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author:("marsland, Dag")
1.  Personality Changes after Deep Brain Stimulation in Parkinson's Disease 
Parkinson's Disease  2015;2015:490507.
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.
PMCID: PMC4325225
2.  Apolipoprotein E ε2 genotype delays onset of dementia with Lewy bodies in a Norwegian cohort 
Results conflict concerning the relevance of APOE alleles on the development of dementia with Lewy bodies (DLB), though they are well established in connection with Alzheimer's disease (AD). The role of APOE alleles in a Norwegian cohort of patients with DLB was therefore examined compared with patients with AD and healthy control individuals.
The study included 156 patients with DLB diagnosed according to the consensus criteria guidelines, 519 patients diagnosed with AD according to the National Institute of Neurological and Communicative Diseases and Stroke/Alzheimer's Disease and Related Disorders Association (NINCDS/ARDRA) criteria and 643 healthy elderly volunteers. Patients were recruited through hospitals, outpatient clinics, nursing homes or from local care authorities in central and south-western parts of Norway. Healthy individuals were recruited from caregivers and societies for retired people.
Subjects carrying an APOE ε2 allele had a reduced risk for developing DLB (OR 0.4, CI 0.3 to 0.8, p=0.004), and the onset of disease was delayed by 4 years (p=0.01, Mann–Whitney U test). Conversely, the APOE ε4 allele increased the risk for development of DLB (OR 5.9, CI 2.7 to 13.0, p<0.0005 for homozygotes). Similar results were found for patients with AD regarding the effect of APOE ε2, though the protective effect appeared to be slightly less pronounced than in DLB. This study is one of the largest regarding DLB and APOE to date.
The results indicate that APOE ε2, a protective factor in AD, has a clear beneficial effect on the development of DLB also.
PMCID: PMC4215279  PMID: 24639435
Dementia; Genetics; Alzheimer's disease
3.  Comorbidity profile in dementia with Lewy bodies versus Alzheimer’s disease: a linkage study between the Swedish Dementia Registry and the Swedish National Patient Registry 
Compared to Alzheimer’s disease (AD), dementia with Lewy bodies (DLB) is usually associated with a more complex clinical picture and higher burden of care. Yet, few investigations have been performed on comorbidities and risk factors of DLB. Therefore, we aimed to compare clinical risk factors and comorbidity profile in DLB and AD patients using two nationwide registries.
This is a linkage study between the Swedish dementia registry (SveDem) and the Swedish National Patient Registry conducted on 634 subjects with DLB and 9161 individuals with AD registered during the years 2007–2012. Comorbidity profile has been coded according to the International Classification of Diseases version 10 (ICD 10) in addition to the date of each event. The main chapters of the ICD-10, the Charlson score of comorbidities and a selected number of neuropsychiatric diseases were compared between the DLB and AD groups. Comorbidity was registered before and after the dementia diagnosis.
“Mental and behavioral disorders”, “diseases of the nervous system”, “diseases of the eye and adnexa”, diseases of the “circulatory”, “respiratory”, and “genitourinary” systems, “diseases of the skin and subcutaneous tissue” and “diseases of the musculoskeletal system and connective tissue” occurred more frequently in the DLB group after multivariate adjustment. Depression [adjusted OR = 2.12 (95%CI 1.49 to 3.03)] and migraine [adjusted OR = 3.65 (95%CI 1.48 to 9.0)] were more commonly recorded before the diagnosis of dementia in the DLB group. Following dementia diagnosis, ischemic stroke [adjusted OR = 1.89 (95%CI 1.21 to 2.96)] was more likely to happen among the DLB patients compared to the AD population.
Our study indicated a worse comorbidity profile in DLB patients with higher occurrence of depression, stroke and migraine compared with the AD group. Deeper knowledge about the underlying mechanisms of these associations is needed to explore possible reasons for the different pattern of comorbidity profile in DLB compared to AD and their prognostic significance.
PMCID: PMC4255539  PMID: 25478027
4.  A systematic review of cognitive decline in dementia with Lewy bodies versus Alzheimer’s disease 
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.
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.
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).
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.
PMCID: PMC4255525  PMID: 25478024
5.  Agitation in Dementia: Relation to Core Cerebrospinal Fluid Biomarker Levels 
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 Aβ1-42.
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 measured using the Cohen-Mansfield Agitation Inventory (CMAI; 46.5 ± 11.8 points).
Total CMAI correlated with T-tau [rs (31) = 0.36, p = 0.04] and P-tau [rs (31) = 0.35, p = 0.05] in patients with Alzheimer's disease (AD; n = 33) but not in the total dementia population (n = 95).
Our results suggest that tau-mediated pathology including neurofibrillary tangles and the intensity of the disease process might be associated with agitation in AD.
PMCID: PMC4176467  PMID: 25298777
Dementia; Agitation; CMAI; Cerebrospinal fluid (CSF); Dementia biomarkers; Neurofibrillary tangles; Behavioral and psychological symptoms in dementia (BPSD)
6.  Treatment effect of memantine on survival in dementia with Lewy bodies and Parkinson's disease with dementia: a prospective study 
BMJ Open  2014;4(7):e005158.
To investigate the effect on survival of treatment with memantine in patients with dementia with Lewy bodies (DLB) and Parkinson's disease with dementia (PDD).
75 patients with DLB and PDD were included in a prospective double-blinded randomised placebo-controlled trial (RCT) of memantine, of whom long-term follow-up was available for 42. Treatment response was recorded 24 weeks from baseline and measured by Clinical Global Impression of Change (CGIC). The participants were grouped as responders (CGIC 1–3) or non-responders (CGIC 4–7). The 24-week RCT was followed by open-label treatment and survival was recorded at 36 months.
After 36-month follow-up, patients in the memantine group had a longer length of survival compared with patients in the placebo group (log rank x²=4.02, p=0.045). Within the active treatment group, survival analysis 36 months from baseline showed that the memantine responders, based on CGIC, had higher rates of survival compared with the non-responders (log rank x²=6.595, p=0.010). Similar results were not seen in the placebo group.
Early treatment with memantine and a positive clinical response to memantine predicted longer survival in patients with DLB and PDD. This suggests a possible disease-modifying effect and also has implications for health economic analysis. However, owing to the small study sample, our results should merely be considered as generating a hypothesis which needs to be evaluated in larger studies.
Trial registration number
PMCID: PMC4091277  PMID: 24993765
7.  Dynamin1 concentration in the prefrontal cortex is associated with cognitive impairment in Lewy body dementia 
F1000Research  2014;3:108.
Dementia with Lewy Bodies (DLB) and Parkinson’s Disease Dementia (PDD) together, represent the second most common cause of dementia, after Alzheimer’s disease (AD). The synaptic dysfunctions underlying the cognitive decline and psychiatric symptoms observed throughout the development of PDD and DLB are still under investigation. In this study we examined the expression level of Dynamin1 and phospho-CaMKII, key proteins of endocytosis and synaptic plasticity respectively, as potential markers of molecular processes specifically deregulated with DLB and/or PDD. In order to measure the levels of these proteins, we isolated grey matter from post-mortem prefrontal cortex area (BA9), anterior cingulated gyrus (BA24) and parietal cortex (BA40) from DLB and PDD patients in comparison to age-matched controls and a group of AD cases. Clinical and pathological data available included the MMSE score, neuropsychiatric history, and semi-quantitative scores for AD pathology (plaques - tangles) and for α-synuclein (Lewy bodies).
Changes in the expression of the synaptic markers, and correlates with neuropathological features and cognitive decline were predominantly found in the prefrontal cortex. On one hand, levels of Dynamin1 were significantly reduced, and correlated with a higher rate of cognitive decline observed in cases from three dementia groups. On the other hand, the fraction of phospho-CaMKII was decreased, and correlated with a high score of plaques and tangles in BA9. Interestingly, the correlation between the rate of cognitive decline and the level of Dynamin1 remained when the analysis was restricted to the PDD and DLB cases, highlighting an association of Dynamin1 with cognitive decline in people with Lewy Body dementia.
PMCID: PMC4309165
Alzheimer’s disease; Dementia with Lewy bodies; Parkinson’s disease with dementia; synaptic dysfunction; vesicle recycling; synaptic plasticity; beta amyloid; tau; cognitive impairment
8.  Mapping Cortical Atrophy in Parkinson's Disease Patients with Dementia 
Cognitive impairment is very common in patients with Parkinson's disease (PD). Brain changes accompanying cognitive decline in PD are still not fully established.
We applied cortical pattern matching and cortical thickness analyses to the three-dimensional T1-weighted brain MRI scans of 14 age-matched cognitively normal elderly (NC), 12 cognitively normal PD (PDC), and 11 PD dementia (PDD) subjects. We used linear regression models to investigate the effect of diagnosis on cortical thickness. All maps were adjusted for multiple comparisons using permutation testing with a threshold p < 0.01.
PDD showed significantly thinner bilateral sensorimotor, perisylvian, lateral parietal, as well as right posterior cingulate, parieto-occipital, inferior temporal and lateral frontal cortices relative to NC (left pcorrected = 0.06, right pcorrected = 0.009). PDD showed significantly thinner bilateral sensorimotor, right frontal and right parietal-occipital cortices relative to PDC (right pcorrected = 0.05). The absolute difference in cortical thickness between PDD and the other diagnostic groups ranged from 3% to 19%.
Our data shows that cognitive decline in PD is associated with cortical atrophy. PDD subjects have the most widespread gray matter atrophy suggesting more cortical involvement as PD patients progress to dementia.
PMCID: PMC4018208  PMID: 23938313
Parkinson's disease; dementia; magnetic resonance imaging; MRI; brain atrophy; cortical atrophy; gray matter atrophy
9.  Grey Matter Changes in Cognitively Impaired Parkinson's Disease Patients 
PLoS ONE  2014;9(1):e85595.
Cortical changes associated with cognitive decline in Parkinson's disease (PD) are not fully explored and require investigations with established diagnostic classification criteria.
We used MRI source-based morphometry to evaluate specific differences in grey matter volume patterns across 4 groups of subjects: healthy controls (HC), PD with normal cognition (PD-NC), PD with mild cognitive impairment (MCI-PD) and PD with dementia (PDD).
We examined 151 consecutive subjects: 25 HC, 75 PD-NC, 29 MCI-PD, and 22 PDD at an Italian and Czech movement disorder centre. Operational diagnostic criteria were applied to classify MCI-PD and PDD. All structural MRI images were processed together in the Czech centre. The spatial independent component analysis was used to assess group differences of local grey matter volume.
We identified two independent patterns of grey matter volume deviations: a) Reductions in the hippocampus and temporal lobes; b) Decreases in fronto-parietal regions and increases in the midbrain/cerebellum. Both patterns differentiated PDD from all other groups and correlated with visuospatial deficits and letter verbal fluency, respectively. Only the second pattern additionally differentiated PD-NC from HC.
Grey matter changes in PDD involve areas associated with Alzheimer-like pathology while fronto-parietal abnormalities are possibly an early marker of PD cognitive decline. These findings are consistent with a non-linear cognitive progression in PD.
PMCID: PMC3897481  PMID: 24465612
10.  White matter integrity and cognition in Parkinson's disease: a cross-sectional study 
BMJ Open  2014;4(1):e003976.
We used diffusion tensor imaging (DTI) to test the following hypotheses: (1) there is decreased white matter (WM) integrity in non-demented Parkinson’s disease (PD), (2) WM integrity is differentially reduced in PD and early Alzheimer’s disease (AD) and (3) DTI changes in non-demented PD are specifically associated with cognitive performance.
This study included 18 non-demented patients with PD, 18 patients with mild cognitive impairment due to incipient AD and 19 healthy elderly normal control (NC) participants in a cross-sectional design. The participants underwent DTI, and tract-based spatial statistics was used to analyse and extract radial diffusivity and fractional anisotropy. Correlations between scores from a battery of neuropsychological tests and DTI were performed in the PD group.
Patients with PD had significant differences in DTI in WM underlying the temporal, parietal and occipital cortex as compared with NC. There were no significant differences between the PD and AD groups in the primary region of interest analyses, but compared with NC there was a tendency for more anterior changes in AD in contrast to more posterior changes in PD. In a secondary whole-brain analysis there were frontoparietal areas with significant differences between AD and PD. In patients with PD, there were significant correlations between DTI parameters in WM underlying the prefrontal cortex and executive and visuospatial abilities.
In early, non-demented PD we found reduced WM integrity underlying the temporal, parietal and occipital cortices. In addition, WM integrity changes in prefrontal areas were associated with executive and visuospatial ability. These findings support that DTI may be an important biomarker in early PD, and that WM changes are related to cognitive impairment in PD.
PMCID: PMC3902504  PMID: 24448846
11.  Large-scale resting state network correlates of cognitive impairment in Parkinson's disease and related dopaminergic deficits 
Cognitive impairment is a common non-motor feature of Parkinson's disease (PD). Understanding the neural mechanisms of this deficit is crucial for the development of efficient methods for treatment monitoring and augmentation of cognitive functions in PD patients. The current study aimed to investigate resting state fMRI correlates of cognitive impairment in PD from a large-scale network perspective, and to assess the impact of dopamine deficiency on these networks. Thirty PD patients with resting state fMRI were included from the Parkinson's Progression Marker Initiative (PPMI) database. Eighteen patients from this sample were also scanned with 123I-FP-CIT SPECT. A standardized neuropsychological battery was administered, evaluating verbal memory, visuospatial, and executive cognitive domains. Image preprocessing was performed using an SPM8-based workflow, obtaining time-series from 90 regions-of-interest (ROIs) defined from the AAL brain atlas. The Brain Connectivity Toolbox (BCT) was used to extract nodal strength from all ROIs, and modularity of the cognitive circuitry determined using the meta-analytical software Neurosynth. Brain-behavior covariance patterns between cognitive functions and nodal strength were estimated using Partial Least Squares. Extracted latent variable (LV) scores were matched with the performances in the three cognitive domains (memory, visuospatial, and executive) and striatal dopamine transporter binding ratios (SBR) using linear modeling. Finally, influence of nigrostriatal dopaminergic deficiency on the modularity of the “cognitive network” was analyzed. For the range of deficits studied, better executive performance was associated with increased dorsal fronto-parietal cortical processing and inhibited subcortical and primary sensory involvement. This profile was also characterized by a relative preservation of nigrostriatal dopaminergic function. The profile associated with better memory performance correlated with increased prefronto-limbic processing, and was not associated with presynaptic striatal dopamine uptake. SBR ratios were negatively correlated with modularity of the “cognitive network,” suggesting integrative effects of the preserved nigrostriatal dopamine system on this circuitry.
PMCID: PMC3982053  PMID: 24765065
parkinson's disease; cognition; dopamine; resting state fMRI; SPECT; graph theory; nodal strength; modularity
12.  Comparing Clinical Profiles in Alzheimer's Disease and Parkinson's Disease Dementia 
Greater understanding of differences in baseline impairment and disease progression in patients with Alzheimer's disease (AD) and Parkinson's disease dementia (PDD) may improve the interpretation of drug effects and the design of future studies.
This was a retrospective analysis of three randomized, double-blind rivastigmine databases (one in PDD, two in AD). Impairment on the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog), Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) scale, 10-item Neuropsychiatric Inventory (NPI-10) and the ADCS-Clinical Global Impression of Change (CGIC) was compared [standardized difference (Cohen's d), similar if <0.1].
Patients with AD or PDD had similar levels of impairment on the ADAS-cog and NPI-10. Scores on the ADCS-ADL scale (standardized difference = 0.47) and the ADAS-cog memory domain (total, 0.33; items, 0.10-0.58) were higher in AD; PDD patients were more impaired in the language (0.23) and praxis (0.34) domains. AD patients receiving placebo showed greater deterioration on the ADAS-cog (0.14) and improvement on the NPI-10 (0.11) compared with patients with PDD.
Differing patterns of impairment occur in AD and PDD.
PMCID: PMC3808221  PMID: 24174923
Alzheimer's disease; Parkinson's disease dementia; Rivastigmine; Alzheimer's Disease Assessment Scale–cognitive subscale; Alzheimer's Disease Cooperative Study–Activities of Daily Living scale; 10-item Neuropsychiatric Inventory; Alzheimer's Disease Cooperative Study–Clinical Global Impression of Change

13.  Correlates of Subjective and Mild Cognitive Impairment: Depressive Symptoms and CSF Biomarkers 
To improve early diagnosis of dementia disease, this study investigates correlates of cognitive complaints and cognitive test performance in patients with subjective (SCI) and mild (MCI) cognitive impairment.
Seventy patients from a memory clinic, aged 45-79, with a score of 2 (n = 23) or 3 (n = 47) on the Global Deterioration Scale, were included. CSF biomarkers [Aβ42, total tau (T-tau) and phosphorylated tau (P-tau)], depressive symptoms, cognitive performance, and complaints were examined.
Correlation analysis showed that cognitive complaints increased with decreasing cognitive performance in SCI and decreased with decreasing performance in MCI. Linear regression models revealed that cognitive complaints were associated with depressive symptoms in both groups of patients, while cognitive performance was associated with CSF Aβ42 and P-tau in SCI and with T-tau and P-tau in MCI.
These results suggest that depressive symptoms are associated with cognitive complaints, while degenerative changes are associated with objective cognitive decline in high-risk predementia states.
PMCID: PMC3808228  PMID: 24174924
Mild cognitive impairment; Subjective cognitive impairment; Cognitive complaints; Depression; CSF biomarkers; Degenerative diseases

15.  Comparing hippocampal atrophy in Alzheimer's dementia and Dementia with Lewy Bodies 
Dementia with Lewy Bodies (DLB) and Alzheimer's disease (AD) are the two most common neurodegenerative dementias. During the early stages, clinical distinction between them is often challenging. Our objective is to compare hippocampal atrophy patterns in mild AD and mild DLB. We hypothesized that DLB subjects have milder hippocampal atrophy relative to AD subjects.
We analyzed the T1-weighted magnetic resonance imaging data from 113 subjects: 55 AD, 16 DLB and 42 cognitively normal elderly (NC). Using the hippocampal radial distance technique and multiple linear regression, we analyzed the effect of clinical diagnosis on hippocampal radial distance, while adjusting for gender and age. 3D statistical maps were adjusted for multiple comparisons using permutation-based statistics with a threshold of p<0.01.
Compared to NC, AD exhibited significantly greater atrophy in the Cornu Ammonis (CA) 1, CA2-3 and subicular regions bilaterally while DLB showed left-predominant atrophy in the CA1 region and subiculum. AD and DLB directly compared did not reveal statistically significant differences.
Hippocampal atrophy, while present in mildly impaired DLB subjects, is less severe than atrophy seen in mildly impaired AD subjects, when compared to NC. Both groups show predominant atrophy of the CA1 subfield and subiculum.
PMCID: PMC3470878  PMID: 22922563
Alzheimer's disease; Dementia with Lewy Bodies; hippocampus; MRI; atrophy
16.  Demography, diagnostics, and medication in dementia with Lewy bodies and Parkinson’s disease with dementia: data from the Swedish Dementia Quality Registry (SveDem) 
Whether dementia with Lewy bodies (DLB) and Parkinson’s disease with dementia (PDD) should be considered as one entity or two distinct conditions is a matter of controversy. The aim of this study was to compare the characteristics of DLB and PDD patients using data from the Swedish Dementia Quality Registry (SveDem).
SveDem is a national Web-based quality registry initiated to improve the quality of diagnostic workup, treatment, and care of patients with dementia across Sweden. Patients with newly diagnosed dementia of various types were registered in SveDem during the years 2007–2011. The current cross-sectional report is based on DLB (n = 487) and PDD (n = 297) patients. Demographic characteristics, diagnostic workup, Mini-Mental State Examination (MMSE) score, and medications were compared between DLB and PDD groups.
No gender differences were observed between the two study groups (P = 0.706). PDD patients were significantly younger than DLB patients at the time of diagnosis (74.8 versus 76.8 years, respectively; P < 0.001). A significantly higher prevalence of patients with MMSE score ≤24 were found in the PDD group (75.2% versus 67.6%; P = 0.030). The mean number of performed diagnostic modalities was significantly higher in the DLB group (4.9 ± 1.7) than in the PDD group (4.1 ± 1.6; P < 0.001). DLB patients were more likely than PDD patients to be treated with cholinesterase inhibitors (odds ratio = 2.5, 95% confidence interval = 1.8–3.5), whereas the use of memantine, antidepressants, and antipsychotics did not differ between the groups.
This study demonstrates several differences in the dementia work-up between DLB and PDD. The onset of dementia was significantly earlier in PDD, while treatment with cholinesterase inhibitors was more common in DLB patients. Severe cognitive impairment (MMSE score ≤24) was more frequent in the PDD group, whereas more diagnostic tests were used to confirm a DLB diagnosis. Some similarities also were found, such as gender distribution and use of memantine, antidepressants, and antipsychotics drugs. Further follow-up cost-effectiveness studies are needed to provide more evidence for workup and treatment guidelines of DLB and PDD.
PMCID: PMC3700781  PMID: 23847419
dementia with Lewy bodies; Parkinson’s disease with dementia; age; diagnostic approach; medication; Mini-Mental State Examination
17.  Relationship between Orthostatic Hypotension and White Matter Hyperintensity Load in Older Patients with Mild Dementia 
PLoS ONE  2012;7(12):e52196.
White matter hyperintensities (WMH) in magnetic resonance imaging (MRI) scans of the brain, and orthostatic hypotension (OH) are both common in older people. We tested the hypothesis that OH is associated with WMH.
Cross-sectional study.
Secondary care outpatient clinics in geriatric medicine and old age psychiatry in western Norway.
160 older patients with mild dementia, diagnosed according to standardised criteria.
OH was diagnosed according to the consensus definition, measuring blood pressure (BP) in the supine position and within 3 minutes in the standing position. MRI scans were performed according to a common protocol at three centres, and the volumes of WMH were quantified using an automated method (n = 82), followed by manual editing. WMH were also quantified using the visual Scheltens scale (n = 139). Multiple logistic regression analyses were applied, with highest vs. lowest WMH quartile as response.
There were no significant correlations between WMH volumes and systolic or diastolic orthostatic BP drops, and no significant correlations between Scheltens scores of WMH and systolic or diastolic BP drops. In the multivariate analyses, only APOEε4 status remained a significant predictor for WMH using the automated method (p = 0.037, OR 0.075 (0.007–0.851)), whereas only age remained a significant predictor for WMH scores (p = 0.019, OR 1.119 (1.018–1.230)).
We found no association between OH and WMH load in a sample of older patients with mild dementia.
PMCID: PMC3526570  PMID: 23284932
18.  The Impact of Autonomic Dysfunction on Survival in Patients with Dementia with Lewy Bodies and Parkinson's Disease with Dementia 
PLoS ONE  2012;7(10):e45451.
Autonomic dysfunction is a well-known feature in neurodegenerative dementias, especially common in α-synucleinopathies like dementia with Lewy bodies and Parkinson's disease with dementia. The most common symptoms are orthostatic hypotension, incontinence and constipation, but its relevance in clinical practice is poorly understood. There are no earlier studies addressing the influence of autonomic dysfunction on clinical course and survival. The aim of this study was to investigate the frequency of the three most common features of autonomic dysfunction and analyze how it affects survival.
Thirty patients with dementia with Lewy bodies and Parkinson's disease with dementia were included in this prospective, longitudinal follow-up study. Presence of incontinence and constipation was recorded at baseline. Blood pressure was measured at baseline, after 3 months and after 6 months according to standardized procedures, with 5 measurements during 10 minutes after rising. Orthostatic hypotension was defined using consensus definitions and persistent orthostatic hypotension was defined as 5 or more measurements with orthostatic hypotension. Difference in survival was analyzed 36 months after baseline.
There was a high frequency of persistent orthostatic blood pressure (50%), constipation (30%) and incontinence (30%). Patients with persistent orthostatic hypotension had a significantly shorter survival compared to those with no or non-persistent orthostatic hypotension (Log rank x2 = 4.47, p = 0.034). Patients with constipation and/or urinary incontinence, in addition to persistent orthostatic hypotension, had a poorer prognosis compared to those with isolated persistent orthostatic hypotension or no orthostatic hypotension (Log rank x2 = 6.370, p = 0.041).
According to our findings, the identification of autonomic dysfunction seems to be of great importance in clinical practice, not only to avoid falls and other complications, but also as a possible predictor of survival.
PMCID: PMC3462171  PMID: 23049679
20.  Optimised Anaesthesia to Reduce Post Operative Cognitive Decline (POCD) in Older Patients Undergoing Elective Surgery, a Randomised Controlled Trial 
PLoS ONE  2012;7(6):e37410.
The study determined the one year incidence of post operative cognitive decline (POCD) and evaluated the effectiveness of an intra-operative anaesthetic intervention in reducing post-operative cognitive impairment in older adults (over 60 years of age) undergoing elective orthopaedic or abdominal surgery.
Methods and Trial Design
The design was a prospective cohort study with a nested randomised, controlled intervention trial, using intra-operative BiSpectral index and cerebral oxygen saturation monitoring to enable optimisation of anaesthesia depth and cerebral oxygen saturation in older adults undergoing surgery.
In the 52 week prospective cohort study (192 surgical patients and 138 controls), mild (χ2 = 17.9 p<0.0001), moderate (χ2 = 7.8 p = 0.005) and severe (χ2 = 5.1 p = 0.02) POCD were all significantly higher after 52 weeks in the surgical patients than among the age matched controls. In the nested RCT, 81 patients were randomized, 73 contributing to the data analysis (34 intervention, 39 control). In the intervention group mild POCD was significantly reduced at 1, 12 and 52 weeks (Fisher’s Exact Test p = 0.018, χ2 = 5.1 p = 0.02 and χ2 = 5.9 p = 0.015), and moderate POCD was reduced at 1 and 52 weeks (χ2 = 4.4 p = 0·037 and χ2 = 5.4 p = 0.02). In addition there was significant improvement in reaction time at all time-points (Vigilance Reaction Time MWU Z =  −2.1 p = 0.03, MWU Z = −2.7 p = 0.004, MWU Z = −3.0 p = 0.005), in MMSE at one and 52 weeks (MWU Z = −2.9 p = 0.003, MWU Z = −3.3 p = 0.001), and in executive function at 12 and 52 weeks (Trail Making MWU Z = −2.4 p = .0.018, MWU Z = −2.4 p = 0.019).
POCD is common and persistent in older adults following surgery. The results of the nested RCT indicate the potential benefits of intra-operative monitoring of anaesthetic depth and cerebral oxygenation as a pragmatic intervention to reduce post-operative cognitive impairment.
Trial Registration ISRCTN39503939
PMCID: PMC3376123  PMID: 22719840
21.  White Matter Hyperintensities and the Course of Depressive Symptoms in Elderly People with Mild Dementia 
To explore the relationship between white matter hyperintensities (WMH) and the prevalence and course of depressive symptoms in mild Alzheimer's disease (AD) and Lewy body dementia. Design: This is a prospective cohort study conducted in secondary care outpatient clinics in western Norway. Subjects: The study population consisted of 77 elderly people with mild dementia diagnosed according to standardised criteria.
Structured clinical interviews and physical, neurological, psychiatric, and neuropsychological examinations were performed and routine blood tests were taken. Depression was assessed using the depression subitem of the Neuropsychiatric Inventory and the Montgomery-Åsberg Depression Rating Scale (MADRS). A standardised protocol for magnetic resonance imaging scan was used, and the volumes of WMH were quantified using an automated method, followed by manual editing.
The volumes of total and frontal deep WMH were significantly and positively correlated with baseline severity of depressive symptoms, and depressed patients had significantly higher volumes of total and frontal deep WMH than non-depressed patients. Higher volumes of WMH were also associated with having a high MADRS score and incident and persistent depression at follow-up. After adjustment for potential confounders, frontal deep WMH, in addition to prior depression and non-AD dementia, were still significantly associated with baseline depressive symptoms (p = 0.015, OR 3.703, 95% CI 1.294–10.593). Similar results emerged for total WMH.
In elderly people with mild dementia, volumes of WMH, in particular frontal deep WMH, were positively correlated with baseline severity of depressive symptoms, and seemed to be associated with persistent and incident depression at follow-up. Further studies of the mechanisms that determine the course of depression in mild dementia are needed.
PMCID: PMC3347877  PMID: 22590471
White matter hyperintensities; Depression; Depressive symptoms; Dementia; Elderly people
22.  Nonmotor Symptoms of Parkinson's Disease 
Parkinson's Disease  2012;2011:351461.
PMCID: PMC3324917  PMID: 22548200
23.  Cerebrospinal Fluid Alzheimer Markers in Depressed Elderly Subjects with and without Alzheimer's Disease 
The aim of this study was to explore the relationship between cerebrospinal fluid Alzheimer's disease (AD) markers and depression in elderly people.
We included subjects with AD as well as persons with subjective cognitive impairment and normal cognition. Depression was assessed with the Cornell Scale for Depression in Dementia, and a cut-off score of >6 was used to define depression. Cerebrospinal fluid was analyzed using commercially available assays for β-amyloid 1–42, total tau, and phosphorylated tau 181.
A total of 183 participants (66.7% female) were included (92 with AD and 91 with subjective cognitive impairment), with a mean age (±SD) of 67.6 ± 7.4 years, a Mini-Mental State Examination score of 26.0 ± 4.0, and a median Cornell Scale for Depression in Dementia score of 5 (range 0–19). Depression scores were not associated with higher phosphorylated tau 181 and total tau or reduced β-amyloid 1–42 in AD or non-demented subjects.
These results suggest that AD pathology does not contribute to depression, indicating that other factors may be more important. Further studies of the aetiology of depression in elderly people with and without AD are warranted.
PMCID: PMC3359911  PMID: 22649429
Depression; Elderly; Alzheimer's disease; Cerebrospinal fluid; β-Amyloid 1–24; Total tau; Phosphorylated tau
24.  Cognitive Profile of Elderly Patients with Mild Stroke 
A pattern characterizing cognitive deficits in mild stroke could help in differential diagnosis and rehabilitation planning.
Fifty patients with mild stroke (modified Rankin scale ≤2 at discharge) aged >60 years were given the Mini Mental State Examination (MMSE), the Hopkins Verbal Learning Test-Revised (HVLT-R) and the Stroop test.
On HVLT-R, significant impairments were found in learning and recall, but not in delayed recall. The Stroop test revealed significant impairments in reading speed, but not in color-word interference. Using the MMSE, significant deficits were only found in the youngest age group.
Elderly patients with mild stroke show deficits in verbal learning/recall and in reading speed, but not in the MMSE, delayed recall or color-word interference. The deficits are consistent with a mild-to-moderate brain dysfunction, with relative sparing of medial brain structures.
PMCID: PMC3243639  PMID: 22187548
Color-word interference; Learning; Memory; Mental state; Mild stroke
25.  Cerebrospinal Fluid Levels of sAPPα and sAPPβ in Lewy Body and Alzheimer's Disease: Clinical and Neurochemical Correlates 
We measured cerebrospinal fluid (CSF) levels of the soluble isoforms of amyloid precursor protein (APP; sAPPα sAPPβ) and other CSF biomarkers in 107 patients with Alzheimer's disease (AD), dementia with Lewy body dementia (DLB), Parkinson's disease dementia (PDD), and normal controls (NC) using commercial kits. DLB and PDD were combined in a Lewy body dementia group (LBD). No differences were observed in sAPPα and sAPPβ levels between the groups. Significant correlations were observed between sAPPα and sAPPβ and between sAPPβ and Mini-Mental State Examination scores in the total group analysis as well as when LBD and AD groups were analyzed separately. sAPPα and sAPPβ levels correlated with Aβ38, Aβ40, Aβ42, and Tau in the LBD group. In AD, sAPPα correlated with p-Tau and sAPPβ with Aβ40. The differential association between sAPPα and sAPPβ with Aβ and Tau species between LBD and AD groups suggests a possible relationship with the underlying pathologies in LBD and AD.
PMCID: PMC3182340  PMID: 21966597

Results 1-25 (32)