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Introduction: Microglial responses are an integral part of Alzheimer's disease (AD) pathology and are associated with amyloid beta (Aβ) deposition. This study aimed to investigate the effects of Aβ and microglial responses on global cognitive impairment., Methods: In this longitudinal study, 28 patients with mild cognitive impairment and 11 healthy controls underwent 11 C-PK11195 and 11 C-Pittsburgh compound B positron emission tomography (PET), structural magnetic resonance imaging scans, and global cognitive ratings at baseline and 2-year follow-up. Correlations between PET uptake and global cognition were assessed. Additionally, the mediation effect of the microglial response on the association between Aβ load and global cognition was assessed., Results: Aβ load and the microglial response were both independently detrimental to global cognitive performance at baseline; however, at 2-year follow-up the association between Aβ load and global cognitive ratings was partially mediated by the microglial response., Discussion: As AD progresses, the associated microglial response partially mediates the detrimental effect of aggregated Aβ on cognition., Highlights: This was a longitudinal study of amyloid beta (Aβ), microglial responses, and global cognitive performance. Aβ and microglial responses both affect cognition in early Alzheimer's disease. Microglial response partially mediates the effect of Aβ on cognition in later stages., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Introduction: The a-Synuclein Origin and Connectome (SOC) model of Lewy body diseases postulates that a-syuclein will be asymmetrically distributed in some patients with Lewy body diseases, potentially leading to asymmetric neuronal dysfunction and symptoms., Methods: We included two patient groups: 19 non-demented Parkinson's disease (nPD) patients with [ 18 F]FDG PET and motor symptoms assessed by UPDRS-III, and 65 Lewy body dementia (LBD) patients with [ 18 F]FDG PET and dopamine radioisotope imaging. Asymmetry indices were calculated for [ 18 F]FDG PET by including the cortex for each hemisphere, for dopamine radioisotope imaging by including the putamen and caudate separately, and for motor symptoms by using the difference between right-left UPDRS-III score. Correlations between these asymmetry indices were explored to test the predictions of the SOC model. To identify cases with a more typical LBD imaging profile, we calculated a Cingulate Island Sign (CIS) index on the [ 18 F]FDG PET image., Results: We found a significant correlation between cortical interhemispheric [ 18 F]FDG asymmetry and motor-symptom asymmetry in nPD patients (r = 0.62, P = 0.004). In patients with LBD, we found a significant correlation between cortical interhemispheric [ 18 F]FDG asymmetry and dopamine transporter asymmetry in the caudate (r = 0.37, P = 0.0019), but not in the putamen (r = 0.15, P = 0.22). We observed that the correlation in the caudate was stronger in LBD subjects with the highest CIS index, i.e., with more typical LBD imaging profiles., Conclusion: Our study partly supports the SOC model, but further investigations are needed - ideally of de novo, non-demented PD patients., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Per Borghammer reports financial support was provided by Lundbeck Foundation. Jacob Horsager reports financial support was provided by Lundbeck Foundation. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Patients with young onset Alzheimer's disease (YOAD) face long diagnostic delays. Prescription medication use may provide insights into early signs and symptoms, which may help facilitate timely diagnosis., Methods: In a register-based nested case-control study, we examined medication use for everyone diagnosed with YOAD in a Danish memory clinic during 2016-2020 compared to cognitively healthy controls. Prescription medication use were grouped into 13 overall categories (alimentary tract and metabolism, blood and blood forming organs, cardiovascular system, dermatologicals, genitourinary system and sex hormones, systemic hormonal preparations, antiinfectives for systemic use, antineoplastic and immunomodulating agents, musculo-skeletal system, nervous system, antiparasitic products, respiratory system, and sensory organs). Further stratifications were done for predetermined subcategories with a use-prevalence of at least 5% in the study population. Conditional logistic regression produced odds ratios, which given the use of incidence-density matching is interpretable as incidence rate ratios (IRRs). The association between prescription medication use and subsequent YOAD diagnosis was examined in the entire 10-year study period and in three time-intervals., Results: The study included 1745 YOAD cases and 5235 controls. In the main analysis, several overall categories showed significant associations with YOAD in one or more time-intervals, namely blood and blood forming organs and nervous system. Prescription medication use in the nervous system category was increased for YOAD cases compared to controls already 10->5 years prior to diagnosis (IRR 1.17, 95% CI 1.05-1.31), increasing to 1.57 (95% CI 1.39-1.78) in the year preceding diagnosis. This was largely driven by antidepressant and antipsychotic use, and especially prominent for first-time users., Conclusions: In this study, medication use in several categories was associated with YOAD. Onset of treatment-requiring psychiatric symptoms such as depression or psychosis in mid-life may serve as potential early indicators of YOAD., (© 2024. The Author(s).)

Introduction: Early symptoms in young onset Alzheimer's disease (YOAD) may be misinterpreted, causing delayed diagnosis. This population-based study aimed to map morbidity prior to YOAD diagnosis., Methods: In a register-based incidence density matched nested case-control study, we examined hospital-diagnosed morbidity for people diagnosed with YOAD in Danish memory clinics during 2016-2020 compared to controls in a 10-year period. Conditional logistic regression produced incidence rate ratios (IRRs)., Results: The study included 1745 cases and 5235 controls. YOAD patients had a higher morbidity burden in the year immediately before dementia diagnosis, for certain disorders up to 10 years before. This was especially evident for psychiatric morbidity with the highest increased IRRs throughout the entire period and IRR 1.43 (95% confidence interval 1.14-1.79) in the 5-10-years before dementia diagnosis., Discussion: YOAD patients display a different pattern of morbidity up to 10 years prior to diagnosis. Awareness of specific alterations in morbidity may improve efforts toward a timely diagnosis., Highlights: Retrospective, nested case-control study of young onset Alzheimer's disease (YOAD). YOAD cases had a higher morbidity burden than controls. YOAD cases had a higher psychiatric morbidity burden up to 10 years before diagnosis. Altered morbidity patterns could serve as an early warning sign of YOAD., (© 2024 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Abstract: The role of placebo analgesia and nocebo hyperalgesia in patients with Alzheimer disease (AD) is largely unknown, with only few studies in the area. Therefore, this study aims to investigate to which extent placebo analgesia and nocebo hyperalgesia effects are present in patients experiencing mild-to-moderate AD. Twenty-one patients with AD (test population) and 26 healthy participants (HP; design validation) were exposed to thermal pain stimulation on 3 test days: Lidocaine condition (open/hidden lidocaine administration), capsaicin condition (open/hidden capsaicin administration), and natural history (no treatment), in a randomized, within-subject design. Open lidocaine and open capsaicin were accompanied by verbal suggestions for pain relief and pain increase, respectively. Expected pain and actual pain intensity were measured on a numerical rating scale (0-10). Placebo and nocebo effects were calculated as pain differences in open-hidden lidocaine and capsaicin, respectively, controlled for no treatment. Healthy participants obtained a placebo effect ( P = 0.01) and a trend for a nocebo effect ( P = 0.07). Patients with AD did not obtain a placebo effect ( P = 0.44) nor a significant nocebo effect ( P = 0.86). Healthy participants expected lower and higher pain with open vs hidden lidocaine and capsaicin, respectively ( P < 0.001). The same expectation effects were seen in patients with AD (open vs hidden lidocaine, P = 0.008; open vs hidden capsaicin, P < 0.001). With a well-controlled experimental setting, this study suggests that patients with AD may not experience placebo analgesia effects. Nocebo hyperalgesia effects in patients with AD needs further research. These findings may have implications for the conduction of clinical trials and the treatment of patients with AD in clinical practice., (Copyright © 2023 International Association for the Study of Pain.)

Dementia with Lewy bodies is characterized by a high burden of autonomic dysfunction and Lewy pathology in peripheral organs and components of the sympathetic and parasympathetic nervous system. Parasympathetic terminals may be quantified with 18F-fluoroetoxybenzovesamicol, a PET tracer that binds to the vesicular acetylcholine transporter in cholinergic presynaptic terminals. Parasympathetic imaging may be useful for diagnostics, improving our understanding of autonomic dysfunction and for clarifying the spatiotemporal relationship of neuronal degeneration in prodromal disease. Therefore, we aimed to investigate the cholinergic parasympathetic integrity in peripheral organs and central autonomic regions of subjects with dementia with Lewy bodies and its association with subjective and objective measures of autonomic dysfunction. We hypothesized that organs with known parasympathetic innervation, especially the pancreas and colon, would have impaired cholinergic integrity. To achieve these aims, we conducted a cross-sectional comparison study including 23 newly diagnosed non-diabetic subjects with dementia with Lewy bodies (74 ± 6 years, 83% male) and 21 elderly control subjects (74 ± 6 years, 67% male). We obtained whole-body images to quantify PET uptake in peripheral organs and brain images to quantify PET uptake in regions of the brainstem and hypothalamus. Autonomic dysfunction was assessed with questionnaires and measurements of orthostatic blood pressure. Subjects with dementia with Lewy bodies displayed reduced cholinergic tracer uptake in the pancreas (32% reduction, P = 0.0003) and colon (19% reduction, P = 0.0048), but not in organs with little or no parasympathetic innervation. Tracer uptake in a region of the medulla oblongata overlapping the dorsal motor nucleus of the vagus correlated with autonomic symptoms (rs = -0.54, P = 0.0077) and changes in orthostatic blood pressure (rs = 0.76, P < 0.0001). Tracer uptake in the pedunculopontine region correlated with autonomic symptoms (rs = -0.52, P = 0.0104) and a measure of non-motor symptoms (rs = -0.47, P = 0.0230). In conclusion, our findings provide the first imaging-based evidence of impaired cholinergic integrity of the pancreas and colon in dementia with Lewy bodies. The observed changes may reflect parasympathetic denervation, implying that this process is initiated well before the point of diagnosis. The findings also support that cholinergic denervation in the brainstem contributes to dysautonomia., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Introduction: Dementia after stroke is common and is a great concern for patients and their caregivers. The objective was to investigate if intravenous thrombolysis (IVT) for acute ischemic stroke (AIS) was associated with lower risk of dementia after stroke., Patients and Methods: When IVT was introduced in Denmark, not all eligible patients were treated due to restricted access. We conducted a nationwide register-based cohort study of all patients with AIS in Denmark from 2004 to 2011. IVT-treated patients were propensity score-matched with comparable non-treated patients. Cox proportional hazards regression was used to estimate the hazard ratio (HR) for all-cause and vascular dementia 2, 5, and 10 years after stroke., Results: Of the 5919 patients eligible for the study, 2305 IVT-treated patients were propensity score-matched with 2305 non-treated patients. Mean (SD) age was 66.6 (13.3) and 61.2% were male. Rate of all-cause dementia was lower for the IVT-treated 2 years (8.4/1000 person years (PY) vs 13.6/1000 PY, HR 0.63 (0.40-0.99)) and 5 years after stroke (7.3/1000 PY vs 11.4/1000 PY, HR 0.65 (0.46-0.91)). 10 years after stroke, the rates of all-cause dementia remained in favor of IVT (8.0/1000 PY vs 9.8/1000 PY, HR 0.83 (0.64-1.07)). IVT-treated had lower rates of vascular dementia 2 years (2.4/1000 PY vs 7.4/1000 PY, HR 0.33 (0.15-0.71)), 5 years (2.3/1000 PY vs 6.2/1000 PY, HR 0.38 (0.23-0.65)), and 10 years after stroke (3.0/1000 PY vs 5.4/1000 PY, HR 0.56 (0.38-0.81))., Conclusion: IVT treatment was associated with lower long-term risk of both vascular and all-cause dementia after AIS., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Neuron-derived extracellular vesicles (NDEVs) in blood may be used to derive biomarkers for the effects of exercise in Alzheimer's disease (AD). For this purpose, we studied changes in neuroprotective proteins proBDNF, BDNF, and humanin in plasma NDEVs from patients with mild to moderate AD participating in the randomized controlled trial (RCT) of exercise ADEX., Methods: proBDNF, BDNF, and humanin were quantified in NDEVs immunocaptured from the plasma of 95 ADEX participants, randomized into exercise and control groups, and collected at baseline and 16 weeks. Exploratorily, we also quantified NDEV levels of putative exerkines known to respond to exercise in peripheral tissues., Results: NDEV levels of proBDNF, BDNF, and humanin increased in the exercise group, especially in APOE ε4 carriers, but remained unchanged in the control group. Inter-correlations between NDEV biomarkers observed at baseline were maintained after exercise. NDEV levels of putative exerkines remained unchanged., Conclusions: Findings suggest that the cognitive benefits of exercise could be mediated by the upregulation of neuroprotective factors in NDEVs. Additionally, our results indicate that AD subjects carrying APOE ε4 are more responsive to the neuroprotective effects of physical activity. Unchanged NDEV levels of putative exerkines after physical activity imply that exercise engages different pathways in neurons and peripheral tissues. Future studies should aim to expand upon the effects of exercise duration, intensity, and type in NDEVs from patients with early AD and additional neurodegenerative disorders., Trial Registration: The Effect of Physical Exercise in Alzheimer Patients (ADEX) was registered in ClinicalTrials.gov on April 30, 2012 with the identifier NCT01681602., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Cholinergic changes play a fundamental role in the natural history of dementia with Lewy bodies and Lewy body disease in general. Despite important achievements in the field of cholinergic research, significant challenges remain. We conducted a study with four main objectives: (i) to examine the integrity of cholinergic terminals in newly diagnosed dementia with Lewy bodies; (ii) to disentangle the cholinergic contribution to dementia by comparing cholinergic changes in Lewy body patients with and without dementia; (iii) to investigate the in vivo relationship between cholinergic terminal loss and atrophy of cholinergic cell clusters in the basal forebrain at different stages of Lewy body disease; and (iv) to test whether any asymmetrical degeneration in cholinergic terminals would correlate with motor dysfunction and hypometabolism. To achieve these objectives, we conducted a comparative cross-sectional study of 25 newly diagnosed dementia with Lewy bodies patients (age 74 ± 5 years, 84% male), 15 healthy control subjects (age 75 ± 6 years, 67% male) and 15 Parkinson's disease patients without dementia (age 70 ± 7 years, 60% male). All participants underwent 18F-fluoroetoxybenzovesamicol PET and high-resolution structural MRI. In addition, we collected clinical 18F-fluorodeoxyglucose PET images. Brain images were normalized to standard space and regional tracer uptake and volumetric indices of basal forebrain degeneration were extracted. Patients with dementia showed spatially distinct reductions in cholinergic terminals across the cerebral cortex, limbic system, thalamus and brainstem. Also, cholinergic terminal binding in cortical and limbic regions correlated quantitatively and spatially with atrophy of the basal forebrain. In contrast, patients without dementia showed decreased cholinergic terminal binding in the cerebral cortex despite preserved basal forebrain volumes. In patients with dementia, cholinergic terminal reductions were most severe in limbic regions and least severe in occipital regions compared to those without dementia. Interhemispheric asymmetry of cholinergic terminals correlated with asymmetry of brain metabolism and lateralized motor function. In conclusion, this study provides robust evidence for severe cholinergic terminal loss in newly diagnosed dementia with Lewy bodies, which correlates with structural imaging measures of cholinergic basal forebrain degeneration. In patients without dementia, our findings suggest that loss of cholinergic terminal function occurs 'before' neuronal cell degeneration. Moreover, the study supports that degeneration of the cholinergic system is important for brain metabolism and may be linked with degeneration in other transmitter systems. Our findings have implications for understanding how cholinergic system pathology contributes to the clinical features of Lewy body disease, changes in brain metabolism and disease progression patterns., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Patients with Lewy body diseases exhibit variable degrees of cortical and subcortical hypometabolism. However, the underlying causes behind this progressive hypometabolism remain unresolved. Generalized synaptic degeneration may be one key contributor., Objective: The objective of this study was to investigate whether local cortical synaptic loss is proportionally linked to the magnitude of hypometabolism in Lewy body disease., Method: Using in vivo positron emission tomography (PET) we investigated cerebral glucose metabolism and quantified the density of cerebral synapses, as measured with [ 18 F]fluorodeoxyglucose ([ 18 F]FDG) PET and [ 11 C]UCB-J, respectively. Volumes-of-interest were defined on magnetic resonance T1 scans and regional standard uptake value ratios-1 values were obtained for 14 pre-selected brain regions. Between-group comparisons were conducted at voxel-level., Results: We observed regional differences in both synaptic density and cerebral glucose consumption in our cohorts of non-demented and demented patients with Parkinson's disease or dementia with Lewy bodies compared to healthy subjects. Additionally, voxel-wise comparisons showed a clear difference in cortical regions between demented patients and controls for both tracers. Importantly, our findings strongly suggested that the magnitude of reduced glucose uptake exceeded the magnitude of reduced cortical synaptic density., Conclusion: Here, we investigated the relationship between in vivo glucose uptake and the magnitude of synaptic density as measured using [ 18 F]FDG PET and [ 11 C]UCB-J PET in Lewy body patients. The magnitude of reduced [ 18 F]FDG uptake was greater than the corresponding decline in [ 11 C]UCB-J binding. Therefore, the progressive hypometabolism seen in Lewy body disorders cannot be fully explained by generalized synaptic degeneration. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Introduction: [ 18 F]fluoroetoxybenzovesamicol ([ 18 F]FEOBV) is a positron emission topography (PET) tracer for the vesicular acetylcholine transporter (VAChT), a protein located predominantly in synaptic vesicles in cholinergic nerve terminals. We aimed to use [ 18 F]FEOBV PET to study the cholinergic topography of the healthy human brain., Materials and Methods: [ 18 F]FEOBV PET brain data volumes of healthy elderly humans were normalized to standard space and intensity-normalized to the white matter. Stereotactic atlases of regions of interest were superimposed to describe and quantify tracer distribution. The spatial distribution of [ 18 F]FEOBV PET uptake was compared with histological and gene expression data., Results: Twenty participants of both sexes and a mean age of 73.9 ± 6.0 years, age-range [64; 86], were recruited. Highest tracer binding was present in the striatum, some thalamic nuclei, and the basal forebrain. Intermediate binding was found in most nuclei of the brainstem, thalamus, and hypothalamus; the vermis and flocculonodular lobe; and the hippocampus, amygdala, insula, cingulate, olfactory cortex, and Heschl's gyrus. Lowest binding was present in most areas of the cerebral cortex, and in the cerebellar nuclei and hemispheres. The spatial distribution of tracer correlated with immunohistochemical post-mortem data, as well as with regional expression levels of SLC18A3, the VAChT coding gene., Discussion: Our in vivo findings confirm the regional cholinergic distribution in specific brain structures as described post-mortem. A positive spatial correlation between tracer distribution and regional gene expression levels further corroborates [ 18 F]FEOBV PET as a validated tool for in vivo cholinergic imaging. The study represents an advancement in the continued efforts to delineate the spatial topography of the human cholinergic system in vivo., Competing Interests: Declarations of Competing Interest None., (Copyright © 2023. Published by Elsevier Inc.)

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., (© 2022 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

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., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Introduction: Aerobic exercise has been shown to modify Alzheimer pathology in animal models, and in patients with multiple sclerosis to reduce neurofilament light (NfL), a biomarker of neurodegeneration., Objective: To investigate whether a 16-week aerobic exercise program was able to reduce serum NfL in patients with mild Alzheimer's disease (AD)., Methods: This is a secondary analysis of data from the multi-center Preserving Cognition, Quality of Life, Physical Health, and Functional Ability in Alzheimer's disease: The Effect of Physical Exercise (ADEX) study. Participants were randomized to 16 weeks of moderate intensity aerobic exercise or usual care. Clinical assessment and measurement of serum NfL was done at baseline and after the intervention., Results: A total of 136 participants were included in the analysis. Groups were comparable at baseline except for APOE ε 4 carriership which was higher in the usual care group (75.3 versus 60.2%; p = 0.04). There was no effect of the intervention on serum NfL [intervention: baseline NfL (pg/mL) 25.76, change from baseline 0.87; usual care: baseline 27.09, change from baseline -1.16, p = 0.09]., Conclusion: The findings do not support an effect of the exercise intervention on a single measure of neurodegeneration in AD. Further studies are needed using other types and durations of exercise and other measures of neurodegeneration., Clinical Trial Registration: clinicaltrials.gov, identifier NCT01681602., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Frederiksen, Jensen, Høgh, Gergelyffy, Waldemar, Andersen, Gottrup, Vestergaard, Wermuth, Søndergaard, Sellebjerg, Hasselbalch and Simonsen.)

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., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: The α-syn Origin site and Connectome model (SOC) proposes that α-synucleinopathies can be divided into two categories: the asymmetrical brain-first, and more symmetrical body-first Lewy body disease. We have hypothesized that most patients with dementia with Lewy bodies (DLB) belong to the body-first subtype, whereas patients with Parkinson's disease (PD) more often belong to the brain-first subtype., Objective: To compare asymmetry of striatal dopaminergic dysfunction in DLB and PD patients using [18F]-FE-PE2I positron emission tomography (PET)., Methods: We analyzed [18F]-FE-PE2I PET data from 29 DLB patients and 76 PD patients who were identified retrospectively during a 5-year period at Dept. of Neurology, Aarhus University Hospital. Additionally, imaging data from 34 healthy controls was used for age-correction and visual comparison., Results: PD patients showed significantly more asymmetry in specific binding ratios between the most and least affected putamen (p < 0.0001) and caudate (p = 0.003) compared to DLB patients. PD patients also had more severe degeneration in the putamen compared to the caudate in comparison to DLB patients (p < 0.0001) who had a more universal pattern of striatal degeneration., Conclusion: Patients with DLB show significantly more symmetric striatal degeneration on average compared to PD patients. These results support the hypothesis that DLB patients may be more likely to conform to the body-first subtype characterized by a symmetrical spread of pathology, whereas PD patients may be more likely to conform to the brain-first subtype with more lateralized initial propagation of pathology.

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 β-amyloid 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., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Author(s).)

Facial expression is a key aspect in observational scales developed to improve pain assessment in individuals with cognitive impairments. Although these scales are used internationally in individuals with different types of cognitive impairments, it is not known whether observing facial expressions of pain might differ between regions or between different types of cognitive impairments. In a pilot study, facial responses to standardized experimental pressure pain were assessed among individuals with different types of cognitive impairments (dementia, mild cognitive impairment, Huntington's disease, and intellectual disability) from different countries (Denmark, Germany, Italy, Israel, and Spain) and were analyzed using facial descriptors from the PAIC scale (Pain Assessment in Impaired Cognition). We found high inter-rater reliability between observers from different countries. Moreover, facial responses to pain did not differ between individuals with dementia from different countries (Denmark, Germany, and Spain). However, the type of cognitive impairment had a significant impact; with individuals with intellectual disability (all being from Israel) showing the strongest facial responses. Our pilot data suggest that the country of origin does not strongly affect how pain is facially expressed or how facial responses are being scored. However, the type of cognitive impairment showed a clear effect in our pilot study, with elevated facial responses in individuals with intellectual disability.

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., (© 2021 International Parkinson and Movement Disorder Society.)

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 < 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)., Conclusion: 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.

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.

Lifestyle factors have been shown to increase the risk of developing Alzheimer's disease (AD) later in life. Specifically, an unfavorable cholesterol profile, and insulin resistance are associated with increased risk of developing AD. One way to non-pharmacologically affect the levels of plasma lipids is by exercise, which has been shown to be beneficial in cognitively healthy individuals. In this randomized controlled trial y, we therefore aimed to clarify the effect of physical exercise on the lipid profile, insulin and glucose in patients with AD. In addition, we investigated the effect of apolipoproteinE genotype on total cholesterol, high-density lipoprotein-cholesterol (HDL-C), low-density lipoprotein-cholesterol (LDL-C), and triglycerides (TG) in plasma from patients with AD. Plasma samples from 172 patients who underwent 16 weeks of moderate-to-high intensity exercise ( n = 90) or treatment as usual ( n = 82) were analyzed change from baseline for the levels of total cholesterol, LDL-C, HDL-C, TG, glucose, and insulin. In addition, we analyzed those from the exercise group who adhered to the protocol with an attendance of 2/3 or more of the exercise session and who followed the protocol of an intensity of 70% of the maximum heart rate. We found a significant increase in plasma HDL-C levels between the "high exercise sub-group" compared to control group. After intervention HDL-C was increased by 4.3% in the high-exercise group, and decreased by 0.7% in the control group, after adjustment for statin use. In conclusion, short term physical activity may be beneficial on the cholesterol profile in patients with AD., (Copyright © 2020 Jensen, Musaeus, Frikke-Schmidt, Andersen, Beyer, Gottrup, Høgh, Vestergaard, Wermuth, Frederiksen, Waldemar, Hasselbalch and Simonsen.)

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., Competing Interests: The Authors declare that there is no conflict of interest., (© 2020 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, Inc. on behalf of the Alzheimer's Association.)

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 11 C-PK11195 PET over 2 years to measure inflammation changes, and 11 C-PiB PET to determine β-amyloid fibril load; 22 also had serial 18 F-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 11 C-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 11 C-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 11 C-PiB uptake that remained stable were classified as non-AD, and they showed no correlated inflammation levels. Finally, MCI cases which showed both high 11 C-PiB and 18 F-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.

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., (© 2019 The Authors. International Journal of Geriatric Psychiatry published by John Wiley & Sons Ltd.)

Background and Purpose: In vivo detection of β-amyloid (Aβ) plaques in Alzheimer's disease (AD) is now possible with 11 C-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 11 C-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 11 C-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., (© 2019 by the American Society of Neuroimaging.)

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  < .001), attention and working memory ( p  < .001), processing speed ( p  < .001), and executive functioning ( p  < .001). Compared to RT- patients, RT + patients scored lower on domains concerning processing speed ( p  = .04) and executive function ( p  = .05) and had higher impairment frequency on verbal fluency ( p  = .02) with 16% of patients exceeding 1.5 SD below normative data. Conclusions: Our results indicate that treatment, including RT, for a primary brain tumor may have negative long-term impact on cognitive function, especially on processing speed and executive function.

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 AP OE 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 ( 11 C-(R)-PK11195), amyloid ( 11 C-PiB) and tau ( 18 F-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 ( 11 C-(R)-PK11195 BP ND ) and tau ( 18 F-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 18 F-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., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Alzheimer's disease (AD) is a progressive neurodegenerative disorder. AD pathology is characterized by abnormal aggregation of the proteins amyloid- β (A β ) 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 A β 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 A β 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.

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 < .001). The only symptom associated with brain tumour was the presence of a focal deficit (p = .002)., 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.

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 (P t O 2 )., Results: At baseline, poor cognitive performance and regional cortical thinning correlated with lower CBF and CBV, with higher MTT and CTH and with low P t O 2 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., (Copyright © 2017 the Alzheimer's Association. Published by Elsevier Inc. All rights reserved.)

See Kreisl (doi:10.1093/awx151) for a scientific commentary on this article.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., (© The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

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 <0.0001) and exercise self-efficacy (1.7 [0.5-2.8] points, P =0.004). Furthermore, an exercise attendance of ≥66.6% resulted in significant positive effects on single-task physical performance and dual-task performance., 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., (Copyright © 2016 the Alzheimer's Association. Published by Elsevier Inc. All rights reserved.)

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.

In animal models, the incretin hormone GLP-1 affects Alzheimer's disease (AD). We hypothesized that treatment with GLP-1 or an analog of GLP-1 would prevent accumulation of Aβ and raise, or prevent decline of, glucose metabolism (CMRglc) in AD. In this 26-week trial, we randomized 38 patients with AD to treatment with the GLP-1 analog liraglutide (n = 18), or placebo (n = 20). We measured Aβ load in brain with tracer [(11)C]PIB (PIB), CMRglc with [(18)F]FDG (FDG), and cognition with the WMS-IV scale (ClinicalTrials.gov NCT01469351). The PIB binding increased significantly in temporal lobe in placebo and treatment patients (both P = 0.04), and in occipital lobe in treatment patients (P = 0.04). Regional and global increases of PIB retention did not differ between the groups (P ≥ 0.38). In placebo treated patients CMRglc declined in all regions, significantly so by the following means in precuneus (P = 0.009, 3.2 μmol/hg/min, 95% CI: 5.45; 0.92), and in parietal (P = 0.04, 2.1 μmol/hg/min, 95% CI: 4.21; 0.081), temporal (P = 0.046, 1.54 μmol/hg/min, 95% CI: 3.05; 0.030), and occipital (P = 0.009, 2.10 μmol/hg/min, 95% CI: 3.61; 0.59) lobes, and in cerebellum (P = 0.04, 1.54 μmol/hg/min, 95% CI: 3.01; 0.064). In contrast, the GLP-1 analog treatment caused a numerical but insignificant increase of CMRglc after 6 months. Cognitive scores did not change. We conclude that the GLP-1 analog treatment prevented the decline of CMRglc that signifies cognitive impairment, synaptic dysfunction, and disease evolution. We draw no firm conclusions from the Aβ load or cognition measures, for which the study was underpowered.

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 changed 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.