bluuebunny/crossref_metadata_2025 huggingface dataset:
Longitudinal motor decline in dementia with Lewy bodies and Parkinson’s disease dementia in a community autopsy cohort
Authors: Choudhury Parichita , Zhang Nan , Shprecher David , Belden Christi , Goldfarb Danielle , Shill Holly , Mehta Shyamal , Driver‐Dunckley Erika , Serrano Geidy E , Beach Thomas G , Adler Charles , Atri Alireza
Published: December 2021

Background

Although parkinsonism is a core feature of Parkinson’s Disease Dementia (PDD) and Dementia with Lewy bodies (DLB), its evolution is less delineated. We aimed to assess differences in severity and progression of parkinsonian motor symptoms and signs in a community autopsy cohort with clinicopathologic diagnosis of DLB, PDD or Alzheimer’s Disease (AD).

Method

Data included were from 194 participants in the Arizona study of Aging and Neurodegenerative Disorders with clinicopathologic diagnosis of DLB (n=48), PDD (n=98) (±AD co‐pathology) or pure AD (n=48), and at least two movement exams performed by movement disorders subspecialists who classified PD and parkinsonism according to MDS‐UPDRS criteria. DLB was subgrouped by presence or absence of parkinsonism at final exam (DLB+Park and DLB–Park). Between group trajectory of UPDRS‐II and UPDRS‐III scores were explored using piecewise‐linear and non‐linear MMRM multivariate analysis.

Result

Over 1435 participant‐years of longitudinal data were included in the analyses (Figure 1). Mean±SD age at baseline movement exam and death were 76.0±7.5 and 83.4±6.8 years, respectively. At baseline, most participants did not have dementia or substantial motor abnormalities (except motor abnormalities in PDD). DLB (73.9%) and PDD (69.2%) groups had more males than AD (33.3%). Parkinsonism was present in 65.6% of DLB at last exam. Piecewise‐linear MMRM analysis showed baseline UPDRS‐II and UPDRS‐III scores were highest (p<0.001) for PDD (mean±SE: 14.3±0.78 and 27.4±1.64), followed by DLB+Park (5.0±1.05 and 17.4±3.10), DLB‐Park (3.7±2.54 and 3.8±1.35) and AD (3.2±0.88 and 8.0±1.94). Annual rate of increase in UPDRS‐II was greatest for DLB+Park (1.44±0.20) and PDD (1.04±0.08), followed by DLB‐Park (0.89±0.18) and AD (0.30±0.11). Annual rate of increase in UPDRS‐III was highest for PDD and DLB+Park (2.12±0.20 vs 2.64±0.42), followed by DLB‐Park and AD (1.31 ± 0.38 and 0.64 ± 0.22). Preliminary non‐linear MMRM models (Figure 2) further supported substantial between group/subgroup differences in motor trajectories, and progression in DLB‐Park.

Conclusion

These preliminary results in a large, well‐characterized clinicopathological community‐based autopsy cohort support that DLB+Park experience comparable, or greater, parkinsonian motor progression to PDD. Future modeling/sensitivity analyses will better delineate expected trajectories of motor progression to add prognostication value in clinic and design of DLB clinical trials.
Microstructural alterations in medial temporal and frontal white matter tracts are associated with subjective cognitive decline
Authors: Archer Derek B , Moore Elizabeth E. , Pamidimukkala Ujwala , Shashikumar Niranjana , Pechman Kimberly R. , Blennow Kaj , Zetterberg Henrik , Landman Bennett A. , Hohman Timothy J. , Jefferson Angela L. , Gifford Katherine A.
Published: December 2021

Background

Subjective cognitive decline (SCD) is a perceived cognitive change prior to objective cognitive deficits, and although it is associated with Alzheimer’s disease (AD) pathology, it likely results from multiple underlying pathologies. We investigated the association of white matter microstructure to SCD as a sensitive and early marker of cognitive decline and quantified the contribution of white matter microstructure separate from amyloidosis.

Method

Vanderbilt Memory & Aging Project participants with diffusion MRI data and a 45‐item measure of SCD were included (n=237, 73±7 years, 37% female). A subset of participants (n=104) underwent a fasting lumbar puncture for quantification of amyloid‐β (CSF Aβ42). Diffusion MRI data was post‐processed using the free‐water (FW) elimination technique, which allowed quantification of extracellular (FW) and intracellular compartment (fractional anisotropy, mean diffusivity, axial diffusivity, and radial diffusivity) microstructure. Microstructural values were quantified within 11 cognitive‐related white matter tracts, including medial temporal lobe, frontal transcallosal, and fronto‐parietal tracts. General linear modeling related each tract to SCD adjusting for age, sex, race/ethnicity, education, Framingham Stroke Risk Profile scores, APOE‐ε4 carrier status, diagnosis, Geriatric Depression Scale scores, and total white matter volume. Competitive model analyses were conducted to determine if white matter microstructural values have a unique role in SCD separate from CSF Aβ42.

Result

FW‐corrected radial diffusivity (RDT) was related to SCD in 6 tracts: cingulum bundle (β=3.52x106; p=0.001), inferior longitudinal fasciculus (β=2.77x106; p=0.005), as well as inferior frontal gyrus (IFG) pars opercularis (β=1.98x106; p=0.008), IFG pars triangularis (β=2.69x106; p=0.008), medial frontal gyrus (β=2.46x106; p=0.007), and middle frontal gyrus (β=2.47x106; p=0.014) transcallosal tracts. While CSF Aβ42 was related to SCD in our cohort (β=‐0.021; p=0.020), competitive model analyses revealed that fornix and IFG pars triangularis transcallosal tract RDT contributed unique variance to SCD beyond CSF Aβ42.

Conclusion

Medial temporal lobe and frontal transcallosal tract microstructure is an important driver of SCD independent of early AD pathology. Given RDT appears to be the most significant predictor of SCD, demyelination may be an early contributor to cognitive decline. These results highlight the value of incorporating multiple biomarkers to help disentangle the mechanistic heterogeneity of SCD as an early stage of cognitive decline.
Implementation of remote neuropsychological assessments in the Insight 46 study: Lessons learned from the transition to videoconferencing and telephone assessments
Authors: Street Rebecca E , Lu Kirsty , Freiberger Tamar , Murray‐Smith Heidi , Keuss Sarah E , Baker John , Wong Andrew , Richards Marcus , Fox Nick C , Crutch Sebastian J , Schott Jonathan M
Published: December 2021

Background

Insight 46 is a longitudinal neuroscience sub‐study of the MRC National Survey of Health and Development (the British 1946 Birth Cohort). In March 2020, the COVID‐19 pandemic, and the introduction of lockdown measures across the UK, demanded a transition from traditional face‐to‐face data collection methods to teleconference‐based testing, to ensure the safety of our vulnerable cohort and the ongoing collection of longitudinal data. We present our approach to adapting and expanding our existing telephone assessment procedures to include as many tests as possible from our standard neuropsychology battery.

Methods

Participants with a computer or tablet with a webcam, microphone, and screen dimensions greater than 9 inches were offered a Microsoft Teams videoconference assessment; those without were offered a telephone visit to ensure maximum data collection. Videoconference and telephone batteries were created under copyright agreements. Item‐by‐item responses were collected digitally, and audio‐recording software was used to capture verbal responses where appropriate. Pre‐visit packs containing assessment materials in sealed envelopes (to prevent advance sight of materials) were sent ahead of each assessment. Due to specific equipment or software requirements, computerised assessments could not be performed (see Table 1).

Result

65% of the remaining eligible participants completed a remote assessment (see table 2). Despite offering one‐to‐one videoconferencing training, a major reason for drop‐out was concerns about technology, in addition to hearing difficulties and other health considerations. During administration, challenges included ensuring a standardised research environment and overcoming technological issues. Detailed scripts and protocols were implemented to guarantee uniform administrations, as well as detailed recording of unexpected events such as distractions and technology failures.

Conclusion

Our methods allowed for the continuation of longitudinal data collection, demonstrating the feasibility of teleneuropsychology in elderly populations. Positive feedback demonstrated participants’ acceptance of telehealth approaches and their appreciation of the value of continuing research. Future implementation of these methods could increase retention in populations previously prevented by physical barriers. However, careful consideration must be given to the validity and reliability of remote administration, and the differences between telephone and videoconferencing methods.
Incidence and prevalence of coexistent retinal diseases and cognitive impairment or dementia: A systematic review
Authors: Xu Ying , Phu Jack , Aung Htein Linn , Hesam‐Shariati Negin , Auty Jack , Keay Lisa , Tully Phillip J , Booth Andrew , Anderson Craig S , Anstey Kaarin J , Peters Ruth
Published: December 2021

Background

As chronic and progressive age‐related diseases, there are commonalities between age‐related macular degeneration (AMD), glaucoma, and diabetic retinopathy (DR), and cognitive impairment (CI) and dementia. We undertook a systematic review to quantify such associations.

Method

MEDLINE, EMBASE, PsycINFO and CINAHL were searched (from inception to June 2020) for observational studies reporting incidence or prevalence of AMD, glaucoma or DR in people with CI or dementia, and CI or dementia among people with AMD, glaucoma or DR. A 9‐item quality assessment tool was used to categorize studies as having low, moderate or high risk of bias. Rates of comorbid disease were extracted and presented in forest plots. Prospero registration [CRD42020189484].

Result

Of 6,803 abstracts reviewed, 76 were considered for full‐text analysis, of which 47 were included for syntheses. There were 27 and 20 assessed as having low and moderate risk of bias, respectively.

Incidence of dementia in people with age‐related retinal diseases ranged from 9.5 to 20 (AMD), from 1.1 to 11.6 (glaucoma) and was 32.9 (DR) per 1000 person‐years, respectively (Figure 1). There were no reports on the incidence of CI in AMD, glaucoma or DR, nor of retinal diseases in CI or dementia.

There were two studies reporting prevalence of AMD or glaucoma in people with CI (Figure 2). Prevalence of DR in those with CI ranged from 11.4% to 70.1%. Prevalence of AMD, glaucoma and DR among people with dementia ranged from 1.4% to 52.6%, from 0.2% to 25.9% and from 11 to 20%, respectively.

Prevalence of CI in people with AMD, glaucoma and DR ranged from 8.4% to 52.4%, from 2.8% to 90.2% and from 3.9% to 45.2%, respectively (Figure 3). Prevalence of dementia in people with AMD, glaucoma and DR ranged from 9.9% to 62.6%, 2.5% to 3% and 0.8% to 12.5%, respectively.

Conclusion

There are wide ranging estimates of incidence and prevalence of retinal diseases in relation to CI/dementia. Further research is required to better understand the reasons for such variations.
Levels of circulating memory CD8 T cells that induce AD‐like pathology in mice correlate with cognition and decreased CSF Aβ1‐42 in AD and control patients
Authors: Wheeler Christopher J. , Van Dam Debby , Vermeiren Yannick , De Reu Hans , De Deyn Peter Paul , Yamamoto Vicky , Trujillo Kristina
Published: December 2021

Background

We previously engineered mice to accumulate age‐related, antigen‐specific memory CD8 T cells as in humans. These mice spontaneously develop all major hallmarks of AD with aging. Analogous T cells reactive to an epitope on Amyloid Precursor Protein (APP) were found in aging humans, accumulated in AD brain, and decreased in AD blood where their levels accurately tracked the disease in initial analysis. Here, we examine whether levels of these blood T cells are associated with established AD biomarkers.

Method

Antigen‐specific CD8 T cells in blood were quantified by flow cytometric analysis after staining with anti‐CD8, anti‐KLRG1 and APP peptide‐HLA‐A2 multimers in normal aging, MCI with or without AD biomarkers, and confirmed late‐onset AD patient cohorts (n = 50). Aβ1‐42, total Tau, and pTau181 were quantified in CSF, and cognitive performance assessed by MMSE.

Result

Percentage of APP‐specific memory CD8 T cells was significantly decreased with dementia (0.68 + 0.29% for MMSE <25; 1.63 + 0.32% for MMSE >24), reaching minimal levels in AD. Although the paucity of APP‐specific CD8 T cells in AD blood precluded meaningful correlations, decreases in the larger parental (KLRG1+) memory CD8 T cell population correlated with decreased CSF Aβ1‐42 in AD (r = 0.511; P = 0.003; n = 31). Decreasing APP‐specific CD8 T cells in blood also correlated with lower CSF Ab1‐42 in normal aging patients (r = 0.518; P = 0.028; n = 18). No significant correlations between T cell levels and total Tau or pTau181 were observed.

Conclusion

Our results reveal that age‐related memory CD8 T cells in blood decrease with dementia, and in proportion to decreased CSF Aβ1‐42 in both AD and normal aging. Given that decreased CSF Aβ1‐42 is among the earliest biomarkers for AD, this validates our previous findings that loss of APP‐specific memory CD8 T cells from blood accurately tracks the AD continuum in humans. Our findings also support the notion that antigen‐specific memory CD8 T cells are associated with the earliest detectable pathologic changes in AD, and as such may represent novel cause‐associated biomarker candidates to predict and track the disease.
How to define ‘N’ in the ATN classification in subjective cognitive decline: The SCIENCe project
Authors: Ebenau Jarith L. , Verberk Inge M.W. , Verfaillie Sander C.J. , van den Bosch Karlijn A. , Scheltens Philip , Prins Niels D. , Barkhof Frederik , Van Berckel Bary N.M. , Teunissen Charlotte E. , van der Flier Wiesje M.
Published: December 2021

Background

Different biomarkers have been suggested to measure neurodegeneration (N) in the ATN classification. We aimed to compare N biomarkers measured with different modalities and assess their association with clinical progression.

Method

We included 401 individuals with subjective cognitive decline (SCD, 61±9y, 42%F, MMSE28±2, follow‐up 3±3y). We used the following biomarkers for N: CSF t‐tau, medial temporal atrophy (MTA) visual rating on MRI, hippocampal volume (HV), serum neurofilament light (NfL) and serum glial fibrillary acidic protein (GFAP). We first compared biomarkers (Pearson correlation) and assessed the association between N biomarkers and progression to mild cognitive impairment or dementia (Cox proportional hazards analysis). We additionally investigated whether the addition of N biomarkers improved a Cox model with CSF abeta and p‐tau as predictors (likelihood ratio test). Last, we compared associations between N biomarkers and MMSE score over time (linear mixed models). Models were corrected for age and sex, and additionally for intracranial volume when HV was used as predictor. P‐tau, t‐tau, NfL and GFAP were log‐transformed, abeta and HV were inverted, and all biomarkers were z‐transformed.

Result

N biomarkers were weakly to moderately correlated (range r ‐0.20 – 0.58, Figure 1). Of these, NfL and GFAP, both serum markers, correlated most strongly (r 0.58). T‐tau was strongly correlated with p‐tau, although these biomarkers supposedly represent separate biomarker groups (r 0.89). T‐tau, HV, NfL and GFAP individually predicted clinical progression (range hazard ratios 1.4 – 2.1). Models including abeta and p‐tau improved when HV, NfL or GFAP were added as predictors (t‐tau not entered due to collinearity with p‐tau, Table 1). Last, t‐tau, HV and GFAP were individually associated with MMSE slope (range betas −0.17 – −0.15).

Conclusion

In a sample of cognitively normal individuals, correlations between different N biomarkers were low, indicating they do not reflect the same underlying pathology. T‐tau was strongly associated with p‐tau, thereby disqualifying as measure for N. HV, NfL and GFAP predicted clinical progression. Our results do not allow to choose one most suitable biomarker for N, but illustrate room for improved prediction beyond abeta and p‐tau.
MIND diet and risk of dementia in a population‐based cohort
Authors: de Crom Tosca , Ikram M Arfan , Voortman Trudy
Published: December 2021

Background

Nutritional approaches are considered a promising strategy for dementia prevention, but the composition of an optimal neuroprotective diet remains undetermined. The Mediterranean‐ DASH Intervention for Neurodegenerative Delay (MIND) diet has been developed which contains food components that are thought to be specifically neuroprotective. However, whether this translates into lower dementia risk in the population is uncertain. We examined the association between the MIND diet and the risk of dementia, and compared this to two general health promoting diets.

Method

In the population‐based Rotterdam Study, dietary intake was assessed with validated food‐frequency questionnaires at two time points: in 6,985 non‐demented participants (median age 65.4 years, 57.8% women) at baseline; and after 10‐20 years of follow‐up in 2,861 non‐demented surviving participants (median age 74.5 years, 57.4% women). We derived adherence scores for the MIND diet, and ‐for comparison‐ for the Dutch dietary guidelines and Mediterranean diet.

Result

Total follow‐up was 25 years from the first and 7 years from the second dietary assessment, during which 1,202 and 152 participants developed dementia, respectively. None of the three diets were associated with dementia over the 25 years since first dietary assessment (Figure 1). However, during the 7‐year follow‐up from the second dietary assessment, higher MIND diet scores were associated with a lower risk of dementia (hazard ratio (HR) [95% confidence interval] per standard deviation increase: 0.869 [0.760‐0.993]). Accordingly, when restricting follow‐up time to 7 years after the first assessment, higher MIND diet scores were also associated with a lower dementia risk (HR 0.714 [0.604‐0.846]). Associations with dementia were generally weaker or absent for the Dutch dietary guideline and Mediterranean diet score.

Conclusion

Better adherence to the MIND diet is associated with a lower risk of dementia but these associations were limited to the first 7 years of follow‐up. Associations were stronger for the MIND diet compared to other healthy diets, suggesting that the MIND diet might be more specific for protecting brain health.
U.S. long‐term services and supports, Covid‐19, & dementia: Impacts and opportunities for policy change
Authors: Dawson Walter D , Stone Robyn I , Van Houtven Courtney H , Boucher Nathan A
Published: December 2021

Background

The COVID‐19 pandemic brings the many historical challenges of the long‐term services and supports (LTSS) system in the United States (U.S.) into clear focus. Inequalities across race, ethnicity, and socioeconomic status (SES) as well as an increased burden on family care partners have been amplified by the pandemic. In spite of multiple reform attempts and an increasing population of older adults living with multiple, chronic health conditions including Alzheimer’s disease and other forms of dementia (ADRD), who will need some form of long‐term care during their lifetime policy reform has remained elusive. Primary blame for the high rates of COVID‐19 infections and deaths have largely been assigned to formal LTSS care settings. Yet, more systemic problems have become clear during the pandemic: the failure of coordination of the U.S. public health system at the federal level and the effects of long‐term disinvestment and neglect of state and local level public health programs. Taken together, these failures contributed to an inability to coordinate with the LTSS system and act early to protect residents and staff in the LTSS care settings.

Method

We analyze several impacts of the COVID‐19 pandemic on the U.S. LTSS system and existing policy arrangements.

Result

Policies U.S. policymakers can implement include uniform public reporting of COVID‐19 cases in licensed LTSS settings, identifying and supporting unpaid care partners, increased support for the direct care workforce, increased coordination between public health departments and LTSS agencies and providers, enhancing collaboration and communication across health, LTSS, and public health systems, further reducing barriers to telehealth in LTSS, and providing incentives to care for our most vulnerable populations. The analysis also demonstrates that comprehensive reform is required in order to build the LTSS system that is needed through comprehensive workforce development, universal coverage through comprehensive financing reform, and the creation of an age‐friendly public health system.

Conclusion

The COVID‐19 pandemic has exposed the deficits of the U.S. LTSS system and made clear the interdependence of LTSS with public health. Several policy responses to the pandemic would help provide the LTSS system that is needed to care for people living with dementia.
Association of physical strength and AD biomarkers in cognitively unimpaired patients
Authors: Kim Aelim , Kim Woo‐Ram , Noh Young
Published: December 2021

Background

In elderly, physical fitness is considered an important factor for well‐being and it has been reported that there is a correlation between brain health and physical fitness in people with neurodegenerative diseases. Physical fitness factors that are especially important for the elderly included muscle strength, aerobic endurance, flexibility, agility/dynamic balance. The purpose of this study was to investigate the relationship between physical fitness and imaging biomarker such as tau deposition and brain atrophy in elderly people.

Method

We recruited elderly participants (age≥65): cognitive impairment (CI, n=49) and cognitive normal(CN, n=45). CI included mild cognitive impairment (MCI) and dementia. All of subjects (Male:Female=33:61, mean age: 72.7 ± 4.97) performed senior fitness test (SFT), 3T magnetic resonance imaging(MRI), [18F] flutemetamol PET and [18F]MK‐6240 positron emission tomography(PET). Physical fitness was measured by muscle strength (upper and lower), aerobic endurance, flexibility (upper and lower), agility/dynamic balance according to the SFT protocol. Mean cortical thickness was calculated by T1‐weighted images. [18F]MK‐6240 Standardized Uptake Value Ratio (SUVR) used cerebellar gray matter as the reference region.

Result

In all, cortical thickness was associated with upper muscle strength, and agility/dynamic balance. The same result was shown in women. In male, only upper muscle strength was associated with cortical thickness. Tau was associated with all physical fitness factors. Physical fitness and tau were related each other in both males and females, except for upper flexibility. In CI, that was shown a significant correlation between tau and lower muscle strength, lower flexibility, and agility/dynamic balance.

Conclusion

In elderly, upper muscle strength and agility/dynamic balance were related to cortical thickness. In addition, the better physical strength was associated with the less tau deposition. This suggests that physical strength including muscle strength can affect to tau and brain atrophy in neurodegenerative diseases including Alzheimer's disease.
Balance and gait disorders in a memory clinic population: A prospective observational cross‐sectional study
Authors: Razay George
Published: December 2021

Background

Balance and gait disorders (B&GDs) increase with ageing, but often they are not adequately evaluated and largely go underdiagnosed. We have therefore investigated the prevalence of B&GDs and the underlying diagnosis among patients with memory impairment.

Method

410 consecutive patients enrolled between 2010 and 2014 from the Memory Disorders Clinic, Launceston, Tasmania. All patients had a detailed history of memory, balance and gait symptoms including features suggesting dementia. A full examination included the Mini‐Mental State Examination (MMSE) and balance/gait functions by observing the patients standing with their eyes closed, on their toes, and doing the tandem test. All patients had a brain CT scan.

Result

218 women and 192 men participated in the study, the median age was 76.5 years (range 32.6‐94.8) and the mean MMSE score was 23.3 (SD 4.9). 214 (52%) had B&GDs of whom, 85 (40%) had mild cognitive impairment (MCI), 25 (12%) had Alzheimer’s disease (AD), 62(29%) had idiopathic normal pressure hydrocephalus (INPH), 11 (5%) had mixed dementia (MD), 10 (5%) had vascular dementia (VD), 9 (4%) had Parkinson’s disease dementia, 2(1%) had Lewy body disease (LBD). 196(48%) didn’t have B&GIs, of whom, 97 (50%) had MCI, 66 (34%) had AD, 13(7%) had MD, 6(3%) had Gertsmann’s syndrome, 4 (2%) had hypogonadism, and 4 (2%) had frontal lobe dementia (FLD). After excluding patients with MCI, patients with B&GDs (n=129); 60 (48%) had INPH, 25 (20%) had AD, 11 (9%) had MD, 10 (8%) had VD, 2 (2%) had LBD. Patients without B&GDs (n=100), 66% had AD, 13% had MD, 1% had VD and 4% had FLD.

Conclusion

The study shows that B&GDs are common among patients with memory impairment, and highlights the high prevalence of INPH, a condition that could be treated with shunt surgery resulting in improvement of cognitive, balance and gait functioning.
The clinical use of Alzheimer’s biomarkers in patients with mild cognitive impairment
Authors: Caprioglio Camilla , Garibotto Valentina , Jessen Frank , Frölich Lutz , Frisoni Giovanni , Altomare Daniele
Published: December 2021

Background

Alzheimer’s disease (AD) is defined as a clinic‐biological disease characterized by the abnormal deposition of amyloid and tau in the brain. AD biomarkers offer the perspective to confirm the presence of amyloid and tau pathology in vivo and supports their increasing use in clinical practice. The aim of this study is to investigate the clinical use of the main AD biomarkers, focusing on amyloid‐PET and tau‐PET, by examining the beliefs and preferences of clinicians (neurologists, geriatricians, psychiatrists) as well as biomarker experts (nuclear medicine, radiology, laboratory physicians) participating in the European Alzheimer’s Disease Consortium (EADC). In the present abstract, we focus on clinicians.

Method

The survey was made accessible from May to September 2020. The questionnaire assessed, among others: respondent’s profile (level of expertise, type of practice), frequency of use of biomarkers, beliefs about the pathogenic role of amyloid and tau in Alzheimer's disease, and perceived clinical utility of amyloid‐PET and tau‐PET.

Result

In total, 150 professionals filled in the survey, with an overall answer rate of 49% (150/306): among them, 100 were clinician experts in the field of neurodegenerative disorders. These clinicians reported a frequent‐to‐constant use of medial temporal atrophy (MTA) in 77% of cases, CSF in 45%, FDG‐PET in 32%, amyloid‐PET in 8%, and tau‐PET in 2%. Clinicians attributed a prevalent pathogenic role in AD pathology and symptoms to amyloid (42%) more frequently than tau (20%, p=0.001). The perceived clinical utility of amyloid‐PET and tau‐PET in supporting an etiological diagnosis in MCI and mild dementia patients was more balanced (35% vs 24%, p=0.121) then clinicians’ beliefs about the pathogenic role of amyloid and tau.

Conclusion

These results highlight the frequent use of traditional AD biomarker (i.e. MTA, FDG‐PET, CSF) and a non‐negligible use of amyloid‐PET. Clinicians consistently attributed a greater pathogenic role in AD pathology and symptoms to amyloid rather than tau. However, when the focus switched from the belief about the pathogenic role of amyloid and tau to their diagnostic contribution, amyloid‐ PET and tau‐PET scans were considered equally useful.
Neuro‐COVID: Does severe COVID‐19 infection increase the risk for cognitive impairment?
Authors: Hagman Göran , Thunborg Charlotta , Andersen Pia , Levak Nicholas , Aspö Malin , Walles Håkan , Jokhader Elias , Kåhlin Jessica , Nelson David , Piehl Fredrik , Tzortzakakis Antonios , Zetterberg Henrik , Granberg Tobias , Eriksson Lars I , Kivipelto Miia
Published: December 2021

Background

Neurocognitive manifestations of the coronavirus disease 2019 (COVID‐19) have been reported in the acute phase, especially in critically ill patients. The potential mechanisms underlying these symptoms are not fully understood but probably involves the inflammatory, vascular, and neurotropic effect of the coronavirus. While short‐, mid‐and long‐term consequences remain unclear, patients with neurocognitive sequelae reminiscent of other cognitive disorders, including AD have been reported. The aim of this study is to investigate if there is an increased risk for long‐term cognitive dysfunction/impairment, biochemical and structural brain changes after a severe COVID‐19.

Method

This is a prospective cohort study of 80 patients surviving intensive‐care for COVID‐19 at Karolinska University Hospital, Stockholm, Sweden. They will be examined at 3, 6 and 12 months after hospital discharge using neurological and neuropsychological (NP) tests combined with novel quantitative brain MRI and serial blood sampling to described relevant blood‐borne molecular patterns. This presentation focuses on NP testing, cognitive, mental, and neurological aspects at 3 months follow‐up. Cognitive testing and questionnaires (NP) include Rey Auditory Verbal Learning Test Rey Complex Figure test, Verbal Fluency Test, Category flow, Trail Making Test Symbol Digit Modalities Test, Mental Fatigue Scale, the Hospital Anxiety and Depression Scale, RAND‐36, AD8 Dementia Screening Interview and Subjective cognitive decline questions. A detailed neurological examination (neurologist), including Expanded Disability Status Scale, an adapted version of the Unified Parkinson's Disease Rating Scale for extrapyramidal dysfunction, and a brief smell test.

Results

At present, 28 participants have completed the 3‐months follow‐up visit, including neuropsychological and neurological examinations. Mean age (SD) at baseline was 57.8 (11.1) years, and 68% were men. Several patients expressed cognitive and/or mental concerns and fatigue. The neuropsychological and neurological examinations have so far revealed varying and mixed patterns. Brain MRI revealed mainly microvascular pathology. Detailed analyses, including blood biomarkers for neuronal injury and astrocytic activation, based on the 3‐months examination will be presented.

Conclusions

Repeated examinations will allow further analyses on longer term impact on cognition and underlying mechanisms. This may identify patients at risk and possible ways to mitigate cognitive complications, which is of great importance to reduce the pandemic's negative effects and socioeconomic burden.
Longitudinal plasma Alzheimer’s disease biomarkers in an Alzheimer’s disease research center cohort suggest pTau181 as the most reliable plasma biomarker for brain Alzheimer’s pathology
Authors: Sudduth Tiffany L. , Winder Zachary , Schmitt Frederick A. , Harp Jordan , Nelson Peter T. , Ali Doaa , Jicha Gregory A. , Wilcock Donna M.
Published: December 2021

Background

Blood‐based biomarkers for the detection and longitudinal tracking of Alzheimer’s disease (AD) brain changes remains a goal for the field. In this study, we set out to evaluate Ab42/40, total tau, and pTau181 in our longitudinal clinical cohort. In most cases we have assessed five separate plasma samples spanning a seven‐year period. A subset of individuals had plasma samples aligning with an amyloid‐PET scan. A second subset of individuals cam to autopsy and had neuropathologic workup for correlation with the findings in the plasma biomarkers.

Method

During their annual visits to the UK‐ADRC clinical core, participants had blood drawn and EDTA plasma was stored at ‐80oC in a standardized manner according to ADRC best practices. Quanterix Simoa assays were performed using Simoa Advantage assay kits and Quanterix Simoa HD‐1 and HD‐X instruments. Ab40, Ab42, total tau, and pTau181 analyses were performed. 96 participants had six annual plasma samples analyzed from an eight year period of collection. Of the samples assessed, 77 participants had plasma data aligning with an amyloid PET scan and 48 cases came to autopsy at the UK‐ADRC.

Result

Looking at longitudinal plasma Total Tau, Ab40, and Ab42, Total Tau and the Ab42/40 ratio fluctuate significantly from year to year. In contrast, pTau181 does not show significant fluctuations year to year. Among those participants with an amyloid PET scan, pTau181 was significantly associated with amyloid SUVr in frontal, parietal, and anterior cingulate regions (R2 = 0.11 P<0.01; R2=0.12 P<0.01; R2=0.13 P<0.005 respectively). In contrast, we did not find statistically significant relationships between amyloid PET SUVr and plasma Ab42/40 ratio. Total tau showed modest associations with amyloid PET SUVr in the frontal, parietal, and anterior cingulate regions (R2=0.1 P<0.01; R2=0.05 P<0.05; R2=0.09 P<0.01 respectively). In our autopsy cases, we found a modest inverse relationship between brain amyloid load and plasma Ab42/40 ratio (P=0.05). Further analyses are required for the autopsy studies.

Conclusion

In a community‐based cohort with longitudinal blood draws, pTau181 is a reliable, consistent plasma biomarker for AD pathology, showing more stability over time in participants than other candidate plasma biomarkers.
APOE Ɛ4 genotype is associated with thicker retinal layers in asymptomatic middle‐aged adults at high Alzheimer’s disease risk
Authors: Sharvit‐Ginon Inbal , Beeri Michal Schnaider , Weller Aron , Sher Ifat , Rotenstreich Ygal , Ravona‐Springer Ramit
Published: December 2021

Background

Retinal abnormalities have been demonstrated in patients with mild cognitive impairment (MCI) and dementia due to Alzheimer's disease (AD), but findings in yet asymptomatic stages of the disease are scarce and inconsistent. This study examined the relationship of retinal thickness with APOE Ɛ4 genotype, the most important genetic risk factor for AD.

Method

Participants (n=245) were cognitively asymptomatic middle aged people taking part in the Israel Registry for Alzheimer's Prevention (IRAP) study, enriched for high AD‐risk due to parental history of the disease. Assessments included a complete ophthalmic examination, best‐corrected visual acuity (BCVA) evaluation and optic coherence tomography (SD‐OCT) imagingAPOE status was determined based on rs429358 and rs7412 SNPs' genotypes. MANCOVA was used to compare retinal thickness between APOE Ɛ4 carriers and non‐carriers adjusting for age, sex, education and BCVA in four retinal quadrants (nasal, inferior, temporal and superior).

Result

Participants' mean age was 59.60 (SD=6.42) years, 66.4% were women. Retinal thickness was significantly greater in APOE Ɛ4 carriers compared to non‐carriers (p=0.005), reaching statistical significance in the nasal (p=0.008) and inferior (p=0.022) regions. A secondary MANCOVA analysis examined differences between APOE4 carriers and non‐carriers in specific retinal layers‐ the neural and glial layers (Retinal Nerve Fiber Layer‐ RNFL, Ganglion Cell Layer– GCL, Inner Plexiform Layer‐IPL, Inner Nuclear Layer‐INL and the Outer Plexiform Layer‐OPL) and the non‐neural layers (Outer Nuclear Layer‐ONL and the Retinal Pigment Epithelium (RPE). In the nasal region, APOE4 carriers had thicker retinal nerve fiber layer (RNFL) (p=0.033), ganglion cell layer (GCL) (p=0.021) and inner plexiform layer (IPL) (p=0.010); in the inferior region, they had thicker GCL (p=0.035); and in the superior region, the APOE4 carriers had thicker IPL (p=0.019).

Conclusion

In asymptomatic individuals enriched for AD risk, APOE4 carriers had thicker retinal nasal and inferior quadrants, which were driven primarily by the neural layers of the retina, but not by non‐neural layers. Our results suggest that retinal layers' thickness measurments may potentially be used as early biomarkers the disease.
COVID‐19 and vaccination programme in one residential home
Authors: Da Silva Miguel Vasconcelos , Velayudhan Latha , Khan Zunera , Manzar Beverley , Aarsland Dag , Ballard Clive
Published: December 2021

Background

Approximately 410 000 people live in care homes (CH) or residential settings in the UK, with the majority of this population being above the age of 85, making this group fall in the category of higher risk of more severe COVID‐19 symptoms and death. CH have been disproportionately affected by COVID‐19, people living and working in these settings have a higher risk of exposure to infection and higher risk of severe disease and mortality. CH residents and staff were prioritised for the vaccination programme in the UK due to increased risk of outbreaks, morbidity and mortality.

Method

One Residential home reported a COVID‐19 outbreak following the vaccination programme. Most staff vaccinated between 16‐18 December 2020, and most residents vaccinated on 30/12/2020. Residents were on isolation from 22/12/2020 prior to vaccination. The first positive COVID‐19 case was on 27th December. Staff and residents were scored according to the World Health Organisation (WHO) Ordinal Scale for Clinical Improvement (OSCI), table 1.

Result

Of staff vaccinated, 20,83% (n=5) tested positive for COVID‐19. Nine staff members (27.28%) didn't have the vaccine, with 7 of these (77.78%) developing more limiting symptoms (OSCI score 2), compared to 8.33% (n=2) of those who had the vaccine. With 100% of residents vaccinated, 21 residents (65,63%) developed COVID‐19 symptoms, and 31.25% (n=10) developing more limiting COVID‐19 symptoms or death. Nineteen residents have a diagnosis of dementia and 63.16% (n=12) developed COVID‐19 symptoms and 50% (n=6) of those with dementia died, whilst those without dementia did not have any deaths reported.

Conclusion

Although this reflects the experience of a single CH, it is of relevance in suggesting substantial protection for staff who have been vaccinated, even though there was only 11 days between vaccination and the start of the outbreak.

The experience in this CH starkly emphasizes the poor outcomes of COVID‐19 for residents, especially those with dementia, and unfortunately suggests that there are no benefits from vaccination as a secondary prevention approach once an outbreak has started. Ongoing evaluation will be important to optimize the delivery of the vaccination programme in CH settings, and to optimize staff take up of the vaccine.
Neuroinflammation, amyloid, NFT markers and initial cognitive status predict cognitive decline in MCI patients
Authors: Leng Fangda , Hinz Rainer , Gentleman Steve , Brooks David J. , Edison Paul
Published: December 2021

Background

Neuroinflammation has been established as a key component of Alzheimer’s pathology. Numerous cross‐sectional studies have found associations between neuroinflammatory markers and neuronal damage in AD, suggesting neuroinflammation as a potential drive force of disease progression. However, there have been debate on whether neuroinflammation has a causal effect on disease progression. Here we questioned whether neuroinflammation is predictive of future cognitive decline in early stage of the disease.

Method

21 MCI patients were recruited and had baseline T1‐MRI and 11C‐PBR28 scans. Patients were followed up for at least one year (mean follow‐up period 3.1±1.3 years) and had mini‐mental state examinations (MMSE) at each visit. 19 of them had baseline 18F‐Flutemetamol PET, 11 had 18F‐AV1451 scans. 18F‐AV1451 and 11C‐PBR28 SUVR in the medial temporal lobe were measured, while PCA analyses were performed to evaluate uptakes in the neocortex for all 3 tracers. Principle components of temporal lobe volumetric measurements were computed as the neurodegeneration marker. A linear growth model was fitted for each subjects using all available time points, giving the intercept and slope of individual cognition trajectory. Age, intercept, 11C‐PBR28, and T1 MRI markers were then put into linear models to predict slope, and a backward model selection procedure was conducted. To further validate that neuroinflammation is not just a mediator of amyloid and tau pathologies, we further included amyloid and tau markers in the sub‐cohorts and inspected the final model.

Result

The average baseline MMSE was 28±1.9 in the study cohort and the average annual change of MMSE was ‐0.46. We found 11C‐PBR28 SUVR in neocortex and MMSE intercept, but not temporal cortical thickness, were predictive of the slope of MMSE decline. In subgroups where 18F‐Flutemetamol and 18F‐AV1451 SUVRs were included respectively, we found neocortical amyloid and tau load were also predictive of MMSE slope, while 11C‐PBR28 SUVR remained its significance in the models.

Conclusion

Our findings suggest that neuroinflammation is an independent factor that drives disease progression and cognitive decline in early stage of AD. Molecular imaging biomarkers may better predict patients’ outcome as they detect underlying biological processes.
Time perception in people living with Alzheimer's disease
Authors: Pai Ming‐Chyi
Published: December 2021

Background

People may perceive time passed and the events happened in it from time to time. This is not only for the events happened outside the brains of the perceivers, but also for their thinking process. To sense the time lapsed as the time goes by is usually operated by a subconscious mechanism until confusion appears. The confusion may manifest as being not sure about something happened or not or something one has done or not, which occur very frequently in people living with Alzheimer's disease (AD). It may also play a role in spatial navigation, which relies on time and distance perceptions. The mechanism of time perception is complicated, and may involve several neural structures, including basal ganglia, insula, cerebellum, prefrontal lobes, and hippocampus. The aim of this study was to examine the perception of time in persons with mild AD, prodromal AD (prAD) and the cognitively unimpaired (CU).

Method

We invited people with mild AD, prAD and CU to participate in this study. We measured verbal time estimation in 10 seconds, 30 seconds, 60 seconds and time production in 10 seconds, 30 seconds, and 60 seconds. The participants were instructed to press a button on a device to measure time perception when they gauged each target of time had passed. The deviation from the correct response was recorded and compared among the three groups.

Result

A total of 22 AD, 58 prAD and 142 CU persons completed the study. Their Mini‐Mental State Examination (MMSE) scores were on the average 22 (SD 4), 22 (5) and 28 (2). The time perception in terms of verbal estimation showed no difference among the three groups in 10 seconds, 30 seconds, or 60 seconds. Regarding time production, difference appeared between prAD and CU (10.8/7.9 [mean/S.D.] vs 7.7/5.4, p<0.01), and no difference was noted in any other group comparisons.

Conclusion

The results provide an insightful information that short‐term time perception is of no difference among mild AD, prAD and CU. A study applying longer term time perception design is needed to show the difference and answer its role in spatial navigation or more complicated cognitive processes.
Recognition memory is impacted in atypical “non‐amnestic” Alzheimer’s disease
Authors: Putcha Deepti , Dev Sheena Isha , Carvalho Nicole , Dickerson Brad C. , Wong Bonnie
Published: December 2021

Background

Memory encoding and retrieval deficits have increasingly been identified in atypical phenotypes of AD, including posterior cortical atrophy (PCA) and logopenic variant primary progressive aphasia (lvPPA), despite traditional assumptions that memory is spared in these groups. There is a critical need to better understand relationships between these encoding deficits and recognition memory performance. Here we aim to build on the current literature by investigating recognition memory performance across the atypical AD syndromic spectrum.

Method

Thirty‐seven amyloid‐positive patients with atypical syndromes of AD (14 PCA, 9 lvPPA, and 14 amnestic dysexecutive) were administered the California Verbal Learning Test (CVLT‐II‐SF). Recognition memory performance (d’) and Total Learning were calculated. Independent samples t‐tests were conducted to test the hypothesis that amnestic dysexecutive patients would show greater d’ impairment compared to non‐amnestic (PCA, lvPPA) groups. Bivariate correlations were conducted to determine if Total Learning was related to d’ performance. Whole‐cortex general linear models, thresholded at p<0.01, were conducted to determine where cortical atrophy was related to d’ and Total Learning across all participants.

Result

Recognition memory was poor across both groups but trended toward worse in the amnestic dysexecutive group (mean d’=1.3) compared to the non‐amnestic group (mean d’=1.9; t=1.8, p=0.08). Total Learning was related to d’ in the non‐amnestic group (r=0.72, p=0.0002), but not in the amnestic dysexecutive group (p<0.7). In the full sample, cortical atrophy was related to Total Learning in a strongly left‐lateralized pattern in the medial parietal and lateral temporoparietal cortices, while atrophy in left>right anterior medial temporal cortices was related to d’.

Conclusion

Recognition memory is not spared in atypical phenotypes of AD traditionally thought to be “non‐amnestic,” such as PCA and lvPPA. In these groups, individuals who showed stronger learning did not show storage decay, while those who struggled to learn showed poor discriminability. In the amnestic dysexecutive group, recognition discriminability was impaired regardless of learning ability, suggesting clearer storage loss. Convergent evidence from this and our prior work (Wolk & Dickerson et al., 2011) shows that when encoding or storage is impaired in atypical or typical AD, it is due to neurodegeneration in common circuits subserving these memory processes.
Cognitive decline at middle age
Authors: Zhu Yingying , Zissimopoulos Julie M , Crimmins Eileen M
Published: December 2021

Background

There is no disease‐modifying treatment for Alzheimer’s Disease and Related Dementia (ADRD). However, its pathology may occur 20 years earlier than its symptoms. Therefore, understanding cognitive decline at middle age, which might be the starting point of dementia, may be particularly important for preventing or delaying the onset of dementia. This study quantified the population with fast rates of cognitive decline at middle age, explored the distribution of cognitive trajectories, and investigated demographic, health, and socioeconomic factors associated with cognitive deterioration for Americans.

Method

We utilized data from Health and Retirement Study (HRS) 1996 to 2014 and restricted the sample to respondents aged 50 to 64 with self‐reported cognitive score (scaling 0 to 27). We computed person‐specific slopes of changes in cognitive score over the study period (an average of 8 years) by running a linear regression of cognitive score on wave. Further, we defined fast rates of cognitive decline as 2 or more points decline (a slope equal to or below ‐2) in one’s cognitive score per wave. We identified persons with rapid cognitive decline . We further examined the distribution of slopes of individual cognitive trajectories over the whole study period. We utilized logistic regression to examine health and socioeconomic factors associated with rapidly declining cognition at middle age.

Result

Overall, 8.7% of the population had rapidly declining cognitive function over the observation period. Being an ethnic minority (ORblack: 2.3 [95%CI: 2.0 – 2.7]), having a less than high school degree (OR: 1.7 [95%CI: 1.4 – 2]), having hypertension (OR: 1.2 [95%CI: 1.1 – 1.4]) and diabetes (OR: 1.5 [95%CI: 1.2 – 1.7], male, low income, not working or working in less cognitively demanding occupations were risk factors for experiencing fast speed of cognitive decline .

Conclusion

Nine percent of the middle‐aged population experienced rapidly deteriorating cognitive abilities. Ethnic minorities, those with cardiovascular risk factors and lower socioeconomic status are more likely to develop rapidly declining cognition and are more vulnerable alleviating the burden of such a decline on their health and productivity.