[Show abstract][Hide abstract] ABSTRACT: 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.Molecular Psychiatry advance online publication, 17 February 2015; doi:10.1038/mp.2015.6.
[Show abstract][Hide abstract] ABSTRACT: Objectives. Deep brain stimulation of the subthalamic nucleus (STN-DBS) is a recognized therapy that improves motor symptoms in advanced Parkinson's disease (PD). However, little is known about its impact on personality. To address this topic, we have assessed personality traits before and after STN-DBS in PD patients. Methods. Forty patients with advanced PD were assessed with the Temperament and Character Inventory (TCI): the Urgency, Premeditation, Perseverance, Sensation Seeking impulsive behaviour scale (UPPS), and the Neuroticism and Lie subscales of the Eysenck Personality Questionnaire (EPQ-N, EPQ-L) before surgery and after three months of STN-DBS. Collateral information obtained from the UPPS was also reported. Results. Despite improvement in motor function and reduction in dopaminergic dosage patients reported lower score on the TCI Persistence and Self-Transcendence scales, after three months of STN-DBS, compared to baseline (P = 0.006; P = 0.024). Relatives reported significantly increased scores on the UPPS Lack of Premeditation scale at follow-up (P = 0.027). Conclusion. STN-DBS in PD patients is associated with personality changes in the direction of increased impulsivity.
[Show abstract][Hide abstract] ABSTRACT: Objective: Knowledge of the cognitive performance associated with REM sleep behavior disorder (RBD) in newly diagnosed Parkinson disease (PD) patients is limited. We thus wanted to explore 1) the frequency of RBD in patients with PD at a relatively early stage and 2) cognitive performance associated with RBD in PD. We hypothesized that RBD would be associated with cognitive impairment in PD. Methods: 29 non-demented patients recently diagnosed with PD (disease duration<5 years, Hoehn and Yahr stage <2.5 and no dementia) were recruited. The diagnosis of PD was supported by dopamine transporter SPECT. RBD was diagnosed based on standardized clinical interview and confirmed by polysomnography. Overall cognition was assessed by screening tests including the Mini-Mental State Examination (MMSE), and neuropsychological tests of memory, language, executive, attentional and visuospatial functions tests were performed. Results: 13 patients (45%) had probable RBD. There were no significant differences between PD with and without RBD in any of the neuropsychological tests, but a numerically lower performance was observed in the PD RBD group on memory tests Conclusions: RBD is common even in early PD without dementia, but was not found to be associated significantly with cognition.
Journal of Alzheimers Disease & Parkinsonism. 12/2014;
[Show abstract][Hide abstract] ABSTRACT: Alzheimer disease (AD) and Parkinson disease (PD) are the most common neurodegenerative disorders. For both diseases, early intervention is thought to be essential to the success of disease-modifying treatments. Cerebrospinal fluid (CSF) can reflect some of the pathophysiological changes that occur in the brain, and the number of CSF biomarkers under investigation in neurodegenerative conditions has grown rapidly in the past 20 years. In AD, CSF biomarkers are increasingly being used in clinical practice, and have been incorporated into the majority of clinical trials to demonstrate target engagement, to enrich or stratify patient groups, and to find evidence of disease modification. In PD, CSF biomarkers have not yet reached the clinic, but are being studied in patients with parkinsonism, and are being used in clinical trials either to monitor progression or to demonstrate target engagement and downstream effects of drugs. CSF biomarkers might also serve as surrogate markers of clinical benefit after a specific therapeutic intervention, although additional data are required. It is anticipated that CSF biomarkers will have an important role in trials aimed at disease modification in the near future. In this Review, we provide an overview of CSF biomarkers in AD and PD, and discuss their role in clinical trials.
[Show abstract][Hide abstract] ABSTRACT: Objectives: To find the frequency of probable REM sleep behavior disorder (RBD) in mild dementia with Lewybodies (DLB) as compared with mild Alzheimer’s dementia (AD).
Method: A well validated sleep questionnaire, The Mayo Sleep Questionnaire (MSQ), was administered to the bed partners and caregivers of patients included in the dementia study of western Norway (Dem-West-study). The questionnaire includes screening questions to detect REM sleep behavior disorder (RBD) and other sleep disturbances. DLB was diagnosed according to the revised consensus criteria which includes RBD as a diagnostic criterion for DLB.
Results: A total of 83 (37, 6%) persons were diagnosed with DLB and 138 (62.4%) persons were diagnosed with AD and were included in this study. Mean age in DLB was 77.0 years (7.2) and in AD 75.5 years (7.8), p=0.260 and mean MMSE scores were 23.0 (3.2) in DLB and 23.8 (2.2) in AD, p=0.028. Sleep partners confirmed probable RBD in 40 % of participants diagnosed with DLB and in 9 % of participants diagnosed with AD. The average duration of RBD symptoms among participants diagnosed with DLB was 6.2 years (SD=7.7) and 4.6 years (SD=4.0) in AD, p=0.583. Two DLB patients and three bed partners were seriously injured under RBD episodes. Twenty patients reported vivid or violent dreams: 16 (55.2%) with DLB and 4 (22.2%) with AD and, p=0.066.
Conclusion: Probable RBD is frequently reported from bed partners of persons diagnosed clinically with mild DLB applying the MAYO sleep questionnaire (MSQ). Probable RBD was also reported in persons diagnosed clinically with AD. Probable RBD is potentially harmful for patients and bed partners in mild dementia. Circularity must be considered in this study as RBD was also part of the diagnostic criteria for DLB.
Non-Motor Dysfunctions in Parkinson's Disease and Related Disorders, Niece, France; 12/2014
[Show abstract][Hide abstract] ABSTRACT: 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.ResultsSubjects 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.
[Show abstract][Hide abstract] ABSTRACT: Introduction: The aim of this review was to investigate whether there is a faster cognitive decline in dementia with Lewy bodies (DLB) than in Alzheimer's disease (AD) over time. Methods: PsycINFO and Medline were searched from 1946 to February 2013. A quality rating from 1 to 15 (best) was applied to the included studies. A quantitative meta-analysis was done on studies with mini mental state examination (MMSE) as the outcome measure. Results: A total of 18 studies were included. Of these, six (36%) reported significant differences in the rate of cognitive decline. Three studies reported a faster cognitive decline on MMSE in patients with mixed DLB and AD compared to pure forms, whereas two studies reported a faster decline on delayed recall and recognition in AD and one in DLB on verbal fluency. Mean quality scores for studies that did or did not differ were not significantly different. Six studies reported MMSE scores and were included in the meta-analysis, which showed no significant difference in annual decline on MMSE between DLB (mean 3.4) and AD (mean 3.3). Conclusions: Our findings do not support the hypothesis of a faster rate of cognitive decline in DLB compared to AD. Future studies should apply recent diagnostic criteria, as well as extensive diagnostic evaluation and ideally autopsy diagnosis. Studies with large enough samples, detailed cognitive tests, at least two years follow up and multivariate statistical analysis are also needed.
Alzheimer's Research and Therapy 09/2014; · 3.50 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Dementia is characterized by a progressive cognitive decline and neuropsychiatric symptoms (NPSD) such as agitation, apathy and sleeping problems. There is some evidence of activation of inflammatory pathways in the brain in dementia, but little research has been performed regarding the role of neuroinflammation in NPSD, which might represent a potential novel target for treatment. The aim of this study was to examine the possible association between NPSD and cerebrospinal fluid (CSF) levels of the cytokines IL-6, TNF-α and IL-10, and the cytokine receptor sIL-1RII, in patients with dementia and NPSD. Ninety-four patients (mean age 79±8; 67% female) with a score on the Neuropsychiatric Inventory (NPI) ≥ 10 points, were included. Clinical assessment included administration of NPI, the Mini-Mental State Examination (MMSE) and the Cohen-Mansfield Agitation Inventory (CMAI). The cytokine levels in CSF samples were analysed by enzyme-linked immunosorbent assay. Correlations were statistically examined using Spearman's rank correlation coefficient (r), and simple- and multiple linear regression. The anti-inflammatory cytokine IL-10 showed reverse correlations with total NPI score (NPI-total=-0.001, t(90)= 8.50, p=0.004) and NPI sub-items agitation (Agitation=-0.007, t(90)=7.02, p=0.009) and night-time behaviour (Night time behaviour=-0.006, t(90)=6.34, p=0.01). There was a trend towards correlation between IL-10 and depression (Depression=-0.004, t(90)=2.96, p=0.09). Also, the soluble cytokine receptor sIL-1RII showed a trend towards correlation with apathy (Apathy=0.82, t(82)=3.62, p=0.06). The levels of IL-6 showed no significant correlations with NPSD. Levels of TNF-α were non-detectable. In Alzheimer's disease (AD) subjects (n=33), IL-6 showed reverse correlation with anxiety (r=-0.35, p=0.049). In mixed AD subjects (n=26), IL-10 showed reverse correlations with the total NPI score (r=-0.46, p=0.02) and depression (r=-0.45, p=0.02). The findings indicate a relationship between neuroinflammation and neuropsychiatric symptoms in AD in which anti-inflammatory signalling by IL-10 is beneficial from a mental health perspective.
Brain Research Bulletin 09/2014; · 2.97 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Pain is common in people with dementia, representing a critical aspect of treatment and care. However, there remain considerable gaps in evidence to support pain assessment and treatment.
British Medical Bulletin 09/2014; 111(1):139-48. · 4.36 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background: The objective of this study was to examine the associations of agitation with the cerebrospinal fluid dementia biomarkers total-tau (T-tau), phosphorylated-tau (P-tau) and Aβ 1–42 . Methods: One hundred patients (mean age ± SD, 78.6 ± 7.5 years) with dementia and neuropsychiatric symptoms, of whom 67% were female, were included. Agitation was mea-sured using the Cohen-Mansfield Agitation Inventory (CMAI; 46.5 ± 11.8 points). Results: To-tal CMAI correlated with T-tau [r s (31) = 0.36, p = 0.04] and P-tau [r s (31) = 0.35, p = 0.05] in patients with Alzheimer's disease (AD; n = 33) but not in the total dementia population (n = 95). Conclusions: Our results suggest that tau-mediated pathology including neurofibrillary tangles and the intensity of the disease process might be associated with agitation in AD. This is an Open Access article licensed under the terms of the Creative Commons Attribution-NonCommercial 3.0 Unported license (CC BY-NC) (www.karger.com/OA-license), applicable to the online version of the article only. Distribution permitted for non-commercial purposes only.
Dementia and geriatric cognitive disorders extra. 08/2014; 4(2).
This article is viewable in ResearchGate's enriched format
RG Format enables you to read in context with side-by-side figures, citations, and feedback from experts in your field.
[Show abstract][Hide abstract] ABSTRACT: Dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD) are characterised by the presence of α-synuclein-containing Lewy bodies and Lewy neurites. However, both dementias also show variable degrees of Alzheimer's disease (AD) pathology (senile plaques and neurofibrillary tangles), particularly in areas of the cortex associated with higher cognitive functions. This study investigates the contribution of the individual and combined pathologies in determining the rate of cognitive decline. Cortical α-synuclein, phosphorylated-tau (phosphotau) and Aβ plaque pathology in 34 PDD and 55 DLB patients was assessed semi-quantitatively in four regions of the neocortex. The decline in cognition, assessed by Mini Mental State Examination, correlated positively with the cortical α-synuclein load. Patients also had varying degrees of senile Aβ plaque and phosphotau pathology. Regression analyses pointed to a combined pathology (Aβ plaque plus phosphotau plus α-synuclein positive features), particularly in the prefrontal cortex (BA9) and temporal lobe neocortex with the superior and middle temporal gyrus (BA 21, 22), being a major determining factor in the development of dementia. Thus, cognitive decline in Lewy body dementias is not a consequence of α-synuclein induced neurodegeneration alone but senile plaque and phosphorylated tau pathology also contribute to the overall deficits.
[Show abstract][Hide abstract] ABSTRACT: The loss of zinc transporter 3 (ZnT3) has been implicated in age-related cognitive decline in mice, and the protein has been associated with plaques. We investigated the levels of ZnT3 and postsynaptic density protein 95 (PSD95), a marker of the postsynaptic terminal, in people with Parkinson's disease dementia (PDD, n = 31), dementia with Lewy bodies (DLB, n = 44), Alzheimer's disease (AD, n = 16), and controls (n = 24), using semiquantitative western blotting and immunohistochemistry in 3 cortical regions. Standardized cognitive assessments during life and semiquantitative scoring of amyloid β (Aβ), tau, and α-synuclein at postmortem were used to investigate the relationship between ZnT3 and PSD95, cognition and pathology. Associations were observed between ZnT3 and PSD95 levels in prefrontal cortex and cognitive impairment (p = 0.001 and p = 0.002, respectively) and between ZnT3 levels in the parietal cortex and cognitive impairment (p = 0.036). Associations were also seen between ZnT3 levels in cingulate cortex and severity of Aβ (p = 0.003) and tau (p = 0.011) pathologies. DLB and PDD were characterized by significant reductions of PSD95 (p < 0.05) and ZnT3 (p < 0.001) in prefrontal cortex compared with controls and AD. PSD95 levels in the parietal cortex were found to be decreased in AD cases compared with controls (p = 0.02) and PDD (p = 0.005). This study has identified Zn(2+) modulation as a possible novel target for the treatment of cognitive impairment in DLB and PDD and the potential for synaptic proteins to be used as a biomarker for the differentiation of DLB and PDD from AD.
Neurobiology of Aging 06/2014; · 4.85 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: DLB (Trønder-Brain) DLB (DemVest) AD (TrønderBrain) Healthy Controls (Trønder-Brain) Cases (Total) 156 103 53 519 643 Probable/Possible DLB 135/21 88/15 47/6 Objective To examine the role of APOE alleles in a Norwegian cohort of patients with dementia with Lewy bodies (DLB), compared to patients with Alzheimer's disease (AD) and healthy control individuals.
The International Parkinson and Movement Disorder Society’s 18th International Congress of Parkinson's Disease and Movement Disorders, Stockholm; 06/2014