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• What is the primary question addressed by this study? Does childhood maltreatment affect the psychological treatment outcomes in late-life depression? • What is the main finding of this study? In older individuals with depression and childhood maltreatment, both specific and non-specific psychotherapy equally reduce depressive symptoms. However, in patients without childhood maltreatment, cognitive behavioral therapy for late-life-depression demonstrates greater efficacy over non-specific supportive psychotherapy. • What is the meaning of the finding? Practioners should consider a history of early trauma in their choice between specific and non-specific interventions. This is the first interventional study to assess the impact of childhood maltreatment (CM) on psychological treatment outcomes in patients with late-life depression (LLD). This is a secondary analysis of a multicenter, randomized controlled trial with 251 participants aged ≥60 years with moderate to severe depression. Participants were randomly assigned to cognitive behavioral therapy for late life depression (LLD-CBT) or to a supportive intervention (SUI). Treatment outcomes were measured by changes in the Geriatric Depression Scale (GDS). In the intention-to-treat sample (n = 229), both LLD-CBT (n = 115) and SUI (n = 114) significantly reduced depressive symptoms in patients with CM, with large effects at post-treatment (d = 0.95 [95% CI: 0.65 to 1.25] in LLD-CBT; d = 0.82 [95% CI: 0.52 to 1.12] in SUI). A significant treatment group*CM interaction (F (1,201.31) = 4.71; p =.031) indicated greater depressive symptom reduction in LLD-CBT compared to SUI at week 5 and post-treatment for patients without CM, but not at 6-month follow-up. Across both treatments, higher severity of the CM subtype 'physical neglect' was associated with a smaller depressive symptom reduction (F (1,207.16) = 5.37; p =.021). Specific and non-specific psychotherapy effectively reduced depressive symptoms in older individuals with depression and early trauma. For patients without early trauma, LLD-CBT may be preferable over SUI. Considering early trauma subtypes may contribute to develop personalized treatment approaches. [ABSTRACT FROM AUTHOR]

A growing awareness about brain health and Alzheimer's disease in the general population is leading to an increasing number of cognitively unimpaired individuals, who are concerned that they have reduced cognitive function, to approach the medical system for help. The term subjective cognitive decline (SCD) was conceived in 2014 to describe this condition. Epidemiological data provide evidence that the risk for mild cognitive impairment and dementia is increased in individuals with SCD. However, the majority of individuals with SCD will not show progressive cognitive decline. An individually tailored diagnostic process might be reasonable to identify or exclude underlying medical conditions in an individual with SCD who actively seeks medical help. An increasing number of studies are investigating the link between SCD and the very early stages of Alzheimer's disease and other neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

Background A significant proportion of patients with Tourette syndrome (TS) continue to experience symptoms across adulthood that in severe cases fail to respond to standard therapies. For these cases, deep brain stimulation (DBS) is emerging as a promising treatment option. Objective We conducted a systematic literature review to evaluate the efficacy of DBS for GTS. Methods Individual data of case reports and series were pooled; the Yale Global Tic Severity Scale (YGTSS) was chosen as primary outcome parameter. Results In total, 57 studies were eligible, including 156 cases. Overall, DBS resulted in a significant improvement of 52.68% (IQR = 40.74, p < 0.001) in the YGTSS. Analysis of controlled studies significantly favored stimulation versus off stimulation with a standardized mean difference of 0.96 (95% CI: 0.36–1.56). Disentangling different target points revealed significant YGTSS reductions after stimulation of the thalamus, the posteroventrolateral part and the anteromedial part of the globus pallidus internus, the anterior limb of the internal capsule and nucleus accumbens with no significant difference between these targets. A significant negative correlation of preoperative tic scores with the outcome of thalamic stimulation was found. Conclusions Despite small patient numbers, we conclude that DBS for GTS is a valid option for medically intractable patients. Different brain targets resulted in comparable improvement rates, indicating a modulation of a common network. Future studies might focus on a better characterization of the clinical effects of distinct regions, rather than searching for a unique target. [ABSTRACT FROM AUTHOR]

The article discusses research which was conducted to investigate the diagnostic accuracy of the Total Score of the Consortium to Establish a Registry for Alzheimer’s Disease neuropsychological assessment battery (CERAD-NP) and its ability to diagnose Alzheimer disease dementia. Researchers evaluated the battery with 1,606 people with a mean age of 84 years. They found that the battery was a highly accurate diagnostic tool.

Objectives: There is an increasing call for a stronger consideration of impairment in instrumental activities of daily living (IADL) in the diagnostic criteria of Mild Cognitive Impairment (MCI) to improve the prediction of dementia. Thus, the aim of the study was to determine the predictive capability of MCI and IADL impairment for incident dementia. Design: Longitudinal cohort study with four assessments at 1.5-year intervals over a period of 4.5 years. Setting: Primary care medical record registry sample. Participants: As part of the German Study on Ageing, Cognition, and Dementia in Primary Care Patients, a sample of 3,327 patients from general practitioners, aged 75 years and omen, was assessed. Measurements: The predictive capability of MCI and IADL impairment for incident dementia was analysed using receiver operating characteristics, Kaplan-Meier survival analyses, and Cox proportional hazards models. Results: MCI and IADL impairment were found to be significantly associated with higher conversion to, shorter time to, and better predictive power for future dementia. Regarding IADL, a significant impact was particularly found for impairment in responsibility for one's own medication, shopping, and housekeeping, and in the ability to use public transport. Conclusions: Combining MCI with IADL impairment significantly improves the prediction of future dementia. Even though information on a set of risk factors is required to achieve a predictive accuracy for dementia in subjects with MCI being clinically useful, IADL impairment should be a very important element of such a risk factor set. [ABSTRACT FROM AUTHOR]

Objectives: To assess the accuracy of the General Practitioner's (GP) judgment in the recognition of incident dementia cases and to explore factors associated with recognition. Design: Prospective observational cohort study, two follow-up assessments (FU I and FU 2) within 3 years after baseline. Setting: One hundred thirty-eight general practice surgeries in the six study centers of a prospective German study. Participants: Participants were between 75 and 89 years of age at baseline and were recruited from the GPs' patient lists. In FU 1, 2,402 patients and in FU 2, 2,177 patients were analyzed. Measurements: GPs' judgments on their patients' cognitive status as index test at-home patient interviews and tests, consensus diagnosis as reference; validity of the GP judgment associations between patient factors and GPs' dementia recognition. Results: One hundred eleven incident dementia cases with complete data were identified in FU 1 and FU 2. Overall sensitivity of the GP judgment was 51.4%, specificity 95.9%, positive predictive value 23.6%, and negative predictive value 98.8%. GPs missed dementia more frequently in patients living alone. GPs overrated the presence of dementia more frequently in patients with problems in mobility or hearing, in patients with memory complaints, and in patients with a GP-documented depression. Conclusion: GPs miss nearly half of incident dementia cases. They should be alert not to miss dementia in patients living alone. Without seeking additional information, a positive GP judgment seems not sufficient for case finding. GPs should be aware of their tendency to overestimate dementia in depressed and frail patients. [ABSTRACT FROM AUTHOR]

Abstract: SORL1 gene variants were described as risk factor of Alzheimer''s disease (AD) additionally SORL1 gene variants were associated with altered Aβ42 CSF levels in AD patients. In the present study we investigated the association of SORL1 gene variants (rs2070045 (SNP19), SORL1-18ex26 (SNP21), rs3824968 (SNP23), rs1010159 (SNP25)) with AD risk by using Cox proportional hazard model and Kaplan–Meier survival analysis in 349 AD patients and 483 controls, recruited from a multicenter study of the German Competence Network Dementias. The SNP21G-allele and a SORL1 haplotype consisting of the SNP19 T-allele, SNP21 G-allele and SNP23 A-allele (T/G/A) were associated with increased hazard ratios and an earlier age at onset of AD (SNP21: p =0.002; T/G/A haplotype: p =0.007). This effect was most pronounced in carriers of an additional APOE4 allele (SNP21: p =0.003; T/G/A haplotype: p =0.005). In conclusion, we found SORL1 gene variants located in the 3′ region of the gene to be associated with increased AD risk and an earlier age at onset of AD in our Central-European population. Thus, our data support a role of SORL1 polymorphisms in AD. [Copyright &y& Elsevier]

Abstract: SORL1 gene variants were described as risk factors of Alzheimer''s disease (AD). We investigated the association of four SORL1 variants with CSF levels of Aβ42 and Aβ40 in 153 AD patients recruited from a multicenter study of the German Competence Net Dementias. Only one SORL1 SNP was associated with altered Aβ42 levels in the single marker analysis (SNP21: p =0.011), the other SNPs did not show an association with Aβ42 or Aβ40 CSF levels. Haplotype analysis identified a three marker SORL1 haplotype consisting of SNP19 T-allele, SNP21 G-allele and SNP23 A-allele (T/G/A) which was associated with reduced Aβ42 CSF levels in AD patients (p =0.003). Aβ40 levels were also lower in carriers of this haplotype; however, this did not reach statistical significance (p =0.15). We found a SORL1 haplotype which was associated with CSF levels of amyloid-β cleavage products, measured as altered levels of Aβ42. Thus our data suggest that SORL1 gene variants might influence AD pathology. [Copyright &y& Elsevier]

Abstract: To examine the biological basis of subjective memory impairment (SMI), defined as the feeling of memory worsening with normal memory performance, we measured the volume of the entorhinal cortex (EC) and the hippocampus in SMI subjects, patients with mild cognitive impairment (MCI), patients with Alzheimer''s disease (AD) and healthy controls (CO). Compared with controls, the EC was smaller in the SMI group (left: p =0.060; right: p =0.045) and in the other two groups in the following order: CO>SMI>MCI>AD. The same sequence was observed with regard to hippocampal volumes, but the volume reduction of the left hippocampus in the SMI group only reached a trend towards significance (p =0.072) and the right was not significantly smaller compared with controls (p =0.37). Compared with controls the average (left/right) volume reduction of the EC was 18% (SMI), 26% (MCI) and 44% (AD). The mean volume reduction of the hippocampus was 6% (SMI), 16% (MCI) and 19% (AD). Our results mirror the temporal sequence of neurodegeneration in AD and support the concept of SMI as the first clinical manifestation of dementia. [Copyright &y& Elsevier]

The recent commercialisation of the first disease-modifying drugs for Alzheimer's disease emphasises the need for consensus recommendations on the rational use of biomarkers to diagnose people with suspected neurocognitive disorders in memory clinics. Most available recommendations and guidelines are either disease-centred or biomarker-centred. A European multidisciplinary taskforce consisting of 22 experts from 11 European scientific societies set out to define the first patient-centred diagnostic workflow that aims to prioritise testing for available biomarkers in individuals attending memory clinics. After an extensive literature review, we used a Delphi consensus procedure to identify 11 clinical syndromes, based on clinical history and examination, neuropsychology, blood tests, structural imaging, and, in some cases, EEG. We recommend first-line and, if needed, second-line testing for biomarkers according to the patient's clinical profile and the results of previous biomarker findings. This diagnostic workflow will promote consistency in the diagnosis of neurocognitive disorders across European countries. [ABSTRACT FROM AUTHOR]

• Objective subtle cognitive difficulties (Obj-SCD) showed Aβ in AD-related regions. • Aβ was associated with cognition in Obj-SCD. • Aβ was only associated with execution in SCD. • FDG was associated with execution only in Obj-SCD. Subjective cognitive decline (SCD) and objective subtle cognitive difficulties (Obj-SCD) are considered the initial stages of aberrant cognition prior to mild cognitive impairment (MCI) due to Alzheimer's disease (AD). We aimed to determine the difference of brain function of SCD and Obj-SCD, furthermore, to figure out which one could be the marker of early AD. One hundred and eighty-five participants were enrolled in this study to determine the amyloid pathology and glucose metabolism changes in SCD and Obj-SCD. The association of amyloid deposition and glucose metabolism with cognitive domains were also investigated. Obj-SCD displayed significantly increased amyloid deposition in frontal and temporal lobes compared to SCD and normal cognitive control (NCC). No difference of amyloid deposition between SCD and NCC, and no difference of glucose metabolism among the three groups were observed. Amyloid deposition was associated with function of memory, language and executive domains, and glucose metabolism was only associated with executive function in Obj-SCD. Amyloid deposition was only associated with executive function in SCD. Obj-SCD could be the early stage of AD, which displayed significant increased amyloid deposition, and the increased amyloid deposition was associated with cognitive function in different domains. [ABSTRACT FROM AUTHOR]

Abstract: Major depressive disorder (MDD) is accompanied by morphological changes of brain structures which are of great importance in the neural circuitry mediating depression like the hippocampus and the amygdala. Hyperactivity of the hypothalamic-pituitary-adrenocortical (HPA) system resulting in enhanced glucocorticoid secretion can often be observed during depression and has been thought to play an important role in inducing these morphological changes. We used magnetic resonance imaging to investigate alterations of amygdala and hippocampal volumes in 86 in-patients with unipolar depression and 87 healthy controls, and we then correlated amygdala and hippocampal volumes of 76 in-patients with the area under the curve of cortisol secretion in the dexamethasone/corticotropin releasing hormone (Dex/CRH) test at baseline and during short-term antidepressant therapy. In line with recently published studies both left and right amygdala volumes of patients in a first depressive episode were smaller than those of healthy controls. Patients with recurrent depressive episodes showed a reduction of hippocampal volumes, while amygdala volumes were normal. Larger left and right amygdala volumes correlated with a more pronounced reduction of HPA activity, measured by the cortisol secretion in the combined DEX/CRH test, during antidepressant therapy in patients with recurrent depressive episodes. [Copyright &y& Elsevier]

Abstract: Cerebral and extracerebral cholesterol metabolism are altered in Alzheimer''s disease (AD) as indicated by reduced plasma levels of the cholesterol elimination products 24S-hydroxycholesterol, which is of cerebral origin, and of 27-hydroxycholesterol, which is formed extracerebrally. However, it has to be evaluated, if changes of cholesterol metabolism in the whole body or in the CNS are exclusively due to the altered elimination of cholesterol or are also due to altered de novo synthesis in AD. We investigated CSF and plasma levels of cholesterol and of its precursors lanosterol, lathosterol and desmosterol in AD patients and non-demented controls. We found CSF levels of cholesterol (p =0.011), absolute levels of all investigated cholesterol precursors (each p <0.001) and ratios of cholesterol precursors/cholesterol (each <0.01) to be lower in AD patients as compared to controls. In plasma, the absolute levels of lanosterol (p =0.026) and lathosterol (p <0.001) and the ratio of lathosterol/cholesterol (p =0.002) but none of the other investigated parameters were reduced in AD patients (p >0.1). Furthermore, ratios of desmosterol/lathosterol in CSF (p =0.023) and plasma (p =0.009) were higher in AD patients as compared to controls. Our data support the hypothesis that cholesterol metabolism is altered in AD and further suggest that especially cholesterol de novo synthesis within the CNS of AD patients might be reduced. These findings raise doubt on a beneficial effect of cholesterol lowering treatment in manifest AD. [Copyright &y& Elsevier]

Cognitive symptoms of Parkinson's disease (PD) have been long underestimated, but are some of the most disabling non-motor features of the disease. In order to establish signs that allow for earlier detection of cognitive decline in PD, the concept of 'subjective cognitive decline´ (SCD) has gained a growing interest. SCD refers to patients who report a decline in subjective cognitive capacities, while their results on neuropsychological tests are within the normal performance range, indicating adequate cognitive functions. The aim of this review was to evaluate the concept of SCD in PD and give an overview of the current research. A systematic literature search in PubMed was performed to identify articles published before December 2020. We included 18 studies with a total of n = 2,654 patients. While there is currently no consensus on research or clinical criteria for SCD in PD, this review presents the accumulated evidence for SCD in PD patients and supports the importance of early identification of cognitive deficits, due to the relatively high prevalence for SCD in PD and the added risk of future cognitive impairment it entails. The publications included in this review indicate that SCD may be part of the PD spectrum but further research is needed. Expanding research on SCD in PD will allow for earlier detection of cognitive impairment and may foster preventive interventions. • High prevalence of mild cognitive impairment in the course of Parkinson's disease. • Subjective cognitive decline marks a growing interest as a preclinical stage. • SCD is a decline in subjective cognitive capacities, while cognitive test results are normal. • SCD is a new concept in persons with Parkinson's disease. • SCD may allow for earlier detection and may be considered for prevention. [ABSTRACT FROM AUTHOR]

• Calcium/Calmodulin-dependent kinase alpha is essential for learning and memory. • We tested the association of CAMK2A SNPs with verbal logical memory in elderly people with cognitive impairments. • rs919741 predicted a higher hippocampal volume and better logical memory in the elderly. • No such association was found in healthy adults. Calcium/Calmodulin-dependent kinase alpha (αCaMKII) has been shown to play an essential role in synaptic plasticity and in learning and memory in animal models. However, there is little evidence for an involvement in specific memories in humans. Here we tested the potential involvement of the αCaMKII coding gene CAMK2A in verbal logical memory in two Caucasian populations from Germany, in a sample of 209 elderly people with cognitive impairments and a sample of 142 healthy adults. The association of single nucleotide polymorphisms (SNPs) located within the genomic region of CAMK2A with verbal logical memory learning and retrieval from the Wechsler Memory Scale was measured and hippocampal volume was assessed by structural MRI. In the elderly people, we found the minor allele of CAMK2A intronic SNP rs919741 to predict a higher hippocampal volume and better logical memory retrieval. This association was not found in healthy adults. The present study may provide evidence for an association of a genetic variant of the CAMK2A gene specifically with retrieval of logical memory in elderly humans. This effect is possibly mediated by a higher hippocampal volume. [ABSTRACT FROM AUTHOR]

Mental disorders (MD) are a common comorbidity in patients with coronary heart disease (CHD) and have a significant impact on morbidity and mortality. The aim of this study was to determine to what extent mental disorders are diagnosed as comorbidity in patients with CHD and whether adequate therapeutic measures are taken. Claims data from 4435 Cologne citizens with diagnosed CHD and a hospital stay due to CHD in 2015 were examined through a longitudinal analysis. The data were analyzed descriptively with regard to mental disorders, investigating diagnostic examinations performed, prescriptions for psychotropic drugs, and utilization of psychotherapy. We differentiated between pre-existing MD, existing in the year before the CHD-related hospital stay, and incident MD with new onset during or within six months after hospitalization. Psychodiagnostic examinations for mental disorders occurred very rarely during cardiological hospitalization (0.04%) and psychiatric/psychosomatic consultation sessions rarely (5%). The longitudinal analysis showed a high rate of pre-existing MDs (56%, n = 2490) and a new diagnosis of mental disorders in 7% (n = 302) of the patients. Within one year after inpatient treatment for CHD, psychotropic medication was prescribed in 64–67% of patients with newly diagnosed affective or neurotic, adjustment/somatoform disorder and 10–13% received outpatient psychotherapy. The results indicate low rates of inpatient diagnostic examinations and low rates of adequate treatment of mental disorders in patients from Cologne with CHD and new onset mental disorders. The rate of prescriptions of psychopharmacotherapy after hospitalization due to CHD exceeds that of the utilization of outpatient psychotherapy. • We examined to what extent mental disorders were considered in patients with CHD. • Few psychodiagnostic examinations in patients with CHD during hospitalization. • Few psychiatric/psychosomatic consultations during hospitalization due to CHD. • Increase in prescriptions for psychotropics after hospitalization due to CHD. • Low rate of outpatient psychotherapy in patients with CHD and mental comorbidity. [ABSTRACT FROM AUTHOR]

There is now converging evidence from studies in animals and humans that the medial temporal lobes (MTLs) harbor anatomically distinct processing pathways for object and scene information. Recent functional magnetic resonance imaging studies in humans suggest that this domain-specific organization may be associated with a functional preference of the anterior-lateral part of the entorhinal cortex (alErC) for objects and the posterior-medial entorhinal cortex (pmErC) for scenes. As MTL subregions are differentially affected by aging and neurodegenerative diseases, the question was raised whether aging may affect the 2 pathways differentially. To address this possibility, we developed a paradigm that allows the investigation of object memory and scene memory in a mnemonic discrimination task. A group of young (n = 43) and healthy older subjects (n = 44) underwent functional magnetic resonance imaging recordings during this novel task, while they were asked to discriminate exact repetitions of object and scene stimuli from novel stimuli that were similar but modified versions of the original stimuli (“lures”). We used structural magnetic resonance images to manually segment anatomical components of the MTL including alErC and pmErC and used these segmented regions to analyze domain specificity of functional activity. Across the entire sample, object processing was associated with activation of the perirhinal cortex (PrC) and alErC, whereas for scene processing, activation was more predominant in the parahippocampal cortex and pmErC. Functional activity related to mnemonic discrimination of object and scene lures from exact repetitions was found to overlap between processing pathways and suggests that while the PrC-alErC pathway was more involved in object discrimination, both pathways were involved in the discrimination of similar scenes. Older adults were behaviorally less accurate than young adults in discriminating similar lures from exact repetitions, but this reduction was equivalent in both domains. However, this was accompanied by significantly reduced domain-specific activity in PrC in older adults compared to what was observed in the young. Furthermore, this reduced domain-specific activity was associated to worse performance in object mnemonic discrimination in older adults. Taken together, we show the fine-grained functional organization of the MTL into domain-specific pathways for objects and scenes and their mnemonic discrimination and further provide evidence that aging might affect these pathways in a differential fashion. Future experiments will elucidate whether the 2 pathways are differentially affected in early stages of Alzheimer's disease in relation to amyloid or tau pathology. [ABSTRACT FROM AUTHOR]

Increased peripheral and central nervous system cortisol levels have been reported in Alzheimer's disease (AD) and may reflect dysfunction of cerebral components of the hypothalamic-pituitary-adrenal (HPA) axis. However, brain exposure to high cortisol concentrations may also accelerate disease progression and cognitive decline. The objectives of this study were to investigate whether HPA-axis dysregulation occurs at early clinical stages of AD and whether plasma and CSF cortisol levels are associated with clinical disease progression. Morning plasma and CSF cortisol concentrations were obtained from the subjects with AD dementia, mild cognitive impairment of AD type (MCI-AD), MCI of other type (MCI-O), and controls with normal cognition included in a multicenter study from the German Dementia Competence Network. A clinical and neuropsychological follow-up was performed in a subgroup of participants with MCI-AD, MCI-O, and AD dementia. CSF cortisol concentrations were increased in the subjects with AD dementia or MCI-AD compared with subjects with MCI-O or normal cognition. After controlling for possible confounders including CSF measures of amyloid beta1–42 and total tau, higher baseline CSF cortisol levels were associated with faster clinical worsening and cognitive decline in MCI-AD. The findings suggest that HPA-axis dysregulation occurs at the MCI stage of AD and may accelerate disease progression and cognitive decline. [ABSTRACT FROM AUTHOR]

Abstract: Objective: To compare the costs of care for community-dwelling dementia patients with the costs of care for dementia patients living in nursing homes from the societal perspective. Design: Cross-sectional bottom-up cost of illness study nested within the multicenter German AgeCoDe-cohort. Setting: Community and nursing homes. Participants: One hundred twenty-eight community-dwelling dementia patients and 48 dementia patients living in nursing homes. Intervention: None. Measurements: Utilization and costs of medical care and long term care, including formal and informal social and nursing care based on proxy interviews. Informal care was valued using the replacement cost method. Results: Unadjusted mean annual total costs including informal care were €29,930 ($43,997) for community-dwelling patients and €33,482 ($49,218) for patients living in nursing homes. However, multiple regression analysis controlling for age, sex, deficits in basic and instrumental activities of daily living and comorbidity showed that living in the community significantly increased total costs by €11,344 ($16,676; P < .01) compared with living in a nursing home, mainly due to higher costs of informal care (+€20,585; +$30,260; P < .001). Conclusion: From the societal perspective care for dementia patients living in the community tends to cost more than care in nursing homes when functional impairment is controlled for. [Copyright &y& Elsevier]

Abstract: The disturbances of the cholesterol synthesis and metabolism described in Alzheimer's disease (AD) may be both a consequence of the neurodegenerative process and a contributor to the pathogenesis. These putative relationships and their underlying mechanisms are not well understood. The aim of this study was to evaluate the relationship between the cerebral and extracerebral cholesterol synthesis and metabolism, and the AD pathology as reflected by CSF markers in humans. We evaluated the relationships between the plasma and the cerebrospinal fluid (CSF) concentrations of cholesterol, the cholesterol precursors lanosterol, lathosterol and desmosterol, and the cholesterol elimination products 24S-hydroxycholesterol and 27-hydroxycholesterol, and the CSF markers for AD pathology Aβ1–42 and p-tau181 in 86 subjects with normal cognition and in 107 AD patients. CSF desmosterol, cholesterol and 24S-hydroxycholesterol in the AD group, and CSF 24S-hydroxycholesterol in the control group correlated with the p-tau181 levels. Neither CSF nor plasma concentrations of the included compounds correlated with the CSF Aβ1–42 levels. In multivariate regression tests including age, gender, albumin ratio, number of the APOEɛ4 alleles, and diagnosis, p-tau181 levels independently predicted the CSF desmosterol, cholesterol and 24S-hydroxycholesterol concentrations. The associations remained significant for CSF cholesterol and 24S-hydroxycholesterol when analyses were separately performed in the AD group. The results suggest that alterations of CNS cholesterol de novo genesis and metabolism are related to neurodegeneration and in particular to the cerebral accumulation of phosphorylated tau. [Copyright &y& Elsevier]

Abstract: Alzheimer''s disease (AD) is a fast growing world-wide epidemic. AD is a genetically complex, slowly progressive, and irreversible neurodegenerative disease of the brain. During decades of asymptomatic progression multiple interactive systems, pathways and molecular mechanisms (e.g. protein processing, aberrant signaling, inflammation and immune system, lipid transport, endocytosis, apoptosis, oxidative damage and response to stress, tau pathology, neuron and synapse loss, energy metabolism), contribute to the development of the early clinical prodromal stage with episodic memory deficits and to further decline and loss of general cognitive functioning during the final syndromal dementia stage. The non-mendelian genetically complex “sporadic” AD type is the most common form of dementia affecting people usually over the age of 65. Despite considerable progress of AD research in recent years and evolving paradigm shifts in both pathophysiological concepts as well as in diagnostic criteria fundamental challenges have not yet been resolved. The strong age-related incidence, the recent failure and complete lack of disease-modifying or preventive therapy that may delay onset or substantially affect the pathophysiology of AD, result in an enormous burden posed both on individuals, their families and care givers, and the societies at large, and these call for urgent concerted worldwide measures. Based on the meeting of the German Task Force on Alzheimer''s Disease (GTF-AD) in Paris on July 19th 2011, the present position paper provides an overview on the current state and future developments in epidemiology, pathophysiology, disease conceptualization, diagnostic criteria and their use in research and clinical practice, as well as preventive and symptomatic therapeutic approaches. Particular emphasis is placed on a discussion of the different approaches to diagnostics and therapy taken by preventive/public health medicine, methodologically advanced academic research propagating the use of sophisticated biomarkers, and everyday clinical practice focusing on patient-centered care. During the next 10 years, major advances both in early detection as well as in therapy and comprehensive AD care seem mandatory. These still unmet needs call for ever more concerted and focused efforts in research across the world to combat the erupting and as yet uncontrolled epidemic of AD. [Copyright &y& Elsevier]

Abstract: Magnetic resonance imaging (MRI)-based volumetry of medial temporal lobe regions is among the best established biomarker candidates of Alzheimer''s disease (AD) to date. This study assessed the effect of multicentre variability of MRI-based hippocampus and amygdala volumetry on the discrimination between patients with Alzheimer''s disease (AD) and mild cognitive impairment (MCI) and on the association of morphological changes with ApoE4 genotype and cognition. We studied 113 patients with clinically probable AD and 150 patients with amnestic MCI using high-resolution MRI scans obtained at 12 clinical sites. We determined effect sizes of group discrimination and random effects linear models, considering multicentre variability. Hippocampus and amygdala volumes were significantly reduced in AD compared with MCI patients using data pooled across centres. Multicentre variability did not significantly affect the power to detect a volume difference between AD and MCI patients. Among cognitive measures, delayed recall of verbal and non-verbal material was significantly correlated with hippocampus and amygdala volumes. Amygdala and hippocampus volumes were not associated with ApoE4 genotype in AD or MCI. Our data indicate that multicentre acquisition of MRI data using manual volumetry is reliable and feasible for cross-sectional diagnostic studies, and they replicate essential findings from smaller scale monocentre studies. [Copyright &y& Elsevier]

Variant p.R47H of triggering receptor expressed on myeloid cells 2 (TREM2) has been associated with Parkinson's disease (PD). We screened this TREM2-variant in 821 PD patients including 261 demented PD patients (PDD) and in healthy controls (n = 919). Neither the entire PD nor the small PDD sample was associated with p.R47H. [ABSTRACT FROM AUTHOR]

Abstract: Inflammatory processes may substantially contribute to the cerebral pathology in Alzheimer’s disease (AD) and accelerate the disease progression. The macrophage migration inhibitory factor (MIF) is a pro-inflammatory cytokine which promotes the production of several inflammatory mediators such as TNF-α, IL-6 and IFN-γ, and plays a central regulatory role in the pathogenesis of several inflammatory and autoimmune diseases. There is now first evidence that MIF may be involved in the neuroinflammation in AD. To determine whether MIF production is up-regulated early in the course of AD, we compared the levels of MIF assessed by ELISA in the cerebrospinal fluid (CSF) of 31 patients with AD, 28 patients with amnestic mild cognitive impairment (MCI), and 19 subjects without cognitive deficits. Additionally, we measured the CSF concentrations of the inflammatory mediators TNF-α, IL-6 and IFN-γ, which are thought to be both up-regulated by MIF and involved in the pathophysiology of AD. CSF MIF concentrations were significantly increased in AD (p =0.003) and MCI patients (p <0.001) compared to controls. The levels of TNF-α, IL-6 and IFN-γ did not differ significantly between the groups. There was a correlation only between the concentrations of MIF and of TNF-α in the AD group (r =0.407; p =0.023). These results demonstrate increased MIF production in AD and MCI suggesting that MIF may be involved in the occurring neuroinflammatory process at a clinical pre-dementia disease stage. [Copyright &y& Elsevier]

Abstract: Background: Depression among the elderly is an important public health issue. The aims of this study were to report the prevalence of depression and to determine the impact of socio-demographic variables, functional impairment and medical diagnoses, lifestyle factors, and mild cognitive impairment on depression as part of the German Study on Ageing, Cognition and Dementia in Primary Care Patients (AgeCoDe Study). Methods: Included in the cross-sectional survey were 3327 non-demented subjects aged 75 and over attending general practitioners (GPs) (n=138) in an urban area of Germany. The GDS-15 Geriatric Depression Scale was used to measure depression with a threshold of <6/6+. Associations with social and clinical risk factors were assessed by means of multiple logistic regression models. Results: The prevalence of depression was 9.7% (95% confidence interval 8.7–10.7). In a univariate analysis, the following variables were significantly associated with depression: female gender, increasing age, living alone, divorce, lower educational status, functional impairment, comorbid somatic disorder, mild cognitive impairment, smoking, and abstinence from alcohol. After full adjustment for confounding variables, odds ratios for depression were significantly higher only for functional impairment, smoking, and multi-domain mild cognitive impairment. Limitations: Recruitment procedures might have led to an underestimation of current prevalence. The cross-sectional data did not allow us to analyze the temporal relationship between risk factors and depression. Conclusions: The prevalence of depression in the elderly is high and remains high into old age. In designing prevention programs, it is important to call more attention to the impact of functional and cognitive impairment on depression. [Copyright &y& Elsevier]

Abstract: Cholesteryl ester transfer protein (CETP) is a component of the high density lipoprotein (HDL). Variations in the CETP gene may cause CETP deficiency, which is characterized by decreased mass and activity of the protein as well as altered HDL and LDL levels. We investigated the effect of three putative functional CETP polymorphisms (-1946 VNTR, C-629A and I405V) on the risk of Alzheimer''s disease (AD) and on cholesterol, lathosterol and 24S-hydroxycholesterol levels in CSF and plasma of AD patients and controls. None of the investigated CETP polymorphisms or haplotypes had any effect on the risk of AD. However, we found that a three marker CETP haplotype (L/C/V) influenced CSF levels of lathosterol and 24S-hydroxycholesterol as well as plasma levels of total cholesterol in controls but not in AD patients. Our data suggest that CETP gene variations influence cerebral and peripheral cholesterol metabolism, but not AD risk. [Copyright &y& Elsevier]

Abstract: In this report we evaluated the clinical performance of APOE genotyping and three protein biomarkers (total tau, β-amyloid1–42, and tau phosphorylated at threonine 181) in a prospective multicenter study using the INNO-BIA AlzBio3 assay applied on Luminex platform. Concentration of biomarkers of Alzheimer''s disease in cerebrospinal fluid (CSF) was measured with multiplexing technology (n =223), and compared to the results of ELISA assays in patients with early dementias or mild cognitive impairment (MCI) collected at 12 gerontopsychiatric university departments, and APOE genotyping was performed. Concentrations of Aβ1–42 were statistically significantly lower in MCI-AD subjects compared to MCI-O, and significantly lower in D-AD patients compared to MCI-O. P-tau181P concentrations were significantly higher in MCI-AD patients compared to MCI-O, and significantly higher in D-AD patients compared to MCI-O. The total tau concentrations in MCI-AD patients were significantly higher compared to MCI-O, and higher in D-AD compared to MCI-O, moreover, the concentration of total tau was significantly higher in D-AD compared to MCI-AD patients. For the differential diagnosis between D-AD and D-O, the optimal cutoff concentration of Aβ1–42 was 197.7pg/mL, and that for P-tau181P was 47.9pg/mL. These cutoff values were also applied to discriminate between MCI-AD and MCI-O subjects. Simultaneous measurement of the biomarkers significantly improves management of the samples and quality control of the assays’ performance. [Copyright &y& Elsevier]

Abstract: The role of the α4β2* nicotinic acetylcholine receptors (nAChR) in tobacco addiction in humans is largely unresolved. We visualized brain α4β2* nicotinic acetylcholine receptors of smokers and non-smokers with positron emission tomography using 2-[18F]fluoro-3-(2(S)azetidinylmethoxy)pyridine, commonly known as 2-[18F]F-A-85380. The total brain distribution volume of 2-[18F]F-A-85380 was significantly increased in smokers. Statistical parametric mapping revealed that the most prominent regional differences of distribution volumes (DV) were found in cerebellum and brainstem with an increased uptake in smokers. The up-regulation of α4β2* nAChR upon chronic nicotine exposure via tobacco smoking incorporates subcortical brain regions which may play an important role in nicotine addiction. [Copyright &y& Elsevier]

Abstract: Cerebral activation in the elderly may depend on general cognitive decline as well as actual retrieval performance. Consequently, activation between subjects with and without Mild Cognitive Impairment (MCI), and between remembered and non-remembered words was compared. Twenty-one MCI and 29 healthy control subjects learned 180 nouns. During retrieval, subjects had to discriminate these and 180 distractor words. fMRI identified response-related activation. Most retrieval-related activation was comparable in both groups. However, MCI subjects showed more activation in the prefrontal cortex than controls during processing of hits and correct rejections. Hits showed increased activation than misses in the precuneus and left lateral parieto-occipital cortex; misses showed more activation than correct rejections in the precuneus to cuneus. Verbal retrieval activated a large common network in the elderly independently of MCI. Increased activation in MCI subjects in prefrontal cortex depends on response category. Activation differences between response categories might reflect success (hits) and effort (misses). Increased retrieval-related activation may be used as early marker in subjects at risk of Alzheimer''s disease. [Copyright &y& Elsevier]

Abstract: Cholesterol metabolism is involved in Alzheimer''s disease (AD) pathogenesis: increased cholesterol blood levels are detected in AD patients, and treatment with statins reduces the risk of AD. The peroxisome proliferator-activated receptor delta protein (PPARδ), is a member of the steroid hormone super family of ligand-inducible transcription factors, and is of major relevance in lipid and cholesterol metabolism. We investigated three frequent polymorphisms located in exons 4 (rs2016520) and 9 (rs3734254 and rs9794) of the PPARδ gene (PPARD) for their putative influence on the risk of AD and on plasma levels of cholesterol, 24S-hydroxycholesterol and 27-hydroxycholesterol. The study population consisted of 167 AD patients (mean age: 74.27±9.37 years; female 78.6%) and 194 controls (mean age: 73.26±8.37 years; female 57.2%). Haplotype analysis was perfomed, however, we did not find PPARD haplotypes to influence the risk of AD. In contrast to these results, a two marker haplotype consisting of rs2016520 and rs9794 in AD patients showed a significant effect on the relative plasma levels of 24S-hydroxycholesterol (carriers: 32.1±2.8ng/mg; non-carriers: 40.3±1.4ng/mg; p =0.016) and 27-hydroxycholesterol (carriers: 40.8±7.7ng/mg; non-carriers: 58.6±2.3ng/mg; p =0.002) but not in non-demented controls. Our results suggest that PPARD haplotypes might influence levels of cholesterol metabolites in AD patients, but act not as risk factors of AD. [Copyright &y& Elsevier]

Abstract: Cerebral activation during memory encoding and retrieval might depend on subjects'' learning capacity, either by corresponding to better performance in superior learners or by reflecting increased effort in inferior learners. To investigate these alternative hypotheses, the study compared cerebral activation during encoding and retrieval of a motor sequence in groups of subjects with superior and inferior learning performances. Ten healthy subjects underwent functional magnetic resonance imaging (fMRI) while performing a motor sequence encoding paradigm (i.e. finger tapping sequence) and a retrieval paradigm (i.e. reproduction of the learned sequence). Subjects were divided into superior and inferior learners according to the correctness of sequence reproduction during retrieval. During encoding, there was strong bilateral activation in the middle frontal gyrus, the supplementary motor area (SMA), the lateral parietal lobe and the cerebellum. During retrieval, again strong activation was found in identical areas of the prefrontal cortex, the parietal lobe and the cerebellum. During encoding, inferior learners showed more left-sided activations in the left middle frontal and inferior parietal gyri. Superior learners showed increased activation in the corresponding right-sided brain areas during encoding as well as during retrieval. Differences of cerebral activations in the prefrontal and parietal cortex during encoding and retrieval were found to be related to retrieval performance, i.e. success and effort. Further intervention studies are needed to assess whether these interindividual differences are the cause or the consequence of differences in memory performance. [Copyright &y& Elsevier]

Abstract: Hypercortisolaemia occurs in Alzheimer''s disease (AD) and may be involved in the AD related neurodegenerative process. In order to determine whether brain structures are exposed to high cortisol concentrations early in AD, we measured cerebrospinal fluid (CSF) cortisol in 66 subjects with AD, 33 subjects with mild cognitive impairment (MCI) and 34 control subjects. CSF cortisol concentrations were higher in AD subjects compared to controls (p <0.001) and to MCI subjects (p =0.002). There was no significant increase of cortisol in MCI subjects compared with controls suggesting that the increase of CSF cortisol is not an early event in the course of AD. [Copyright &y& Elsevier]