Functional connectivity differences in Alzheimer's disease and amnestic mild cognitive impairment associated with AT(N) classification and anosognosia

Alzheimer's continuum biological profiles (A+T-N-, A+T+N-, A+T-N+, and A+T+N+) were established in the 2018 National Institute on Aging and Alzheimer's Association research framework for Alzheimer's disease (AD). We aim to assess the relation between AT(N) biomarker profiles and brain functional connectivity (FC) and assess the neural correlates of anosognosia. We assessed local functional coupling and between-network connectivity through between-group intrinsic local correlation and independent component analyses. The neural correlates of anosognosia were assessed via voxel-wise linear regression analysis in prodromal AD. Statistical significance for the FC analysis was set at p ≤ 0.05 false discovery rate (FDR)-corrected for cluster size. One hundred and twenty-one and 73 participants were included in the FC and the anosognosia analysis, respectively. The FC in the default mode network is greater in prodromal AD than AD with dementia (i.e., local correlation: T = 8.26, p-FDR &lt; 0.001, k = 1179; independent component analysis: cerebellar network, T = 4.01, p-FDR = 0.0012, k = 493). The default mode network is persistently affected in the early stages of Alzheimer's biological continuum. The anterior cingulate cortex (T = 2.52, p-FDR = 0.043, k = 704) is associated with anosognosia in prodromal AD.</p

Alzheimer’s disease in people with Down syndrome

Samenvatting Mensen met het syndroom van Down (trisomie 21) hebben een bijzonder hoog risico op het ontwikkelen van dementie door de ziekte van Alzheimer. Op 65-jarige leeftijd heeft 68–80% van hen dementie ontwikkeld, tegen 8–11% van de mensen in de algemene bevolking (zonder downsyndroom). Dit hoge risico wordt grotendeels verklaard door de aanwezigheid van het gen voor het amyloïd voorlopereiwit (APP) op chromosoom 21. Het gevolg is dat bij mensen met downsyndroom een overmatige hoeveelheid bèta-amyloïd wordt gevormd, een eiwit dat gemakkelijk samenklontert in extracellulaire plaques, een van de twee karakteristieke pathologische alzheimerkenmerken. Hoewel uitgebreide alzheimerpathologie aanwezig is vanaf 40-jarige leeftijd, kan het nog vele jaren duren voordat klinische dementiesymptomen optreden. Bij de ene persoon treden symptomen vroegtijdig op, terwijl anderen tot op hogere leeftijd symptoomvrij blijven. De zeer variabele tijdspanne waarin symptomen optreden, maakt het voorspellen van het ziekteverloop bijzonder lastig. Ten opzichte van de algemene bevolking, wordt dementiediagnostiek bij downsyndroom verder gecompliceerd door de (levenslange) aanwezigheid van een verstandelijke beperking, evenals karakteristiek gedrag en comorbiditeiten die dementieachtige symptomen kunnen geven. Dit artikel beschrijft de genetische link tussen het syndroom van Down en de ziekte van Alzheimer, diagnostische aspecten en het belang van dementiegerelateerde gedragsveranderingen. Hoewel bij dementie meestal direct wordt gedacht aan cognitieve problematiek, blijkt uit ons onderzoek dat gedragsveranderingen bij mensen met downsyndroom én dementie veel voorkomen. Specifieke gedragsveranderingen zijnmogelijk vroege alarmsignalen. Vroegsignalering van tekenen van dementie is van het allergrootste belang omde zorg tijdig aan te passen, de kwaliteit van leven zo langmogelijk op peil te houden en het lijden tot een minimumte beperken

Short- and Long-Term Functional Connectivity Differences Associated with Alzheimer's Disease Progression

Introduction: Progression of amnestic mild cognitive impairment (aMCI) to Alzheimer’s disease (AD) is a clinical event with highly variable progression rates varying from 10–15% up to 30–34%. Functional connectivity (FC), the temporal similarity between spatially remote neurophysiological events, has previously been reported to differ between aMCI patients who progress to AD (pMCI) and those who do not (i.e., remain stable; sMCI). However, these reports had a short-term follow-up and do not provide insight into long-term AD progression. Methods: Seventy-nine participants with a baseline and 78 with a 12-month, 51 with a 24-month, and 22 with a +48-month follow-up resting-state fMRI with aMCI diagnosis from the Alzheimer’s Disease Neuroimaging Initiative database were included. FC was assessed using the CONN toolbox. Local correlation and group independent component analysis were utilized to compare regional functional coupling and between-network FC, respectively, between sMCI and pMCI groups. Two-sample t tests were used to test for statistically significant differences between groups, and paired t-tests were used to assess cognitive changes over time. Results: All participants (i.e., 66 sMCI and 19 pMCI) had a baseline and a year follow-up fMRI scan. Progression from aMCI to AD occurred in 19 patients (10 at 12 months, 5 at 24 months, and 4 at &#x3e;48 months), while 73 MCI patients remained cognitively stable (sMCI). The pMCI and sMCI cognitive profiles were different. More between-network FC than regional functional coupling differences were present between sMCI and pMCI patients. Activation in the salience network (SN) and the default mode network (DMN) was consistently different between sMCI and pMCI patients across time. Discussion: sMCI and pMCI patients have different cognitive and FC profiles. Only pMCI patients showed cognitive differences across time. The DMN and SN showed local correlation and between-network FC differences between the sMCI and pMCI patient groups at multiple moments in time

Sleep architecture changes in the APP23 mouse model manifest at onset of cognitive deficits

Alzheimer's disease (AD), which accounts for most of the dementia cases, is, aside from cognitive deterioration, often characterized by the presence of non-cognitive symptoms such as activity and sleep disturbances. AD patients typically experience increased sleep fragmentation, excessive daytime sleepiness and night-time insomnia. Here, we sought to investigate the link between sleep architecture, cognition and amyloid pathology in the APP23 amyloidosis mouse model for AD. By means of polysomnographic recordings the sleep-wake cycle of freely-moving APP23 and wild-type (WT) littermates of 3, 6 and 12 months of age was examined. In addition, ambulatory cage activity was assessed by interruption of infrared beams surrounding the home cage. To assess visuo-spatial learning and memory a hidden-platform Morris-type Water Maze (MWM) experiment was performed. We found that sleep architecture is only slightly altered at early stages of pathology, but significantly deteriorates from 12 months of age, when amyloid plaques become diffusely present. APP23 mice of 12 months old had quantitative reductions of NREM and REM sleep and were more awake during the dark phase compared to WT littermates. These findings were confirmed by increased ambulatory cage activity during that phase of the light-dark cycle. No quantitative differences in sleep parameters were observed during the light phase. However, during this light phase, the sleep pattern of APP23 mice was more fragmented from 6 months of age, the point at which also cognitive abilities started to be affected in the MWM. Sleep time also positively correlated with MWM performance. We also found that spectral components in the EEG started to alter at the age of 6 months. To conclude, our results indicate that sleep architectural changes arise around the time the first amyloid plaques start to form and cognitive deterioration becomes apparent. These changes start subtle, but gradually worsen with age, adequately mimicking the clinical condition

Dementia symptoms in persons with severe/profound intellectual disability: Expertise of practice

Aim Life expectancy of people with severe or profound intellectual disability (SPID) increases, which contributes to the risk of developing dementia. However, early detection and diagnosing dementia is complex, because of their low-level baseline functioning. Therefore, the aim is to identify observable dementia symptoms in adults with SPID in available literature. Method A systematic literature search, in line with PRISMA guidelines, was conducted in PubMed, PsycINFO and Web of Science using a combination of search terms for SPID, dementia/aging and aged population. Results In total, fifteen studies met inclusion criteria. Cognitive, behavioral and psychological symptoms (BPSD) and a decline in the ability to perform activities of daily living as well as neurological and physical changes were found. This presentation gives an overview of reported symptoms of (possible) dementia-related symptoms in SPID. Conclusions Despite growing attention for dementia in people with ID in literature, only very few studies have studied dementia symptoms in SPID. Given the complexity of signaling and diagnosing dementia in SPID, dedicated studies are required to unravel the natural history of dementia in SPID, specifically focusing on observable symptoms for caregivers of (early) dementia in this population

Dementia in People with Severe/Profound Intellectual (and Multiple) Disabilities::practice-Based Observations of Symptoms

Introduction Observable dementia symptoms are hardly studied in people with severe/profound intellectual (and multiple) disabilities (SPI(M)D). Insight in symptomatology is needed for timely signaling/diagnosis. This study aimed to identify practice-based observations of dementia symptoms in this population. Methods Care professionals and family members were invited to complete a survey about symptoms. Quantitatively analyzed survey data were further deepened through semi-structured interviews with care professionals having vast experience in signaling/diagnosing dementia in this population. Symptoms were categorized using a symptom matrix. Results Survey respondents and interviewees frequently observed a decline in activities of daily living (ADL) functioning and behavioral and psychological changes, like increased irritability, anxiety, apathy and decreased eating/drinking behavior. Cognitive symptoms were particularly recognized in persons with verbal communication and/or walking skills. To lesser extent motor changes and medical comorbidities were reported. Conclusion Increased insight in dementia symptoms contributes to developing a dedicated screening instrument for dementia in people with SPI(M)D

The Anaesthetic Biobank of Cerebrospinal fluid:a unique repository for neuroscientific biomarker research

Background: The pathophysiology of numerous central nervous system disorders remains poorly understood. Biomarker research using cerebrospinal fluid (CSF) is a promising way to illuminate the neurobiology of neuropsychiatric disorders. CSF biomarker studies performed so far generally included patients with neurodegenerative diseases without an adequate control group. The Anaesthetic Biobank of Cerebrospinal fluid (ABC) was established to address this. The aims are to (I) provide healthy-control reference values for CSF-based biomarkers, and (II) to investigate associations between CSF-based candidate biomarkers and neuropsychiatric symptoms.&amp; nbsp; &amp; nbsp;Methods: In this cross-sectional study, we collect and store CSF and blood from adult patients undergoing spinal anaesthesia for elective surgery. Blood (20.5 mL) is collected during intravenous cannulation and CSF (10 mL) is aspirated prior to intrathecal local anaesthetic injection. A portion of the blood and CSF is sent for routine laboratory analyses, the remaining material is stored at &amp; minus;80 ?. Relevant clinical, surgical and anaesthetic data are registered. A neurological examination and Montreal Cognitive Assessment (MoCA) are performed pre-operatively and a subset of patients fill in questionnaires on somatic and mental health (depression, anxiety and stress).&amp; nbsp; Results: Four-hundred-fifty patients (58% male; median age: 56 years) have been enrolled in the ABC. The planned spinal anaesthetic procedure was not attempted for various reasons in eleven patients, in fourteen patients the spinal puncture failed and in twelve patients CSF aspiration was unsuccessful. A mean of 9.3 mL CSF was obtained in the remaining 413 of patients. Most patients had a minor medical history and 60% scored in the normal range on the MoCA (median score: 26).&amp; nbsp; Conclusions: The ABC is an ongoing biobanking project that can contribute to CSF-based biomarker research. The large sample size with constant sampling methods and extensive patient phenotyping provide excellent conditions for future neuroscientific research.</p