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Behavioral evidence indicates that working memory (WM) in schizophrenia is already impaired at the encoding stage. However, the neurophysiological basis of this primary deficit remains poorly understood. Using event-related fMRI, we assessed differences in brain activation and functional connectivity during the encoding, maintenance and retrieval stages of a visual WM task with 3 levels of memory load in 17 adolescents with early-onset schizophrenia (EOS) and 17 matched controls. The amount of information patients could store in WM was reduced at all memory load levels. During encoding, activation in left ventrolateral prefrontal cortex (VLPFC) and extrastriate visual cortex, which in controls positively correlated with the amount of stored information, was reduced in patients. Additionally, patients showed disturbed functional connectivity between prefrontal and visual areas. During retrieval, right inferior VLPFC hyperactivation was correlated with hypoactivation of left VLPFC in patients during encoding. Visual WM encoding is disturbed by a failure to adequately engage a visual-prefrontal network critical for the transfer of perceptual information into WM. Prefrontal hyperactivation appears to be a secondary consequence of this primary deficit. Isolating the component processes of WM can lead to more specific neurophysiological markers for translational efforts seeking to improve the treatment of cognitive dysfunction in schizophrenia., (© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Background: Recently, a single point mutation in the presenilin 1 (PSEN1) gene of the first described Alzheimer's disease (AD) patient Auguste D was reported by Müller and co-workers. However, the sequencing results of the DNA from a 100-year-old tissue contained some uncertainties., Methods: We heat extracted DNA from an original histological slice of Auguste D's brain and used nested polymerase chain reaction for the amplification of different exons of genes known to be affected in familial forms of AD., Results: Our sequencing analysis did not validate the reported mutation. Furthermore, an extended sequencing analysis of Auguste D's DNA revealed no indication of a nonsynonymous hetero- or homozygous mutation in the exons of APP, PSEN1, and PSEN2 genes comprising the already known familial AD mutations., Conclusion: Despite the wealth of data from Müller and co-workers, our results emphasize the requirement of more detailed analysis of Auguste D's DNA in future., (Copyright © 2014 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved.)

Background: Deficits in visual processing are a prominent feature of Alzheimer's disease (AD), yet the cognitive and neuropathological mechanisms underlying these deficits are poorly understood. In the current study, we examined the hypothesis that perceptual organization is specifically impaired in AD compared to other dementias., Methods: We examined perceptual organization with a psychophysically well-controlled measure of contour integration in patients with AD (n = 17), vascular dementia (n = 5), frontotemporal dementia (n = 5) and mild cognitive impairment (n = 10) and 11 age-matched healthy controls., Results: Patients with AD differed significantly in their ability to detect contours comprised of Gabor elements as detection relied increasingly on long-range spatial interactions. Impairments in contour integration were particularly pronounced in AD patients with atrophy and gliosis of white matter in the occipital lobe. Deficits in perceptual organization were not found in patients with other dementias and participants with mild cognitive impairment., Conclusions: These results suggest that a subgroup of AD patients is characterized by a specific deficit in visual perceptual organization, which might reflect the impaired functional integrity of occipital cortico-cortical pathways., ((c) 2008 S. Karger AG, Basel)

Neuroinflammation is observed in neurodegenerative diseases like Alzheimer's disease (AD). However, a little is known about the mechanisms of neural-immune interactions. The involvement of peripheral T-cell function in AD is still far from clear, though it plays an important role in immunotherapy. The aim of this study was to determine peripheral T-cell reactivity in AD patients and in an AD mouse model. Mitogenic activation via ligation of the T-cell receptor (TCR) with PHA-L was measured in T lymphocytes from AD patients and Thy1(APP 751SL) x HMG(PS1 M146L)-transgenic mice (APP x PS1). In order to uncover failures in TCR signaling, the TCR was also bypassed by PMA and ionomycin treatment. All patients were sporadic late onset cases and the transgenic mice expressed no mutant APP in lymphocytes, so that direct interactions of mutant APP on T-cell function can be excluded. CD4+ and CD8+ T-cell showed increased reactivity (tyrosine phosphorylation, CD69 expression, and proliferation) in AD, while APP x PS1 transgenic mice displayed hyporeactive CD8+ T-cells after TCR ligation. Increased levels of CD8+ T memory cells and down regulation of CD8 receptor were found in AD and the animal model. Anergic TCR uncoupling was associated with loss of MAPK signaling (p38, ERK1 and ERK2) in APP x PS1. Our data implicate the generation of reactive memory T-cell in AD and of anergic memory T-cells in transgenic mice and should be taken into concern when designing immunotherapy.

With life expectancy increasing continuously, the effects of neurodegeneration on brain function are a topic of ever increasing importance. Thus there is a need for tools and models that probe both the functional consequences of neurodegenerative processes and compensatory mechanisms that might occur. As neurodegenerative burden and compensatory mechanisms may change over time, these tools will ideally be applied multiple times over the lifespan. Specifically, in order to elucidate whether brain-activation patterns in Alzheimer's disease (AD) and in healthy aging follow general rules in the context of degeneration and compensation, it is necessary to compare functional brain-activation patterns during different states of neurodegeneration. This article integrates the findings of functional activation studies at different stages of neurodegeneration: in healthy aging, in subjects at high risk of developing dementia, in subjects with mild cognitive impairment (MCI), and in patients suffering from AD. We review existing theoretical models that aim to explain the underlying mechanisms of functional activation changes in aging and dementia, and we propose an integrative account, which allows for different neural response patterns depending on the amount of neuronal damage and the recruitment of compensatory pathways.

Diagnosis and therapy of dementia have made considerable progress in recent years. Drugs have been developed which improve cognitive performance, delay the loss of abilities of daily living and prevent early nursing home placement in a considerable number of patients. With the various pharmacological and non-pharmacological approaches, effective treatment options of AD are available at present and the therapeutic potential will even increase in future. Thus, the treatment of dementia should more focused and explicit in its goals for the doctor, the patient and the relatives. Therapeutic targets must be defined on the basis of the individual needs and deficits and with regard to different levels of the disease process. Ideally, treatment should always aim at an etiological and/or a pathophysiological level. At present, however, aiming at the neurotransmitter level, the core syndrome of cognitive deficits can be approached by treatment options. Further therapeutic targets can be defined on the level of activities of daily living, following a resource focused approach, as well as on the level of behavioral disturbances. Additional therapeutic targets should be seen under a humanitarian or palliative perspective. And finally, family members are also targets for therapy in dementia, even if such therapy is not directed towards the demented patient. All these treatment targets have to be evaluated and adapted under the perspective of time because prominent symptoms in AD change considerably with disease progression. Selection and adaptation of medication becomes easier if such targets are considered and if therapeutic effects are monitored target-specifically.

Proton magnetic resonance spectroscopy (MRS) allows the assessment of various cerebral metabolites non-invasively in vivo. Among 1H MRS-detectable metabolites, N-acetyl-aspartate and N-acetyl-aspartyl-glutamate (tNAA), trimethylamines (TMA), creatine and creatine phosphate (tCr), inositol (Ins) and glutamate (Gla) are of particular interest, since these moieties can be assigned to specific neuronal and glial metabolic pathways, membrane constituents, and energy metabolism. In this study on 94 subjects from a memory clinic population, 1H MRS results (single voxel STEAM: TE 20 ms, TR 1500 ms) on the above metabolites were assessed for five different brain regions in probable vascular dementia (VD), probable Alzheimer's disease (AD), and age-matched healthy controls. In both VD and AD, ratios of tNAA/tCr were decreased, which may be attributed to neuronal atrophy and loss, and Ins/tCr-ratios were increased indicating either enhanced gliosis or alteration of the cerebral inositol metabolism. However, the topographical distribution of the metabolic alterations in both diseases differed, revealing a temporoparietal pattern for AD and a global, subcortically pronounced pattern for VD. Furthermore, patients suffering from vascular dementia (VD) had remarkably enhanced TMA/tCr ratios, potentially due to ongoing degradation of myelin. Thus, the metabolic alterations obtained by 1H MRS in vivo allow insights into the pathophysiology of the different dementias and may be useful for diagnostic classification.

The identification of specific genetic (presenilin-1 [PS1] and amyloid precursor protein [APP] mutations) and environmental factors responsible for Alzheimer's disease (AD) has revealed evidence for a shared pathway of neuronal death. Moreover, AD-specific cell defects may be observed in many other nonneuronal cells (e.g., lymphocytes). Thus, lymphocytes may serve as a cellular system in which to study risk factors of sporadic, as well as genetic AD in vivo. The aim of our present study was to clarify whether lymphocytes bearing genetic or sporadic risk factors of AD share an increased susceptibility to cell death. Additionally we examined whether a cell typespecific vulnerability pattern was present and how normal aging, the main risk factor of sporadic AD, contributes to changes in susceptibility to cell death. Here, we report that lymphocytes affected by sporadic or genetic APP and PS1 AD risk factors share an increased vulnerability to cell death and exhibit a similar cell type-specific pattern, given that enhanced vulnerability was most strongly developed in the CD4+ T-cell subtype. In this paradigm, sporadic risk factors revealed the highest impact on cell type-specific sensitivity of CD4+ T cells to apoptosis. In contrast, normal aging results in an increased susceptibility to apoptosis of both, CD4+ and CD8+ T cells.

Depressive symptoms are often found in dementia (up to 86 %). Therefore, adequate treatment is necessary. Depressive symptoms appear significantly more often in vascular dementia than in dementia in Alzheimer's disease, but severity and profile of depressive symptomatology are independent of the etiology of dementia. The aim of this review is to help clinicians to select appropriate psychometric instruments to identify and measure depressive symptomatology in dementia. Frequently used scales are described, e.g. the Dementia Mood Assessment Scale and the Cornell Scale for Depression in Dementia - specific scales developed for rating severity of depression in dementia - and the Geriatric Depression Screening Scale. Methodological problems and limitations of psychopathological assessment in dementia caused by restriction of self-report, information gathered by collateral sources, manifestations of age and interference of somatic symptoms are discussed.