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Introduction: The established link between DNA methylation and pathophysiology of dementia, along with its potential role as a molecular mediator of lifestyle and environmental influences, positions blood-derived DNA methylation as a promising tool for early dementia risk detection., Methods: In conjunction with an extensive array of machine learning techniques, we employed whole blood genome-wide DNA methylation data as a surrogate for 14 modifiable and non-modifiable factors in the assessment of dementia risk in independent dementia cohorts., Results: We established a multivariate methylation risk score (MMRS) for identifying mild cognitive impairment cross-sectionally, independent of age and sex (P = 2.0 × 10 -3 ). This score significantly predicted the prospective development of cognitive impairments in independent studies of Alzheimer's disease (hazard ratio for Rey's Auditory Verbal Learning Test (RAVLT)-Learning = 2.47) and Parkinson's disease (hazard ratio for MCI/dementia   = 2.59)., Discussion: Our work shows the potential of employing blood-derived DNA methylation data in the assessment of dementia risk., Highlights: We used whole blood DNA methylation as a surrogate for 14 dementia risk factors. Created a multivariate methylation risk score for predicting cognitive impairment. Emphasized the role of machine learning and omics data in predicting dementia. The score predicts cognitive impairment development at the population level., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Introduction: Pain assessment in people with dementia is difficult, and withdrawal of analgesics may allow for assessment of treatment efficacy whilst decreasing pill burden, adverse events and interactions. We aimed to describe the use of analgesics among elderly in Denmark and to compile the evidence for withdrawal of analgesics among people with dementia., Methods: With respect to analgesics use, we employed data from national registries on the analgesic prescription use (opioids, nonsteroidal anti-inflammatory drugs (NSAIDs) and acetaminophen) in 2017 among elderly people with and without dementia. Trial evidence was produced by performing a systematic search in MEDLINE, Embase and Cinahl for trials evaluating withdrawal of analgesics in people with dementia., Results: Opioids were prescribed more frequently (p = 0.026) and NSAIDs less frequently (p = 0.026) to people with dementia. With respect to trial evidence, we identified two studies: An observational cross-over study (n = 3) reporting acetaminophen withdrawal leading to increases in pain frequency and duration, and a cluster-randomised clinical trial (n = 352) reporting changes in mobilization-observation-behaviour-intensity-dementia-2 (MOBID-2) pain score during a four-week withdrawal period (acetaminophen, opioids and/or pregabaline) from a mean ± standard deviation of 2.3 ± 2.1 to 2.9 ± 2.6 compared with 3.5 ± 2.6 to 3.5 ± 2.5 in the control group., Conclusions: In Denmark, use of opioids is higher in elderly with dementia compared to elderly without dementia. The evidence suggests that withdrawal of analgesics may aggravate pain but increases in pain scores may be of little clinical relevance in most people. Clinical trials investigating analgesics withdrawal are warranted., (Articles published in the DMJ are “open access”. This means that the articles are distributed under the terms of the Creative Commons Attribution Non-commercial License, which permits any non-commercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited.)

Background: Two dementia quality registries have been developed in Denmark and Sweden with the aim to assess quality of dementia care based on adherence to national guidelines., Objective: To compare patient characteristics, diagnostics, treatment, and quality indicators of dementia care among patients referred to specialist units in Sweden and Denmark., Methods: Data from the Swedish Dementia Registry (SveDem) and the Danish Dementia Registry were merged. Newly diagnosed dementia cases referred to memory clinics during 2007-2012 were included (19,629 Swedish and 6,576 Danish patients)., Results: The median duration between initial assessment and confirmed diagnosis was 56 and 57 days in Sweden and Denmark, respectively. Brain imaging using MRI was twice as common in Sweden. A diagnosis of dementia was established at an average MMSE of 21. An etiological diagnosis was concluded in 89.6% of the Swedish and 87.3% of the Danish cases. Alzheimer's disease (AD) was the most common disorder (47.7% in Denmark and 36.6% in Sweden); however, more cases were diagnosed as mixed AD in Sweden (24.7% versus 10.6% ). More than 80% of patients with AD, dementia with Lewy bodies, and Parkinson's disease with dementia were treated with anti-dementia drugs., Conclusion: The targets of several quality indicators in both registries were met, such that structural brain imaging and MMSE were performed in >90% and an etiological diagnosis was concluded in >80% of the patients. However, there were also results of concern. The diagnosis of dementia was established at a mean MMSE of 21, which is already late in the course of most dementia disorders. A higher chance of vascular findings following the higher rate of MRI in Sweden may have resulted in more mixed AD diagnosis, which could be one explanation for diagnostic differences but also highlights the need to harmonize diagnostic criteria.

Background/aim: Semantic memory deficits have been shown in dementia and mild cognitive impairment (MCI) by group comparisons. The aim of this study is to investigate the frequency of impairments on tests with semantic content in patients with dementia, MCI (amnestic and non-amnestic) and affective disorders., Methods: A Famous faces test, Boston Naming Test and Category fluency were applied in 114 consecutive memory clinic patients and 95 healthy participants (all participants were 60 years old or older; dementia/MCI patients had Mini-Mental State Examination scores ≥20)., Results: Fifty-three patients were classified with dementia, 36 with MCI (14 amnestic, 22 non-amnestic) and 25 with affective disorders. Dementia and MCI patients differed significantly from the control group on all tests. Patients with dementia and MCI had impairments in about 40% of the cases (on the most sensitive tests). However, patients with affective disorders also had mild impairments on tests tapping semantic memory (25% were impaired on the most sensitive tests). Impairments on the Famous faces test were more frequently found in dementia and MCI as compared to patients with affective disorders., Conclusion: Short tests with semantic memory content are sensitive to changes in dementia and MCI, but impairments on such tests may also be found in other diseases, e.g. affective disorders., (© 2014 S. Karger AG, Basel)

Background and Purpose: The European Federation of the Neurological Societies (EFNS) guidelines on the use of neuroimaging in the diagnosis and management of dementia are designed to revise and expand previous EFNS recommendations for the diagnosis and management of patients with Alzheimer's disease (AD) and to provide an overview of the evidence for the use of neuroimaging techniques in non-AD dementias, as well as general recommendations that apply to all types of dementia in clinical practice., Methods: The task force working group reviewed evidence from original research articles, meta-analyses and systematic reviews, published before April 2012. The evidence was classified, and consensus recommendations were given and graded according to the EFNS guidance regulations., Results: Structural imaging, which should be performed at least once in the diagnostic work-up of patients with cognitive impairment, serves to exclude other potentially treatable diseases, to recognize vascular lesions and to identify specific findings to help distinguish different forms of neurodegenerative types of dementia. Although typical cases of dementia may not benefit from routine functional imaging, these tools are recommended in those cases where diagnosis remains in doubt after clinical and structural imaging work-up and in particular clinical settings. Amyloid imaging is likely to find clinical utility in several fields, including the stratification of patients with mild cognitive impairment into those with and without underlying AD and the evaluation of atypical AD presentations., Conclusions: A number of recommendations and good practice points are made to improve the diagnosis of AD and other dementias., (© 2012 The Author(s) European Journal of Neurology © 2012 EFNS.)

Objective: Increased focus on the quality of health care requires tools and information to address and improve quality. One tool to evaluate and report the quality of clinical health services is quality indicators based on a clinical database., Method: The Capital Region of Denmark runs a quality database for dementia evaluation in the secondary health system. One volume and seven process quality indicators on dementia evaluations are monitored. Indicators include frequency of demented patients, percentage of patients evaluated within three months, whether the work-up included blood tests, Mini Mental State Examination (MMSE), brain scan and activities of daily living and percentage of patients treated with anti-dementia drugs. Indicators can be followed over time in an individual clinic. Up to 20 variables are entered to calculate the indicators and to provide risk factor variables for the data analyses., Results: The database was constructed in 2005 and covers 30% of the Danish population. Data from all consecutive cases evaluated for dementia in the secondary health system in the Capital Region of Denmark are entered. The database has shown that the basic diagnostic work-up programme with MMSE, and a brain scan is performed in almost all patients. Differences in the prevalence of etiological diagnoses indicate differences in the application of the diagnostic criteria. This has initiated a process to harmonize the use of diagnostic criteria and the MMSE including administration guide., Conclusion: Clinical quality indicators based on all patients evaluated for dementia can be used to standardize and harmonize the evaluation process and improve clinical health services.

Frontotemporal dementia constitutes the third most prevalent neurodegenerative disease with dementia. We compared cortical structural changes in nine presymptomatic CHMP2B frontotemporal dementia mutation positive individuals with seven mutation negative family members. Using serial MRI scans with a mean interval of 16 months and surface based cortical segmentation we measured cortical thickness and volume, and quantified atrophy rates. Cortical thickness and atrophy rates were averaged within major lobes and focal effects were determined by parametric statistical maps. The volumetric atrophy rates in the presymptomatic CHMP2B mutation carriers were statistically significant, though of a lower magnitude than those previously reported in patients of other types of frontotemporal dementia. Cortical thickness measurements revealed cortical thinning in mutation carriers bilaterally in the frontal and occipital lobes, and in the left temporal lobe. Results indicated that cortical thickness has a higher sensitivity for detecting small changes than whole-brain volumetric measures. Comparing mutation carriers with non-carriers revealed increased atrophy rates in mutation carriers bilaterally in the inferio-temporal cortex, the superior frontal cortex, and the insular cortex. These findings indicated impairment of regions involved in both behaviour and language. The symptoms previously reported in clinical CHMP2B frontotemporal dementia patients are associated with the anatomically affected regions here found in the presymptomatic mutation carriers.

Background/aims: CHMP2B mutations are a rare cause of familial frontotemporal dementia (FTD). The clinical syndrome is dominated by personality change and behavioural symptoms, but language, memory, calculation and praxis impairments are also seen early in the course of the disease. There are no detailed studies of brain imaging in CHMP2B mutation-associated FTD. This study aimed to investigate whether there were early or presymptomatic changes in this group of patients., Methods: Subjects comprised 16 members of a Danish family with CHMP2B mutation-associated FTD. Nine subjects were presymptomatic mutation carriers with a control group of 7 mutation-negative family members. Volumetric MRI brain scans were performed on all subjects at two time points, and rates of volume change were compared between the two groups., Results: We demonstrate that generalized atrophy occurs presymptomatically in CHMP2B gene mutation carriers., Conclusions: This finding suggests that mutations in CHMP2B have widespread effects throughout the brain, leading to a neuro-anatomical signature distinct from other diseases in the frontotemporal lobar degeneration spectrum., (Copyright 2009 S. Karger AG, Basel.)

A large Danish family has previously been reported in which autosomal dominant frontotemporal dementia (FTD) is genetically linked to chromosome 3 (FTD-3). A mutation was recently identified in the CHMP2B gene that is probably responsible for causing disease in this family. Because of its neuropathologic findings, FTD-3 was originally categorized as a subtype of frontotemporal lobar degeneration, termed "dementia lacking distinctive histopathology." We now report a reevaluation of the neuropathologic changes in this family. Postmortem material from 4 affected family members was available for examination. Gross examination revealed generalized cortical atrophy that was most severe in frontal and temporal cortices. Microscopy showed loss of cortical neurons, microvacuolation of layer II, mild gliosis, and demyelination of the deep white matter. Results of immunohistochemical staining for alpha-synuclein, prion protein, neurofilament, and tau protein were unremarkable. Variable numbers of small, round, ubiquitin-positive cytoplasmic inclusions were present in the dentate granule layer of the hippocampus in all 4 cases. Rare ubiquitin-positive inclusions were also found in frontal and temporal cortical neurons. These inclusions were also positive for p62 but not for TDP-43. The finding of ubiquitin- and p62-positive, TDP-43-negative cytoplasmic inclusions in the hippocampus and neocortex suggests reclassification of the neuropathology of FTD-3 as a unique subtype of frontotemporal lobar degeneration with ubiquitin-positive inclusions that are TDP-43-negative.

We have previously reported a large Danish pedigree with autosomal dominant frontotemporal dementia (FTD) linked to chromosome 3 (FTD3). Here we identify a mutation in CHMP2B, encoding a component of the endosomal ESCRTIII complex, and show that it results in aberrant mRNA splicing in tissue samples from affected members of this family. We also describe an additional missense mutation in an unrelated individual with FTD. Aberration in the endosomal ESCRTIII complex may result in FTD and neurodegenerative disease.

A large pedigree with autosomal dominant frontotemporal dementia has been identified. Positional cloning has linked the disease gene to the pericentromeric region of chromosome 3. Clinical, neuropsychological, imaging, pathological and molecular genetic data are presented. The genetic mutation responsible for the disease has not been identified., (Copyright 2004 S. Karger AG, Basel)

Background: The authors have identified and studied a large kindred in which frontotemporal dementia (FTD) is inherited as an autosomal dominant trait. The trait has been mapped to the pericentromeric region of chromosome 3., Methods: The authors report on the clinical, neuroimaging, neuropsychological, and pathologic features in this unique pedigree collected during 17 years of study., Results: Twenty-two individuals in three generations have been affected; the age at onset varies between 46 and 65 years. The disease presents with a predominantly frontal lobe syndrome but there is also evidence for temporal and dominant parietal lobe dysfunction. Late in the illness individuals develop a florid motor syndrome with pyramidal and extrapyramidal features. Structural imaging reveals generalized cerebral atrophy; H2 15 O-PET scanning in two individuals relatively early and late in the disease shows a striking global reduction in cerebral blood flow affecting all lobes. On macroscopic pathologic examination, there is generalized cerebral atrophy affecting the frontal lobes preferentially. Microscopically, there is neuronal loss and gliosis without specific histopathologic features., Conclusions: FTD-3 shares clinical and pathologic features with other forms of FTD and fulfills international consensus criteria for FTD. There is involvement of the parietal lobes clinically, radiologically, and pathologically in FTD-3 in contrast to some forms of FTD. This more diffuse involvement of the cerebral cortex leads to a distinctive, global pattern of reduced blood flow on PET scanning.

Certain genotypes of apolipoprotein E (apoE, locus APOE) are associated with an increased risk for development of Alzheimer's disease. We present the distribution of the APOE alleles (E2, E3 and E4) in 50 Danish patients referred to a dementia clinic. The distribution of alleles in patients with dementia was E2: 2, E3: 36 and E4: 38; and in 12 patients without dementia E2: 1, E3: 18, and E4: 5. The frequency of E4 alleles was significantly increased (chi 2 = 42; df = 1; p < 10(-4)) among patients with Alzheimer's disease compared with a Danish control population. The study demonstrates a strong association between Alzheimer's disease and the E4 allele. No difference was found in the frequency of the E4 allele between Alzheimer and non-Alzheimer demented patients.

Case reports of 110 patients referred to a neurological dementia clinic were reviewed to evaluate a standardized diagnostic program. The patients were evaluated by a neurologist, a gerontopsychiatrist, and a neuropsychologist. ICD-10 criteria were used. Fifty-two patients had dementia while 58 had not; of these, 27 suffered from other non-dementia diseases and 31 were without dementia or other psychiatric or neurological disease. Thirteen patients with Alzheimer's disease were treated with tacrine. Four patients underwent cobalamin substitution treatment and seven started antidepressant medication. Ten patients received acetylsalicylic acid (150 mg Q.D.) and two a levo-dopa-type drug. Twenty-six patients were followed by gerontopsychiatric district care. Because only 47% of the patients suspected of dementia actually fulfilled dementia criteria, the evaluation suggests that patients suspected of dementia benefit from a standardized diagnostic program in a specialist setting.

The prevalence of clinical dementia was assessed in three age groups of patients with Down syndrome in the county of Aarhus, Denmark: Group I: 14-16 years (n = 13), group 2: 23-29 years (n = 34), group 3: 50-60 years (n = 25). Seventy-two (85%) of 85 patients participated. Caregivers were interviewed and a neurological examination was performed. An EEG was recorded in 50 patients. Definite clinical dementia was defined as an acquired and progressive decline in 4 or more out of 17 items that are considered to indicate dementia in Down syndrome. Possible dementia was considered when 1-3 items were affected. Six (24%) in group 3 had definite clinical dementia. A further 6 patients in group 3 and 2 (6%) in group 2 had possible dementia. This is the first population-based study with a clinical assessment of the prevalence of dementia in Down syndrome.

This paper investigates the working practices of the Genetic Choir and the “Stem&Luister” project, in which the ensemble uses voice, sound and improvisation to explore and develop ways of connecting with people with dementia, thereby seeking to improve the experience of care. Their musical sessions are multilayered. First, through listening they develop a sense of the people and the environment. Then through introducing their vocal practices, they breach the prevailing sonic regime. Second, through immersing the residents in sound-making and singing, they draw on the material and sensorial qualities of sound. This gives access to those who were difficult to reach and offers both an alternative means of communication and enables the recognition of selves. A third layer concerns the strategic use of improvisation, of which the deployment of “ensemble” and “instant composition” are analysed. Recognising the compositional efforts in improvisation shows their work to be a form of design. It facilitates attention to personhood, relations, and diversity. This specific practice appears as an untapped resource for the health and wellbeing of people with cognitive and speech impairments. Theoretically, the findings have implications for the notion of care and provide support from practice to existing neurological evidence of the significance of music as a fundamental faculty for survival and wellbeing.

BackgroundLoss-of-function mutations in GRN cause frontotemporal lobar degeneration (FTLD). Patients with GRN mutations present with a uniform subtype of TAR DNA-binding protein 43 (TDP-43) pathology at autopsy (FTLD-TDP type A); however, age at onset and clinical presentation are variable, even within families. We aimed to identify potential genetic modifiers of disease onset and disease risk in GRN mutation carriers.MethodsThe study was done in three stages: a discovery stage, a replication stage, and a meta-analysis of the discovery and replication data. In the discovery stage, genome-wide logistic and linear regression analyses were done to test the association of genetic variants with disease risk (case or control status) and age at onset in patients with a GRN mutation and controls free of neurodegenerative disorders. Suggestive loci (p

ImportanceCerebral amyloid-β aggregation is an early event in Alzheimer disease (AD). Understanding the association between amyloid aggregation and cognitive manifestation in persons without dementia is important for a better understanding of the course of AD and for the design of prevention trials.ObjectiveTo investigate whether amyloid-β aggregation is associated with cognitive functioning in persons without dementia.Design, setting, and participantsThis cross-sectional study included 2908 participants with normal cognition and 4133 with mild cognitive impairment (MCI) from 53 studies in the multicenter Amyloid Biomarker Study. Normal cognition was defined as having no cognitive concerns for which medical help was sought and scores within the normal range on cognitive tests. Mild cognitive impairment was diagnosed according to published criteria. Study inclusion began in 2013 and is ongoing. Data analysis was performed in January 2017.Main outcomes and measuresGlobal cognitive performance as assessed by the Mini-Mental State Examination (MMSE) and episodic memory performance as assessed by a verbal word learning test. Amyloid aggregation was measured with positron emission tomography or cerebrospinal fluid biomarkers and dichotomized as negative (normal) or positive (abnormal) according to study-specific cutoffs. Generalized estimating equations were used to examine the association between amyloid aggregation and low cognitive scores (MMSE score ≤27 or memory z score≤-1.28) and to assess whether this association was moderated by age, sex, educational level, or apolipoprotein E genotype.ResultsAmong 2908 persons with normal cognition (mean [SD] age, 67.4 [12.8] years), amyloid positivity was associated with low memory scores after age 70 years (mean difference in amyloid positive vs negative, 4% [95% CI, 0%-7%] at 72 years and 21% [95% CI, 10%-33%] at 90 years) but was not associated with low MMSE scores (mean difference, 3% [95% CI, -1% to 6%], P = .16). Among 4133 patients with MCI (mean [SD] age, 70.2 [8.5] years), amyloid positivity was associated with low memory (mean difference, 16% [95% CI, 12%-20%], P

Abstract Introduction Underdetection of dementia in areas with low socioeconomic status (SES) may interfere with findings concerning associations between SES and dementia. Methods Using administrative registers we assessed the associations between age‐ and sex‐adjusted dementia incidence and neighborhood socioeconomic status (nSES) in 94 Danish municipalities. Wealth was divided into income quartiles and other nSES variables were dichotomized into high versus low according to the median. Results High population density (odds ratio [OR] 1.21, 95% confidence interval [CI] 1.18–1.24), higher proportion of inhabitants in higher income quartiles (P for trend

ImportanceCerebral amyloid-β aggregation is an early pathological event in Alzheimer disease (AD), starting decades before dementia onset. Estimates of the prevalence of amyloid pathology in persons without dementia are needed to understand the development of AD and to design prevention studies.ObjectiveTo use individual participant data meta-analysis to estimate the prevalence of amyloid pathology as measured with biomarkers in participants with normal cognition, subjective cognitive impairment (SCI), or mild cognitive impairment (MCI).Data sourcesRelevant biomarker studies identified by searching studies published before April 2015 using the MEDLINE and Web of Science databases and through personal communication with investigators.Study selectionStudies were included if they provided individual participant data for participants without dementia and used an a priori defined cutoff for amyloid positivity.Data extraction and synthesisIndividual records were provided for 2914 participants with normal cognition, 697 with SCI, and 3972 with MCI aged 18 to 100 years from 55 studies.Main outcomes and measuresPrevalence of amyloid pathology on positron emission tomography or in cerebrospinal fluid according to AD risk factors (age, apolipoprotein E [APOE] genotype, sex, and education) estimated by generalized estimating equations.ResultsThe prevalence of amyloid pathology increased from age 50 to 90 years from 10% (95% CI, 8%-13%) to 44% (95% CI, 37%-51%) among participants with normal cognition; from 12% (95% CI, 8%-18%) to 43% (95% CI, 32%-55%) among patients with SCI; and from 27% (95% CI, 23%-32%) to 71% (95% CI, 66%-76%) among patients with MCI. APOE-ε4 carriers had 2 to 3 times higher prevalence estimates than noncarriers. The age at which 15% of the participants with normal cognition were amyloid positive was approximately 40 years for APOE ε4ε4 carriers, 50 years for ε2ε4 carriers, 55 years for ε3ε4 carriers, 65 years for ε3ε3 carriers, and 95 years for ε2ε3 carriers. Amyloid positivity was more common in highly educated participants but not associated with sex or biomarker modality.Conclusions and relevanceAmong persons without dementia, the prevalence of cerebral amyloid pathology as determined by positron emission tomography or cerebrospinal fluid findings was associated with age, APOE genotype, and presence of cognitive impairment. These findings suggest a 20- to 30-year interval between first development of amyloid positivity and onset of dementia.

Through an international consortium, we have collected 37 tau- and TAR DNA-binding protein 43 (TDP-43)-negative frontotemporal lobar degeneration (FTLD) cases, and present here the first comprehensive analysis of these cases in terms of neuropathology, genetics, demographics and clinical data. 92% (34/37) had fused in sarcoma (FUS) protein pathology, indicating that FTLD-FUS is an important FTLD subtype. This FTLD-FUS collection specifically focussed on aFTLD-U cases, one of three recently defined subtypes of FTLD-FUS. The aFTLD-U subtype of FTLD-FUS is characterised clinically by behavioural variant frontotemporal dementia (bvFTD) and has a particularly young age of onset with a mean of 41 years. Further, this subtype had a high prevalence of psychotic symptoms (36% of cases) and low prevalence of motor symptoms (3% of cases). We did not find FUS mutations in any aFTLD-U case. To date, the only subtype of cases reported to have ubiquitin-positive but tau-, TDP-43- and FUS-negative pathology, termed FTLD-UPS, is the result of charged multivesicular body protein 2B gene (CHMP2B) mutation. We identified three FTLD-UPS cases, which are negative for CHMP2B mutation, suggesting that the full complement of FTLD pathologies is yet to be elucidated.