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There has been increasing interest in finding non-invasive biomarkers for neurodegenerative diseases such as Alzheimer's disease (AD). This observational study investigated AD-specific biomarkers in tear fluid. Tear fluid was collected from a total of 65 subjects, including 23 patients with subjective cognitive decline (SCD), 22 patients with mild cognitive impairment (MCI), 11 dementia patients and 9 healthy controls (HC). Levels of amyloid-beta peptides (AB38, AB40, AB42), total-tau (t-tau) and phosphorylated-tau (p-tau) were determined using multiplex immunoassays. Levels of AB40 and t-tau were detectable in the vast majority (> 94%) of tear fluid samples. Cerebrospinal fluid (CSF) was available from a subset of patients. In this group, tear t-tau levels were significantly higher in people with dementia compared to SCD patients. Tear t-tau levels were elevated in patients with neurodegeneration (classified according to the A/T/N system) compared to patients without neurodegeneration. Negative correlations were found between CSF AB42 and CSF t-tau, and between CSF AB42 and tear t-tau. In summary, this study shows the potential of tau proteins in tear fluid to be associated with disease severity and neurodegeneration. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: Studies investigating associations between kynurenines and cognitive function have generally been small, restricted to clinical samples or have found inconsistent results, and associations in the general adult population, and in individuals with type 2 diabetes in particular, are not clear. Therefore, the aim of the present study was to investigate cross-sectional associations between plasma kynurenines and cognitive function in a cohort of middle-aged participants with normal glucose metabolism, prediabetes (defined as impaired fasting glucose and/or impaired glucose tolerance) and type 2 diabetes. Methods: Plasma kynurenines were quantified in 2358 participants aged 61 ± 8 years. Cross-sectional associations of kynurenines with cognitive impairment and cognitive domain scores were investigated using logistic, multiple linear and restricted cubic spline regression analyses adjusted for several confounders. Results: Effect modification by glucose metabolism status was found for several associations with cognitive impairment, hence analyses were stratified. In individuals with prediabetes, 3-hydroxykynurenine (OR per SD 0.59 [95% CI 0.37, 0.94]) and 3-hydroxyanthranilic acid (0.67 [0.47, 0.96]) were associated with lower odds of cognitive impairment after full adjustment. In individuals with type 2 diabetes, kynurenine (0.80 [0.66, 0.98]), 3-hydroxykynurenine (0.82 [0.68, 0.99]), kynurenic acid (0.81 [0.68, 0.96]), xanthurenic acid (0.73 [0.61, 0.87]) and 3-hydroxyanthranilic acid (0.73 [0.60, 0.87]) were all associated with lower odds of cognitive impairment. Kynurenic acid (β per SD 0.07 [95% CI 0.02, 0.13]) and xanthurenic acid (0.06 [0.01, 0.11]) were also associated with better executive function/attention. No associations were observed in individuals with normal glucose metabolism. Conclusions/interpretation: Several kynurenines were cross-sectionally associated with lower odds of cognitive impairment and better cognitive functioning in type 2 diabetes, while less widespread associations were seen in prediabetes. Low levels of kynurenines might be involved in the pathway of type 2 diabetes and cognitive decline but this needs further studies. [ABSTRACT FROM AUTHOR]

To investigate whether blood–brain barrier (BBB) disruption is a potential mechanism of usual age-related cognitive decline, we conducted dynamic contrast–enhanced (DCE) MRI to measure BBB leakage in a healthy sample, and investigated the association with longitudinal cognitive decline. In a sample of neurologically and cognitively healthy, older individuals, BBB leakage rate in the white and grey matter and hippocampus was measured using DCE MRI with pharmacokinetic modelling. Regression analysis was performed to investigate whether the leakage rate was associated with decline in cognitive performance (memory encoding, memory retrieval, executive functioning and processing speed) over 12 years. White and grey matter BBB leakages were significantly associated with decline in memory retrieval. No significant relations were found between hippocampal BBB leakage and cognitive performance. BBB disruption already being associated with usual cognitive ageing, supports that this neurovascular alteration is a possible explanation for the cognitive decline inherent to the ageing process. More insight into BBB leakage during the normal ageing process could improve estimation and interpretation of leakage rate in pathological conditions. The current results might also stimulate the search for strategies to maintain BBB integrity and help increase the proportion people experiencing successful ageing. Netherlands Trial Register number: NL6358, date of registration: 2017-03-24. [ABSTRACT FROM AUTHOR]

The Locus Coeruleus (LC) and the Substantia Nigra (SN) are small brainstem nuclei that change with aging and may be involved in the development of various neurodegenerative and psychiatric diseases. Magnetization Transfer (MT) MRI has been shown to facilitate LC and the SN visualization, and the observed contrast is assumed to be related to neuromelanin accumulation. Imaging these nuclei may have predictive value for the progression of various diseases, but interpretation of previous studies is hindered by the fact that the precise biological source of the contrast remains unclear, though several hypotheses have been put forward. To inform clinical studies on the possible biological interpretation of the LC- and SN contrast, we examined an agar-based phantom containing samples of natural Sepia melanin and synthetic Cys-Dopa-Melanin and compared this to the in vivo human LC and SN. T1 and T2* maps, MT spectra and relaxation times of the phantom, the LC and the SN were measured, and a two-pool MT model was fitted. Additionally, Bloch simulations and a transient MT experiment were conducted to confirm the findings. Overall, our results indicate that Neuromelanin-MRI contrast in the LC likely results from a lower macromolecular fraction, thus facilitating interpretation of results in clinical populations. We further demonstrate that in older individuals T1 lengthening occurs in the LC. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: Depression is twice as common in individuals with type 2 diabetes as in the general population. However, it remains unclear whether hyperglycaemia and insulin resistance are directly involved in the aetiology of depression. Therefore, we investigated the association of markers of hyperglycaemia and insulin resistance, measured as continuous variables, with incident depressive symptoms over 4 years of follow-up. Methods: We used data from the longitudinal population-based Maastricht Study (n = 2848; mean age 59.9 ± 8.1 years, 48.8% women, 265 incident depression cases, 10,932 person-years of follow-up). We assessed hyperglycaemia by fasting and 2 h post-load OGTT glucose levels, HbA1c and skin autofluorescence (reflecting AGEs) at baseline. We used the Matsuda insulin sensitivity index and HOMA-IR to calculate insulin resistance at baseline. Depressive symptoms (nine-item Patient Health Questionnaire score ≥10) were assessed at baseline and annually over 4 years. We used Cox regression analyses, and adjusted for demographic, cardiovascular and lifestyle risk factors. Results: Fasting plasma glucose, 2 h post-load glucose and HbA1c levels were associated with an increased risk for incident depressive symptoms after full adjustment (HR 1.20 [95% CI 1.08, 1.33]; HR 1.25 [1.08, 1.44]; and HR 1.22 [1.09, 1.37] per SD, respectively), while skin autofluorescence, insulin sensitivity index and HOMA-IR were not (HR 0.99 [0.86, 1.13]; HR 1.02 [0.85, 1.25]; and HR 0.93 [0.81, 1.08], per SD, respectively). Conclusions/interpretation: The observed temporal association between hyperglycaemia and incident depressive symptoms in this study supports the presence of a mechanistic link between hyperglycaemia and the development of depressive symptoms. [ABSTRACT FROM AUTHOR]

Blood–brain barrier (BBB) breakdown can disrupt nutrient supply and waste removal, which affects neuronal functioning. Currently, dynamic contrast-enhanced (DCE) MRI is the preferred in-vivo method to quantify BBB leakage. Dedicated DCE MRI studies in normal aging individuals are lacking, which could hamper value estimation and interpretation of leakage rate in pathological conditions. Therefore, we applied DCE MRI to investigate the association between BBB disruption and age in a healthy sample. Fifty-seven cognitively and neurologically healthy, middle-aged to older participants (mean age: 66 years, range: 47–91 years) underwent MRI, including DCE MRI with intravenous injection of a gadolinium-based contrast agent. Pharmacokinetic modeling was applied to contrast concentration time-curves to estimate BBB leakage rate in each voxel. Subsequently, leakage rate was calculated in the white and gray matter, and primary (basic sensory and motor functions), secondary (association areas), and tertiary (higher-order cognition) brain regions. A difference in vulnerability to deterioration was expected between these regions, with especially tertiary regions being affected by age. Higher BBB leakage rate was significantly associated with older age in the white and gray matter, and also in tertiary, but not in primary or secondary brain regions. Even in healthy individuals, BBB disruption was stronger in older persons, which suggests BBB disruption is a normal physiologically aging phenomenon. Age-related increase in BBB disruption occurred especially in brain regions most vulnerable to age-related deterioration, which may indicate that BBB disruption is an underlying mechanism of normal age-related decline. Netherlands Trial Register number: NL6358, date of registration: 2017-03-24. [ABSTRACT FROM AUTHOR]

Pattern separation (PS) describes the process by which the brain discriminates similar stimuli from previously encoded stimuli. This fundamental process requires the intact processing by specific subfields in the hippocampus and can be examined using mnemonic discrimination tasks. Previous studies reported different patterns for younger and older individuals between mnemonic discrimination performance and hippocampal subfield activation. Here, we investigated the relationship between the lure discrimination index (LDI) and hippocampal subfield volume and activity across the adult lifespan (20–70 years old). Using ultra-high field functional and structural magnetic resonance imaging at 7 T, we found that lower DG volume and higher CA3 activation was associated with worse LDI performance in individuals (>60 years), suggesting that this higher activation may be an indication of aberrant neurodegenerative-related processes. In fact, higher activation in the CA1 and DG was associated with lower volumes in these subfields. For individuals around 40–50 years old, we observed that greater left and right DG volume, and greater activity in the CA3 was associated with lower LDI performance. Taken together, these results suggest that the relationship between memory and hippocampal subfield structure or function varies nonlinearly and possibly reciprocally with age, with midlife being a critically vulnerable period in life. [ABSTRACT FROM AUTHOR]

Background: Delirium in older hospitalised patients is a common and serious disorder. Polypharmacy and certain medications are risk factors for developing delirium. A medication review could benefit older hospitalised patients with delirium.Objectives: (1) Evaluate the effects of medication review on length of delirium, length of hospital stay, mortality, and discharge destination; and (2) describe and analyse the proposed changes to medication and its implementation by the treating physician.Setting: The study was conducted at Maastricht University Medical Centre+.Methods: We compared two cohorts of older patients with delirium: the first cohort from before introducing the medication review, and a second cohort 5 months after introduction of the medication review. Data were extracted from the patients’ digital medical records.Results: A significant interaction effect of cohort and number of medications taken by the patient was found for duration of delirium: patients from the second cohort taking between zero and six medications had significantly shorter delirious episodes than patients in the first cohort. This effect bordered on significance for patients taking between seven and 11 medications, but disappeared for patients taking 12 or more medications. No other statistically significant differences were found between the cohorts. The proposed changes in medication were implemented for 71% of the patients.Conclusion: A medication review seems to significantly decrease the length of an older patient’s delirious episode. Given the clinical relevance of these findings, we advise medication reviews for all older patients who are delirious or are at risk of developing delirium. [ABSTRACT FROM AUTHOR]

The serotonergic hypothesis for depression in Parkinson's disease (PD) states that the reduced cerebral serotonergic activity that occurs in PD constitutes a biological risk factor for depression. The aim of our study was to assess the serotonergic hypothesis of depression in PD patients using an experimental approach. In a double-blind, randomized order, placebo-controlled crossover design, the response on the Profile of Mood States (POMS) questionnaire to acute tryptophan depletion (ATD) was studied in 15 PD nondepressed patients and 15 control subjects, without a prior personal or family history of depression. PD patients had lower (worse) baseline scores on the sadness, fatigue and vigor subscales of the POMS, in both ATD and the placebo condition, but not on the tension and anger subscales. There was however neither a significe between group effect, nor significe within-group effect due to ATD. We could find no evidence of a specific serotonergic vulnerability of PD patients for depression. Therefore, our results do not support the serotonergic hypothesis for depression in PD.Neuropsychopharmacology (2006) 31, 1009–1015. doi:10.1038/sj.npp.1300914; published online 5 October 2005 [ABSTRACT FROM AUTHOR]

Objective: Although antipsychotics are important in the treatment of behavioural and psychological symptoms of dementia (BPSD), they have moderate efficacy and often cause adverse events. Recent safety warnings about increased frequency of cerebrovascular adverse events in elderly patients who use atypical antipsychotics mean that physicians now face a dilemma when weighing the benefits and risks of use of antipsychotics in this patient group. This study systematically reviews the reporting of adverse events of antipsychotics used to treat BPSD in randomised, controlled trials (RCTs). Methods: We searched the MEDLINE, EMBASE, PsychInfo and CINAHL databases (search period 1980 or 1986-April 2005) and the Cochrane controlled trials register (2005) for RCTs that used intention-to-treat analysis to evaluate the efficacy and harms of antipsychotics used to treat BPSD. Two independent reviewers assessed the reporting of adverse events. Results: Screening of 930 abstracts identified 12 eligible RCTs (2809 patients). Most participants were elderly people (mean age 80 years) with Alzheimer’s, vascular or mixed dementia. Studies lasted from 3 to 16 weeks. Adverse events, though common, were described heterogeneously and incompletely. No RCT fulfilled all Consolidated Standards of Reporting Trials requirements for the reporting of harms. Atypical antipsychotics caused fewer extrapyramidal symptoms and less somnolence than typical antipsychotics, but these differences disappeared when dosages were increased. Only one trial reported cerebrovascular adverse events, with a number needed to harm of 14 (95% CI 8, 41). Conclusions: At lower doses atypical antipsychotics may cause fewer adverse events in the treatment of BPSD, but there is uncertainty about their cerebrovascular safety profile. The RCTs included in this systematic review described adverse events too incompletely and heterogeneously to allow generation of clear treatment recommendations, and they do not provide sufficient evidence to support recent safety warnings. Better reporting on harms in RCTs is needed to enable rational treatment decisions with respect to use of antipsychotics for BPSD. [ABSTRACT FROM AUTHOR]

The Preclinical AD Scale (PAS) is a newly developed scale for the diagnosis of preclinical Alzheimer's disease (AD). The PAS combines six markers of preclinical AD, namely age, MMSE score, functional impairment, cognitive test performance, medial temporal lobe atrophy, and the apolipoprotein E (APOE) genotype. The aim of the study was to investigate whether the PAS can accurately identify subjects with preclinical AD who become demented during a 2 or 5 year follow-up from among subjects with mild cognitive impairment for other reasons. We also investigated whether a step-wise scoring of the PAS could reduce the number of elaborate or expensive diagnostic procedures. The PAS was scored retrospectively in two independent samples of non-demented subjects with mild cognitive impairment older than 55 years (average age 65.6 years), who were selected from a memory clinic population. In the first sample, the follow-up was 5 years (5-year follow-up sample; n=69). In the second sample, the follow-up was 2 years (2-year follow-up sample; n=23). The PAS item medial temporal lobe atrophy was not scored in the 5-year follow-up sample. A PAS cut-off score of 4/5 could best identify subjects with AD-type dementia at follow-up (n=25) in the 5-year follow-up sample with a sensitivity of 80 % and a positive predictive value of 77 %. A PAS cut-off score of 5/6 could best identify subjects with AD-type dementia at follow-up (n=8) in the 2-year follow-up sample with a sensitivity of 88 % and a positive predictive value of 70 %. The positive predictive value could be increased to 94 % in the 5-year follow-up sample and to 80 % in the 2-year follow-up sample by using higher cut-off scores, but this reduced the sensitivity. Step-wise scoring of the PAS had the same diagnostic accuracy as the total PAS score and reduced the number of cognitive assessments by 22 to 38 %, the number of assessments of medial temporal lobe atrophy by 57 to 74 %, and the number of APOE genotypings by 74 %. It is concluded that the PAS is a useful scale to identify subjects with preclinical AD who will become demented during the next 2 or 5 years. Step-wise scoring of the PAS can reduce the number of elaborate or expensive diagnostic procedures considerably. [ABSTRACT FROM AUTHOR]

To determine whether the medial temporal lobe is atrophic in subjects with mild cognitive impairment, and whether atrophy of this structure is a better predictor of dementia than memory dysfunction. Forty-five noninstitutionalized subjects aged 65–85 years were randomly selected from a population based study to obtain a sample with Alzheimer’s disease (AD; n = 7), and a clinically nondemented sample ( n = 38). Twenty of the latter subjects displayed some cognitive impairment and fulfilled CAMDEX criteria for “minimal dementia.” Coronal T1-weighted magnetic resonance imaging was used to visualize the medial temporal lobe. The volume of the parahippocampal gyrus and hippocampus was measured, and medial temporal lobe atrophy was assessed qualitatively. The memory subscore from the CAMCOG was used as a measure of memory functioning. The follow-up period was 3 years. Nine subjects who were diagnosed as being minimally demented at baseline met the criteria for AD during follow-up. At baseline the volume of the parahippocampal gyrus of these subjects was smaller than that of the other subjects with minimal dementia. The memory score was the best predictor of clinical outcome. All medial temporal lobe measures increased the accuracy of prediction compared with only the memory score, by reducing the number of false-negative classifications of dementia. Severe medial temporal lobe atrophy is present even in some subjects with mild cognitive impairment and is an indicator of subsequent AD. The absence of medial temporal lobe atrophy, however, does not exclude the development of dementia. In the majority of subjects memory impairment was a better predictor of dementia than atrophy of the medial temporal lobe. The combination of the two increased predictive accuracy. Nondemented subjects with severe atrophy of the medial temporal lobe could be enrolled in drug trials aimed at slowing the progression of AD. [ABSTRACT FROM AUTHOR]

A biography of the German neuropsychiatrist Alois Alzheimer is presented. He was born on June 14, 1864 in Marktbreit am Main, Bavaria, and studied medicine in Tübingen, Berlin and Würzburg, Germany. He gave a lecture for South German neuropsychiatrists on November 3, 1906 entitled "Ueber eine eigenartige Erkrankung der Hirnrinde" which is all about a remarkable illness of the cerebral cortex.

Purpose: The Quality of Life Alzheimer's Disease Scale (QoL-AD) is commonly used to assess disease specific health-related quality of life (HRQoL) as rated by patients and their carers. For cost-effectiveness analyses, utilities based on the EQ-5D are often required. We report a new mapping algorithm to obtain EQ-5D indices when only QoL-AD data are available.Methods: Different statistical models to estimate utility directly, or responses to individual EQ-5D questions (response mapping) from QoL-AD, were trialled for patient-rated and proxy-rated questionnaires. Model performance was assessed by root mean square error and mean absolute error.Results: The response model using multinomial regression including age and sex, performed best in both the estimation dataset and an independent dataset.Conclusions: The recommended mapping algorithm allows researchers for the first time to estimate EQ-5D values from QoL-AD data, enabling cost-utility analyses using datasets where the QoL-AD but no utility measures were collected. [ABSTRACT FROM AUTHOR]