available clinical scales in FTD. In 176 FTD patients (64 bvFTD, 40 PPAs, 32 PSP, …40 CBS), instrumental activities of daily living (ADLs), FTLD-modified CDR, Mini-Mental State Examination (MMSE), Frontal Behavioral Inventory (FBI), and Neuropsychiatry Inventory (NPI) were administered and MRI performed. Whole-brain linear correlation between each clinical rating scale and brain volume was performed. In bvFTD and PPAs, FTLD-modified CDR was associated with regional brain volume, thereby providing evidence for validity of the FTLD-modified CDR. In PSP, none of the clinical indicators were associated with regional brain volume. In CBS, ADLs and MMSE correlated with frontotemporal lower volume. Considering monogenic disease, FTLD-modified CDR was the best measure. In FTD continuum, different measures able to correlate with brain damage should be considered for the different clinical phenotypes or genetic traits. Show more

Keywords: Activities of daily living, Frontal Behavioral Inventory, frontotemporal dementia continuum, FTLD-modified CDR, Mini-Mental State Examination, Neuropsychiatry Inventory, voxel-based morphometry

DOI: 10.3233/JAD-160178

Citation: Journal of Alzheimer's Disease, vol. 52, no. 4, pp. 1227-1235, 2016

Authors: Ye, Byoung Seok | Lee, Yoonju | Kwak, Kichang | Park, Yeong-Hun | Ham, Jee Hyun | Lee, Jae Jung | Shin, Na-Young | Lee, Jong-Min | Sohn, Young H. | Lee, Phil Hyu

Article Type: Research Article

Abstract: Background: Enlargement of the lateral ventricle is observed in dementia associated with Alzheimer’s disease (AD) and dementia with Lewy bodies (DLB). Objective: The degree of anteroposterior ventricular enlargement and its correlation with clinical and neuropsychological features were investigated in DLB patients. Methods: Forty-eight patients with DLB, 76 with AD, and 45 subjects with normal cognition (NC) underwent structural brain MRI and detailed neuropsychological tests. Ventricular shape was compared among the groups by visual inspection. Posterior ventricle enlargement (PVE) was defined as the ratio of the distance between the temporal and occipital horns of the lateral …ventricle to the distance between the temporal horn of the lateral ventricle and occipital pole of the brain. Results: After controlling for age, sex, and education, higher PVE was observed in the DLB group than in the AD group (68.5 ± 7.9% versus 62.8 ± 9.0%, respectively; p  = 0.001) or the NC group (61.9 ± 9.9%, p  = 0.002). However, higher PVE was not associated with poorer neuropsychological performance, nor was it associated with any clinical features in the DLB group after controlling for age, sex, and education. Conclusion: PVE occurs more often in DLB than in AD and NC. However, it is unclear how PVE is related to the clinical and neuropsychological features of DLB. Show more

Keywords: Alzheimer’s disease, dementia with Lewy bodies, ventricular enlargement

DOI: 10.3233/JAD-160062

Citation: Journal of Alzheimer's Disease, vol. 52, no. 4, pp. 1237-1243, 2016

Authors: Ahmed, Samrah | Baker, Ian | Husain, Masud | Thompson, Sian | Kipps, Christopher | Hornberger, Michael | Hodges, John R. | Butler, Christopher R.

Article Type: Research Article

Abstract: Posterior cortical atrophy (PCA) is characterized by core visuospatial and visuoperceptual deficits, and predominant atrophy in the parieto-occipital cortex. The most common underlying pathology is Alzheimer’s disease (AD). Existing diagnostic criteria suggest that episodic memory is relatively preserved. The aim of this study was to examine memory performance at initial clinical presentation in PCA, compared to early-onset AD patients (EOAD). 15 PCA patients and 32 EOAD patients, and 34 healthy controls were entered into the study. Patients were tested on the Addenbrooke’s Cognitive Examination (ACE-R), consisting of subscales in memory and visuospatial skills. PCA and EOAD patients were significantly impaired …compared to controls on the ACE total score (p  < 0.001), visuospatial skills (p  < 0.001), and memory (p  < 0.001). Consistent with the salient diagnostic deficits, PCA patients were significantly more impaired on visuospatial skills compared to EOAD patients (p  < 0.001). However, there was no significant difference between patient groups in memory. Further analysis of learning, recall, and recognition components of the memory subscale showed that EOAD and PCA patients were significantly impaired compared to controls on all three components (p  < 0.001), however, there was no significant difference between EOAD and PCA patients. The results of this study show that memory is impaired in the majority of PCA patients at clinical presentation . The findings suggest that memory impairment must be considered in assessment and management of PCA. Further study into memory in PCA is warranted, since the ACE-R is a brief screening tool and is likely to underestimate the presence of memory impairment. Show more

Keywords: Diagnosis, early onset Alzheimer’s disease, memory, neuropsychology

DOI: 10.3233/JAD-160018

Citation: Journal of Alzheimer's Disease, vol. 52, no. 4, pp. 1245-1250, 2016

Authors: Bensaïdane, Mohamed Reda | Beauregard, Jean-Mathieu | Poulin, Stéphane | Buteau, François-Alexandre | Guimond, Jean | Bergeron, David | Verret, Louis | Fortin, Marie-Pierre | Houde, Michèle | Bouchard, Rémi W. | Soucy, Jean-Paul | Laforce Jr, Robert

Article Type: Research Article

Abstract: Recent studies have supported a role for amyloid positron emission tomography (PET) imaging in distinguishing Alzheimer’s disease (AD) pathology from other pathological protein accumulations leading to dementia. We investigated the clinical utility of amyloid PET in the differential diagnosis of atypical dementia cases and its impact on caregivers. Using the amyloid tracer 18 F-NAV4694, we prospectively scanned 28 patients (mean age 59.3 y, s.d. 5.8; mean MMSE 21.4, s.d. 6.0) with an atypical dementia syndrome. Following a comprehensive diagnostic workup (i.e., history taking, neurological examination, blood tests, neuropsychological evaluation, MRI, and FDG-PET), no certain diagnosis could be arrived at. Amyloid …PET was then conducted and classified as positive or negative. Attending physicians were asked to evaluate whether this result led to a change in diagnosis or altered management. They also reported their degree of confidence in the diagnosis. Caregivers were met after disclosure of amyloid PET results and completed a questionnaire/interview to assess the impact of the scan. Our cohort was evenly divided between positive (14/28) and negative (14/28) 18 F-NAV4694 cases. Amyloid PET resulted in a diagnostic change in 9/28 cases (32.1%: 17.8% changed from AD to non-AD, 14.3% from non-AD to AD). There was a 44% increase in diagnostic confidence. Altered management occurred in 71.4% (20/28) of cases. Knowledge of amyloid status improved caregivers’ outcomes in all domains (anxiety, depression, disease perception, future anticipation, and quality of life). This study suggests a useful additive role for amyloid PET in atypical cases with an unclear diagnosis beyond the extensive workup of a tertiary memory clinic. Amyloid PET increased diagnostic confidence and led to clinically significant alterations in management. The information gained from that test was well received by caregivers and encouraged spending quality time with their loved ones. Show more

Keywords: Alzheimer’s disease, Alzheimer variants, amyloid PET imaging, atypical dementia, caregivers, differential diagnosis, frontotemporal lobar degeneration, impact, primary progressive aphasia, clinical utility

DOI: 10.3233/JAD-151180

Citation: Journal of Alzheimer's Disease, vol. 52, no. 4, pp. 1251-1262, 2016