The value of cerebrospinal fluid α-synuclein and the tau/α-synuclein ratio for diagnosis of neurodegenerative disorders with Lewy pathology.

BACKGROUND AND PURPOSE: Parkinson's disease (PD), dementia with Lewy bodies (DLB) and Alzheimer's disease (AD) are three of the most common neurodegenerative disorders. Up to 20% of these patients have the wrong diagnosis, due to overlapping symptoms and shared pathologies. A cerebrospinal fluid (CSF) biomarker panel for AD is making its way into the clinic, but an equivalent panel for PD and DLB and for improved differential diagnoses is still lacking. Using well-defined, community-based cohorts and validated analytical methods, the diagnostic value of CSF total-α-synuclein (t-α-syn) alone and in combination with total tau (t-tau) in newly diagnosed patients with PD, DLB and AD was determined. METHODS: Cerebrospinal fluid concentrations of t-α-syn were assessed using our validated in-house enzyme-linked immunosorbent assay in 78 PD patients, 20 AD patients, 19 DLB patients and 32 controls. t-tau was measured using a commercial assay. Diagnostic performance was assessed by receiver operating characteristic curve analysis. RESULTS: Compared to controls (mean 517 pg/ml), significantly lower levels of CSF t-α-syn in patients with PD (434 pg/ml, 16% reduction, P = 0.036), DLB (398 pg/ml, 23% reduction, P = 0.009) and AD (383 pg/ml, 26% reduction, P = 0.014) were found. t-α-syn levels did not differ significantly between PD, DLB and AD. The t-tau/t-α-syn ratio showed an improved performance compared to the single markers. CONCLUSION: This is the first study to compare patients with PD, DLB and AD at the time of diagnosis. It was found that t-α-syn can contribute as a teammate with tau in a CSF biomarker panel for PD and DLB, and strengthen the existing biomarker panel for AD.

Age-related neurochemical and behavioural changes in D409V/WT GBA1 mouse: Relevance to lewy body dementia.

Heterozygous mutations in GBA1, the gene which encodes the lysosomal enzyme glucocerebrosidase (GCase), are a strong genetic risk factor for the development of Lewy body dementia (LBD). Until this point however, recapitulation of the symptoms and pathology of LBD has been limited to a homozygous GBA1 mouse model which genetically and enzymatically reflects the lysosomal storage disorder Gaucher's disease. This study reports for the first time cognitive impairment by two independent behavioural tests in heterozygous GBA1 mutant mice (D409V/WT) which demonstrate significant cognitive impairment by the age of 12 months. Furthermore, reductions in GBA1 GCase enzyme activity within the brain reflects levels seen in sporadic and GBA1 mutant LBD patients. While there is no overt deposition of Lewy bodies within the hippocampus, alterations to cholinergic machinery and glial proliferation are evident, both pathological features of LBD. Interestingly, we also describe the novel finding of significantly reduced GBA2 GCase enzyme activity specifically within the hippocampus. This suggests that reduced GBA1 GCase enzyme activity dis-equilibrates the finely balanced glycosphingolipid metabolism pathway and that reductions in GBA2 GCase enzyme could contribute to the pathological and behavioural effects seen. Overall, this study presents evidence to suggest that pathological hallmarks associated with LBD specifically affecting brain regions intrinsically linked with cognition are present in the D409V/WT mice. In the absence of Lewy body deposition, the D409V/WT mice could be considered an early pre-clinical model of LBD with potential for drug discovery. Since few robust pre-clinical models of LBD currently exist, with further characterization, the mouse model described here may contribute significantly to developments in the LBD field.

Longitudinal relationships among depressive symptoms, cortisol, and brain atrophy in the neocortex and the hippocampus.

OBJECTIVE: Depression is associated with accelerated aging and age-related diseases. However, mechanisms underlying this relationship remain unclear. The aim of this study was to longitudinally assess the link between depressive symptoms, brain atrophy, and cortisol levels. METHOD: Participants from the Betula prospective cohort study (mean age = 59 years, SD = 13.4 years) underwent clinical, neuropsychological and brain 3T MRI assessments at baseline and a 4-year follow-up. Cortisol levels were measured at baseline in four saliva samples. Cortical and hippocampal atrophy rates were estimated and compared between participants with and without depressive symptoms (n = 81) and correlated with cortisol levels (n = 49). RESULTS: Atrophy in the left superior frontal gyrus and right lingual gyrus developed in parallel with depressive symptoms, and in the left temporal pole, superior temporal cortex, and supramarginal cortex after the onset of depressive symptom. Depression-related atrophy was significantly associated with elevated cortisol levels. Elevated cortisol levels were also associated with widespread prefrontal, parietal, lateral, and medial temporal atrophy. CONCLUSION: Depressive symptoms and elevated cortisol levels are associated with atrophy of the prefrontal and limbic areas of the brain.

Frequency and subgroups of neuropsychiatric symptoms in mild cognitive impairment and different stages of dementia in Alzheimer's disease.

BACKGROUND: Neuropsychiatric symptoms (NPS), such as depression, apathy, agitation, and psychotic symptoms are common in mild cognitive impairment (MCI) and dementia in Alzheimer's disease (AD). Subgroups of NPS have been reported. Yet the relationship of NPS and their subgroups to different stages of cognitive impairment is unclear. Most previous studies are based on small sample sizes and show conflicting results. We sought to examine the frequency of NPS and their subgroups in MCI and different stages of dementia in AD. METHODS: This was a cross-sectional study using data from a Norwegian national registry of memory clinics. From a total sample of 4,571 patients, we included those with MCI or AD (MCI 817, mild AD 883, moderate-severe AD 441). To compare variables across groups ANOVA or χ 2-test was applied. We used factor analysis of Neuropsychiatric Inventory Questionnaire (NPI-Q) items to identify subgroups of NPS. RESULTS: The frequency of any NPS was 87.2% (AD 91.2%, MCI 79.5%; p < 0.001) and increased with increasing severity of cognitive decline. The most frequent NPS in MCI was depression. Apathy was the most frequent NPS in AD across different stages of severity. The factor analysis identified three subgroups in MCI and mild AD, and a fourth one in moderate-severe AD. We labelled the subgroups "depression," "agitation," "psychosis," and "elation." CONCLUSIONS: The frequency of NPS is high in MCI and AD and increases with the severity of cognitive decline. The subgroups of NPS were relatively consistent from MCI to moderate-severe AD. The subgroup elation appeared only in moderate-severe AD.

Psychometric properties of the mutuality scale in Swedish dyads with Parkinson's disease.

OBJECTIVES: The 15-item mutuality scale (MS) has been used in several neurological conditions assessing the quality of relationship associations with negative effects of the caregiving situation. The aim of this study was to translate the original MS into Swedish and assess its psychometric properties in Parkinson's disease (PD). MATERIALS AND METHODS: Following the forward-backward translation method, the scale was evaluated regarding linguistic correctness at a conceptual level and user-friendliness. The scale was filled out by a sample of 50 care dyads where one was having PD. Scale assumptions and scale structure were evaluated using floor/ceiling effect and principal component analyses (PCA) with promax rotation. Internal consistency was evaluated using Cronbach's alpha and mean inter-item correlation coefficients. RESULTS: The Swedish MS was evaluated as user-friendly and relevant by the participants. The scale demonstrated no floor/ceiling effect and showed high internal consistency (α≥0.93) with a mean inter-item correlation coefficient of ≥0.5. Through the PCA, a two factor solution emerged, which accounted for 67% and 64% of the variance of the MS score by PD-partners and PD-patients, respectively. However, some variables were complex and discarded in the final solution. CONCLUSION: Our findings provide initial support of the Swedish MS as a user-friendly and useful instrument with acceptable psychometric properties even though more research is needed to evaluate the existence of subscales.

Antidepressants and mortality risk in a dementia cohort: data from SveDem, the Swedish Dementia Registry.

BACKGROUND: The association between mortality risk and use of antidepressants in people with dementia is unknown. OBJECTIVE: To describe the use of antidepressants in people with different dementia diagnoses and to explore mortality risk associated with use of antidepressants 3 years before a dementia diagnosis. METHODS: Study population included 20 050 memory clinic patients from the Swedish Dementia Registry (SveDem) diagnosed with incident dementia. Data on antidepressants dispensed at the time of dementia diagnosis and during 3-year period before dementia diagnosis were obtained from the Swedish Prescribed Drug Register. Cox regression models were used. RESULTS: During a median follow-up of 2 years from dementia diagnosis, 25.8% of dementia patients died. A quarter (25.0%) of patients were on antidepressants at the time of dementia diagnosis, while 21.6% used antidepressants at some point during a 3-year period before a dementia diagnosis. Use of antidepressant treatment for 3 consecutive years before a dementia diagnosis was associated with a lower mortality risk for all dementia disorders and in Alzheimer's disease. CONCLUSION: Antidepressant treatment is common among patients with dementia. Use of antidepressants during prodromal stages may reduce mortality in dementia and specifically in Alzheimer's disease.

Cognitive decline in dementia with Lewy bodies: a 5-year prospective cohort study.

OBJECTIVES: We report the cognitive decline in persons diagnosed with mild dementia with Lewy bodies (DLB) and mild Alzheimer's disease (AD) during 5 years of annual follow-ups. METHODS: Patients were recruited into the study from geriatric, psychiatric and neurology clinics in Western Norway during 2005-2013. They were diagnosed according to clinical consensus criteria, based on standardised clinical rating scales. Autopsy-based diagnoses were available for 20 cases. Cognitive decline for up to 5 years was assessed using the Clinical Dementia Rating (CDR) scale and the Mini-Mental State Examination (MMSE). Survival analysis including Cox regression (time to reach severe dementia) and linear mixed-effects (lme) modelling were used to model the decline on MMSE. RESULTS: At least one follow-up assessment was available for 67 patients with DLB and 107 patients with AD, with a median follow-up time of 4.3 years. The time to reach severe dementia was significantly shorter in DLB (median 1793 days) compared with AD (1947 days; p=0.033), and the difference remained significant in the multiple Cox regression analysis (HR=2.0, p<0.02). In the adjusted lme model, MMSE decline was faster in DLB (annual decline 4.4 points) compared with AD (3.2 points; p<0.008). CONCLUSIONS: Our findings show that from the mild dementia stage, patients with DLB have a more rapid cognitive decline than in AD. Such prognostic information is vital for patients and families and crucial for planning clinical trials and enabling health economic modelling.

MMSE and MoCA in Parkinson's disease and dementia with Lewy bodies: a multicenter 1-year follow-up study.

The Mini-Mental State Examination (MMSE) and the Montreal Cognitive Assessment (MoCA) are the most commonly used scales to test cognitive impairment in Lewy body disease (LBD), but there is no consensus on which is best suited to assess cognition in clinical practice and most sensitive to cognitive decline. Retrospective cohort study of 265 LBD patients [Parkinson's disease (PD) without dementia (PDnD, N = 197), PD with dementia (PDD, N = 40), and dementia with Lewy bodies (DLB, N = 28)] from an international consortium who completed both the MMSE and MoCA at baseline and 1-year follow-up (N = 153). Percentage of relative standard deviation (RSD%) at baseline was the measure of inter-individual variance, and estimation of change (Cohen's d) over time was calculated. RSD% for the MoCA (21 %) was greater than for the MMSE (13 %) (p = 0.03) in the whole group. This difference was significant only in PDnD (11 vs. 5 %, p < 0.01), but not in PDD (30 vs. 19 %, p = 0.37) or DLB (15 vs. 14 %, p = 0.78). In contrast, the 1-year estimation of change did not differ between the two tests in any of the groups (Cohen's effect <0.20 in each group). MMSE and MoCA are equal in measuring the rate of cognitive changes over time in LBD. However, in PDnD, the MoCA is a better measure of cognitive status as it lacks both ceiling and floor effects.

Genetic overlap between Alzheimer's disease and Parkinson's disease at the MAPT locus.

We investigated the genetic overlap between Alzheimer's disease (AD) and Parkinson's disease (PD). Using summary statistics (P-values) from large recent genome-wide association studies (GWAS) (total n=89 904 individuals), we sought to identify single nucleotide polymorphisms (SNPs) associating with both AD and PD. We found and replicated association of both AD and PD with the A allele of rs393152 within the extended MAPT region on chromosome 17 (meta analysis P-value across five independent AD cohorts=1.65 × 10(-7)). In independent datasets, we found a dose-dependent effect of the A allele of rs393152 on intra-cerebral MAPT transcript levels and volume loss within the entorhinal cortex and hippocampus. Our findings identify the tau-associated MAPT locus as a site of genetic overlap between AD and PD, and extending prior work, we show that the MAPT region increases risk of Alzheimer's neurodegeneration.

Neurobiological correlates of depressive symptoms in people with subjective and mild cognitive impairment.

OBJECTIVE: To test the hypothesis that depressive symptoms correlate with Alzheimer's disease (AD) type changes in CSF and structural and functional imaging including hippocampus volume, cortical thickness, white matter lesions, Diffusion tensor imaging (DTI), and fluoro-deoxy-glucose positron emission tomography (FDG-PET) in patient with subjective (SCI) and mild (MCI) cognitive impairment. METHOD: In 60 patients, depressive symptoms were assessed using the Geriatric Depression Scale. The subjects underwent MRI, 18F-FDG PET imaging, and lumbar CSF extraction. RESULTS: Subjects with depressive symptoms (n=24) did not have more pathological AD biomarkers than non-depressed. Uncorrected there were trends towards larger hippocampal volumes (P=0.06), less orbital WM damage measured by DTI (P=0.10), and higher orbital glucose metabolism (P=0.02) in the depressed group. The findings were similar when SCI and MCI were analyzed separately. Similarly, in patients with pathological CSF biomarkers (i.e., predementia AD, n=24), we found that correlations between scores on GDS and CSF Aß42 and P-tau indicated less severe AD-specific CSF changes with increasing depression. CONCLUSION: Depressive symptoms are common in SCI/MCI, but are not associated with pathological imaging or CSF biomarkers of AD. Depression can explain cognitive impairment in SCI/MCI or add to cognitive impairment leading to an earlier clinical investigation in predementia AD.

Random Forest ensembles for detection and prediction of Alzheimer's disease with a good between-cohort robustness.

Computer-aided diagnosis of Alzheimer's disease (AD) is a rapidly developing field of neuroimaging with strong potential to be used in practice. In this context, assessment of models' robustness to noise and imaging protocol differences together with post-processing and tuning strategies are key tasks to be addressed in order to move towards successful clinical applications. In this study, we investigated the efficacy of Random Forest classifiers trained using different structural MRI measures, with and without neuroanatomical constraints in the detection and prediction of AD in terms of accuracy and between-cohort robustness. From The ADNI database, 185 AD, and 225 healthy controls (HC) were randomly split into training and testing datasets. 165 subjects with mild cognitive impairment (MCI) were distributed according to the month of conversion to dementia (4-year follow-up). Structural 1.5-T MRI-scans were processed using Freesurfer segmentation and cortical reconstruction. Using the resulting output, AD/HC classifiers were trained. Training included model tuning and performance assessment using out-of-bag estimation. Subsequently the classifiers were validated on the AD/HC test set and for the ability to predict MCI-to-AD conversion. Models' between-cohort robustness was additionally assessed using the AddNeuroMed dataset acquired with harmonized clinical and imaging protocols. In the ADNI set, the best AD/HC sensitivity/specificity (88.6%/92.0% - test set) was achieved by combining cortical thickness and volumetric measures. The Random Forest model resulted in significantly higher accuracy compared to the reference classifier (linear Support Vector Machine). The models trained using parcelled and high-dimensional (HD) input demonstrated equivalent performance, but the former was more effective in terms of computation/memory and time costs. The sensitivity/specificity for detecting MCI-to-AD conversion (but not AD/HC classification performance) was further improved from 79.5%/75%-83.3%/81.3% by a combination of morphometric measurements with ApoE-genotype and demographics (age, sex, education). When applied to the independent AddNeuroMed cohort, the best ADNI models produced equivalent performance without substantial accuracy drop, suggesting good robustness sufficient for future clinical implementation.

Efficacy of pain treatment on mood syndrome in patients with dementia: a randomized clinical trial.

BACKGROUND: Depression is common in nursing home (NH) patients with dementia, and often clustered with anxiety and other mood symptoms. An association between pain and depressive symptoms has been reported, but the impact of pain management on depression and other mood symptoms has not been investigated. OBJECTIVE: Secondary analyses of a cluster randomized clinical trial examine the response of dementia-related mood symptoms to a Stepwise Protocol of Treating Pain. METHOD: Three-hundred fifty-two patients with moderate and severe dementia and significant behavioural disturbances, related to 60 clusters (i.e. clusters defined as single independent NH units) in 18 NHs of Western Norway, were included. All patients in the intervention group received individual daily pain treatment with paracetamol, extended release morphine, buprenorphine transdermal patch or pregabaline for 8 weeks, with additional follow-up assessment 4 weeks after completion of the intervention. Clusters randomized to control received usual treatment. A mood cluster consisting of depression, anxiety, sleep disorders, apathy and appetite items from the Neuropsychiatric Inventory-Nursing Home (NPI-NH) was the primary outcome. RESULTS: Analysed by Mann-Whitney U-tests, Stepwise Protocol of Treating Pain conferred significant benefit in treatment of the NPI-NH mood cluster (F = 13.4, df = 1;299, p < 0.001) and depression (F = 2.0, df = 1;301, p = 0.025). Further analyses highlighted improvements in apathy (F = 5.3, df = 1;300, p = 0.017), night-time behaviours (F = 3.1, df = 1;301, p = 0.050), and appetite items (F = 11.6, df = 1;301, p = 0.005), but not irritability (p = 0.092) and anxiety (p = 0.125). CONCLUSION: Mood symptoms including depression significantly improved with pain treatment, emphasizing the importance of more rigorous treatment of pain in agitated people with dementia. Findings have potentially immediate clinical relevance.

Impact of a stepwise protocol for treating pain on pain intensity in nursing home patients with dementia: a cluster randomized trial.

BACKGROUND: Pain is frequent and distressing in people with dementia, but no randomized controlled trials have evaluated the effect of analgesic treatment on pain intensity as a key outcome. METHODS: Three hundred fifty-two people with dementia and significant agitation from 60 nursing home units were included in this study. These units, representing 18 nursing homes in western Norway, were randomized to a stepwise protocol of treating pain (SPTP) or usual care. The SPTP group received acetaminophen, morphine, buprenorphine transdermal patch and pregabalin for 8 weeks, with a 4-week washout period. Medications were governed by the SPTP and each participant's existing prescriptions. We obtained pain intensity scores from 327 patients (intervention n = 164, control n = 163) at five time points assessed by the primary outcome measure, Mobilization-Observation-Behaviour-Intensity-Dementia-2 (MOBID-2) Pain Scale. The secondary outcome was activities of daily living (ADL). We used a linear intercept mixed model in a two-way repeated measures configuration to assess change over time and between groups. RESULTS: The SPTP conferred significant benefit in MOBID-2 scores compared with the control group [average treatment effect (ATE) -1.388; p < 0.001] at week 8, and MOBID-2 scores worsened during the washout period (ATE = -0.701; p = 0.022). Examining different analgesic treatments, benefit was conferred to patients receiving acetaminophen compared with the controls at week 2 (ATE = -0.663; p = 0.010), continuing to increase until week 8 (ATE = -1.297; p < 0.001). Although there were no overall improvements in ADL, an increase was seen in the group receiving acetaminophen (ATE = +1.0; p = 0.022). CONCLUSION: Pain medication significantly improved pain in the intervention group, with indications that acetaminophen also improved ADL function.

Influence of age, disease onset and ApoE4 on visual medial temporal lobe atrophy cut-offs.

BACKGROUND: Visual assessment of medial temporal lobe atrophy (MTA; range 0-4, from no atrophy to increasing atrophy of the choroid fissure, temporal horns and hippocampus) is a sensitive radiological marker of Alzheimer's disease (AD). One of the critical elements for visual MTA assessment is the cut-off score that determines deviation from normality. METHODS: In this study, we assessed the sensitivity and specificity of different MTA cut-off scores to classify control subjects, individuals with mild cognitive impairment (MCI) and AD patients from two large independent cohorts, AddNeuroMed and Alzheimer's Disease Neuroimaging Initiative. Of note, we evaluated the effects of clinical, demographic and genetic variables on the classification performance according to the different cut-offs. RESULTS: A cut-off of ≥1.5 based on the mean MTA scores of both hemispheres showed higher sensitivity in classifying patients with AD (84.5%) and MCI subjects (75.8%) who converted to dementia compared to an age-dependent cut-off. The age-dependent cut-off showed higher specificity or ability to correctly identify control subjects (83.2%) and those with MCI who remained stable (65.5%). Increasing age, early-onset disease and absence of the ApoE ε4 allele had a stronger influence on classifications using the ≥1.5 cut-off. Above 75 years of age, an alternative cut-off of ≥2.0 should be applied to achieve a classification accuracy for both patients with AD and control subjects that is clinically useful. CONCLUSION: Clinical, demographic and genetic variables can influence the classification of MTA cut-off scores, leading to misdiagnosis in some cases. These variables, in addition to the differential sensitivity and specificity of each cut-off, should be carefully considered when performing visual MTA assessment.

Multivariate classification of patients with Alzheimer's and dementia with Lewy bodies using high-dimensional cortical thickness measurements: an MRI surface-based morphometric study.

CONTEXT: Alzheimer's disease (AD) and dementia with Lewy bodies (DLB) are the most common neurodegenerative dementia types. It is important to differentiate between them because of the differences in prognosis and treatment approaches. OBJECTIVE: Investigate if sparse partial least squares (SPLS) classification of cortical thickness measurements could differentiate between AD and DLB. METHODS: Two independent cohorts without MR-protocol alignment in Norway and Slovenia with 97 AD and DLB subjects were enrolled. Cortical thickness measurements acquired with Freesurfer were used in subsequent SPLS classification runs. The cohorts were analyzed separately and afterwards combined. The models were trained with leave-one-out cross validation and test datasets where used when available. To study the impact of MR-protocol alignment, the classifiers were additionally tested on sets drawn exclusively from the independent cohorts. RESULTS: The obtained sensitivity/specificity/AUC values were 94.4/88.89/0.978 and 88.2/94.1/0.969 in the Norwegian and Slovenian cohorts, respectively. Both cohorts showed AD-associated pattern of thinning in mid-anterior temporal, occipital and subgenual cingulate cortex, whereas the pattern supportive for DLB included thinning in dorsal cingulate, posterior temporal and lateral orbitofrontal regions. When combining the cohorts, sensitivity/specificity/AUC were 82.1/85.7/0.948 for the training and 77.8/75/0.731 for the testing datasets with the same pattern-of-difference. The models tested on datasets drawn exclusively from the independent cohorts did not produce adequate accuracy. CONCLUSION: SPLS classification of cortical thickness is a good method for differentiating between AD and DLB, relatively stable even for mixed data, but not when tested on completely independent data drawn from different cohorts (without MR-protocol alignment).

White matter hyperintensities in mild lewy body dementia.

BACKGROUND: The objective of this study was to explore the load of white matter hyperintensities (WMH) in patients with Lewy body dementia (LBD) and compare to Alzheimer's disease (AD) and normal controls (NC). METHODS: Diagnosis of LBD and AD was made according to consensus criteria and cognitive tests were administered. MRI scans for 77 (61 AD and 16 LBD) patients and 37 healthy elderly control subjects were available for analysis. We segmented WMH from FLAIR images using an automatic thresholding technique and calculated the volume of WMH in several regions of the brain, using non-parametric tests to compare groups. Multivariate regression was applied. RESULTS: There were no significant differences in WMH between AD and LBD. We found a significant correlation between total and frontal WMH and Mini-Mental State Examination (MMSE) and verbal fluency scores in the AD group, but not in the LBD group. CONCLUSION: The WMH load in LBD was similar to that of AD. A correlation between WMH load and cognition was found in the AD group, but not in the LBD group, suggesting that vascular disease contributes to cognitive impairment in AD but not LBD.

Neuropsychiatric symptoms in mild dementia with lewy bodies and Alzheimer's disease.

BACKGROUND/AIMS: To compare neuropsychiatric symptoms in patients with Alzheimer's disease (AD) and dementia with Lewy bodies(DLB). METHODS: Neuropsychiatric symptoms and caregiver distress were assessed using the Neuropsychiatric Inventory (NPI) in mild DLB (n = 57) and AD (n = 126), and compared across the two groups using non-parametric tests. RESULTS: The DLB patients had a higher NPI totalscore (median 24 vs. 11.5, p < 0.005), more numerous symptoms (median 5 vs. 4, p = 0.001) and more clinically significant symptoms (3 vs. 1, p = 0.001). They also had higher item hallucinations (6 vs. 2, p < 0.005) and apathy (7 vs. 5, p = 0.002) subscores. Caregivers scored higher on the NPI total caregiver distress scale (12.5 vs. 6, p = 0.003). CONCLUSIONS: In mild dementia, DLB patients have more neuropsychiatric symptoms and more associated caregiver distress compared with AD.

Clinical trials of dementia with Lewy bodies and Parkinson's disease dementia.

Despite the frequency and importance of dementia associated with Parkinson's disease (PDD) and dementia with Lewy bodies (DLB), there is relatively little evidence on which to base treatment. Evidence from meta-analysis suggests that rivastigmine can improve cognition and functioning in PDD and also reduce risk of falling. There is also evidence supporting its use in DLB. Recent evidence suggests that memantine may also be effective, particularly for PDD, although evidence is more conflicting. Memantine may also improve parkinsonism and dyskinesias. Few clinical trials of cognition in PD without dementia exist, but there is preliminary evidence for atomoxetine, memantine, and piribedil. There is a lack of systematic evidence for the treatment of visual hallucinations and depression in PDD and DLB. In addition, there is a need for studies of whether potentially disease-modifying agents can prevent or delay the progression to dementia in PD.

Cerebrovascular diseases and depression: epidemiology, mechanisms and treatment.

Both cerebrovascular disease (CVD) and depression are common conditions in the elderly, and there is emerging evidence of a bi-directional relationship: 1) depression can cause CVD and stroke, transient ischemic attack; and 2) subcortical CVD are associated with increased risk for depression. The frequency of poststroke depression is highest during the first month after the stroke, but remains high even after several years. Depression is associated with poorer functional prognosis and higher mortality after stroke. There is good evidence that severity of functional impairment, high neuroticism, low social support as well as genetic factors are associated with an increased risk for post-stroke depression. Deep white matter lesions are the most consistent imaging correlate of depression. Potential mechanisms mediating the association between depression and CVD are neuroinflammation and HPA-axis activation, fronto-subcortical circuit lesions, and serotonergic dysfunction. Antidepressants have demonstrated effect on poststroke depression in meta-analyses, and such drugs as well as vitamin B can reduce the incidence of depression in stroke survivors. In addition, serotonergic drugs may strengthen poststroke motor and cognitive recovery, potentially through restorative mechanisms. Psychotherapeutic strategies such as problem-solving therapy seem to be effective. There is emerging evidence that treatment of cardiovascular disease and risk-factors can reduce the risk for late-life depression, but more studies are needed to test this hypothesis.

Age and diagnostic performance of Alzheimer disease CSF biomarkers.

OBJECTIVES: Core CSF changes in Alzheimer disease (AD) are decreased amyloid ß(1-42), increased total tau, and increased phospho-tau, probably indicating amyloid plaque accumulation, axonal degeneration, and tangle pathology, respectively. These biomarkers identify AD already at the predementia stage, but their diagnostic performance might be affected by age-dependent increase of AD-type brain pathology in cognitively unaffected elderly. METHODS: We investigated effects of age on the diagnostic performance of CSF biomarkers in a uniquely large multicenter study population, including a cross-sectional cohort of 529 patients with AD dementia (median age 71, range 43-89 years) and 304 controls (67, 44-91 years), and a longitudinal cohort of 750 subjects without dementia with mild cognitive impairment (69, 43-89 years) followed for at least 2 years, or until dementia diagnosis. RESULTS: The specificities for subjects without AD and the areas under the receiver operating characteristics curves decreased with age. However, the positive predictive value for a combination of biomarkers remained stable, while the negative predictive value decreased only slightly in old subjects, as an effect of the high AD prevalence in older ages. CONCLUSION: Although the diagnostic accuracies for AD decreased with age, the predictive values for a combination of biomarkers remained essentially stable. The findings highlight biomarker variability across ages, but support the use of CSF biomarkers for AD even in older populations.