Memory Center Research Articles

Sleep‐mediated cognitive assessment and sleep architecture associations for real‐world diagnostic phenotyping of neurocognitive disorders

AbstractBackgroundSleep disorders precede cognitive deficits by an average of four years in Alzheimer’s disease, and disrupted sleep has been associated with worse cognitive performance. We examined the association of a novel sleep‐mediated cognitive assessment to sleep architecture in people with and without cognitive impairment, towards earlier diagnosis of cognitive impairment.MethodForty‐three participants from the Sleep & Memory Center at the Neurological Institute of Athens cohort underwent a comprehensive evaluation that included polysomnography and pre‐ and post‐ sleep cognitive assessments of a novel short term verbal memory test as well as phonemic fluency testing. We examined the correlation of sleep‐mediated cognitive performance to sleep metrics of total sleep time, NREM/REM sleep, as well as respiratory metrics of Apnea‐Hypopnea Index and oxygen saturation during sleep.ResultSleep‐mediated spontaneous recall and phonemic fluency metrics were not associated to sleep architecture metrics. Instead, sleep‐mediated cued recall and recognition was positively associated to REM metrics of sleep time and relative REM/NREM ratio (R > 0.39; p < 0.039). On individual metrics, pre‐sleep verbal learning was positively associated to total sleep time (R > 0.30; p<0.05) as well as a larger REM/NREM ratio (R 0.52; p = 0.003). Finally, higher levels of oxygen during sleep, especially REM sleep, were associated with better pre‐sleep verbal learning (R > 0.39; p < 0.44).ConclusionOur results on people across a spectrum of cognitive abilities suggest that sleep‐mediated cognitive performance is significantly affected by shorter sleep times, and to a large extent these effects are dependent to the integrity of REM sleep. It is possible that both late evening learning abilities and sleep‐mediated memory reflects a person’s cholinergic capacity, as represented in subsequent REM sleep.

White matter hyperintensities in behavioral variant frontotemporal dementia and semantic variant of primary progressive aphasia

AbstractBackgroundWhite matter hyperintensities (WMHs) are imaging abnormalities of white matter noted by hyperintense signals on fluid attenuated inversion recovery (FLAIR) magnetic resonance imaging (MRI). When present among patients with CVRF (hypertension, diabetes, hypercholesteremia and smoking), WMHs are interpreted as cerebral vascular changes. However, WMHs in older individuals can be a feature of late onset leukodystrophies or varied neurodegenerative diseases such as Alzheimer disease (AD), Parkinson’s disease, and Frontotemporal Lobar Degeneration (FTLD). Additionally, WMHs can be present before symptom onset in neurodegenerative disorders and have been linked to the presence of some mutations, including progranulin (GRN). A clearer understanding of the underling etiology of WMHs in bvFTD and svPPA may improve management and treatment considerations.MethodsIn this cross‐sectional study, we included all participants meeting research diagnostic criteria for bvFTD (n = 152) and svPPA (n = 49) from ongoing studies at the UCSF Memory and Aging Center between the dates of September 2008 and December 2021 in comparison to a group of healthy controls enrolled at the same center with similar imaging parameters (n = 152, 1:1 matching for age and sex). All participants underwent a 3T FLAIR MRI and automated quantification of WMHs was performed. Linear regression analyses were performed to determine if WMHs were more frequent in participants with bvFTD or svPPA in comparison to controls and to explore associations with CVRF.ResultsAfter adjusting for age, sex, apolipoprotein E4 (APO‐E 4) status, and intracranial volume (ICV), both groups demonstrated a higher burden compared to controls (bvFTD (p = 0.012, R2 = 0.146) and svPPA (p = 0.008, R2 = 0.329). Modeling cardiovascular risk factors (CVRFs) as none or at least one, we did not find an association between CVRFs and WMH volume in models adjusting for ICV, ApoE4, and age among those with svPPA and bvFTD combined (p = 0.450).ConclusionIndividuals with bvFTD and svPPA appear to face a greater burden of WMHs compared to age‐ and sex‐matched healthy controls. WMHs in bvFTD and svPPA do not appear to be related CVRF.

Using data‐driven approaches to reveal distinct neurocognitive profiles in posterior cortical atrophy

AbstractBackgroundPosterior cortical atrophy (PCA) is a clinically defined syndrome characterized by impairment in higher‐order visual processing due to neurodegeneration of posterior brain regions (occipito‐parietal and occipito‐temporal areas). Previous findings have reported broader cognitive impairment profiles, but their association with neural correlates remains unclear. In this project we aimed to use principal component analysis to explore the relationship between various cognitive dimensions and FDG‐PET hypometabolism in PCA patients.MethodWe included 59 patients with a clinical diagnosis of PCA (with supporting radiological evidence) from the Memory and Aging Center database at the University of California in San Francisco (Table 1). The sample consisted of 64.4% females, mean age was 63.0 ± 7.6, and mean MMSE was 20.7 ± 5.6 at the diagnostic visit. Participants underwent extensive neuropsychological assessment; these scores were subsequently entered into an orthogonally‐rotated principal component analysis. In a subset of patients with FDG‐PET (N = 24), associations between the emergent cognitive components and whole‐brain hypometabolism were examined to explore neural correlates of cognitive heterogeneity.ResultFive components explained 72% of overall performance variation in PCA patients: episodic memory, visuospatial function, working memory, verbal generation, and naming/depression (Figure 1). Labels were assigned base on the primary area of greatest cognitive dysfunction. Visualization of component scores suggested systematic performance variation within the PCA sample. The mean metabolism map showed, as expected, predominant hypometabolism in occipito‐parietal and occipito‐temporal regions (Figure 2A). Voxel‐wise correlations revealed that hypometabolism in distinct frontoparietal regions underpinned episodic memory and visuospatial (inferior/superior parietal lobes), working memory and verbal generation (superior/middle frontal gyrus) performance (Figure 2B).ConclusionPCA is a cognitively heterogeneous syndrome, where patients can show varying levels of cognitive deficits across episodic and working memory, executive functions, language and affect, over and above canonical visuospatial impairments.

Plasma rejuvenation factor GDF11 associates with amyloid‐related cognitive decline in older adults across the Alzheimer’s Disease spectrum

AbstractBackgroundThrough studies of animal heterochronic parabiosis (fusion of juvenile and older adult animal circulatory systems), growth differentiation factor 11 (GDF11) has been identified as a blood rejuvenation factor that can promote neurogenesis, vascular remodeling, and memory improvement in the presence of age‐related declines. However, it is unknown whether GDF11’s associations with cognitive and neural outcomes translate to humans. We assessed the relationship between plasma GDF11, cerebral amyloid pathology, and cognitive performance in older adults across the Alzheimer’s disease (AD) spectrum.MethodParticipants were 71 older adults from the UCSF Memory and Aging Center who ranged in age from 63 to 93 (Meanage = 79.5; Meanedu = 17.5, 66 cognitively unimpaired, 56% women, 38% amyloid PET positive) and completed blood draws with plasma analyzed on Somascan (version 4.1), neuropsychological evaluations, and amyloid PET scans (18‐AV‐45). Cognition was operationalized as a of validated tests of memory and executive function. Pearson’s correlations examined interrelationships among plasma GDF11, cognition, and amyloid PET centiloids. To determine whether plasma GDF11 moderated the effects of amyloid on cognition, linear regression examined cognition as a function of GDF11, amyloid, and their interaction, controlling for age, sex, and education.ResultHigher amyloid PET centiloids correlated with worse cognition (r = ‐0.20, p = 0.09) and lower levels of GDF11 (r = ‐0.15, p = 0.20), though relationships did not reach statistical significance. GDF11 also did not strongly univariately correlate with cognition (r = ‐0.07, p = 0.59). However, there was a significant interaction between GDF11 and amyloid PET centiloids on cognition (β = 0.55, 95% CI = 0.15, 0.95, p = 0.008) such that the negative relationship between amyloid PET centiloids and cognition was significantly in participants with higher levels of GDF11.ConclusionGDF11 is a blood‐based rejuvenation factor that supports neurogenesis and cognition in animal models and attenuates the association between higher amyloid burden and worse cognition in cognitively unimpaired older adults. These results coupled with prior findings provide translational evidence that GDF11 supports brain resilience and further examination of GDF11 as a therapeutic target for Alzheimer’s disease is warranted.

Clinical Manifestations.

Repetitive head impacts (RHI) occur routinely in sports like American football (AmFootball) and are the most well-established risk factor for chronic traumatic encephalopathy, a neurodegenerative tauopathy. However, RHI is not routinely evaluated in older adults with other suspected neurodegenerative diseases. The prevalence of RHI among older adults with neurodegenerative diseases and the influence on clinical symptoms is unknown. RHI was defined by AmFootball participation and analyzed based on frequency of any and "substantial" exposure (> 4 years). The Boston University Head Impact Exposure Assessment was administered to 195 older adult males at the UCSF Memory and Aging Center. Of these 106 (54%) were clinically normal (CN) participants in the Brain Aging Network for Cognitive Health (BRANCH) study and 89 (46%) were cognitively impaired participants from the Alzheimer's Disease Research Center. Diagnostic groups included AD-related phenotypes ("clinAD"; amnestic-predominant MCI/dementia, logopenic PPA; N = 26) and frontotemporal dementia spectrum conditions ("FTD"; behavioral variant FTD, semantic PPA, nonfluent PPA; N = 46). Our aims were: 1) investigate frequency of prior RHI between diagnostic groups (chi square), 2) compare age of symptom onset between participants with and without prior RHI (ANOVA), and 3) evaluate associations between RHI and cognition within the largest single diagnostic group (bvFTD N = 20; ANCOVA adjusted for age and education). Cohen's d effect sizes are reported. Males with clinAD (27%; χ2 = 8.3, p = .009; d = 0.53) and FTD (21%; χ2 = 5.6, p = .02, d = 0.40) were more likely than CN (7%) to have had substantial prior RHI. Prior RHI was associated with younger age of symptom onset (62.1±7.6 vs. 56.7±7.7 years old; p = .001, d = 0.69). This effect was stronger within clinAD (63.1±7.2 vs. 53.3±7.5; d = 1.3) than FTD (60.1±7.0 vs. 55.9±6.0; d = 0.54). In participants with bvFTD, those with prior RHI scored significantly worse on memory testing (w-scores -2.6±1.1 vs. -1.1±1.2, p = .02, d = 1.4). RHI through AmFootball is more common in AD and FTD than healthy controls. Prior RHI may contribute to variability in age of symptom onset in both AD and FTD. Exposure to RHI may also partly explain why some participants with bvFTD, a classically nonamnestic syndrome, develop memory decline. Prior RHI should be routinely evaluated in neurodegenerative disease workups.

The frequency of psychotropic drug use in early‐onset Alzheimer’s disease ‐ experience from the Center for Memory Disorders in Serbia

AbstractBackgroundNeuropsychiatric symptoms (NPS) occur frequently in patients with young onset Alzheimer’s Disease (YOAD). However, studies on psychotropic drug use (PDU) mainly focus on elderly patients with dementia. It is important to know the prevalence of PDU in patients with YOAD in order to reduce excess use of these medications in this group. Our study aim is to investigate the frequency of PDU among patients with YOAD.MethodThis is a retrospective study on 135 patientsfrom Memory Centre of Neurology Clinic, Clinical Centre of Serbia, with clinical diagnosis of YOAD. We included outpatients that had first visit to our clinic from 01.04.2012. to 01.04.2017. The data on psychotropic drug use werecollected from medical records. Statistical analyses were done using SPSS20.ResultMean age of our patients at inclusion was 60.07±5.27 and mean disease duration was 3.42±1.53. 85.18% patients received PT drugs. Antidepressants were prescribed most frequently, in 63.7% of patients, while antipsychotics were used by 45.93% of patients, and benzodiazepines by 61.5%. The earliest prescribed PTs were antidepressants, 3.66 years from the first symptoms and 1.45 years after diagnosis and antidepressants were used the longest in our group, 3.15 years.ConclusionThe frequency pf PDU in our cohort is high and comes close to PDU in patients in nursing homes in other European countries. The reason might be the high frequency of NPS in YOAD but also prescribing practice in the absence of systematic non pharmacological measures and that is something we have to take notice of.

Evaluation of the association between circulatory markers of neuroinflammation and Alzheimer’s disease pathology

AbstractBackgroundIncreasing evidence suggests that neuroinflammation and astrogliosis have a prominent role in the spread of pathology and the development of cognitive impairment in Alzheimer’s disease (AD). Circulating plasma markers of neuroinflammation, such as the glial fibrillary acid protein (GFAP), have recently become available, and early observations suggest a robust association with brain pathology. Positron emission tomography (PET) is a molecular imaging technique that allows visualisation and quantification of AD pathology in vivo. The aim of this study was to evaluate the association between GFAP and AD pathology, and its interaction with cognitive decline.Method121 subjects from the Geneva Memory Centre underwent amyloid and tau PET, blood collection, and mini‐mental state examination (MMSE). Amyloid uptake was calculated as centiloid whereas tau was quantified as standardised uptake value ratio. Association of centiloid and tau with GFAP was assessed using a multivariate linear regression model, corrected for age, gender, and MMSE. Mediation analysis described the mediating effect of GFAP on the association between centiloid and tau. Ninety‐four subjects had a follow‐up MMSE after at least 12 months. Linear regression was used to assess the effect of GFAP on the annual rate of change of MMSE (corrected for centiloid, global tau, age, and gender). Mediation analysis was used to test whether the relationship between rate of MMSE change and tau could be explained by a mediation of GFAP.ResultThe mean (SD) age of the participants was 72.6 (7.6) years, and 61 of 121 subjects were men. GFAP was significantly associated with increased tau, but not with centiloid. GFAP partially mediated the effect of centiloid on global tau (mediated proportion = 14%, p = 0.03). The rate of MMSE change was significantly associated with GFAP, and global tau, but not with centiloid. Moreover, GFAP partially mediated the effect between global tau SUVR and change of MMSE scores (52%, p<0.01).ConclusionElevated GFAP is associated with tau. GFAP also partially explains the effect of amyloid pathology on tau accumulation and of tau pathology on subsequent cognitive decline. These results support neuroinflammation and astrogliosis as a relevant contributor to AD pathology, which can be monitored in blood.

Time Together: An Intergenerational Respite, Mentorship and Training Program

AbstractPeople living with dementia (PLWD) and their care partners (CP) experience physical and emotional stressors that are exacerbated by social isolation. Paying for in‐home respite care can be out of reach for many; the average cost of in‐home care is $28.00 with a three‐hour minimum. Furthermore, there is a critical gap in the dementia workforce (Weiss, 2020), leaving CP without access to affordable respite care, and PLWD without access to social engagement. The Penn Memory Center’s (PMC) Time Together (TT) and Weekly Smile (WS) programs are two low‐cost intergenerational respite and engagement programs that aim to increase social engagement for PLWD, reduce CP burden, and develop a geriatric care workforce. College students are trained to provide respite care and engagement for community‐dwelling PLWD and their CP. Families pay up to $10.00 (sliding scales offered) for up to 10 hours/week of companion/respite care. The student receives $10.00 an hour for their service. The PMC launched Time Together in 2019, delivering respite services in‐person. In 2020, the pandemic forced the program to pivot to a virtual model called WS. In January 2023 we began offering TT both in‐person and virtually to maximize accessibility and flexibility. Both the in‐person and virtual component are now called Time Together (TT).To assess the impact of the WS model we used a mixed‐methods design, using qualitative and quantitative assessments. The exploratory qualitative arm used conventional content analysis methods to describe the experiences of PLWD, CP, and student participants through semi‐structured interviews. In our findings from interviews with 3 PLWD, 3 CP, and 3 student participants, PLWD cited meaningful engagement and improved mood. CPs described the importance of protected time for self‐care. Student respite workers appreciated learning about aging and dementia and especially enjoyed developing empathy and relational practice. Participation was mutually beneficial to all and created a lasting impact.We continue to collect additional qualitative and quantitative to further evaluate findings from both the virtual and in‐person arms of Time Together for this updated abstract submission. Policy implications include recommendations for respite program structure and composition.

Three‐objects‐three‐places test as a screening test for prodromal and mild dementia: validation in a memory clinic population

AbstractBackgroundThe Three‐Objects‐Three‐Places (3O3P) test has been developed as a quick screen for episodic memory impairment due to Alzheimer’s Disease (AD). The examiner shows the patient three objects and hides them in three separate places. The patient is later asked what the objects and hiding places were, and which object was hidden where, producing a score out of 9. The aim of this study was to investigate the convergent, discriminant, and diagnostic validity of the test.Method1685 unselected patients from the Geneva Memory Center cohort who underwent the 3O3P test as a screen test in the context of routine assessment were included. The convergent and discriminant validity of the 3O3P test was assessed using an exploratory factor analysis. The known‐group validity was assessed in Cognitively Unimpaired (CU) vs Mild Cognitive Impairment (MCI) and demented using the Area Under the Curve (AUC) and comparing AUCs of the 3O3P test with those of other widely used cognitive tests (MMSE and Delayed recall ‐ DTR). The known‐group validity of the 3O3P was tested also in patients with AD biomarkers.ResultsMean age was 72 years (SD 11.5), 53% were female, mean years of education was 13 (SD 4.4), and mean MMSE was 28.5 (SD 1.5, N = 436) for CU, 25.6 (3.0, N = 767) for MCI and 19.5 (SD 5.2, N = 481). The 3O3P and DTR tests loaded strongly on the same (“memory”) factor, with a saturation of ‐0.89 and ‐0.88 respectively, and weakly on other (“non‐memory”) factors. The 3O3P test can discriminate CU versus MCI with an AUC of 0.71 and versus dementia with an AUC of 0.91. However, MMSE (AUC = 0.83 CU vs MCI; 0.97 CU vs dementia) and DTR (AUC = 0.78 CU vs MCI; 0.93 CU vs dementia) performed significantly better (p<0.001). Patients who were amyloid positive, tau positive, and with significant neurodegeneration achieved lower 3O3P scores.ConclusionThe 3O3P test has demonstrated good convergent and discriminant validity supporting the notion that the test assesses the construct of episodic memory. Although the MMSE and DTR tests generally distinguished between diagnostic groups more effectively, the 3O3P test carries several advantages over these tests, such as its short duration, easy administration, culture‐ and language‐ free nature.

Use of cerebrospinal fluid biomarkers for accurate diagnosis of Alzheimer’s disease in a tertiary care memory center

AbstractBackgroundAccurate clinical‐biological diagnosis of dementia and of Alzheimer’s disease (AD) is important for exclusion of treatable modifiable conditions, to differentiate AD from conditions with similar clinical manifestations, and for consideration of novel disease‐modifying therapeutic agents. Recently, it has become possible to measure protein biomarkers that reflect the pathology of AD. Our aim was to examine our initial experience of running a “cognitive” CSF biomarker service and bank at our institute.MethodThe service operates since June 2020. All subjects underwent physical, neurological and cognitive evaluation, imaging and laboratory work‐up. Consenting patients presenting at young age or with atypical or unclear manifestations of cognitive and/or behavioral deterioration underwent lumbar puncture for CSF examination, tailored according to the clinical differential diagnosis [cells, protein, glucose, chloride, cytology, AD biomarkers‐ total tau (tTau), 181‐phosphorylated tau (pTau181), amyloid‐β42 (Aβ42)]. When appropriate, antibody analysis and microbiological studies were added.ResultAD biomarkers results were available for 63 subjects presenting with cognitive/behavioral impairment, mean age 59 (range 31‐78) years, 34 (54%) were men. Mean MMSE score was 21/30 (range 6‐30), mean MoCA score was 18/30 (range 6‐28). Pre CSF analysis, 27 (43%) subjects were clinically diagnosed with possible AD (CDAD) and 36 (57%) with clinically diagnosed possible non‐AD (CDNAD) (FTD, LBD, CBD, vascular disease, autoimmune encephalopathy, unclear etiology). In our sample 28 (44%) were biomarkers positive for AD. Among 27 subjects with CDAD in 5 AD was excluded and among 36 with CDNAD 6 were biomarker positive AD (clinical sensitivity 78%, false positive 18.5%, false negative 16.6%).ConclusionOur study emphasizes the added value of biomarker supported diagnosis in subjects with cognitive/behavioral impairment, to avoid incorrectly labeling AD or misdiagnosis and for disclosure recommendation in the era of disease‐modifying therapies.

Association of AD risk factors with plasma GFAP levels in a memory clinic population

AbstractBackgroundPlasma glial fibrillary acidic protein (GFAP) is an emerging AD biomarker. We aimed to study how plasma GFAP correlated with age, clinical stage, sex, and the APOE4 status and whether amyloid pathology may mediate these associations.MethodsCohort of 330 individuals ranging from cognitively unimpaired to dementia due to AD from the Geneva Memory Center. Plasma GFAP was measured using Single molecule array (Simoa) technology. The effect of the variables of interest on plasma GFAP levels was assessed using linear regression models and partial eta squared (eta2 p). In a subset of 169 subject with amyloid PET, mediation analysis was performed to test the mediating effect of amyloid levels on the association between variable of interest and plasma GFAP.ResultsAge had the strongest effect on plasma GFAP levels (eta2 p = 0.39, p< 0.0001), followed by clinical stage (eta2 p = 0.10, p< 0.0001), sex (eta2 p = 0.06, p< 0.0001), and APOE4 (eta2 p = 0.02, p = 0.007). The effect of APOE4 status on plasma GFAP was fully mediated via the cortical amyloid uptake. The bootstrapped indirect effect was 0.09 (p< 0.0001) and the proportion of the effect of APOE4 status on GFAP that goes through the cortical amyloid uptake was 69%. No mediating effect by amyloid was found for age and sex.ConclusionThese results show that in a memory clinic population, i) AD risk factors and severity affected plasma GFAP levels and, ii) the effect of APOE4 on GFAP is amyloid‐dependent whereas that of age and sex is amyloid‐independent. GFAP cut‐offs for the early diagnosis of AD should take age and sex into account.

Survival and anti‐psychotic treatment in young onset Alzheimer’s disease

AbstractIntroductionPsychosis and agitation represent a major therapeutic problem in young onset Alzheimer’s disease (YOAD), given that these symptoms pose a great risk to the patient, but treatment options are limited. Anti‐psychotic use is connected to different side effects, but increased mortality noted in older demented population is particularly worrying. Since YOAD patients are younger we wanted to examine if anti‐psychotic use is connected to decreased survival in these patients as well.AimTo examine the association between the use of anti‐psychotics and the length of survival in YOAD.Material and methodsThis is a retrospective study on 135 patients from Memory Center of Neurology Clinic, Clinical Center of Serbia, with clinical diagnosis of YOAD. We included outpatients that had first visit to our clinic from 01.04.2012. do 01.04.2017. The need to introduce anti‐psychotics was noted during the follow‐up period and the difference in the survival of patients who at some point during the observation (from inclusion in the register until 2019) received anti‐psychotic therapy and those who did not. In this analysis we used Kaplan Meier survival analysis with log rank test with the time from the onset of symptoms to the outcome as an independent variable. Outcome was survived/died (at 2019.) and dependent variable was whether or not the patient received anti‐psychotics.ResultsDuring the period covered by this analysis, ending in 2019, among patients who received anti‐psychotics, 42 patients died while 20 remained alive. In patients who did not receive anti‐psychotics, 47 patients died while 26 remained alive. There was no statistically significant difference between the number of deaths in the group of patients who were and were not treated with anti‐psychotics (p = 0.682). Kaplan Meier analysis showed that the use of anti‐psychotics (at any point during observation) did not significantly affected survival measured as the time elapsed from the onset of symptoms to the outcome (death or 2019).ConclusionThe use of anti‐psychotics in patients with YOAD is not associated with reduced lifespan.

Survival and pharmacotherapy delay in young onset Alzheimer’s disease

AbstractIntroductionSpecific feature of young onset Alzheimer’s disease (YOAD) patients is that their diagnosis and therefore their treatment is usually delayed. Firstly, they present atypically, secondly, they have a higher cognitive reserve and symptoms are later recognized and finally at that age, the family, and the patients themselves, do not think about the possibility of dementia, which prolongs the time period to seeking medical help (on average 2‐3 years).AimTo examine the association of survival in YOAD with time elapsed from the onset of symptoms to the initiation of pharmacotherapy.Material and methodsThis is a retrospective study on 135 patients from Memory Center of Neurology Clinic, Clinical Center of Serbia, with clinical diagnosis of YOAD. We included outpatients that had first visit to our clinic from 01.04.2012. do 01.04.2017. The association of survival with time elapsed from onset of symptoms to initiation of therapy was examined by Kaplan Meier survival analysis with log rank test.ResultsFrom 2012, when the registry was created, till 2019, 89 out of 135 included patients died. Kaplan Meier survival analysis showed that patients with lower MMSE score (from 15 points and below) and who could not dress themselves or perform personal hygiene at the time of inclusion in our registry have a shorter expected survival than those who had MMSE 16 and above (p = 0.019) and who functioned independently in terms of these activities of daily living (p = 0.041 for dressing and p = 0.018 for performing personal hygiene). Patients in whom the introduction of therapy was delayed 3 or less years survived for a year longer than patients in whom therapy was introduced 4 or more years after the onset of dementia symptoms (p = 0.004).ConclusionOur study clearly showed that certain clinical parameters (degree of cognitive and functional damage at the time of therapy introduction), but also delay in introducing therapy from symptoms onset determine the length of survival in YOAD.

Effect of COVID‐19 and telehealth implementation on Patient Centered Outcome Measures completion by patients with Alzheimer’s and related disorders in an academic memory center

AbstractBackgroundPatient Centered Outcome Measures (PCOMs) are increasingly recognized as a means of improving clinical efficiency, particularly when completed electronically ahead of clinic visits. However, PCOM completion is often far from consistent. The shift to telehealth introduced by the Covid‐19 pandemic changed how patients and caregivers engaged with medical care, possibly encouraging increased participation in electronic assessments. We questioned how the pandemic influenced electronic PCOM completion by our patients with Alzheimer’s disease (AD) and their caregivers.MethodsPatients and caregivers were routinely invited to fill electronic PCOM questionnaires prior to visits both before and during the Covid‐19 pandemic. PCOMs assessed the predominant cognitive domain of concern, other diagnostically useful symptoms, disease severity, neuropsychiatric symptoms, and caregiver wellbeing. A date of 3/15/2020 was set as the onset of the pandemic for this study, after which time our clinic converted to telehealth visits only. We tallied rates of completion of electronic surveys by patients and/or caregivers three and a half months before and after that time, comparing completion rates by two proportion Z‐test.ResultsDuring this timeframe, across a total of 402 visits (total: 333 individuals, 69 returns; AD: 73 individuals, 6 returns), caregivers and/or patients were offered an opportunity to fill PCOMs ahead of the visit. Across all clinical diagnoses combined, the probability of a visit being associated with filled PCOMS was greater after switching to only telehealth (caregivers: P = 0.005, patients: P = 0.016). Additionally, after the shift to telehealth, AD‐related visits were twice as likely to have completed preclinical electronic PCOMs (caregivers: P = 0.002, patients: P = 0.008). Approximately 33.3% of PCOMS to be filled by AD caregivers were completed before the telehealth shift, and 67.5% were afterwards. Approximately 26.7% of patient PCOMs were filled before the change, and afterwards this percentage rose to 55.0%.ConclusionThe beginning of the Covid‐19 pandemic and subsequent shift towards telehealth‐only practice was associated with greater use of electronic PCOMs by all patients, including those with AD and their caregivers. Increased acceptance of electronic PCOMs seems to offer promising opportunities for remote assessment in the future of dementia diagnosis and care.

6 The Moderating Role of Physical Activity on Hippocampal Iron Deposition and Memory Outcomes in Typically Aging Older Adults

Objective:Quantitative Susceptibility Mapping (QSM) is an MRI-based technique that sensitively measures in-vivo iron deposition via relaxation and magnetic susceptibility of brain tissue. Iron is essential for brain homeostasis, including oxidative metabolism, formation and maintenance of neural networks, and myelin synthesis. While increased levels of iron deposition occur during normal aging, high levels may have detrimental effects. Previous work has linked excessive brain iron accumulation to oxidative stress, beta-amyloid and tau toxicity, neurodegeneration, and cognitive dysfunction, particularly memory loss. Physical activity, on the other hand, correlates with higher synaptic integrity and memory performance, even in the presence of neuropathology. To date, it is unknown how physical activity may affect iron deposition-related cognition changes. We examined the moderating role of physical activity on the relationship between QSM hippocampal iron deposition and verbal memory in typically aging adults.Participants and Methods:62 cognitively unimpaired older adults from the UCSF Memory and Aging Center (age mean(SD) = 78.34(7.28) years; 56% women; education mean(SD) = 17.94(1.72) years; 85% non-Hispanic White) completed neuropsychological testing and brain MRI during annual research visits, followed by Fitbit™ physical activity monitoring for 30 days. Average total daily steps were aggregated. Participants completed 3T Prisma neuroimaging with QSM, and regional iron deposition levels were quantified. All subjects also underwent diffusion tensor imaging (fractional anisotropy). Verbal memory was assessed via long delay free recall scores from the California Verbal Learning Test II (CVLT-II). Linear regression examined verbal memory as a function of hippocampal QSM (bilateral), physical activity, and their interaction. Models covaried for age, sex, and education. Additional models separately examined left and right hippocampal QSM, as well as subcortical QSM to determine lateralization and specificity of verbal memory effects to hippocampal iron deposition, respectively.Results:Univariably, higher bilateral hippocampal QSM correlated with worse verbal memory (r= 0.35; p= 0.015). Adjusting for demographics, physical activity moderated the relationship between bilateral hippocampal QSM and verbal memory (ß= 0.41, p= 0.011), such that at higher levels of physical activity, the negative relationship between hippocampal QSM and verbal memory was significantly attenuated. Results persisted when adjusting for DTI integrity of the uncinate fasciculus and fornix white matter tracts. Lateralization models were both significant, suggesting that results were not dominantly driven by either left (ß= 0.34, p= 0.048), or right (ß=0.31, p= 0.035) hippocampal QSM. In contrast, subcortical QSM did not correlate with memory performance (r= 0.13, p > 0.05) or interact with physical activity on verbal memory outcomes (p > 0.05).Conclusions:Physical activity significantly moderated the negative relationship between hippocampal QSM and verbal memory performance. Higher exercise engagement may buffer the adverse effect of hippocampal iron deposition on memory, potentially through its role in maintenance of myelin and synaptic integrity and/or protecting against other neurotoxic events (e.g., oxidative stress, neuronal cell death). Our results support that physical activity continues to be a modifiable risk factor that may offer a protective role in neurobiological pathways of memory and cognitive decline.

64 Neuroimaging Evidence of Neurodegenerative Disease in Former Professional American Football Players Who “Fail” Validity Testing: A Case Series

Objective:Former professional American football players have a high relative risk for neurodegenerative diseases like chronic traumatic encephalopathy (CTE). Interpreting low cognitive test scores in this population occasionally is complicated by performance on validity testing. Neuroimaging biomarkers may help inform whether a neurodegenerative disease is present in these situations. We report three cases of retired professional American football players who completed comprehensive neuropsychological testing, but “failed” performance validity tests, and underwent multimodal neuroimaging (structural MRI, Aß-PET, and tau-PET).Participants and Methods:Three cases were identified from the Focused Neuroimaging for the Neurodegenerative Disease Chronic Traumatic Encephalopathy (FIND-CTE) study, an ongoing multimodal imaging study of retired National Football League players with complaints of progressive cognitive decline conducted at Boston University and the UCSF Memory and Aging Center. Participants were relatively young (age range 55-65), had 16 or more years of education, and two identified as Black/African American. Raw neuropsychological test scores were converted to demographically-adjusted z-scores. Testing included standalone (Test of Memory Malingering; TOMM) and embedded (reliable digit span, RDS) performance validity measures. Validity cutoffs were TOMM Trial 2 < 45 and RDS < 7. Structural MRIs were interpreted by trained neurologists. Aß-PET with Florbetapir was used to quantify cortical Aß deposition as global Centiloids (0 = mean cortical signal for a young, cognitively normal, Aß negative individual in their 20s, 100 = mean cortical signal for a patient with mild-to-moderate Alzheimer’s disease dementia). Tau-PET was performed with MK-6240 and first quantified as standardized uptake value ratio (SUVR) map. The SUVR map was then converted to a w-score map representing signal intensity relative to a sample of demographically-matched healthy controls.Results:All performed in the average range on a word reading-based estimate of premorbid intellect. Contribution of Alzheimer’s disease pathology was ruled out in each case based on Centiloids quantifications < 0. All cases scored below cutoff on TOMM Trial 2 (Case #1=43, Case #2=42, Case #3=19) and Case #3 also scored well below RDS cutoff (2). Each case had multiple cognitive scores below expectations (z < -2.0) most consistently in memory, executive function, processing speed domains. For Case #1, MRI revealed mild atrophy in dorsal fronto-parietal and medial temporal lobe (MTL) regions and mild periventricular white matter disease. Tau-PET showed MTL tau burden modestly elevated relative to controls (regional w-score=0.59, 72nd%ile). For Case #2, MRI revealed cortical atrophy, mild hippocampal atrophy, and a microhemorrhage, with no evidence of meaningful tau-PET signal. For Case #3, MRI showed cortical atrophy and severe white matter disease, and tau-PET revealed significantly elevated MTL tau burden relative to controls (w-score=1.90, 97th%ile) as well as focal high signal in the dorsal frontal lobe (overall frontal region w-score=0.64, 74th%ile).Conclusions:Low scores on performance validity tests complicate the interpretation of the severity of cognitive deficits, but do not negate the presence of true cognitive impairment or an underlying neurodegenerative disease. In the rapidly developing era of biomarkers, neuroimaging tools can supplement neuropsychological testing to help inform whether cognitive or behavioral changes are related to a neurodegenerative disease.

5 Rejuvenating Blood Factor TIMP2 Relates to Physical Activity and Cognitive Functioning in Older Adults on The Alzheimer’s Disease Continuum

Objective:Tissue inhibitor of metalloproteinases 2 (TIMP2) is produced peripherally, crosses the blood-brain barrier, and improves synaptic plasticity and hippocampal-dependent cognition in aged mice; however, the role of TIMP2 in human cognitive aging is unclear. We examined associations of circulating TIMP2 levels in blood with a known plasticity-inducing behavior, physical activity, and cognitive functioning among older adults along the Alzheimer’s disease continuum.Participants and Methods:Participants included 84 community-dwelling older adults (meanage = 78.8; 57% female; 82% cognitively normal; 14% MCI; 4% mild dementia; 35% PET Aß+) enrolled in the UC San Francisco Memory and Aging Center. All participants completed 30 days of observational FitbitTM monitoring to quantify physical activity (average daily steps), as well as a comprehensive in-person visit including blood draw (proteins assayed on SOMAscan platform), [18F]AV-45 positron emission tomography (PET) to quantify brain beta-amyloid (centiloids), and neuropsychological assessment. Composite cognitive z-scores were calculated for memory (California Verbal Learning Test-II [CVLT-II] and Benson Figure Recall), semantic processing (animal fluency and Boston Naming Test), and executive functioning (digits backwards span, Stroop inhibition, modified trail making test, lexical fluency, and design fluency). Multiple linear regression examined TIMP2 as a function of physical activity, covarying for age and PET centiloids. Additional regression models separately examined cognitive z-scores as a function of TIMP2, covarying for age, sex, education, PET centiloids, and body mass index (BMI).Results:TIMP2 was not significantly correlated with age, sex, education, or PET centiloids (ps > 0.05); however, TIMP2 was negatively correlated with BMI (r = -0.23, p = 0.036). Greater average daily steps related to higher levels of TIMP2 (b = 0.30, 95%CI = 0.04-0.55, p = 0.022). TIMP2 also related to better semantic processing (b = 0.28, 95%CI = 0.04-0.51, p = 0.021) and executive functioning (b = 0.26, 95%CI = 0.03-0.49, p = 0.028). TIMP2 did not significantly relate to memory (p > 0.05).Conclusions:Greater physical activity was associated with higher concentrations of blood factor TIMP2, which in turn related to better cognitive functioning independent of Alzheimer’s disease pathology burden. These results support previous mouse models by broadly replicating relationships between TIMP2 and cognition in humans, while also uniquely demonstrating an association between TIMP2 and physical activity, a modifiable protective factor in both typical and diseased cognitive aging. Our domain-specific results, however, suggest that benefits of TIMP2 in humans may involve a broader neuroanatomical network than the hippocampal-specific effects previously shown in mice. Although exact mechanisms of TIMP2 need further examination, TIMP2 is known to be enriched in human umbilical cord plasma, has been shown to be involved in cell-growth promoting activities, and may relate to increased neural plasticity in older age. Further examination of TIMP2 and other novel blood-based proteins as potential therapeutic targets for improved cognitive aging, including in the presence of Alzheimer’s disease, is warranted.

Glycolysis-derived alanine from glia fuels neuronal mitochondria for memory in Drosophila

Glucose is the primary source of energy for the brain; however, it remains controversial whether, upon neuronal activation, glucose is primarily used by neurons for ATP production or if it is partially oxidized in astrocytes, as proposed by the astrocyte–neuron lactate shuttle model for glutamatergic neurons. Thus, an in vivo picture of glucose metabolism during cognitive processes is missing. Here, we uncover in Drosophila melanogaster a glia-to-neuron alanine transfer involving alanine aminotransferase that sustains memory formation. Following associative conditioning, glycolysis in glial cells produces alanine, which is back-converted into pyruvate in cholinergic neurons of the olfactory memory center to uphold their increased mitochondrial needs. Alanine, as a mediator of glia–neuron coupling, could be an alternative to lactate in cholinergic systems. In parallel, a dedicated glial glucose transporter imports glucose specifically for long-term memory, by directly transferring it to neurons for use by the pentose phosphate pathway. Our results demonstrate in vivo the compartmentalization of glucose metabolism between neurons and glial cells during memory formation.

Adult neurogenesis does not explain the extensive post-eclosion growth of Heliconius mushroom bodies.

Among butterflies, Heliconius have a unique behavioural profile, being the sole genus to actively feed on pollen. Heliconius learn the location of pollen resources, and have enhanced visual memories and expanded mushroom bodies, an insect learning and memory centre, relative to related genera. These structures also show extensive post-eclosion growth and developmental sensitivity to environmental conditions. However, whether this reflects plasticity in neurite growth, or an extension of neurogenesis into the adult stage, is unknown. Adult neurogenesis has been described in some Lepidoptera, and could provide one route to the increased neuron number observed in Heliconius. Here, we compare volumetric changes in the mushroom bodies of freshly eclosed and aged Heliconius erato and Dryas iulia, and estimate the number of intrinsic mushroom body neurons using a new and validated automated method to count nuclei. Despite extensive volumetric variation associated with age, our data show that neuron number is remarkably constant in both species, suggesting a lack of adult neurogenesis in the mushroom bodies. We support this conclusion with assays of mitotic cells, which reveal very low levels of post-eclosion cell division. Our analyses provide an insight into the evolution of neural plasticity, and can serve as a basis for continued exploration of the potential mechanisms behind brain development and maturation.

Rewarding Capacity of Optogenetically Activating a Giant GABAergic Central-Brain Interneuron in Larval Drosophila.

Larvae of the fruit fly Drosophila melanogaster are a powerful study case for understanding the neural circuits underlying behavior. Indeed, the numerical simplicity of the larval brain has permitted the reconstruction of its synaptic connectome, and genetic tools for manipulating single, identified neurons allow neural circuit function to be investigated with relative ease and precision. We focus on one of the most complex neurons in the brain of the larva (of either sex), the GABAergic anterior paired lateral neuron (APL). Using behavioral and connectomic analyses, optogenetics, Ca2+ imaging, and pharmacology, we study how APL affects associative olfactory memory. We first provide a detailed account of the structure, regional polarity, connectivity, and metamorphic development of APL, and further confirm that optogenetic activation of APL has an inhibiting effect on its main targets, the mushroom body Kenyon cells. All these findings are consistent with the previously identified function of APL in the sparsening of sensory representations. To our surprise, however, we found that optogenetically activating APL can also have a strong rewarding effect. Specifically, APL activation together with odor presentation establishes an odor-specific, appetitive, associative short-term memory, whereas naive olfactory behavior remains unaffected. An acute, systemic inhibition of dopamine synthesis as well as an ablation of the dopaminergic pPAM neurons impair reward learning through APL activation. Our findings provide a study case of complex circuit function in a numerically simple brain, and suggest a previously unrecognized capacity of central-brain GABAergic neurons to engage in dopaminergic reinforcement.SIGNIFICANCE STATEMENT The single, identified giant anterior paired lateral (APL) neuron is one of the most complex neurons in the insect brain. It is GABAergic and contributes to the sparsening of neuronal activity in the mushroom body, the memory center of insects. We provide the most detailed account yet of the structure of APL in larval Drosophila as a neurogenetically accessible study case. We further reveal that, contrary to expectations, the experimental activation of APL can exert a rewarding effect, likely via dopaminergic reward pathways. The present study both provides an example of unexpected circuit complexity in a numerically simple brain, and reports an unexpected effect of activity in central-brain GABAergic circuits.