Current Alzheimer Research (v.14, #10)

Meet Our Editorial Board Member by Claudio Babiloni (1017-1017).

Light exerts influences on many physiological and behavioural functions in humans. These functions can be described as image-forming (IF) and non-image forming (NIF) visual processes, both originating in the retina of the eye. Image-forming refers to vision; the process of detecting and distinguishing shapes and colour of objects. Non-image forming refers to detecting level of light intensity or brightness of ambient space, which affects basal physiology such as cycles of rest and activity or the endocrine system. Rod and cone photoreceptors in the outer retinal layer are most important for imageforming vision, while non-image forming functions depend upon additional input from the photopigment melanopsin, which is expressed in retinal ganglion cells (RGC) that makes these cells photosensitive (pRGC). Projections of these pRGCs convey light-induced electrical impulses to a number of brain regions. Visual acuity and colour contrast naturally diminishes with age but dementia often has major effects on the visual processing systems, which impact on the quality of life. The ability of humans to manipulate their light exposure has the immediate potential to either create problems with human physiology (as in shift workers) or to compensate physiological disadvantages (of IF and NIF visual impairment). This mini-review describes the impact of aging on the function of the eye with respect to nonimage forming effects of light, summarises light intervention studies for sleep and neuropsychiatric symptoms and considers implications from photoreceptor-weighted light intensities for biologically effective light intervention and lighting solutions for patients with dementia.

Objective: Age-related cognitive impairment and the prevalence of neurodegenerative disease contribute to decreasing quality of life in affected individuals and their families as well as demand considerable societal responsibility. Sleep supports overall brain activity and contributes to both physical and mental health. As a result, sleep is an attractive target for exploring ways to promote health in accelerated cognitive aging. The aims of this study were to characterise cognitive performance and sleepwake behaviour in older adults with different degrees of cognitive impairment. <P></P> Methods: Cognitive ability in a variety of domains of amnestic mild cognitive impairment (aMCI) individuals, moderate AD patients and cognitively healthy adults was assessed with the Mini-Mental-State- Examination and five computerised tests (CANTABeclipse™). It was imperative to exclude mixed diagnosis, comorbidities (psychiatric, neurological, sleep disorders), anti-dementia medication, institutionalised subjects, and to study participants within their home to minimise confounders. Sleep profiles were assessed with the Jupiter Sleep Questionnaire and Pittsburgh Sleep Quality Index completed by participants and carers. Participants’ sleep-wake activity was monitored for three weeks using a wrist-worn actigraph and a semi-standardised diary. Groups were compared according to their diagnostic category and then pooled to correlate sleep data with cognitive performance. <P></P> Results: Mild cognitive impairment in aMCI individuals was reflected in domains of verbal and visuospatial memory but not attentional capacity or episodic memory. All self-reported and objective measures of sleep quality and sleep quantity of the aMCIs were within the normal range and comparable to those of cognitively healthy controls. Moderate AD patients scored significantly lower on all cognitive tests and had lower rest-activity amplitudes and distinctively longer nightly sleep periods that were not associated with sleep disorders, sleep medication or poor sleep efficiency. Self-rated and actigraphic quality of sleep was equally good (i.e. 90% sleep efficiency) in all groups. <P></P> Conclusion: This investigation is of clinical importance, because major confounding variables were excluded. The lack of comorbidities might be responsible for the absence of sundown syndrome and sleep disturbances commonly reported in AD patients. Whether there is interdependence between progressive decline in cognition and long sleep duration remains elusive. Future studies should address whether prolonged sleep at night and decreased day-time activity can be altered to delay the progression of cognitive decline.

Applying Melanopic Lux to Measure Biological Light Effects on Melatonin Suppression and Subjective Sleepiness by Claudia Nowozin, Amely Wahnschaffe, Andrea Rodenbeck, Jan de Zeeuw, Sven Hädel, Ruslan Kozakov, Heinz Schöpp, Mirjam Münch, Dieter Kunz (1042-1052).
Objective: At the beginning of this century, a novel photopigment, melanopsin, was discovered in a sub-class of retinal ganglion cells and its action spectrum was described. Shortly after, it became evident that melanopsin is a major contributor to non-visual eye-mediated effects of light on e.g. the circadian, neuroendocrine and neurobehavioral systems. First applied studies pointed out that these non-visual effects of light are relevant for wellbeing, performance and general health. A standardized measurement metric for these nonvisual effects does not exist, but would ease application. Such a metric termed as ‘melanopic lux’ has been recently introduced and was shown to be superior to describe non-visual effects in animal studies compared to standard metrics. <P></P> Methods: We aimed at showing some validity of melanopic lux in humans using a seminaturalistic setting. Therefore, we analyzed the impact of different lighting conditions on melatonin suppression and subjective sleepiness by calculating effective illuminance based on single photopigment sensitivities. We retrospectively analyzed data from our laboratory, where young participants were exposed to a total of 19 different polychromatic lighting conditions, for 30 minutes in the evening, one hour prior to habitual bedtime. Saliva samples for melatonin concentration measures and subjective sleepiness were regularly assessed. The photopic illuminance of all lighting conditions ranged from 3 to 604 lx. Stepwise for- and backward regression analyses showed that melanopic lux was the best predictor for changes in melatonin concentrations (but not subjective sleepiness); R²=0.16 (p<0.05). In addition, we found a significant dose-response relationship between melanopic lux and changes in melatonin concentrations for 18 different lighting conditions (adjusted R²=0.52; p=0.004), similarly to what was previously reported for photopic lux. <P></P> Results: Our results indicate some new relevance for the application of melanopic lux as an additional metric to predict non-visual light effects of electrical light sources for nursing homes, work places, and homes.

Blue-Enriched Lighting for Older People Living in Care Homes: Effect on Activity, Actigraphic Sleep, Mood and Alertness by Samantha Hopkins, Peter Lloyd Morgan, Luc J.M. Schlangen, Peter Williams, Debra J. Skene, Benita Middleton (1053-1062).
Objective: Environmental (little outdoor light; low indoor lighting) and age-related physiological factors (reduced light transmission through the ocular lens, reduced mobility) contribute to a light-deprived environment for older people living in care homes. <P></P> Methods: This study investigates the effect of increasing indoor light levels with blue-enriched white lighting on objective (rest-activity rhythms, performance) and self-reported (mood, sleep, alertness) measures in older people. Eighty residents (69 female), aged 86 ± 8 yrs (mean ± SD), participated (MMSE 19 ± 6). Overhead fluorescent lighting was installed in communal rooms (n=20) of seven care homes. Four weeks of blue-enriched white lighting (17000 K ≅ 900 lux) were compared with four weeks of control white lighting (4000 K ≅ 200 lux), separated by three weeks wash-out. Participants completed validated mood and sleep questionnaires, psychomotor vigilance task (PVT) and wore activity and light monitors (AWL). Rest-activity rhythms were assessed by cosinor, non-parametric circadian rhythm (NPCRA) and actigraphic sleep analysis. Blue-enriched (17000 K) light increased wake time and activity during sleep decreasing actual sleep time, sleep percentage and sleep efficiency (p < 0.05) (actigraphic sleep). Compared to 4000 K lighting, blue-enriched 17000 K lighting significantly (p < 0.05) advanced the timing of participants’ rest-activity rhythm (cosinor), increased daytime and night-time activity (NPCRA), reduced subjective anxiety (HADA) and sleep quality (PSQI). There was no difference between the two light conditions in daytime alertness and performance (PVT). <P></P> Conclusion: Blue-enriched lighting produced some positive (increased daytime activity, reduced anxiety) and negative (increased night-time activity, reduced sleep efficiency and quality) effects in older people.

Bright Light Delights: Effects of Daily Light Exposure on Emotions, Restactivity Cycles, Sleep and Melatonin Secretion in Severely Demented Patients by Mirjam Münch, Michael Schmieder, Katharina Bieler, Rolf Goldbach, Timo Fuhrmann, Naomi Zumstein, Petra Vonmoos, Jean-Louis Scartezzini, Anna Wirz-Justice, Christian Cajochen (1063-1075).
Objective: We tested whether the effects of a dynamic lighting system are superior to conventional lighting on emotions, agitation behaviour, quality of life, melatonin secretion and circadian restactivity cycles in severely demented patients. As a comparison, an age matched control patient group was exposed to conventional lighting. For none of the output measures were significant differences between the two lighting conditions found during the 8 study weeks in fall/winter. <P></P> Methods: Thus, we divided the patient cohort (n = 89) into two groups, solely based on the median of their daily individual light exposure. Patients with higher average daily light exposure (> 417 lx) showed significantly longer emotional expressions of pleasure and alertness per daily observations than patients with lower daily light exposure. Moreover, they had a higher quality of life, spent less time in bed, went to bed later and initiated their sleep episodes later, even though the two groups did not differ with respect to age, severity of cognitive impairment and mobility. In general, men were more agitated, had shorter sleep with more wake episodes, had a lower circadian amplitude of relative rest-wake activity and interdaily circadian stability than women. In particular, lower daily light exposures significantly predicted lower circadian amplitudes of rest-activity cycles in men but not in women. This may indicate sex specific susceptibility to daily light exposures for rest-activity regulation in older demented patients. <P></P> Results: Our results provide evidence that a higher daily light exposure has beneficial effects on emotions and thus improved quality of life in a severely demented patient group.

Implementation of Dynamic Lighting in a Nursing Home: Impact on Agitation but not on Rest-Activity Patterns by Amely Wahnschaffe, Claudia Nowozin, Sven Haedel, Andreas Rath, Stefan Appelhof, Mirjam Münch, Dieter Kunz (1076-1083).
Objective: Disturbances of circadian rest-activity rhythms in demented patients often culminate in the clinical problem of evening and nighttime agitation. The aim of the current study was to test the impact of a dynamic lighting system on agitation and rest-activity cycles in patients with dementia. <P></P> Methods: From midwinter on, a ceiling mounted dynamic lighting system was installed in the common room of a nursing home and programmed to produce high illuminance with higher blue light proportions during the day and lower illuminance without blue light in the evening. Fifteen residents with dementia were regularly assessed with the Cohen Mansfield Agitation Index (CMAI) before and after the lighting intervention. Additionally rest-activity cycles were continuously monitored for 6 months by a wrist worn activity watch. Analysis of CMAI data was performed by using the Wilcoxon-Test for matched pairs (before vs. after the lighting installation). Rest-activity data was compared with t-tests for dependent samples. <P></P> The dynamic lighting significantly reduced the CMAI sum-scores from 30.2±5.1 to 27.9±2.6 (mean ± SD; N = 12; p<0.05). Analysis of the CMAI subscores revealed that under the dynamic lighting mainly non-physically aggressive behaviors were reduced. <P></P> Results: Results from the rest-activity analysis did not show differences of circadian amplitude and other circadian variables before and after the lighting installation. <P></P> The dynamic lighting in the living room significantly reduced agitated behavior in demented patients, indicating short-term benefits from higher daily light exposures. Whether such lighting also impacts long-term (circadian) rest-activity cycles needs to be further investigated.

Objectives: REM sleep behavior disorder (RBD), with its main clinical symptoms of nightmares with dream-enacting behavior, is considered as a possible precursor of neurodegenerative disease. Obstructive Sleep Apnea Syndrome (OSAS) is known to be capable of provoking RBD-like symptoms by apneic event related arousals. The two sleep related pathologies must coincide in a relevant number of individuals because of overlapping prevalence in similar age groups. Until now RBD symptoms coexisting with OSAS are rarely described in scientific literature and in fact considered as OSAS mimicking RBD. <P></P> Methods: We report four cases with a severe clinical RBD syndrome which were polysomnographically also diagnosed with concomitant OSAS (AHI range: 10.1 -53.2/h). <P></P> Results: Treatment with 2 mg prolonged release melatonin led to a relevant clinical improvement of RBD symptoms in all patients, so far untreated for the sleep related breathing disorder. Measure of REM sleep without atonia (RSWA) in polysomnography showed values ranging from 5.1 to 20.4% determined with the Montplaisir method. Surprisingly, RSWA values in PSG with melatonin were high, probably because of the still untreated OSAS. <P></P> Conclusion: We presume that in patients with RBD and OSAS both pathologies contribute in varying degrees to the emergence of RBD symptoms by a destabilization of REM sleep. We suggest by consequence to consider a therapeutic strategy including the treatment of both disorders for an optimal therapeutic response.

The Proinflammatory Cytokine GITRL Contributes to TRAIL-mediated Neurotoxicity in the HCN-2 Human Neuronal Cell Line by Giulia Di Benedetto, Salvatore Saccone, Laurence Lempereur, Nicole Ronsisvalle, Giuseppe Nocentini, Rodolfo Bianchini, Carlo Riccardi, Renato Bernardini, Giuseppina Cantarella (1090-1101).
Background: Cytokines belonging to the TNF superfamily play a relevant role in neurodegenerative processes. Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL), released during neuronal injury, has proven to potently mediate and sustain neurotoxic processes leading to neuronal death. Similarly to TRAIL, the cytokine Glucocorticoid-induced TNF receptor ligand (GITRL) is able to transduce proapoptotic signals. In spite of the array of reports suggesting relationships between TRAIL and other cytokines, scanty data are, so far, available about a GITRL/TRAIL crosstalk. <P></P> Methods: Here, we investigated possible interactions between TRAIL and the GITRL system in an in vitro model of neurodegeneration, using the human cortical neuronal cell line HCN-2. Cultured HCN-2 neurons were incubated at different times with GITRL and/or TRAIL, and thereafter nucleic acid and protein expression were measured. Real-time PCR analysis showed that the human cortical neuronal cell line HCN-2 does not express GITRL mRNA, but the latter is induced after treatment with TRAIL. In addition, HCN-2 cells did not express the GITRL receptor GITR mRNA, neither in control cultures, nor after treatment with TRAIL. All mRNA data were confirmed by western blot analysis of proteins. Cell viability assay showed that TRAIL, when associated to GITRL, was able to exert additive toxic effects. A counterproof was provided in experiments performed blocking GITRL, in which TRAIL-mediated toxicity appeared significantly reduced. Results suggest that GITRL/TRAIL redundancy during neurodegenerative processes implies extended potentiation of detrimental effects of both cytokines on neurons, eventually leading to larger cell damage and death. <P></P> Conclusion: Finally, characterization of novel molecular targets within the TRAIL/GITRL interplay may represent a platform for innovative therapy of neurodegenerative disorders.

Genetic Features of MAPT, GRN, C9orf72 and CHCHD10 Gene Mutations in Chinese Patients with Frontotemporal Dementia by Xiang-Qian Che, Qian-Hua Zhao, Yue Huang, Xia Li, Ru-Jing Ren, Sheng-Di Chen, Gang Wang, Qi-Hao Guo (1102-1108).
Background: Mutations in microtubule associated protein tau (MAPT), progranulin (GRN), chromosome 9 open-reading frame 72 (C9orf72) and CHCHD10 genes have been reported causing frontotemporal dementia (FTD) in different populations. However, collective analysis of mutations in these four genes in Chinese FTD patients has not been reported yet. <P></P> Methods: The aim of this study was to investigate the genetic features of Chinese patients with MAPT, GRN, C9orf72 or CHCHD10 gene mutations in an FTD cohort recruited from multi clinical centers in Shanghai metropolitan areas, China. MAPT, GRN and CHCHD10 genes were analysed by direct sequencing, and C9orf72 hexanucleotide repeat expansion was analysed by repeat-primed PCR in 82 patients with sporadic FTD. The identified gene variants were screened in 400 age matched controls. <P></P> Results: We found one known pathogenic variant (rs63750959) and one novel mutation (NG_007398.1: g.120962C>T; H299Y) of MAPT gene, one novel variant (c.750C>A; D250E) of GRN gene and two novel mutations in CHCHD10 gene (c.63C>T, no AA change; c.71G>A, P24L). No abnormal C9orf72 gene hexanucleotide repeat expansion was identified in this cohort. Collectively, genetic testing could discover 4.9% sporadic FTD patients with genetic causes. In addition, MAPT and CHCHD10 might be more important genes affecting Chinese with FTD.

iTRAQ-based Proteomic Analysis of APPSw,Ind Mice Provides Insights into the Early Changes in Alzheimer's Disease by Nan Li, Pinghong Hu, Tiantian Xu, Huan Chen, Xiaoying Chen, Jianwen Hu, Xifei Yang, Lei Shi, Jian-hong Luo, Junyu Xu (1109-1122).
Background: Several proteins have been identified as potential diagnostic biomarkers in imaging, genetic, or proteomic studies in Alzheimer disease (AD) patients and mouse models. However, biomarkers for presymptom diagnosis of AD are still under investigation, as are the presymptom molecular changes in AD pathogenesis. <P></P> Objective: In this study, we aim to analyzed the early proteomic changes in APPSw,Ind mice and to conduct further functional studies on interesting proteins. <P></P> Methods: We used the isobaric tags for relative and absolute quantitation (iTRAQ) approach combined with mass spectrometry to examine the early proteomic changes in hippocampi of APPSw,Ind mice. Quantitative reverse transcription polymerase chain reaction (RT-PCR) and immuno-blotting were performed for further validation. Finally, the functions of interesting proteins β-spectrin and Rab3a in APP trafficking and processing were tested by shRNA knockdown, in N2A cells stably expressing β-amyloid precursor protein (APP). <P></P> Results: The iTRAQ and RT-PCR results revealed the detailed molecular changes in oxidative stress, myelination, astrocyte activation, mTOR signaling and Rab3-dependent APP trafficking in the early stage of AD progression. Knock down of β -spectrin and Rab3a finally led to increased APP fragment production, indicating key roles of β-spectrin and Rab3a in regulating APP processing. <P></P> Conclusion: Our study provides the first insights into the proteomic changes that occur in the hippocampus in the early stages of the AD mouse model. In addition to improving the understanding of molecular alterations and functional cascades involved in early AD pathogenesis, our findings raise the possibility of developing potential biomarkers and therapeutic targets for early AD.

Objective: The etiological initiators of neuroinflammation remain inconclusive, and effective interventions to block neurodegeneration are unavailable. Surprisingly, we found collagen II-combined complete Freund’s adjuvant (CC) that usually induces rheumatoid arthritis (RA) also drives Alzheimer’s disease (AD)-like neurodegeneration in mice. CC not only upregulates the cerebral pro-inflammatory cytokines including tumor necrosis factor α (TNF-α) and interleukin 8 (IL-8), but also downregulates the cerebral interleukin 10 (IL-10), an anti-inflammatory cytokine, and tyrosine hydroxylase (TH), a ratelimiting enzyme for biosynthesis of the anti-inflammatory neurotransmitter dopamine. In contrast, electroacupuncture (EA) elevates TNF-α/IL-8 and declines IL-10/TH at first, but declines TNF-α/IL-8 and elevates IL-10/TH later. Upon impact on mitochondrial biogenesis, ubiquitination, and autophagy, EA firstly potentates but secondly attenuates CC-triggered signaling cascades leading to oxidation, nitrosylation, hypoxia, and angiogenesis. Eventually, EA compromises neurodegeneration by decreasing amyloid- β peptide (Aβ) and phosphorylated tau protein (p-tau), and also rectifies neuronal dysfunctions by increasing the cholinergic neurotransmitter acetylcholine (Ach) and its rate-limiting biosynthetic enzyme choline acetyltransferase (ChAT). <P></P> Results: Conclusively, EA initially aggravates and subsequently ameliorates CC-evoked AD-like earlyphase brain pathogenesis via conversion from pro-inflammatory microglia to anti-inflammatory microglia.