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Alterations in cerebral perfusion is increasingly considered to play a crucial role in Alzheimer’s disease (AD) and together with accumulated amyloid-β, deficiencies in the brain microvascular circulation may result in local hypoxia. Here, we studied alterations in cerebral circulation and the correlation between amyloid-β load and cerebral perfusion in prodromal AD (pAD). Using dynamic susceptibility contrast MRI and PET, we evaluated cerebral perfusion and amyloid-β levels in 19 individuals with mild cognitive impairment (MCI) and high amyloid-β load (pAD-MCI), 13 MCI individuals without AD pathology and 21 healthy controls. The pAD-MCI group showed significantly lower microvascular blood flow and significantly higher heterogeneity of microvascular blood transit times (p < 0.01) compared with the other 2 groups. Additionally, in the pAD-MCI group raised amyloid-β levels correlated with decreased microvascular blood flow and increased heterogeneity of microvascular blood flow in frontal and temporal areas (p < 0.01). These results indicate a close connection between levels of amyloid-β deposition and brain microvascular perfusion in pAD. A vicious cycle may be established where amyloid-β load and deficiencies in brain perfusion may reinforce each other.

Background: Analysis of beta-amyloid 1–42 (Aβ42), total tau (t-tau) and phosphorylated-tau 181 (p-tau) in the cerebrospinal fluid (CSF) is often performed as a part of the diagnostic work-up in case of suspected Alzheimer's dementia (AD). Unfortunately, studies on optimal CSF biomarker cut-offs in a real-world clinical setting are scarce. Methods: We retrospectively evaluated the biomarker levels of 264 consecutive patients referred to our dementia clinic. The biomarkers were analysed with the Elecsys(R) assays. Diagnoses were based on all available clinical information, including FDG-PET scans. Results: In total, we identified 233 patients diagnosed with dementia. The median MMSE score was 22 (IQR 18–25). AD pathophysiology was suspected in 156 patients, and the corresponding cut-offs based on the Youden index were: Aβ42: 903 ng/L (ROC-AUC 0.78); t-tau: 272 ng/L (ROC-AUC 0.78); p-tau: 24 ng/L (ROC-AUC 0.85); t-tau/Aβ42 ratio: 0.34 (ROC-AUC 0.91); p-tau/Aβ42 ratio: 0.029 (ROC-AUC 0.92). Conclusions: We found the tau/Aβ42 ratios to possess the best diagnostic performance, but our estimated cut-off values for the ratios were somewhat higher than previously reported. Consequently, if the CSF analyses are used to support a diagnosis of AD in a heterogeneous high-prevalence cohort, adjustment of the cut-offs may be warranted.

Background: Non-specific treatment effects, such as expectations, contribute to the effectiveness of pharmacological treatments across diseases. However, the contribution of expectancy, i.e., certainty of receiving treatment, in patients with Alzheimer’s disease (AD) is unknown. Objective: The aim is to investigate whether certainty of receiving a genuine treatment influences the response to active treatment in AD patients. Methods: The efficacy of active treatments in open-label trials, where patients are certain of receiving treatment (100%certainty), was compared to the same active treatments in randomized controlled trials (RCT), where patients are uncertain of receiving treatment or placebo (50%certainty). Results: In the seven open-label trials, there was no significant difference between post- and pre-treatment scores (difference in means = 0.14, 95%CI [–0.51; 0.81], p = 0.66). In the eight RCT trials, there was a significant difference between post- and pre-treatment (difference in means = –0.91, 95%CI [–1.43; –0.41], p

The aims of this study were to examine the psychometric properties of the Brief Assessment of Impaired Cognition (BASIC) case-finding instrument in clinical settings focusing on (i) test–retest reliability, (ii) the discriminative validity of BASIC and its components for identification of Alzheimer disease (AD) dementia and non-AD dementia, and (iii) the association of expert clinical rating of cognitive status with BASIC performance Background and purpose: The aims of this study were to examine the psychometric properties of the Brief Assessment of Impaired Cognition (BASIC) case-finding instrument in clinical settings focusing on (i) test–retest reliability, (ii) the discriminative validity of BASIC and its components for identification of Alzheimer disease (AD) dementia and non-AD dementia, and (iii) the association of expert clinical rating of cognitive status with BASIC performance. Methods: The test–retest reliability analysis was based on a sample of general practice patients (n = 59) retested with a mean interval of 19 days. Discriminative validity analyses and analysis of the association of cognitive status with BASIC performance were based on data from the primary validation study of BASIC in memory clinics. Results: The test–retest reliability of BASIC was high (r = 0.861). No significant difference in discriminative validity was found for identification of AD dementia (sensitivity = 0.99, specificity = 0.98) and non-AD dementia (sensitivity = 0.90, specificity = 0.98). All components of BASIC contributed to the high discriminative validity of both AD and non-AD dementia. BASIC performance was significantly correlated with expert clinical rating of the cognitive status of patients. A crude staging model for cognitive status using BASIC score intervals had superior classification accuracy (70%) compared to a Mini-Mental State Examination (MMSE) score range-based model (58% accuracy). Conclusions: BASIC is a reliable and valid case-finding instrument for AD dementia and non-AD dementia in clinical settings. BASIC performance is significantly associated with the degree of cognitive impairment, and BASIC seems to be superior to MMSE for staging of impairment.

BACKGROUND: Patients with Parkinson's disease (PD) often develop dementia, but the underlying substrate is incompletely understood. Generalized synaptic degeneration may contribute to dysfunction and cognitive decline in Lewy body dementias, but in vivo evidence is lacking.OBJECTIVE: The objective of this study was to assess the density of synapses in non-demented PD (nPD) subjects (N = 21), patients with PD-dementia or Dementia with Lewy bodies (DLB) (N = 13), and age-matched healthy controls (N = 15).METHOD: Using in vivo PET imaging and the novel synaptic-vesicle-glycoprotein 2A (SV2A) radioligand [11C]UCB-J, SUVR-1 values were obtained for 12 pre-defined regions. Volumes-of-interest were defined on MRI T1 scans. Voxel-level between-group comparisons of [11C]UCB-J SUVR-1 were performed. All subjects underwent neuropsychological assessment. Correlations between [11C]UCB- J PET and domain-specific cognitive functioning were examined.RESULTS: nPD patients only demonstrated significantly reduced SUVR-1 values in the substantia nigra (SN) compared to HC. DLB/PDD patients demonstrated reduced SUVR-1 values in SN and all cortical VOIs except for the hippocampus and amygdala. The voxel-based analysis supported the VOI results. Significant correlation was seen between middle frontal gyrus [11C]UCB-J SUVR-1 and performance on tests of executive function.CONCLUSION: Widespread cortical reduction of synaptic density was documented in a cohort of DLB/PDD subjects using in vivo [11C]UCB-J PET. Our study confirms previously reported synaptic loss in SN of nPD patients. [11C]UCB-J binding in selected cortical VOIs of the DLB/PDD patients correlated with their levels of cognitive function across relevant neuropsychological domains. These findings suggest that the loss of synaptic density contributes to cognitive impairment in nPD and DLB/PDD. © 2021 International Parkinson and Movement Disorder Society.

Cardiovascular risk factors are associated with the development of Alzheimer’s disease (AD), and increasing evidence suggests that cerebral microvascular dysfunction plays a vital role in the disease progression. Using magnetic resonance imaging, we investigated the two-year changes of the cerebral microvascular blood flow in 11 mild cognitively impaired (MCI) patients with prodromal AD compared to 12 MCI patients without evidence of AD and 10 cognitively intact age-matched controls. The pAD-MCI patients displayed widespread deterioration in microvascular cerebral perfusion associated with capillary dysfunction. No such changes were observed in the other two groups, suggesting that the dysfunction in capillary perfusion is linked to the AD pathophysiology. The observed capillary dysfunction may limit local oxygenation in AD leading to downstream bamyloid aggregation, tau hyperphosphorylation, neuroinflammation and neuronal dysfunction. The findings are in agreement with the capillary dysfunction hypothesis of AD, suggesting that increasing heterogeneity of capillary blood flow is a primary pathological event in AD.

Non-specific treatment effects, such as expectations, contribute to the effectiveness of pharmacological treatments across diseases. However, the contribution of expectancy, i.e., certainty of receiving treatment, in patients with Alzheimer's disease (AD) is unknown.The aim is to investigate whether certainty of receiving a genuine treatment influences the response to active treatment in AD patients.The efficacy of active treatments in open-label trials, where patients are certain of receiving treatment (100%certainty), was compared to the same active treatments in randomized controlled trials (RCT), where patients are uncertain of receiving treatment or placebo (50%certainty).In the seven open-label trials, there was no significant difference between post- and pre-treatment scores (difference in means = 0.14, 95%CI [-0.51; 0.81], p = 0.66). In the eight RCT trials, there was a significant difference between post- and pre-treatment (difference in means = -0.91, 95%CI [-1.43; -0.41], p 0.001). There was a statistically significant difference between open-label and RCT trials (difference = 1.06, 95%CI [0.23; 1.90], p = 0.001).Patients with AD did not benefit from certainty of receiving genuine treatment. This could be due to the nature/progression of the disease, but it could also be related to an order effect in the practice of running AD trials, where RCTs are conducted prior to open label. These findings have implications for the understanding of non-specific treatment effects in AD patients as well as for the design of clinical trials that test pharmacological treatments in AD.

OBJECTIVES: The aim of this study was to develop and validate a new brief and accurate case-finding instrument for dementia and cognitive impairment. Previous research indicates that combining cognitive tests with informant and/or patient report may improve accuracy in dementia case-finding. The Brief Assessment of Impaired Cognition (BASIC) integrates these three sources of information.METHODS: BASIC was prospectively validated in five memory clinics. Patients consecutively referred from general practice were tested at their initial visit prior to diagnosis. Control participants were primarily recruited among participating patients' relatives. Expert clinical diagnosis was subsequently used as gold standard for estimation of the classification accuracy of BASIC.RESULTS: A very high discriminative validity (specificity 0.98, sensitivity 0.95) for dementia (n = 122) versus socio-demographically matched control participants (n = 109) was found. In comparison, the MMSE had 0.90 specificity and 0.82 sensitivity. Extending the discriminative validity analysis to cognitive impairment (both dementia and MCI, n = 162) only slightly reduced the discriminative validity of BASIC whereas the discriminative validity of the MMSE was substantially attenuated. Administration time for BASIC was approximately 5 minutes compared with 10 to 15 minutes for the MMSE.CONCLUSIONS: BASIC was found to be an efficient and valid case-finding instrument for dementia and cognitive impairment in a memory clinic setting.

Background: The extent of radiation therapy (RT)-induced changes in cognitive function is unknown. RT with protons instead of photons spares the healthy brain tissue more and is believed to reduce the risk of cognitive dysfunction. There is modest knowledge on which parts of the brain we need to spare, to prevent cognitive dysfunction. To uncover which cognitive domains is most affected, we compared cognitive functioning in brain tumor patients treated with neurosurgery and RT with brain tumor patients treated with neurosurgery alone. Methods: A cross-sectional study assessing cognitive function in 110 patients with a primary brain tumor grades I-III or medulloblastoma (grade IV) treated at Aarhus University Hospital (AUH), Denmark between 2006 and 2016. Two cohorts were established: a cohort of 81 brain tumor patients who had received neurosurgery followed by RT (RT+), and a cohort of 29 brain tumor patients who had only received neurosurgery (RT-). The patients underwent questionnaires and neuropsychological assessment with standardized tests. Results: Mean age was 53.5 years with an average time since diagnosis of 7.3 years. Compared with normative data, lower average scores were observed for the entire group on domains concerning of verbal learning and memory ( p

Patients with Parkinson's disease (PD) often develop dementia, but the underlying substrate is incompletely understood. Generalized synaptic degeneration may contribute to dysfunction and cognitive decline in Lewy body dementias, but in vivo evidence is lacking.The objective of this study was to assess the density of synapses in non-demented PD (nPD) subjects (N = 21), patients with PD-dementia or Dementia with Lewy bodies (DLB) (N = 13), and age-matched healthy controls (N = 15).Using in vivo PET imaging and the novel synaptic-vesicle-glycoprotein 2A (SV2A) radioligand [11C]UCB-J, SUVR-1 values were obtained for 12 pre-defined regions. Volumes-of-interest were defined on MRI T1 scans. Voxel-level between-group comparisons of [11C]UCB-J SUVR-1 were performed. All subjects underwent neuropsychological assessment. Correlations between [11C]UCB- J PET and domain-specific cognitive functioning were examined.nPD patients only demonstrated significantly reduced SUVR-1 values in the substantia nigra (SN) compared to HC. DLB/PDD patients demonstrated reduced SUVR-1 values in SN and all cortical VOIs except for the hippocampus and amygdala. The voxel-based analysis supported the VOI results. Significant correlation was seen between middle frontal gyrus [11C]UCB-J SUVR-1 and performance on tests of executive function.Widespread cortical reduction of synaptic density was documented in a cohort of DLB/PDD subjects using in vivo [11C]UCB-J PET. Our study confirms previously reported synaptic loss in SN of nPD patients. [11C]UCB-J binding in selected cortical VOIs of the DLB/PDD patients correlated with their levels of cognitive function across relevant neuropsychological domains. These findings suggest that the loss of synaptic density contributes to cognitive impairment in nPD and DLB/PDD. © 2021 International Parkinson and Movement Disorder Society.

Background Several factors may play a role in the ability of patients with Alzheimer’s disease to perform activities of daily living (ADL). The aim of this study was to examine the impact of different aspects of physical performance and cognitive functions on ADL in patients suffering from mild-to-moderate Alzheimer’s disease. Methods We conducted secondary analyses on cross-sectional baseline data from the randomized controlled multicentre study “Preserving quality of life, physical health and functional ability in Alzheimer’s Disease: The effect of physical exercise” (ADEX). In total, 185 AD patients (76 women and 109 men), with a mean age on 70,4 years, were included. Data from physical performance tests (Astrand cycle test, Timed up & Go (TUG), Sit to Stand test (STS)) and cognitive tests (Mini Mental Status Examination (MMSE), Symbol Digit Modalities Test (SDMT), Stroop Color and Word test (Stroop)) were used. Their associations with ADL, measured on the ADCS-ADL scale was assessed in multivariable regression analyses. Results SDMT and MMSE had significant, moderate correlations with total ADL (SDMT: r = 0.33, MMSE: r = 0.42) and instrumental ADL (SDMT: r = 0.31, MMSE: r = 0.42), but not with basic ADL. Adjusting for age and sex, the associations between SDMT and MMSE to total ADL and instrumental ADL persisted. No significant associations were found between Astrand, TUG, STS or Stroop and total ADL, basic ADL or instrumental ADL. Conclusion Total ADL and instrumental ADL are associated with cognitive functions, including executive function. No significant association between examined physical performance parameters and ADL functions was observed, and consequently does not support an impact of physical function on ADL functions in patients with mild-to-moderate Alzheimer’s disease and relatively well-preserved physical function. Strategies aimed to improve cognition may be better suited to improve ADL function in patients with mild-to-moderate Alzheimer’s disease. Trial registration NCT01681602. Registered 10 September 2012, retrospectively registered.

Background The aim of this longitudinal study was to assess with positron emission tomography (PET) the relationship between levels of inflammation and the loads of aggregated β-amyloid and tau at baseline and again after 2 years in prodromal Alzheimer's disease. Methods Forty-three subjects with mild cognitive impairment (MCI) had serial 11C-PK11195 PET over 2 years to measure inflammation changes, and 11C-PiB PET to determine β-amyloid fibril load; 22 also had serial 18F-Flortaucipir PET to determine tau tangle load. Cortical surface statistical mapping was used to localise areas showing significant changes in tracer binding over time and to interrogate correlations between tracer binding of the tracers at baseline and after 2 years. Results Those MCI subjects with high 11C-PiB uptake at baseline (classified as prodromal Alzheimer’s disease) had raised inflammation levels which significantly declined across cortical regions over 2 years although their β-amyloid levels continued to rise. Those MCI cases who had low/normal 11C-PiB uptake at baseline but their levels then rose over 2 years were classified as prodromal AD with low Thal phase 1-2 amyloid deposition at baseline. They showed levels of cortical inflammation which correlated with their rising β-amyloid load. Those MCI cases with baseline low 11C-PiB uptake that remained stable were classified as non-AD, and they showed no correlated inflammation levels. Finally, MCI cases which showed both high 11C-PiB and 18F-Flortaucipir uptake at baseline (MCI due to AD) showed a further rise in their tau tangle load over 2 years with a correlated rise in levels of inflammation. Conclusions Our baseline and 2-year imaging findings are compatible with a biphasic trajectory of inflammation in Alzheimer’s disease: MCI cases with low baseline but subsequently rising β-amyloid load show correlated levels of microglial activation which then later decline when the β-amyloid load approaches AD levels. Later, as tau tangles form in β-amyloid positive MCI cases with prodromal AD, the rising tau load is associated with higher levels of inflammation.

Background Although general recommendations for diagnostic disclosure of dementia are available, little is known about how these recommendations are implemented. The aim of the current study was to investigate the process and content of dementia diagnostic disclosure meetings, and to compare key aspects of disclosing a diagnosis of dementia and mild cognitive impairment. Method A total of 54 specialist physicians in Danish dementia diagnostic departments completed an online survey on their practices regarding diagnostic disclosure of dementia and mild cognitive impairment. The influence of respondent characteristics was assessed, and differences on key aspects of disclosing a diagnosis of dementia and mild cognitive impairment were analyzed. Results The results suggest that among Danish specialist physicians, there is a general consensus regarding the organization of diagnostic disclosure meetings. However, differences in employed terminology and information provided when disclosing a dementia diagnosis were evident. Significant differences were present on key aspects of the diagnostic disclosure of dementia and mild cognitive impairment. For instance, 91% would use the term dementia during diagnostic disclosures compared to just 72% for mild cognitive impairment. Conclusion The range of practices reflected in the present study confirms the complexity of diagnostic disclosure and highlights the importance of preparation and follow-up strategies to tailor the disclosure process to the needs of individual patients with dementia and their caregivers. Due to earlier diagnosis of neurodegenerative disorders, more research is urgently needed on this aspect of the diagnostic process, especially to develop evidence-based models for the disclosure of mild cognitive impairment.

Introduction: Cardiovascular disease increases the risk of developing Alzheimer's disease (AD), and growing evidence suggests an involvement of cerebrovascular pathology in AD. Capillary dysfunction, a condition in which capillary flow disturbances rather than arterial blood supply limit brain oxygen extraction, could represent an overlooked vascular contributor to neurodegeneration. We examined whether cortical capillary transit-time heterogeneity (CTH), an index of capillary dysfunction, is elevated in amyloid-positive patients with mild cognitive impairment (prodromal AD [pAD]).Methods: We performed structural and perfusion weighted MRI in 22 pAD patients and 21 healthy controls.Results: We found hypoperfusion, reduced blood volume, and elevated CTH in the parietal and frontal cortices of pAD-patients compared to controls, while only the precuneus showed focal cortical atrophy.Discussion: We propose that microvascular flow disturbances antedate cortical atrophy and may limit local tissue oxygenation in pAD. We speculate that capillary dysfunction contributes to the development of neurodegeneration in AD.

BACKGROUND: To improve the quality of care for brain cancer patients, the Danish Ministry of Health has set standards for the diagnosis and treatment. When a patient is suspected of having a malignant tumour involving the brain, it is required that a magnetic resonance imaging of the cerebrum (MRI-C) be obtained within seven calendar days of referral from a primary care provider. This standard has the potential to consume MR imaging time that might otherwise be used for evaluation or treatment monitoring of other patients. This study primarily aims to assess the sensitivity of computed tomography of the brain (CT-C) for the detection of intracranial tumour as the initial diagnostic imaging.METHODS: This is a single-center retrospective study of patients referred to the IBCP with brain cancer suspicion. The average follow-up was 37 months. All included patients underwent a CT-C scan and subsequently a MRI-C if deemed necessary. The study population was divided into two groups based on the findings: tumour versus non-tumour. Sensitivity and specificity of the CT-C was calculated.RESULTS: Eight hundred seventeen patients were included. Median age was 55 years and 50% were male. CT-C had a sensitivity of 98.5% and a specificity of 98.4%. The overall mortality rate was 7% in the non-tumour group and 58% in the tumour group over the course of the study period. The tumour group was on average older compared to the non-tumour group (65 years [55-75 years] vs 52 years [38-65 years]) p CONCLUSION: This study shows that CT-C scans are highly sensitive and specific and can be used as the primary screening tool for patients referred with a suspicion for brain cancer.

BACKGROUND AND PURPOSE: In vivo detection of β-amyloid (Aβ) plaques in Alzheimer's disease (AD) is now possible with 11C-PiB positron emission tomography (PET). Conventionally, a cortical:cerebellar PiB uptake ratio threshold of 1.4-1.5 has been used to categorize at-risk subjects as “amyloid-positive” and “amyloid-negative.” It has been suggested that this threshold is too conservative and may miss early amyloid pathology. We investigated the relationship between conventional and lower baseline 11C-PiB PET thresholds for raised amyloid load and the subsequent clinical and radiological progression of mild cognitive impairment (MCI) cases longitudinally. METHODS: We serially determined the cortical amyloid load with 11C-PiB PET of 44 MCI subjects over 2 years and compared findings with those for 12 healthy controls (HC) and 5 AD cases. RESULTS: Twenty-four subjects were classified as normal at baseline with mean cortical PiB standard uptake value ratios (SUVR) between 1.2 and 1.5. Their cognitive status remained stable over time. Three of these cases increased their amyloid load above a threshold of 1.5 over 2 years. Twenty-seven “raised amyloid” MCI cases with baseline cortical SUVRs above 1.5, showed deteriorating cognition. Note that 50% of these cases converted clinically to AD during the follow-up period. CONCLUSION: Use of a PiB SUVR threshold of >1.5 for raised amyloid missed 14.3% of MCI cases who likely had Thal stage 1 or 2 pathology and showed a progressive amyloid increase over 2 years. Lowering the threshold for abnormality to 1.3 abolished all false negatives but resulted in 75% of HCs being falsely diagnosed as raised amyloid subjects.

Introduction Our group has completed an exercise study of 200 patients with mild Alzheimer's disease. We found improvements in cognitive, neuropsychiatric, and physical measures in the participants who adhered to the protocol. Epidemiological studies in healthy elderly suggest that exercise preserves cognitive and physical abilities to a higher extent in APOE ε4 carriers. Methods In this post hoc subgroup analysis study, we investigated whether the beneficial effect of an exercise intervention in patients with mild AD was dependent on the patients' APOE genotype. Results We found that patients who were APOE ε4 carriers benefitted more from the exercise intervention by preservation of cognitive performance and improvement in physical measures. Discussion This exploratory study establishes a possible connection between the beneficial effects of exercise in AD and the patients' APOE genotype. These findings, if validated, could greatly impact the clinical management of patients with AD and those at risk for developing AD.

Objective: Our aim was to assess with positron emission tomography (PET) the temporal and spatial inter-relationships between levels of cortical microglial activation and the aggregated amyloid-β and tau load in mild cognitive impairment (MCI) and early Alzheimer's disease (AD).Methods: Six clinically probable AD and 20 MCI subjects had inflammation (11C-(R)-PK11195), amyloid (11C-PiB) and tau (18F-flortaucipir) PET, magnetic resonance imaging (MRI) and a neuropsychological assessment. Parametric images of tracer binding were interrogated at a voxel level and by region of interest analyses.Results: 55% of MCI and 83% of AD subjects had a high amyloid-β load. We have previously reported that clusters of correlated amyloid and inflammation levels are present in cortex. Here we found no correlation between levels of inflammation (11C-(R)-PK11195 BPND) and tau (18F-flortaucipir SUVR) or MMSE scores in high amyloid-β cases.Interpretation: While correlated levels of amyloid-β and inflammation can be seen in MCI, we did not detect an association between levels of cortical tau tangles and inflammation in our series of high amyloid-β cases. High levels of inflammation could be seen in amyloid-β positive MCI cases where 18F-flortaucipir signals were low suggesting microglial activation precedes tau tangle formation. Inflammation levels were higher in high amyloid-β MCI than in early AD cases, compatible with it initially playing a protective role.

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder. AD pathology is characterized by abnormal aggregation of the proteins amyloid-β (Aβ) and hyperphosphorylated tau. No effective disease modifying therapies are currently available. A short-duration intervention with 40 Hz light flicker has been shown to reduce brain Aβ load in transgenic mice. We aimed to test the effect of a similar short-duration 40 Hz light flicker regime in human AD patients. We utilized a Light Emitting Diode (LED) light bulb with a 40 Hz flicker. Six Aβ positive patients received 10 days of light therapy, had 2 hours of daily exposure, and underwent a postintervention PiB PET on day 11. After 10 days of light therapy, no significant decrease of PiB SUVR values was detected in any volumes of interest tested (primary visual cortex, visual association cortex, lateral parietal cortex, precuneus, and posterior cingulate) or in the total motor cortex, and longer treatments may be necessary to induce amyloid removal in humans.

OBJECTIVE: Alzheimer's disease (AD) causes a gradual decline in cognition, limitations of dual-tasking and physical function leading to total dependence. Hence, information about the interaction between physical function, dual-task performance and cognition may lead to new treatment strategies with the purpose of preserving function and quality of life. The objective of this study was to investigate the associations between physical function, dual-task performance and cognition in community-dwelling patients with mild AD.METHODS: Baseline results from 185 participants (50-90 years old) in the single blinded multicenter RCT 'ADEX' (Alzheimer's disease: the effect of physical exercise) were used. Assessments included tests of physical function: 400-m walk test, 10-m walk test, Timed Up and Go test and 30-s chair stand test; dual-task performance, i.e., 10-m walk while counting backwards from 50 or naming the months backwards; and cognition, i.e., Mini Mental State Examination, Symbol Digit Modalities Test, the Stroop Color and Word Test, and Lexical verbal fluency test.RESULTS: Results in the 30-s chair stand test correlated significantly with all tests of cognition (r = .208-.242) while the other physical function tests only randomly correlated with tests of cognition. Results in the dual-task counting backwards correlated significantly with results in all tests of cognition (r = .259-.388), which accounted for 7%-15% of the variation indicating that a faster time to complete dual-task performance was associated with better cognitive performance.CONCLUSION: The evidence of the associations between physical function, dual-task performance and cognition is important when creating new rehabilitation interventions to patients with mild AD.

Frontotemporal dementia (FTD) refers to the clinical syndromes caused by various neurodegenerative diseases in the frontal and temporal lobes. Advances in the knowledge and understanding of these diseases have resulted in changes in the clinical as well as the genetic and pathological classification. This is a short review of the current classification and understanding of FTD.

INTRODUCTION:Knowledge about the feasibility and effects of exercise programs to persons with Alzheimer's disease is lacking. This study investigated the effect of aerobic exercise on physical performance in community-dwelling persons with mild Alzheimer's disease.METHODS: The single blinded multi-center RCT (ADEX) included 200 patients, median age 71 yrs (50-89). The intervention group received supervised moderate-to-high intensity aerobic exercise 1 hour × 3/week for 16 weeks. Assessments included cardiorespiratory fitness, single-task physical performance, dual-task performance and exercise self-efficacy.RESULTS:Significant between-group differences in change from baseline (mean [95%CI]) favored the intervention group for cardiorespiratory fitness (4.0 [2.3-5.8] ml/kg/min, P DISCUSSION:Aerobic exercise has the potential to improve cardiorespiratory fitness, single-task physical performance, dual-task performance and exercise self-efficacy in community-dwelling patients with mild Alzheimer's disease.

Subjects with mild cognitive impairment associated with cortical amyloid-β have a greatly increased risk of progressing to Alzheimer’s disease. We hypothesized that neuroinflammation occurs early in Alzheimer’s disease and would be present in most amyloid-positive mild cognitive impairment cases. 11C-Pittsburgh compound B and 11C-(R)-PK11195 positron emission tomography was used to determine the amyloid load and detect the extent of neuroinflammation (microglial activation) in 42 mild cognitive impairment cases. Twelve age-matched healthy control subjects had 11C-Pittsburgh compound B and 10 healthy control subjects had 11C-(R)-PK11195 positron emission tomography for comparison. Amyloid-positivity was defined as 11C-Pittsburgh compound B target-to-cerebellar ratio above 1.5 within a composite cortical volume of interest. Supervised cluster analysis was used to generate parametric maps of 11C-(R)-PK11195 binding potential. Levels of 11C-(R)-PK11195 binding potential were measured in a selection of cortical volumes of interest and at a voxel level. Twenty-six (62%) of 42 mild cognitive impairment cases showed a raised cortical amyloid load compared to healthy controls. Twenty-two (85%) of the 26 amyloid-positive mild cognitive impairment cases showed clusters of increased cortical microglial activation accompanying the amyloid. There was a positive correlation between levels of amyloid load and 11C-(R)-PK11195 binding potentials at a voxel level within subregions of frontal, parietal and temporal cortices. 11C-(R)-PK11195 positron emission tomography reveals increased inflammation in a majority of amyloid positive mild cognitive impairment cases, its cortical distribution overlapping that of amyloid deposition.

INTRODUCTION: We examined whether cortical microvascular blood volume and hemodynamics in Alzheimer's disease (AD) are consistent with tissue hypoxia and whether they correlate with cognitive performance and the degree of cortical thinning.METHODS: Thirty-two AD patients underwent cognitive testing, structural magnetic resonance imaging (MRI), and perfusion MRI at baseline and after 6 months. We measured cortical thickness, microvascular cerebral blood volume (CBV), cerebral blood flow (CBF), mean transit time (MTT), and capillary transit time heterogeneity (CTH) and estimated tissue oxygen tension (PtO2).RESULTS: At baseline, poor cognitive performance and regional cortical thinning correlated with lower CBF and CBV, with higher MTT and CTH and with low PtO2 across the cortex. Cognitive decline over time was associated with increasing whole brain relative transit time heterogeneity (RTH = CTH/MTT).DISCUSSION: Our results confirm the importance of microvascular pathology in AD. Deteriorating microvascular hemodynamics may cause hypoxia, which is known to precipitate amyloid retention.

BACKGROUND: Studies of physical exercise in patients with Alzheimer's disease (AD) are few and results have been inconsistent.OBJECTIVE: To assess the effects of a moderate-to-high intensity aerobic exercise program in patients with mild AD.METHODS: In a randomized controlled trial, we recruited 200 patients with mild AD to a supervised exercise group (60-min sessions three times a week for 16 weeks) or to a control group. Primary outcome was change from baseline in cognitive performance estimated by Symbol Digit Modalities Test (SDMT) in the intention-to-treat (ITT) group. Secondary outcomes included changes in quality of life, ability to perform activities of daily living, and in neuropsychiatric and depressive symptoms.RESULTS: The ITT analysis showed no significant differences between intervention and control groups in change from baseline of SDMT, other cognitive tests, quality of life, or activities of daily living. The change from baseline in Neuropsychiatric Inventory differed significantly in favor of the intervention group (mean: -3.5, 95% confidence interval (CI) -5.8 to -1.3, p = 0.002). In subjects who adhered to the protocol, we found a significant effect on change from baseline in SDMT as compared with the control group (mean: 4.2, 95% CI 0.5 to 7.9, p = 0.028), suggesting a dose-response relationship between exercise and cognition.CONCLUSIONS: This is the first randomized controlled trial with supervised moderate-to-high intensity exercise in patients with mild AD. Exercise reduced neuropsychiatric symptoms in patients with mild AD, with possible additional benefits of preserved cognition in a subgroup of patients exercising with high attendance and intensity.

This study examined aftersensations after repetitive pinprick stimulation in nerve injury patients with allodynia and in capsaicin sensitized skin in control subjects. Forty-one patients and 12 male control subjects were stimulated repetitively with a computer-driven von Frey hair in sensitized skin and in contralateral normal skin at 0.2 and 2.0 Hz. Pain during and after stimulation was scored on an electronic visual analogue scale and sampled on a computer. Maximum evoked pain, time to pain onset, duration of pain and duration of aftersensations were calculated from stored data. Aftersensations were significantly more frequent in sensitized skin than in contralateral normal skin in both control subjects and patients. Pain was evoked more frequently and maximum evoked pain score was significantly higher in sensitized skin compared to contralateral normal skin in both groups. Furthermore, evoked pain score was frequency dependent with a significantly higher pain score at 2.0 than at 0.2 Hz. There was a significant positive correlation between maximum evoked pain scores and duration of aftersensations both in patients and control subjects. No difference was observed in maximum pain score, time to pain onset and duration of aftersensations between the groups. Findings suggest that aftersensations and evoked pain are mediated by a common mechanism, which most likely is central. The clinical manifestation of aftersensations can be mimicked in an experimental pain model so aftersensations may be another useful parameter in assessment of central sensitization.

Treatment of central neuropathic pain (CP) following lesions of the CNS is a great challenge to the clinician. Preclinical and clinical studies indicate that neuronal hyperexcitability in damaged areas of the central nervous system plays a major role in the development of CP. Anticonvulsants are thought to act by increasing gamma-aminobutyric acid-mediated inhibition, decreasing abnormal neuronal hyperexcitability by modulating sodium and calcium channels or by inhibiting excitatory amino acid actions. The resulting inhibition of excess neuronal activity is thought to be the basis for the use of anticonvulsants in epilepsy as well as neuropathic pain. Both first-generation anticonvulsant drugs (e.g., phenytoin, benzodiazepines, valproate and carbamazepine) and second-generation anticonvulsant drugs (e.g., lamotrigine, gabapentin and topiramate) are used in CP conditions. However, few randomised controlled trials on the treatment of this condition have been published. Present suggestions for anticonvulsant treatment of CP are lamotrigine as the first choice, followed by gabapentin or carbamazepine/oxcarbazepine. These compounds are considered as effective as the antidepressant amitriptyline.

Background and Purpose— Remote ischemic preconditioning is neuroprotective in models of acute cerebral ischemia. We tested the effect of prehospital rPerC as an adjunct to treatment with intravenous alteplase in patients with acute ischemic stroke. Methods— Open-label blinded outcome proof-of-concept study of prehospital, paramedic-administered rPerC at a 1:1 ratio in consecutive patients with suspected acute stroke. After neurological examination and MRI, patients with verified stroke receiving alteplase treatment were included and received MRI at 24 hours and 1 month and clinical re-examination after 3 months. The primary end point was penumbral salvage, defined as the volume of the perfusion–diffusion mismatch not progressing to infarction after 1 month. Results— Four hundred forty-three patients were randomized after provisional consent, 247 received rPerC and 196 received standard treatment. Patients with a nonstroke diagnosis (n=105) were excluded from further examinations. The remaining patients had transient ischemic attack (n=58), acute ischemic stroke (n=240), or hemorrhagic stroke (n=37). Transient ischemic attack was more frequent ( P =0.006), and National Institutes of Health Stroke Scale score on admission was lower ( P =0.016) in the intervention group compared with controls. Penumbral salvage, final infarct size at 1 month, infarct growth between baseline and 1 month, and clinical outcome after 3 months did not differ among groups. After adjustment for baseline perfusion and diffusion lesion severity, voxelwise analysis showed that rPerC reduced tissue risk of infarction ( P =0.0003). Conclusions— Although the overall results were neutral, a tissue survival analysis suggests that prehospital rPerC may have immediate neuroprotective effects. Future clinical trials should take such immediate effects, and their duration, into account. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00975962.

Our understanding of nociceptive processing and of plastic changes after persistent noxious input has increased immensely within the last two decades. It is now clear that long-lasting noxious stimulation or damage to the nervous system give rise to a neuronal hyperexcitability and that this sensitisation of the nervous system plays an important role for development and maintenance of chronic pain. The manifestations of such hyperexcitability are numerous and include among others: increased neuronal response to a suprathreshold stimulus, expansion of the peripheral areas from where a central neurone can be activated and the recruitment of previous non-responding nociceptive neurones. Furthermore, it has been possible to modulate this neuronal hyperexcitability by the discovery of molecular targets for pain, by sequencing DNA of ion channels and receptors and by development of new molecules that exert their effects on these molecular targets. The changes in responsiveness appear to be partly time and intensity dependent and partly dependent on the cause of injury. Whereas relatively short-lasting and moderate noxious input leads to reversible plastic changes, more intense and long-lasting noxious stimulation implies a risk for persistent and more profound alterations in transmitters, receptors, ion channels and in neuronal connectivity. Despite the explosion of new knowledge in pain processing and in molecular background for neuroplasticity, this progress has unfortunately not resulted in a corresponding improvement of our ability to treat chronic pain. The number of patients with chronic unrelieved pain is still high and newer types of treatment have so far not resulted in a substantially better treatment. Nevertheless, there is now an ongoing systematic research in which chronic pain conditions are assessed in a fashion so that mechanisms underlying pain can be dissected. Moreover, controlled clinical trials together with systematic reviews are carried out which in the future should permit formulation of treatment algorithms for chronic pain. Finally, it is likely that the development of new specific types of treatment will show efficacy if they are evaluated and analysed not on the global pain experience, but more specifically on those targets and elements of the pain experience they are aimed to deal with.

Objective: Central poststroke pain (CPSP) is usually difficult to treat. Amitriptyline, the only oral preparation shown to be effective in a randomized controlled trial, is often associated with a range of side effects related to the many mechanisms of actions of tricyclic antidepressants. We investigated the effect of lamotrigine, a drug that reduces neuronal hyperexcitability, on poststroke pain. Methods: Thirty consecutive patients with CPSP (median age 59 years, range 37 to 77; median pain duration 2.0 years, range 0.3 to 12) from two centers participated in a randomized, double-blind, placebo-controlled cross-over study. The study consisted of two 8-week treatment periods separated by 2 weeks of wash-out. The primary endpoint was the median value of the mean daily pain score during the last week of treatment while treated with 200 mg/d lamotrigine. Secondary endpoints were median pain scores while on lamotrigine 25 mg/d, 50 mg/d, and 100 mg/d; a global pain score; assessment of evoked pain; areas of spontaneous pain; and allodynia/dysesthesia. Results: Lamotrigine 200 mg/d reduced the median pain score to 5, compared to 7 during placebo (p = 0.01) in the intent-to-treat population of 27 patients. No significant effect was obtained at lower doses. Twelve patients (44%) responded to the treatment. There was a uniform tendency to reduction of all secondary outcome measures, but lamotrigine only had significant effects on some of the secondary outcome measures. Lamotrigine was well tolerated with few and transient side effects. Two mild rashes occurred during lamotrigine treatment, one causing withdrawal from study. Conclusions: Oral lamotrigine 200 mg daily is a well tolerated and moderately effective treatment for central poststroke pain. Lamotrigine may be an alternative to tricyclic antidepressants in the treatment of CPSP.

Chronic pain, lymphoedema, post-irradiation neuropathy and other symptoms are reported in as many as 75% of women following breast cancer treatment. This study examined pain and sensory abnormalities in women following breast cancer surgery. Sensory tests were carried out on operated and contralateral sides in 15 women with spontaneous pain and sensory abnormalities and 11 pain-free women. Testing included the VAS score of spontaneous pain, detection and pain threshold to thermal and mechanical stimuli, temporal summation to repetitive heat and pinprick stimuli, and assessment of skin blood flow during repetitive brush and pinprick stimulation. Sensory threshold to pinprick and thermal stimuli was significantly higher on the operated side in both groups while pressure pain threshold was significantly lower in pain patients on the operated side compared to the contralateral side. No side to side difference was seen in pressure pain threshold in the pain-free group. Evoked pain intensity to repetitive stimuli at 0.2 and 2.0 Hz was significantly higher on the operated side in pain patients compared to the control area while no such difference was seen in pain-free patients. Cutaneous blood flow measured by laser Doppler (flux) was significantly higher when the skin was tapped at 2.0 Hz on the operated side compared to contralaterally in pain patients, while no side to side difference was seen in pain-free patients. Pinprick-evoked pain was correlated to spontaneous pain but not to flux. Spontaneous pain was not correlated to flux. Sensitization seems to be a feature in breast cancer-operated women with pain, but not in pain-free women.