Dementia Continuum Research Articles

Investigating the association between the GAP-43 concentration with diffusion tensor imaging indices in Alzheimer’s dementia continuum

BackgroundSynaptic degeneration, axonal injury, and white matter disintegration are among the pathological events in Alzheimer’s disease (AD), for which growth-associated protein 43 (GAP-43) and diffusion tensor imaging (DTI) could be an indicator. In this study, the cerebrospinal fluid (CSF) GAP-43 clinical trajectories and their association with progression and AD hallmarks with white matter microstructural changes were evaluated.MethodsA total number of 133 participants were enrolled in GAP-43 and DTI values were compared between groups, both cross-sectionally and longitudinally with two and four-year follow-ups. Subsequently, the correlation between GAP-43 levels in the CSF and DTI values was investigated using Spearman’s correlation.ResultsThe CSF level of GAP-43 is negatively correlated with the mean diffusivity measures in Fornix (Cres)/Stria terminals in early and late MCI (rs=-0.478 p = 0.021 and rs=-0.425 p = 0.038). Additionally, the CSF level of GAP-43 is negatively correlated with fractional anisotropy in the cingulum in late MCI (rs=-0.437 p = 0.033). Moreover, the axial diffusivity in superior corona radiate (rs=-0.562 p = 0.005 and rs=-0.484 p = 0.036) and radial diffusivity in superior fronto-occipital fasciculus was negatively correlated with GAP-43 level in the early and mid-MCI participants (rs=-0.520 p = 0.011 and rs=-0.498 p = 0.030).ConclusionsPresynaptic marker GAP-43 in combination with DTI can be used as a novel biomarker to identify microstructural synaptic degeneration in the early MCI. In addition, it can be used as a biomarker for tracking the progression of AD and monitoring treatment efficacy.

Assessing the Linguistic Capacity Across Alzheimer's Disease and Its Preclinical Stages: Evidence from Narrative Macrostructure in Elderly Speakers of Greek.

The assessment of language deficits can be valuable in the early clinical diagnosis of neurodegenerative disorders, including Alzheimer's disease (AD). The present study aims to explore whether language markers at the macrostructural level could assist with the placement of an individual across the dementia continuum employing production data from structured narratives. We administered a Picture Sequence Narrative Discourse Task to 170 speakers of Greek: young healthy controls (yHC), cognitively intact healthy elders (eHC), elder participants with subjective cognitive impairment (SCI), with mild cognitive impairment (MCI), and with AD dementia at the mild/moderate stages. Structural MRIs, medical history, neurological examination, and neuropsychological/cognitive screening determined the status of each speaker to appropriately groupthem. The data analysis revealed that the Macrostructure Index, Irrelevant Info, and Narration Density markers can track cognitive decline and AD (p < 0.001; Macrostructural Index: eHC versus AD Sensitivity 93.8%, Specificity 74.4%, MCI versus AD Sensitivity 93.8%, Specificity 66.7%; Narration Density: eHC versus AD Sensitivity 90.6%, Specificity 71.8%, MCI versus AD Sensitivity 93.8%, Specificity 66.7%). Moreover, Narrative Complexity was significantly affected for subjects with AD, Irrelevant Info increased in the narrations of speakers with MCI and AD, while Narration Length did not appear to indubitably differentiate between the cognitively intact groups and the clinical ones. Narrative Macrostructure Indices provide valuable information on the language profile of speakers with(out) intact cognition revealing subtle early signs of cognitive decline and AD suggesting that the inclusion of language-based assessment tools would facilitate the clinical process.

Hand motor dysfunction is associated with both subjective and objective cognitive impairment across the dementia continuum.

Motor dysfunction is an important feature of early-stage dementia. Gait provides a non-invasive biomarker across the dementia continuum. Gait speed and rhythm aid risk stratification of incident dementia in subjective cognitive impairment (SCI) and associate with cognitive domains in mild cognitive impairment (MCI) and dementia. However, hand movement analysis, which may be more accessible, has never been undertaken in SCI, and rarely in MCI or dementia. We aimed to address this gap and improve understanding of hand motor-cognitive associations across the dementia continuum. 208 participants were recruited: 50 with dementia, 58 MCI, 40 SCI and 60 healthy controls. Consensus diagnoses were made after comprehensive gold-standard assessments. A computer key-tapping test measured frequency, dwell-time, rhythm, errors and speed. Associations between key-tapping and cognitive domains and diagnoses were analysed using regression. Classification accuracy was measured using Area under Receiver-Operating-Characteristic curves. Hand frequency and speed were associated with memory and executive domains (P≤.001). Nondominant hand rhythm was associated with all cognitive domains. Frequency, rhythm and speed were associated with SCI, MCI and dementia. Frequency and speed classified ≥94% of dementia, and ≥88% of MCI, from controls. Rhythm of nondominant hand classified ≥86% of dementia and MCI and 69% of SCI. Our findings show hand motor dysfunction occurs across the dementia continuum and, similar to gait, associates with executive and memory domains, and with cognitive diagnoses. Key-tapping performance differentiated dementia and MCI from healthy controls. More research is required before recommending key-tapping as a non-invasive motor biomarker of cognitive impairment.

Development of a smartphone screening test for preclinical Alzheimer’s disease and validation across the dementia continuum

BackgroundDementia prevalence is predicted to triple to 152 million globally by 2050. Alzheimer’s disease (AD) constitutes 70% of cases. There is an urgent need to identify individuals with preclinical AD, a 10–20-year period of progressive brain pathology without noticeable cognitive symptoms, for targeted risk reduction. Current tests of AD pathology are either too invasive, specialised or expensive for population-level assessments. Cognitive tests are normal in preclinical AD. Emerging evidence demonstrates that movement analysis is sensitive to AD across the disease continuum, including preclinical AD. Our new smartphone test, TapTalk, combines analysis of hand and speech-like movements to detect AD risk. This study aims to [1] determine which combinations of hand-speech movement data most accurately predict preclinical AD [2], determine usability, reliability, and validity of TapTalk in cognitively asymptomatic older adults and [3], prospectively validate TapTalk in older adults who have cognitive symptoms against cognitive tests and clinical diagnoses of Mild Cognitive Impairment and AD dementia.MethodsAim 1 will be addressed in a cross-sectional study of at least 500 cognitively asymptomatic older adults who will complete computerised tests comprising measures of hand motor control (finger tapping) and oro-motor control (syllabic diadochokinesis). So far, 1382 adults, mean (SD) age 66.20 (7.65) years, range 50–92 (72.07% female) have been recruited. Motor measures will be compared to a blood-based AD biomarker, phosphorylated tau 181 to develop an algorithm that classifies preclinical AD risk. Aim 2 comprises three sub-studies in cognitively asymptomatic adults: (i) a cross-sectional study of 30–40 adults to determine the validity of data collection from different types of smartphones, (ii) a prospective cohort study of 50–100 adults ≥ 50 years old to determine usability and test-retest reliability, and (iii) a prospective cohort study of ~1,000 adults ≥ 50 years old to validate against cognitive measures. Aim 3 will be addressed in a cross-sectional study of ~200 participants with cognitive symptoms to validate TapTalk against Montreal Cognitive Assessment and interdisciplinary consensus diagnosis.DiscussionThis study will establish the precision of TapTalk to identify preclinical AD and estimate risk of cognitive decline. If accurate, this innovative smartphone app will enable low-cost, accessible screening of individuals for AD risk. This will have wide applications in public health initiatives and clinical trials.Trial registrationClinicalTrials.gov identifier: NCT06114914, 29 October 2023. Retrospectively registered.

Plasma biomarkers of Alzheimer's disease in the continuum of dementia with Lewy bodies.

Patients with dementia with Lewy bodies (DLB) may have Alzheimers disease (AD) pathology that can be detected by plasma biomarkers. Our objective was to evaluate plasma biomarkers of AD and their association with positron emission tomography (PET) biomarkers of amyloid and tau deposition in the continuum of DLB, starting from prodromal stages of the disease. The cohort included patients with isolated rapid eye movement (REM) sleep behavior disorder (iRBD), mild cognitive impairment with Lewy bodies (MCI-LB), or DLB, with a concurrent blood draw and PET scans. Abnormal levels of plasma glial fibrillary acidic protein (GFAP) were found at the prodromal stage of MCI-LB in association with increased amyloid PET. Abnormal levels of plasma phosphorylated tau (p-tau)-181 and neurofilament light (NfL) were found at the DLB stage. Plasma p-tau-181 showed the highest accuracy in detecting abnormal amyloid and tau PET in patients with DLB. The range of AD co-pathology can be detected with plasma biomarkers in the DLB continuum, particularly with plasma p-tau-181 and GFAP.

Plasma biomarkers of Alzheimer´s disease in the continuum of dementia with Lewy bodies

AbstractBackgroundPatients with dementia with Lewy bodies (DLB) may have Alzheimer´s disease (AD) pathology. Plasma biomarkers of beta‐amyloid (Aβ), phosphorylated tau (pTau), and neurodegeneration are sensitive to AD neuropathologic changes in AD dementia. While these plasma biomarkers are well tested in the AD continuum, their performance for concomitant AD pathology in the DLB continuum is still unclear.MethodWe included patients with isolated REM sleep behavior disorder (iRBD; n = 15), with mild cognitive impairment with Lewy bodies (MCI‐LB; n = 37), and with DLB (n = 70) from the Mayo Clinic Alzheimer’s Disease Research Center. Cognitively unimpaired individuals (CU; n = 100) included from the Mayo Clinic Study of Aging were balanced on age and sex. A panel of plasma biomarkers of Aβ40, Aβ42, p‐tau181, neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP) measures was obtained. We calculated the ratio of plasma Aβ40/42. Lower Aβ40/42 indicates increased Aβ pathology. Plasma Aβ40, Aβ42, GFAP, and NfL were measured using the Simoa® Neurology 4‐Plex E Advantage kit and pTau‐181 was measured with the Simoa® pTau‐181 Advantage V2 kit. Both were run on a Quanterix HD‐X analyzer. AD imaging biomarkers were assessed on PET using Pittsburgh compound B (PiB) for Aβ and 18F‐Flortaucipir for tau.ResultHigher levels of plasma GFAP were observed in the MCI‐LB (p = 0.014) and DLB (p&lt;0.001) groups compared to CU (Figure). DLB patients also showed higher levels of plasma pTau181 (p&lt;0.001) and NfL (p&lt;0.001). Higher amyloid and tau PET standardized uptake value ratio (SUVr) in the DLB continuum were associated with higher levels of plasma p‐tau181, NfL, and GFAP (p&lt;0.001). After accounting for age, plasma Aβ40/42 did not correlate with amyloid or tau PET SUVr.ConclusionIn the DLB continuum, abnormal levels of GFAP in plasma can be detected as early as the prodromal stages of the disease. Plasma pTau181 reached abnormal levels in the DLB stage. Higher plasma GFAP, NfL, and p‐tau181 are associated with higher amyloid and tau PET SUVr in the DLB continuum. Plasma biomarkers have the potential to contribute to screening and early diagnosis in the DLB continuum, which has implications in designing new treatments.

Plasma biomarkers of Alzheimer´s disease in the continuum of dementia with Lewy bodies

AbstractBackgroundPatients with dementia with Lewy bodies (DLB) may have Alzheimer´s disease (AD) pathology. Plasma biomarkers of beta‐amyloid (Aß), phosphorylated tau (pTau), and neurodegeneration are sensitive to AD neuropathologic changes in AD dementia. While these plasma biomarkers are well tested in the AD continuum, their performance for concomitant AD pathology in the DLB continuum is still unclear.MethodWe included patients with isolated REM sleep behavior disorder (iRBD; n = 15), with mild cognitive impairment with Lewy bodies (MCI‐LB; n = 37), and with DLB (n = 70) from the Mayo Clinic Alzheimer’s Disease Research Center. Cognitively unimpaired individuals (CU; n = 100) included from the Mayo Clinic Study of Aging were balanced on age and sex. A panel of plasma biomarkers of Aß40, Aß42, p‐tau181, neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP) measures was obtained. We calculated the ratio of plasma Aß40/42. Lower Aß40/42 indicates increased Aß pathology. Plasma Aß40, Aß42, GFAP, and NfL were measured using the Simoa® Neurology 4‐Plex E Advantage kit and pTau‐181 was measured with the Simoa® pTau‐181 Advantage V2 kit. Both were run on a Quanterix HD‐X analyzer. AD imaging biomarkers were assessed on PET using Pittsburgh compound B (PiB) for Aß and 18F‐Flortaucipir for tau.ResultHigher levels of plasma GFAP were observed in the MCI‐LB (p = 0.014) and DLB (p&lt;0.001) groups compared to CU (Figure). DLB patients also showed higher levels of plasma pTau181 (p&lt;0.001) and NfL (p&lt;0.001). Higher amyloid and tau PET standardized uptake value ratio (SUVr) in the DLB continuum were associated with higher levels of plasma p‐tau181, NfL, and GFAP (p&lt;0.001). After accounting for age, plasma Aß40/42 did not correlate with amyloid or tau PET SUVr.ConclusionIn the DLB continuum, abnormal levels of GFAP in plasma can be detected as early as the prodromal stages of the disease. Plasma pTau181 reached abnormal levels in the DLB stage. Higher plasma GFAP, NfL, and p‐tau181 are associated with higher amyloid and tau PET SUVr in the DLB continuum. Plasma biomarkers have the potential to contribute to screening and early diagnosis in the DLB continuum, which has implications in designing new treatments.

Clinical validation of TAS Test automated hand motor analysis to discriminate subjective cognitive decline, mild cognitive impairment and dementia in a multidisciplinary cognitive clinic

AbstractBackgroundGait analysis studies have shown that motor function declines across the Alzheimer’s disease (AD) continuum and may aid early detection of dementia risk. Hand movement analysis has been poorly investigated in comparison to gait but may be easier to assess using computer keyboards. TAS Test is a new automated online test of hand movements. The aim of this study was to evaluate TAS Test keyboard tapping tests compared to gold standard consensus diagnosis in a multidisciplinary team (MDT) cognitive clinic.MethodParticipants attending the ISLAND Cognitive Clinic in Tasmania, Australia underwent extensive neuropsychological, medical and MRI assessments before an MDT consensus diagnosis was formulated. They also completed 5 minutes of TAS Test keyboard tapping tests including single‐, alternate‐ and 3 step‐ key tapping tests. Motor features of frequency, rhythm, accuracy, and dwell time were extracted. Healthy controls (HC) with normal cognition also completed TAS Test. Accuracy to discriminate diagnostic groups using TAS Test motor features, adjusted for age, in ridge regression models was assessed using area under ROC curves (AUC) and compared to a null model which comprised only confounding variables.Result205 participants were recruited (mean [SD] age 69.0 [8.9] years): 91 from the Cognitive Clinic with Subjective Cognitive Decline (SCD, N = 16), Mild Cognitive Impairment (MCI, N = 40) or Dementia (N = 35) and 114 HCs. TAS Test discriminated better than null models with the following AUCs [95% CI]: SCD from HC: 0.82 [0.73‐0.91], MCI from HC: 0.78 [0.69‐0.86], Dementia from HC: 0.91 [0.86‐0.97], MCI from SCD: 0.7 [0.63‐ 0.92], Dementia from MCI: 0.82 [0.82‐0.97], all p &lt;0.01. Hand tests were characterized by progressively slower, less rhythmic movements, with more pauses and less accuracy across the dementia continuum. Dominant hand features were more discriminatory than non‐dominant hand features.ConclusionA simple brief battery of keyboard tapping tests via the TAS Test website aids stratification of diagnostic groups. This novel hand motor approach is more accessible than gait analysis and opens new opportunities for objective motor measure in clinical and research applications. Longitudinal research is underway to assess if TAS Test can aid prediction of cognitive decline in cognitively healthy controls.

Associations between ruminative brooding and white matter change amongst healthy middle‐aged and older adults

AbstractBackgroundRepetitive Negative Thinking (RNT) includes negative thoughts about the future (worry) and past (ruminative brooding). RNT has been associated with Alzheimer’s disease (AD) pathology (Marchant et al. Alzheimers Dement. 2020;16(7)) and different patterns of functional connectivity of the triple network of attention, namely, the default mode, executive control and anterior salience networks (Solé‐Padullés et al. Front Aging Neurosci. 2022;14). However, the association between RNT and white matter microstructure is unclear (Demnitz‐King et al. Psychiatry Res Neuroimaging. 2021;316) and no existing studies have examined this association longitudinally among non‐clinical adults.MethodHealthy adults (age range: 50‐70, 51.2% women) from the Barcelona Brain Health Initiative (Cattaneo et al. Front Aging Neurosci. 2018 11;10) completed the Perseverative Thinking Questionnaire (PTQ), Rumination Response Scale (RRS), and Penn‐State Worry Questionnaire (PSWQ) at baseline to measure RNT levels. Participants underwent a magnetic resonance imaging (MRI) with T1 and T2‐weighted acquisitions to assess volume of white matter hypointensities (WMH) at baseline (N = 588) and two years later (N = 425). Change in WMH was computed taking into account time interval between scans. Stepwise linear regression analyses were conducted to investigate associations between change in WMH and baseline age, sex, PTQ, PSWQ and RRS subscale scores (brooding, reflection and depression).ResultBaseline age (t = 3.71, p&lt;0.0001) and brooding (t = 2.82, p = 0.005) were associated with increased WMH across scans (see partial regression plots, Fig 1A/B). No cross‐sectional associations were observed between volume of WMH and RNT‐related variables.ConclusionBrooding was associated with increase of WMH in healthy adults. Brooding, a maladaptive form of emotion regulation, enhances repetitive focus on one’s distress and is associated with altered connectivity of attentional networks and greater asymmetry of the Superior Longitudinal Fasciculus in depressed adults (Pisner et al. Neuroimage Clin. 2019;24). Our results are of importance considering that: WMH correlate with CSF‐amyloid in cognitively unimpaired older adults (Wei et al. Brain Behav. 2019;9(12)) and this is the first longitudinal study focusing on white matter change as related to psychological variables linked to cognitive decline and AD‐related pathology. The putative impact of psychological factors on brain integrity can be detected even at sub‐clinical levels and in earlier stages within the dementia continuum.

The electronic Person Specific Outcome Measure (ePSOM) development program in the US: A survey to understand what matters to individuals most about their brain health

AbstractBackgroundIt is essential both drug and lifestyle‐based interventions aimed to delay the onset of advanced cognitive decline deliver a meaningful outcome for the patient. In the early stages of Alzheimer’s disease and related dementias (ADRDs), patient‐reported outcome (PRO) measures should be used in parallel with biological investigations of ADRDs to provide a complementary endpoint offering further proof of intervention’s effectiveness from the patients’ point of view. The aim of the electronic Person‐Specific Outcome Measure (ePSOM) programme is to develop a scalable, easily accessible and efficient PRO tool for monitoring personally meaningful outcomes in early ADRD.MethodWe designed and ran an online nation‐wide study to understand what matters to people about their brain health in the US. The ePSOM US survey started in Jan 2023 and collects primarily free‐text responses along with sociodemographic information and self‐reported neurodegenerative disease diagnosis. Respondents are presented with five domains and asked to describe in their own words their brain‐health priorities. Free‐text data will be analysed using Natural Language Processing (NLP) techniques to identify the most common brain‐health priorities by key sociodemographic groups. We will also compare these results with previously published UK results to look for any notable differences between the US and UK respondents’ priorities.ResultThe survey aims to recruit n = 6,000 respondents. Data collection started early 2023 and is planned to be complete by Spring/Summer 2023. The previously published ePSOM UK study (Saunders et al., 2021) with n = 5,808 respondents resulted in over 80,000 free‐text responses and 184 unique priority themes about brain health. We will present the preliminary results of the US study at AAIC and contextualising the results in light of new pharmacological treatments approved for AD.ConclusionThis large‐scale population‐based study will offer an evidence base for what outcomes constitute a meaningful impact of new treatments. Previous work from our group suggests that brain health priorities shift along the preclinical, prodromal and dementia continuum. The ultimate aim of the ePSOM programme is to design an electronic outcomes app which would allow an individual to define the most important outcomes against which we should measure treatment success across a range of severities.

Clinical validation of TAS Test automated hand motor analysis to discriminate subjective cognitive decline, mild cognitive impairment and dementia in a multidisciplinary cognitive clinic

AbstractBackgroundGait analysis studies have shown that motor function declines across the Alzheimer’s disease (AD) continuum and may aid early detection of dementia risk. Hand movement analysis has been poorly investigated in comparison to gait but may be easier to assess using computer keyboards. TAS Test is a new automated online test of hand movements. The aim of this study was to evaluate TAS Test keyboard tapping tests compared to gold standard consensus diagnosis in a multidisciplinary team (MDT) cognitive clinic.MethodParticipants attending the ISLAND Cognitive Clinic in Tasmania, Australia underwent extensive neuropsychological, medical and MRI assessments before an MDT consensus diagnosis was formulated. They also completed 5 minutes of TAS Test keyboard tapping tests including single‐, alternate‐ and 3 step‐ key tapping tests. Motor features of frequency, rhythm, accuracy, and dwell time were extracted. Healthy controls (HC) with normal cognition also completed TAS Test. Accuracy to discriminate diagnostic groups using TAS Test motor features, adjusted for age, in ridge regression models was assessed using area under ROC curves (AUC) and compared to a null model which comprised only confounding variables.Result205 participants were recruited (mean [SD] age 69.0 [8.9] years): 91 from the Cognitive Clinic with Subjective Cognitive Decline (SCD, N = 16), Mild Cognitive Impairment (MCI, N = 40) or Dementia (N = 35) and 114 HCs. TAS Test discriminated better than null models with the following AUCs [95% CI]: SCD from HC: 0.82 [0.73‐0.91], MCI from HC: 0.78 [0.69‐0.86], Dementia from HC: 0.91 [0.86‐0.97], MCI from SCD: 0.7 [0.63‐ 0.92], Dementia from MCI: 0.82 [0.82‐0.97], all p &lt;0.01. Hand tests were characterized by progressively slower, less rhythmic movements, with more pauses and less accuracy across the dementia continuum. Dominant hand features were more discriminatory than non‐dominant hand features.ConclusionA simple brief battery of keyboard tapping tests via the TAS Test website aids stratification of diagnostic groups. This novel hand motor approach is more accessible than gait analysis and opens new opportunities for objective motor measure in clinical and research applications. Longitudinal research is underway to assess if TAS Test can aid prediction of cognitive decline in cognitively healthy controls.

Investigating biological age as a predictor of symptom progression in Alzheimer’s disease

AbstractBackgroundAge is the strongest risk factor for dementia, including Alzheimer’s disease (AD). However, across individuals of the same chronological age there is considerable heterogeneity in rates of cognitive decline. These differences have been attributed to individual differences in age‐related biological processes, including brain protein expression. To capture these differences, we developed a measure of protein brain age from cerebrospinal fluid (CSF)‐proteins, and validated its predictive utility.MethodsIn older adults across the dementia continuum enrolled in DELCODE (training cohort; N = 488, 5‐year follow‐up) and patients with subjective cognitive decline and mild cognitive impairment (MCI) from the memory‐clinic based Fundació ACE (FACE) cohort (test cohort; N = 509, 3‐year follow‐up), 1063 CSF‐proteins were measured using OLINK‐technology. Proteins optimally predicting chronological age in A/T/N‐negative individuals without dementia from DELCODE (N = 196) were selected based on a LASSO‐regression and summarized into a BrainProteinAge‐score for all participants. A harmonized, age‐sensitive cognitive composite was created and the association between BrainProteinAge and cognitive decline assessed using structural equation modeling. Further, the predictive utility of ProteinBrainAge for incident all‐cause‐dementia was examined using time‐dependent ROC analysis in MCI patients from the test cohort.Results118 CSF‐proteins were selected and used to calculate BrainProteinAge. In the training (Est[SE] = 0.06[0.02],p&lt;0.001) and test (Est[SE] = 0.04[0.02],p = 0.013) cohorts, BrainProteinAge predicted cognitive decline beyond demographic characteristics (chronological age, sex, education) and A/T/N profiles. ProteinBrainAge captured 40% of the processes linking chronological age and cognitive decline, and improved prediction to all‐cause dementia beyond demographic characteristics and A/T/N profiles in MCI‐patients (1‐year AUC: 0.78 versus 0.82, p(difference) = 0.006). Specifically, within the AD‐continuum, BrainProteinAge (HR[CI] = 1.056[1.004‐1.110]), compared to chronological age (HR[CI] = 1.022[0.990‐1.054]), has greater predictive utility. Whilst an 8.6‐year ProteinBrainAge difference corresponded to the same risk increase observed between A+/T+ and A+/T‐ MCI patients, a difference of 24.6‐years was required for chronological age. All results remained substantively unchanged when using an optimized BrainProteinAge based on 10 proteins most strongly linked to cognitive decline.ConclusionsA new measure of biological age improves individualized prediction of cognitive decline and conversion to dementia in memory clinic patients. This provides an opportunity for precision medicine and a better understanding of age‐related biological processes contributing to dementia.

Associations between white matter integrity of the cingulum bundle, surrounding gray matter regions, and cognition across the dementia continuum.

Previous Alzheimer's disease and related dementias (AD/ADRD) research studies have illustrated the significance of studying alterations in white matter (WM). Fewer studies have examined how WM integrity, measured with diffusion tensor imaging (DTI), is associated with volume of gray matter (GM) regions and measures of cognitive function in aged participants spanning the dementia continuum. Magnetic resonance imaging and cognitive data were collected from 241 Boston University Alzheimer's Disease Research Center participants who spanned from cognitively normal controls to amnestic mild cognitive impairment to having dementia. Primary DTI tracts of interest were the cingulum ventral (CV) and cingulum dorsal (CD) pathways. GM regions of interest (ROIs) were in the medial temporal lobe (MTL), prefrontal cortex, and retrosplenial cortex. Analyses of covariance models were used to assess differences in WM integrity across groups (control, amnestic mild cognitive impairment, and dementia). Multiple linear regression models were used to assess associations between WM integrity and GM volume, and with measures of memory and executive function. Differences in WM integrity were shown in both cingulum pathways in participants across the dementia continuum. Associations between WM integrity of both cingulum pathways and volume of selected GM ROIs were widespread. Functionally significant associations were found between WM of the CV pathway and memory, independent of MTL GM volume. Differences in WM integrity of the cingulum bundle and surrounding GM ROI are likely related to the progression of AD/ADRD. Such differences should continue to be studied, particularly in association with memory performance.

Change in Purpose in Life Before and After Onset of Cognitive Impairment

Purpose in life is a critical aspect of psychological well-being that is associated with better cognitive outcomes across the continuum of dementia. To our knowledge, the natural history of purpose with onset of cognitive impairment has yet to be evaluated. To evaluate changes in purpose in life prior to and after onset of cognitive impairment. This cohort study used assessments of purpose in life and cognitive status from March 2006 to May 2021 in the Health and Retirement Study (HRS) and from May 2011 to November 2021 in the National Health and Aging Trends Study (NHATS). Cognitive impairment at each wave based on established thresholds in HRS and NHATS. The main outcome was purpose in life, measured with the Ryff Measures of Psychological Well-Being in HRS and a validated item in NHATS. In HRS, 22 668 participants provided 50 985 assessments of purpose across all waves. In NHATS, 10 786 participants provided 53 880 assessments of purpose across all waves. In HRS, 58.3% of participants were female, with mean (SD) age of 64.76 (10.41) years at baseline; in NHATS, 57.4% were female, with mean (SD) age of 76.82 (7.71) years at baseline. Across waves, 6794 HRS participants (30%) and 4446 NHATS participants (41.2%) were in the cognitive impairment range. Accounting for demographic covariates and normative change in purpose, multilevel modeling indicated that standardized purpose in life declined significantly prior to onset of cognitive impairment (estimate for 10 years) in both HRS (b = -0.12; 95% CI, -0.17 to -0.07; P < .001) and NHATS (b = -0.10; 95% CI, -0.20 to -0.01; P = .03). Purpose declined significantly more rapidly following onset of cognitive impairment, with a standardized decline nearly 3 times larger compared with prior to impairment in HRS (b = -0.35; 95% CI, -0.41 to -0.29; P < .001) and 4 times larger in NHATS (b = -0.44; 95% CI, -0.53 to -0.34; P < .001). In this cohort study, purpose in life declined with emergence of cognitive impairment. The decline before onset was too small to be useful to detect impending impairment in clinical settings. The steeper decline following impairment suggests that individuals are aware that their purpose is declining. Purpose may be an intervention target following cognitive impairment to maintain well-being and to reduce or slow emergence of behavioral symptoms associated with low purpose.

β-Amyloid Load on PET Along the Continuum of Dementia With Lewy Bodies.

β-Amyloid (Aβ) plaques can co-occur with Lewy-related pathology in patients with dementia with Lewy bodies (DLB), but Aβ load at prodromal stages of DLB still needs to be elucidated. We investigated Aβ load on PET throughout the DLB continuum, from an early prodromal stage of isolated REM sleep behavior disorder (iRBD) to a stage of mild cognitive impairment with Lewy bodies (MCI-LB), and finally DLB. We performed a cross-sectional study in patients with a diagnosis of iRBD, MCI-LB, or DLB from the Mayo Clinic Alzheimer Disease Research Center. Aβ levels were measured by Pittsburgh compound B (PiB) PET, and global cortical standardized uptake value ratio (SUVR) was calculated. Global cortical PiB SUVR values from each clinical group were compared with each other and with those of cognitively unimpaired (CU) individuals (n = 100) balanced on age and sex using analysis of covariance. We used multiple linear regression testing for interaction to study the influences of sex and APOE ε4 status on PiB SUVR along the DLB continuum. Of the 162 patients, 16 had iRBD, 64 had MCI-LB, and 82 had DLB. Compared with CU individuals, global cortical PiB SUVR was higher in those with DLB (p < 0.001) and MCI-LB (p = 0.012). The DLB group included the highest proportion of Aβ-positive patients (60%), followed by MCI-LB (41%), iRBD (25%), and finally CU (19%). Global cortical PiB SUVR was higher in APOE ε4 carriers compared with that in APOE ε4 noncarriers in MCI-LB (p < 0.001) and DLB groups (p = 0.049). Women had higher PiB SUVR with older age compared with men across the DLB continuum (β estimate = 0.014, p = 0.02). In this cross-sectional study, levels of Aβ load was higher further along the DLB continuum. Whereas Aβ levels were comparable with those in CU individuals in iRBD, a significant elevation in Aβ levels was observed in the predementia stage of MCI-LB and in DLB. Specifically, APOE ε4 carriers had higher Aβ levels than APOE ε4 noncarriers, and women tended to have higher Aβ levels than men as they got older. These findings have important implications in targeting patients within the DLB continuum for clinical trials of disease-modifying therapies.

Stimulus material selection for the Dutch famous faces test for older adults.

Worldwide, approximately 22% of all individuals aged 50 years and older are currently estimated to fall somewhere on the Alzheimer's disease (AD) continuum, which can be roughly divided into preclinical AD, mild cognitive impairment (MCI), and AD dementia. While episodic memory loss (among other aspects) is typically required for a diagnosis of AD dementia, MCI is said to have occurred when cognitive impairment (including memory loss) is worse than expected for the person's age but not enough to be classified as dementia. On the other hand, preclinical AD can currently only be detected using biomarkers; clinical symptoms are not apparent using traditional neuropsychological tests. The main aim of the current paper was to explore the possibility of a test which could distinguish preclinical AD from normal aging. Recent scientific evidence suggests that the Famous Faces Test (FFT) could differentiate preclinical AD from normal aging up to 5 years before a clinical AD diagnosis. Problematic with existing FFTs is the selection of stimulus material. Faces famous in a specific country and a specific decade might not be equally famous for individuals in another country or indeed for people of different ages. The current article describes how famous faces were systematically selected and chosen for the Dutch older (60+) population using five steps. The goal was to design and develop short versions of the FFT for Dutch older adults of equivalent mean difficulty. In future work, these nine parallel versions will be necessary for (a) cross-sectional comparison as well as subsequent longitudinal assessment of cognitively normal and clinical groups and (b) creating personalized norms for the normal aged controls that could be used to compare performance within individuals with clinical diagnoses. The field needs a simple, cognitive test which can distinguish the earliest stages of the dementia continuum from normal aging.

Functional profiles of older adults from the dementia continuum: Analyzing critical errors that occurred during an IADL ecological evaluation

AbstractBackgroundOlder adults with Alzheimer disease (AD) or mild cognitive impairment (MCI) experience challenges that affect their independence. Instrumental activities of daily living (IADLs) are critical in assessing the independence. Single errors can have considerable impact, as they can lead to institutionalization. Thus, optimal recommendations regarding independence depends on an accurate analysis of IADL, including a fine grain analysis of the type of critical errors. Our study aim to describe the errors produced by older adults from the dementia continuum (AD, MCI and older adults living in the community with no dementia) when performing IADL. More specifically, our objectives are to understand: (1) What are the main types of errors occurring during IADL and (2) When are these errors more likely to occur.MethodWe conducted a performance based IADL assessment with older adults (n = 24), including 7 with AD, 8 with MCI, and 9 without dementia. We used the IADL Profile[1], which is a standardized assessment based on ecological observation of 8 IADL tasks. For each task, observations of performance are grouped into 4 operations: (1) formulate a goal, (2) plan, (3) execute, and (4) achieve the goal. Based on video recordings of the sessions, participants performances were transcribed into verbatim reports of all the errors that occurred. Deductive qualitative analysis and descriptive statistical analysis (standard deviation and correlation) were used to categorize/count the main type of errors for each task.ResultOur results highlighted that (1) older adults make several errors while performing IADLs, with a higher occurrence according to the advancement along the dementia continuum and some of which may be crucial to the person’s independence; (2) the most frequent errors for all participants were in formulating a goal and in planning a task and (3) these errors are likely to occur during grocery shopping and meal preparation.ConclusionThe fine grain analysis of errors during the performance of IADL allows us to better identify the needs of older adults from the dementia continuum that can service to guide the selection of effective strategies that can optimize their safety and functional independence.[1] Bottari et al. (2009)

Innovative Methods to Gather, Understand, And Incorporate Diverse Lived Experiences Into Dementia Research

AbstractBackgroundAging and dementia researchers continue to face challenges in recruiting and retaining participants who represent demographically diverse communities. This continued and critical lack of representation threatens the generalizability and applicability of countless study findings and severely diminishes the field’s impact on clinical outcomes. Recruitment science evidence strongly recommends that to achieve equity researchers should design and conduct research hand‐in‐hand with the input of potential and current participants, as well as their loved ones. To do so, partnerships between researchers and demographically diverse communities must be built and maintained before, during, and after individual studies. Indeed, literature indicates that persons from demographically diverse communities want to contribute to research, even beyond traditional research participation, including serving on community advisory boards and sharing their lived experiences in public forums. This symposium will discuss innovative methods currently being used to gather, understand, and incorporate diverse lived experiences with the goal of improving aging and dementia research generalizability and applicability.MethodWe will discuss research methods that various stakeholders—including researchers, study sponsors, funders, and participant groups—can utilize throughout the research process, from conceptualization and conduct to dissemination.ResultThis presentation will highlight community‐based and participant‐centered recruitment and retention approaches that promote understanding and incorporating diverse older adults’ and carers’ lived experiences. Approaches that will be discussed include, lived experiences panels, community and/or participant advisory boards, research ambassadors, and inclusion in scientific conferences. Furthermore, this session will feature a lived experience panel comprised of demographically diverse persons along the dementia continuum, from at‐risk to living with dementia, and their care partners. This session can benefit researchers, clinical trialists, and the field of aging and dementia research, by expounding on the importance of and developing strategies to meaningfully engage with demographically diverse communities.ConclusionMeaningful understanding and incorporation of the lived experiences of persons representing demographically diverse backgrounds offers clear benefits to aging and dementia researchers to improve the applicability and translatability of research findings. The participant’s voice is essential in setting research priorities and addressing research‐related challenges to ultimately increase diverse research participation and facilitate equity in aging.

Manejo das demências em fase avançada: recomendações do Departamento Científico de Neurologia Cognitiva e do Envelhecimento da Academia Brasileira de Neurologia

ABSTRACT Alzheimer’s disease (AD) and other neurodegenerative dementias have a progressive course, impairing cognition, functional capacity, and behavior. Most studies have focused on AD. Severe dementia is associated with increased age, higher morbidity-mortality, and rising costs of care. It is fundamental to recognize that severe dementia is the longest period of progression, with patients living for many years in this stage. It is the most heterogeneous phase in the process, with different abilities and life expectancies. This practice guideline focuses on severe dementia to improve management and care in this stage of dementia. As it is a long period in the continuum of dementia, clinical practice should consider non-pharmacological and pharmacological approaches. Multidisciplinary interventions (physical therapy, speech therapy, nutrition, nursing, and others) are essential, besides educational and support to caregivers.

Management in severe dementia: recommendations of the Scientific Department of Cognitive Neurology and Aging of the Brazilian Academy of Neurology.

Alzheimer's disease (AD) and other neurodegenerative dementias have a progressive course, impairing cognition, functional capacity, and behavior. Most studies have focused on AD. Severe dementia is associated with increased age, higher morbidity-mortality, and rising costs of care. It is fundamental to recognize that severe dementia is the longest period of progression, with patients living for many years in this stage. It is the most heterogeneous phase in the process, with different abilities and life expectancies. This practice guideline focuses on severe dementia to improve management and care in this stage of dementia. As it is a long period in the continuum of dementia, clinical practice should consider non-pharmacological and pharmacological approaches. Multidisciplinary interventions (physical therapy, speech therapy, nutrition, nursing, and others) are essential, besides educational and support to caregivers.