Current Alzheimer Research (v.13, #10)

Meet Our Editorial Board Member by Frank LaFerla (1065-1065).

Neuropsychiatric Disturbances in Mild Cognitive Impairment (MCI): A Systematic Review of Population-Based Studies by Cristiano A. Köhler, Thaís F. Magalhaes, Joao M.M.P. Oliveira, Gilberto S. Alves, Christian Knochel, Viola Oertel-Knöchel, Johannes Pantel, André F. Carvalho (1066-1082).
Mild cognitive impairment (MCI) is a nosological entity associated with a higher risk of developing dementia. Previous evidence indicates that behavioral and psychological symptoms of dementia (BPSDs) frequently occur in individuals of MCI. These neuropsychiatric manifestations may predict conversion to dementia. However, no updated systematic review has been conducted aiming to investigate the prevalence of BPSDs in MCI in general population samples. We conducted a systematic review to summarize research results regarding the prevalence of any or specific BPSDs in MCI subjects out of the clinical setting, compared to subjects who are either cognitively intact and/or demented. The PubMed/MEDLINE, EMBASE, and PsycInfo databases were searched from January 1st, 1990 to January 3rd, 2015 for general population studies in which the prevalence of BPSDs in individuals with MCI was estimated. Twenty-one studies met inclusion criteria. Studies varied in overall methodological quality as evaluated with a modified version of the New Castle-Ottawa Scale for cross-sectional studies. Depression (median prevalence: 29.8%; range: 6.8-63.3%), sleep disturbances (median prevalence: 18.3%; range: 7.9-49.0%), and apathy (median prevalence: 15.2%; range: 2.3-18.5%) were the more frequent BPSDs across studies. The prevalence range for any BPSD was 12.8-66.0%. No consistent pattern for differences in the prevalence of BPSDs according to MCI subtype emerged. Studies considered different diagnostic criteria for MCI and used different instruments to assess BPSDs in this population. In conclusion, BPSDs are prevalent among communitydwelling individuals with MCI. However, consistent socio-demographic and clinical correlates for BPSDs in this population remains to be established.

Suicide Risk in Alzheimer's Disease: A Systematic Review by Gianluca Serafini, Pietro Calcagno, David Lester, Paolo Girardi, Mario Amore, Maurizio Pompili (1083-1099).
Suicidal behavior is a common cause of death in the elderly and is often accompanied in this population by disabilities and psychosocial impairment. Alzheimer's-related neuropathological changes are commonly found in the brains of older people. Although Alzheimer's disease (AD) has been reported to be a potential predictor for suicidal behavior, the relationship between suicidal behavior and AD has not been systematically explored. The aim of this paper is to review the current literature regarding the association between suicide risk and AD in an effort to identify the most relevant risk and protective factors for suicide. A detailed strategy was used to search for relevant articles in Pubmed, Scopus, PsycINFO, and Science Direct on suicidal behavior and AD for the period of January 1980 to August 2015. The search yielded 164 articles, of which 21 met our inclusion criteria. Eight crosssectional, two longitudinal, 3 retrospective, and eight case reports (of 11 patients) examined the association between suicide risk and AD. Suicide occurs in AD even many years after the diagnosis of dementia, and patients who have attempted suicide once are at a higher risk of dying from suicide. AD is associated with a moderate risk of suicide, and clinicians working with AD patients should undertake an appropriate assessment of their suicidal risk. However, more prospective studies are needed to clarify the association between AD and suicide risk.

The occurrence of the neuropsychiatric disturbances is common feature in dementia. Nonpharmacological interventions are the first approach to manage these symptoms. We reviewed the available literature data on psychological interventions for neuropsychiatric disturbances in Alzheimer's disease (AD) focusing on the significant impact on people with dementia and their caregivers. Reminiscence interventions showed evidences of an improvement in cognition and mood in people with dementia as well as a decrease in caregiver burden. Reality orientation therapy was related to an increase in cognition, a decrease in dysfunctional behaviors and a reduced risk of institutionalization among people with AD. However, the potential benefits need a continued program. Cognitive stimulation therapy showed improvement on the functional ability and decrease negative emotional symptoms, when combined with acetylcholinesterase inhibitor. Studies based on behavioral approaches found a significant reduction in disruptive behaviors following intervention, agitated speech, a reduction in entry into a restricted area and a reduction in wandering frequency across participants. There is evidence that only multicomponent interventions can decrease caregivers' psychological morbidity and reduce their burden. The challenge for future research in psychological approaches in dementia is related to the need of larger and high quality evidence-base studies with well define outcomes aiming their effectiveness through a well-design protocol to evaluate their benefits.

Behavioral and psychological symptoms of dementia (BPSD), also known as neuropsychiatric or non-cognitive symptoms are common and often distressing features of Alzheimer's Dementia. BPSD significantly increase patient suffering, early institutionalization and caregiver's burden. The clinical management of BPSD is dominated by a pharmacological approach, although these medications often come with serious adverse side-effects. There are only few nonpharmacological treatment strategies for BPSD. A substantial amount of intervention studies that have investigated non-pharmacological treatment options for BPSD have focused on physical exercise. Although these studies are very heterogeneous in terms of type and severity of dementia, as well as type and duration of the exercise intervention, the overall picture shows a positive effect of physical exercise in alleviating BPSD. There is evidence that numerous mechanisms contribute to the positive effect of physical exercise on BPSD. No attempt has been undertaken so far to give an overview of the existing knowledge regarding these mechanisms. Therefore, the current review aims to integrate the existing evidence on psychological and neurobiological mechanisms that contribute to the beneficial effects of physical exercise in ameliorating BPSD in Alzheimer's dementia. A discussion of psychological mechanisms such as improved sleep and stress reduction will be followed by a discussion of neurobiological mechanisms including the exercise induced change in neurotransmitter concentrations, increased synthesis of neurotrophins and immune activation. The review closes with recommendations for future research to overcome the shortcomings of existing studies and broaden the current knowledge on the positive effects of physical exercise on BPSD.

The Treatment of Behavioral and Psychological Symptoms of Dementia: Weighing Benefits and Risks by Kristina F. Zdanys, André F. Carvalho, Rajesh R. Tampi, David C. Steffens (1124-1133).
Behavioral and psychological symptoms of dementia (BPSD) are common among patients with dementia. BPSD have significant implications on outcomes for patients and caregivers. Available literature for pharmacological approaches to BPSD is sparse and at times inconsistent. There are no FDA-approved medications for the management of BPSD, and the use of available medications is associated with significant adverse effects among aged populations with dementia. This review outlines the assessment of BPSD, discusses general principles of management, and examines current evidence for non-pharmacologic and pharmacologic treatment strategies as well as associated risks.

Pharmacological Management of Agitation and Aggression in Alzheimer's Disease: A Review of Current and Novel Treatments by Celina S. Liu, Myuri Ruthirakuhan, Sarah A. Chau, Nathan Herrmann, André F. Carvalho, Krista L. Lanctôt (1134-1144).
Agitation and aggression are common neuropsychiatric symptoms of Alzheimer's disease and are highly prevalent in people with dementia. When pharmacological intervention becomes necessary, current clinical practice guidelines recommend antipsychotics, cholinesterase inhibitors, and some antidepressants. However, those interventions have modest to low efficacy, and those with the highest demonstrated efficacy have significant safety concerns. As a result, current research is focusing on novel compounds that have different mechanisms of action and that may have a better balance of efficacy over safety. The purpose of this review is to evaluate novel pharmacological therapies for the management of agitation and aggression in AD patients. We performed a comprehensive literature search to identify recent novel drugs that are not included in most clinical practice guidelines or are currently undergoing clinical trials for the treatment of agitation and/or aggression in AD. This review suggests that novel treatments, such as cannabinoids, lithium, non-steroidal anti-inflammatory drugs, analgesics, narcotics, and newer antiepileptic drugs, may provide a safer alternative treatment option for the management of agitation and aggression in AD and requires further study in order to clarify their risks and benefits.

Neuropsychiatric Disturbances in Alzheimer's Disease: What Have We Learned from Neuropathological Studies? by Debby Van Dam, Yannick Vermeiren, Alain D. Dekker, Petrus J.W. Naudé, Peter P. De Deyn (1145-1164).
Neuropsychiatric symptoms (NPS) are an integral part of the dementia syndrome and were therefore recently included in the core diagnostic criteria of dementia. The near universal prevalence of NPS in Alzheimer's disease (AD), combined with their disabling effects on patients and caregivers, is contrasted by the fact that few effective and safe treatments exist, which is in part to be attributed to our incomplete understanding of the neurobiology of NPS. In this review, we describe the pathological alterations typical for AD, including spreading and evolution of burden, effect on the molecular and cellular integrity, functional consequences and atrophy of NPS-relevant brain regions and circuits in correlation with specific NPS assessments. It is thereby clearly established that NPS are fundamental expressions of the underlying neurodegenerative brain disease and not simply reflect the patients' secondary response to their illness. Neuropathological studies, moreover, include a majority of end-stage patient samples, which may not correctly represent the pathophysiological environment responsible for particular NPS that may already be present in an early stage, or even prior to AD diagnosis. The burdensome nature and high prevalence of NPS, in combination with the absence of effective and safe pharmacotherapies, provide a strong incentive to continue neuropathological and neurochemical, as well as imaging and other relevant approaches to further improve our apprehension of the neurobiology of NPS.

Alzheimer's Disease is Associated with Increased Risk of Osteoporosis: The Chongqing Aging Study by Dong Liu, Huadong Zhou, Yong Tao, Jun Tan, Lin Chen, Haiyang Huang, Yang Chen, Yafei Li, Rui Zhou (1165-1172).
Objective: The aim of this study was to analyze the relationship between Alzheimer's disease (AD) and a risk of osteoporosis in the elderly cohort of Chongqing, China.
Methods: A prospective study with 6 years of follow-up in 1802 patients aged 60- 75 was conducted from January 2007 to June 2013. Dual energy X-ray absorptiometry was utilized to evaluate bone mineral density (BMD). Their cognitive function was detected using the Chinese version of the Mini-Mental State Examination (MMSE) and a detection of the instrumental activities of daily living (ADL). Cox proportional hazards models were used to detect the association between AD and the risk of osteoporosis.
Results: After adjusting for age, female, AD, 25-hydroxyvitamine D (25(OH)D), smoking, drinking and stroke, AD (Hazard ratio, HR 2.48, 95%CI 1.66-2.94), age (HR 1.36, 95% CI 1.14-1.60), female (HR 1.39, 95% CI 1.17-1.65), 25(OH)D (HR1.34, 95%CI 1.11-1.59), current smoking (HR 1.27, 95%CI 1.22-1.43), daily drinking (HR 1.33, 95%CI 1.11-1.52) and stroke (HR 1.26, 95%CI 1.14-1.58) were associated with increased risk of osteoporosis. In osteoporosis fracture group, osteoporosis with AD was more common than osteoporosis with normal cognition function.
Conclusion: AD was associated with an increased risk of osteoporosis in the elderly cohort of Chongqing, China.

The serine hydrolase butyrylcholinesterase (BChE), like the related enzyme acetylcholinesterase (AChE), co-regulates metabolism of the neurotransmitter acetylcholine. In the human brain BChE is mainly expressed in white matter and glia and in distinct populations of neurons in regions that are important in cognition and behavior, functions compromised in Alzheimer's disease (AD). AD is a neurodegenerative disorder causing dementia with no cure nor means for definitive diagnosis during life. In AD, BChE is found in association with pathology, such as ?-amyloid (A?) plaques, particularly in the cerebral cortex where BChE is not normally found in quantity. Up to 30% of cognitively normal older adults have abundant A? deposition in the brain. We have designed an imaging agent that can detect, through autoradiography, BChE-associated A? plaques in the cerebral cortex of AD brains, but does not visualize A? plaques in brains of cognitively normal individuals. Furthermore, in an AD mouse model with BChE gene knocked out, there are up to 70% fewer fibrillar A? brain plaques, suggesting diminished BChE activity could prove beneficial as a curative approach to AD. To that end, we have examined numerous N-10-carbonyl phenothiazines that are specific inhibitors of human BChE, revealing important details of the enzyme's active site gorge. These phenothiazines can be designed without potential side effects caused by neurotransmitter receptor interactions. In conclusion, BChE is potentially an important target for diagnosis and treatment of AD.

The Brainstem Tau Cytoskeletal Pathology of Alzheimer's Disease: A Brief Historical Overview and Description of its Anatomical Distribution Pattern, Evolutional Features, Pathogenetic and Clinical Relevance by Udo Rüb, Katharina Stratmann, Helmut Heinsen, Domenico Del Turco, Kay Seidel, Wilfred den Dunnen, Horst-Werner Korf (1178-1197).
The human brainstem is involved in the regulation of the sleep/waking cycle and normal sleep architectonics and is crucial for the performance of a variety of somatomotor, vital autonomic, oculomotor, vestibular, auditory, ingestive and somatosensory functions. It harbors the origins of the ascending dopaminergic, cholinergic, noradrenergic, serotonergic systems, as well the home base of the descending serotonergic system. In contrast to the cerebral cortex the affection of the brainstem in Alzheimer's disease (AD) by the neurofibrillary or tau cytoskeletal pathology was recognized only approximately fourty years ago in initial brainstem studies. Detailed pathoanatomical investigations of silver stained or tau immunostained brainstem tissue sections revealed nerve cell loss and prominent ADrelated cytoskeletal changes in the raphe nuclei, locus coeruleus, and in the compact parts of the substantia nigra and pedunculopontine nucleus. An additional conspicuous AD-related cytoskeletal pathology was also detected in the auditory brainstem system of AD patients (i.e. inferior colliculus, superior olive, dorsal cochlear nucleus), in the oculomotor brainstem network (i.e. rostral interstitial nucleus of the medial longitudinal fascicle, Edinger-Westphal nucleus, reticulotegmental nucleus of pons), autonomic system (i.e. central and periaqueductal grays, parabrachial nuclei, gigantocellular reticular nucleus, dorsal motor vagal and solitary nuclei, intermediate reticular zone). The alterations in these brainstem nuclei offered for the first time adequate explanations for a variety of less understood disease symptoms of AD patients: Parkinsonian extrapyramidal motor signs, depression, hallucinations, dysfunctions of the sleep/wake cycle, changes in sleeping patterns, attentional deficits, exaggerated pupil dilatation, autonomic dysfunctions, impairments of horizontal and vertical saccades, dysfunctional smooth pursuits. The very early occurrence of the AD-related cytoskeletal pathology in some of these brainstem nuclei points to a major and strategic role of the brainstem in the induction and brain spread of the AD-related cytoskeletal pathology.

Erratum (1198-1198).