Risk Of Future Cognitive Decline Research Articles

Brain structure, amyloid, and behavioral features for predicting clinical progression in subjective cognitive decline.

As a potential preclinical stage of Alzheimer's dementia, subjective cognitive decline (SCD) reveals a higher risk of future cognitive decline and conversion to dementia. However, it has not been clear whether SCD status increases the clinical progression of older adults in the context of amyloid deposition, cerebrovascular disease (CeVD), and psychiatric symptoms. We identified 99 normal controls (NC), 15 SCD individuals who developed mild cognitive impairment in the next 2 years (P-SCD), and 54 SCD individuals who did not (S-SCD) from ADNI database with both baseline and 2-year follow-up data. Total white matter hyperintensity (WMH), WMH in deep (DWMH) and periventricular (PWMH) regions, and voxel-wise grey matter volumes were compared among groups. Furthermore, using structural equation modelling method, we constructed path models to explore SCD-related brain changes longitudinally and to determine whether baseline SCD status, age, and depressive symptoms affect participants' clinical outcomes. Both SCD groups showed higher baseline amyloid PET SUVR, baseline PWMH volumes, and larger increase of PWMH volumes over time than NC. In contrast, only P-SCD had higher baseline DWMH volumes and larger increase of DWMH volumes over time than NC. No longitudinal differences in grey matter volume and amyloid was observed among NC, S-SCD, and P-SCD. Our path models demonstrated that SCD status contributed to future WMH progression. Further, baseline SCD status increases the risk of future cognitive decline, mediated by PWMH; baseline depressive symptoms directly contribute to clinical outcomes. In conclusion, both S-SCD and P-SCD exhibited more severe CeVD than NC. The CeVD burden increase was more pronounced in P-SCD. In contrast with the direct association of depressive symptoms with dementia severity progression, the effects of SCD status on future cognitive decline may manifest via CeVD pathologies. Our work highlights the importance of multi-modal longitudinal designs in understanding the SCD trajectory heterogeneity, paving the way for stratification and early intervention in the preclinical stage. PRACTITIONER POINTS: Both S-SCD and P-SCD exhibited more severe CeVD at baseline and a larger increase of CeVD burden compared to NC, while the burden was more pronounced in P-SCD. Baseline SCD status increases the risk of future PWMH and DWMH volume accumulation, mediated by baseline PWMH and DWMH volumes, respectively. Baseline SCD status increases the risk of future cognitive decline, mediated by baseline PWMH, while baseline depression status directly contributes to clinical outcome.

Unveiling the role of subjective cognitive complaints in predicting cognitive impairment in Parkinson´s Disease- A longitudinal study with 4year of follow up.

Emerging data associated subjective cognitive complaints (SCC) with a heightened risk of future cognitive decline in Parkinson´s Disease (PD). To determine whether SCC may predict the development of cognitive impairment in PD patients at baseline. Over 4years, major aspects of motor and non-motor symptoms were assessed. SCC were evaluated by non-motor symptoms scale domain-5 (NMSS5). The predictor value of SCC in cognitive change was assessed with univariate linear regression analyses, with NMSS5 at baseline as predictor. Change in cognition (ΔMoCA) was calculated by subtracting Montreal Cognitive Assessment Scale (MoCA) scores at baseline from scores obtained at reassessment and employed as the outcome. We replicated these analyses by employing alterations in MoCA subdomains as outcomes. 134 patients were evaluated at baseline, of those 73 PD patients were reassessed four years later. In our study, SCC didn´t act as a predictor for future cognitive decline. However, baseline NMSS5 was associated significantly with variation in attention, naming, and orientation domains. Our findings did not support that SCC in PD patients acts as a predictor of global cognitive decline. However, our findings enhance comprehension of how SCC correlates with performance in distinct cognitive areas, thereby providing better guidance for patients on their current complaints.

348 Alexithymia impacts vulnerability for cognitive decline in healthy elders via frontal lobe connectivity during response inhibition, especially in women

OBJECTIVES/GOALS: This project aimed to examine the impacts of biological sex and alexithymia on frontal lobe connectivity in executive functioning (EF)-related neural networks during successful inhibition as a means to index vulnerability for future cognitive decline. METHODS/STUDY POPULATION: Healthy, cognitively intact older adults (n=43, 33 female, Mage=79) completed the 20-item Toronto Alexithymia Scale (TAS-20) and the stop-signal task in this study. We used electroencephalography (EEG) source estimation to investigate EF-related frontal connectivity during successful inhibition in stop-signal task trials. Connectivity was measured in bilateral frontal ROIs relevant to inhibition using time series correlations over the N200 (186-350ms) and P300 (340-616ms) time windows, associated with the inhibitory subprocesses of conflict processing and performance evaluation, respectively. RESULTS/ANTICIPATED RESULTS: Those with higher alexithymia, as measured by the difficulty identifying feelings (DIF) facet of the TAS-20, had lower right anterior cingulate cortex (ACC)-left superior frontal gyrus (SFG) connectivity in the P300 window, suggesting impaired performance evaluation. Further, in females specifically, those with higher DIF had greater right inferior frontal gyrus (rIFG)-bilateral ACC connectivity in the N200 window than those with lower DIF, suggesting greater resources were allocated for conflict processing and inhibition. Right ACC-rIFG connectivity also correlated with better stop accuracy and faster stop-signal reaction time, supporting this network’s role in successful inhibition. DISCUSSION/SIGNIFICANCE: Overall, during successful inhibition, higher DIF was associated with reduced performance monitoring efficiency as well as greater resource allocation for conflict processing during motor stopping in women only. Thus, alexithymia (via DIF) may exacerbate age-related EF dysfunction and risk for future cognitive decline, especially for females.

B - 31 Association of Hippocampal Volume with Subjective and Objective Cognitive Functioning in a Diverse Sample.

Individuals with subjective cognitive complaints (SCCs) and reduced hippocampal volumes (HV) may be at increased risk of future cognitive decline, though findings regarding the relationship between SCCs and HV have been mixed. The current study explores the association of HV with SCCs and objective cognitive performance in a diverse sample. Participants in a population-based cardiovascular risk study (N = 1754; MAge = 58.8, 59% Female, 50% Black, 10% Hispanic) responded to three subjective cognitive functioning questions prior to completing the Montreal Cognitive Assessment (MoCA): 1) Do you have consistent memory problems, 2) If YES, do they interfere with everyday activities, and 3) do you have trouble figuring things out/solving problems. HV were derived from a 3-tesla MRI and normalized using total intracranial volume. Partial correlations examined associations between HV, MoCA scores, and SCCs, while one-way ANCOVA compared HV by SCC endorsement pattern, controlling for demographics. Findings revealed smaller HV in those who endorsed all SCC questions (n = 27; MHV =0.34) compared to those without any SCC (n = 631, MHV = 0.36, p = 0.001), though effect size was small (η2 = 0.015). HV were not correlated with SCCs (r = -0.06, p = 0.10) or cognitive performance (r = 0.01, p = 0.75), and SCCs had a small correlation with MoCA scores (r = -0.18, p < 0.001). Subjective cognitive functioning was minimally associated with HV and cognitive performance in this sample, and as a result the clinical significance of these findings is unclear. Further research is needed to understand the possible neuroanatomical correlates of SCC, along with the predictive utility of SCCs in the early identification of cognitive decline.

A - 31 Perceived Discrimination, Socioeconomic Factors & Subjective Cognitive Decline in Ethnoracially Diverse Older Adults Living in the United States.

Perceived discrimination (PD) is linked to poorer well-being and a higher risk of future cognitive decline. Higher levels of PD are frequently reported by people of color. Subjective cognitive decline (SCD), the self-perceived cognitive decline, has been associated with increased risk for dementia. The present study aimed to examine the relationship among PD, race, socio-economic factors and SCD. A total of 870 community-dwelling older adults (mean age = 67.0, SD = 7.6; range = 55-94; 76% female) living in the United States who self-identified as Latino (n = 126), Black (n = 74), Asian (n = 33), and White (n = 637) completed an online survey during the COVID-19 pandemic. Socio-economic factors included access to resources and resource insecurity. PD was measured with the 7-item Everyday Discrimination Scale, and SCD was measured with the Everyday Cognition scale (ECOG). Higher levels of PD predicted higher SCD in the entire sample (p-values 0.05). There were no significant associations between PD, socio-economic factors, race, and SCD (p-values >0.05). Experiences of discrimination negatively impact health outcomes and risk. Our findings provide further evidence of a relationship between PD and SCD although, this relationship was not moderated by race. Future research should aim to examine the relationship between different forms of discrimination (e.g., systemic discrimination) and SCD.

Gait variability-based classification of the stages of the cognitive decline using partial least squares-discriminant analysis.

The purpose of the present study was to examine the differences in gait variability in terms of spatiotemporal, sub-gait cycle, ground reaction force, and the joint profiles of kinematics and kinetics between older individuals with and without risk of potential cognitive impairment, and to derive the crucial features to discriminating the older adults with future risk cognitive decline by using partial least squares-discriminant analysis. A total of 90 community-dwelling older adults aged over 65 years underwent cognitive function assessment and were divided into three groups depending on cognitive assessment score. The participants' level-walking was analyzed by using three-dimensional instrumented gait analysis. The coefficient of variation was extracted and then comparatively analyzed depending on the stages of the cognitive decline. To identify the most important contributor when differentiating the older adults with a risk of future cognitive decline, partial least squares-discriminant analysis was applied, and the discriminative power of the coefficients confirmed as features of great importance were investigated via the receiver operating characteristic area under the curve. The differences in gait variability were found mainly between the suspected dementia groups and other groups, especially in joint dynamics variables. Through the partial least squares-discriminant analysis, the discriminative features were found as follows: the mid-stance, the moments, and the power in the hip, knee, and ankle joints. In addition, the discrimination model was found to differentiate well between the three groups. The classification accuracy of intact cognition, diminished cognition, and suspected dementia was 0.857, 0.710, and 0.857, respectively. These findings mean that gait variability changes according to continuous cognitive decline, especially in sub-gait cycles and joint biomechanics, and suggest that measures of variation can be used as predictors to identify older individuals with a risk of potential cognitive impairment.

The impact of mental health outcomes on cognition during the COVID‐19 pandemic in older adults with remitted depression, mild cognitive impairment, or normal cognition

AbstractBackgroundOlder adults may be vulnerable to worsening cognition during pandemics because of public health restrictions that increase social isolation and negatively impact mental health. In the current study, we assessed mental health outcomes during the COVID‐19 pandemic and their relationship with cognitive status at 6 months in older adults with remitted major depressive disorder (rMDD), mild cognitive impairment (MCI), or normal cognition (NC).MethodThe sample consisted of 108 older adults enrolled from ongoing studies [37M, mean age = 70.6 (SD = ±5.75)], including 71 NC, 21 rMDD, and 16 MCI]. Participants completed self‐report measures including the Patient Health Questionnaire‐9 to assess depression, Patient Reported Outcomes Measurement Information System to assess anxiety, Perceived Stress Scale to assess general stress, Impact of Events Scale‐Revised to assess post‐traumatic stress, and the Clinical Dementia Rating Scale (CDR) at baseline, 3 and 6 months. Repeated measures ANCOVA of mood and cognitive measures with time as a within‐subject factor and covariates of parent study and mood/memory diagnosis assessed change over time in mental health and cognition. Regression modelling of CDR Sum of Boxes (CDR‐SB) score at 6 months with baseline mood and anxiety scores as predictors and age, gender, parent study, and mood/memory diagnosis as covariates were used to assess the association between mental health and future cognition.ResultMood and cognition did not significantly vary over the three time‐points. Depression and general stress at baseline were predictive of CDR‐SB at 6‐month follow‐up, accounting for 14% of its variance (F(6,55) = 2.69, p = .023, B = .28, p = .038; F(6,72) = 3.16, p = .008, B = .21, p = .088, respectively). Neither anxiety nor post‐traumatic stress symptom severity predicted CDR‐SB.ConclusionThese findings are consistent with epidemiological studies supporting associations between depression or stress and risk of dementia (Byers &amp; Yaffe, 2011; Stuart &amp; Padgett, 2020). Limitations of the study include non‐random sampling and small rMDD and MCI samples. Nevertheless, these preliminary findings suggest the need to address adverse mental health outcomes in seniors during the COVID‐19 pandemic to potentially reduce risk of future cognitive decline.

CSF neurodegeneration biomarkers predict MTL atrophy over time in cognitively healthy older adults

AbstractBackgroundStructural decline in the medial temporal lobe is an unspecific biomarker of neurodegeneration, assessed in normal older adults (OA) and Alzheimer’s Disease (AD). We investigated, in OA, whether CSF biomarkers of neurodegeneration (t‐tau, NFL, Ng, FABP3) predict longitudinal brain atrophy, whether this association is moderated by core AD biomarkers of beta‐amyloid (Aβ) and phosphorylated tau (p‐tau) and whether it is related to specific cellular and molecular mechanisms by using neurogenetic profiles.MethodLongitudinal structural MRI up to 7 years and baseline CSF biomarkers levels were collected in 189 OA (mean age = 74.8 years). Hippocampus (HC) and entorhinal cortex (EC) were selected as regions of interest. Linear mixed and generalized additive mixed models (GAMM) were used to assess the effects of Biomarker, Time, and Time×Biomarker on EC thickness and HC volume. Similar models were used to assess the interaction with core AD biomarkers. Correlation between cortical decline maps, associated with CSF biomarkers, and gene‐expression maps (Allen Human Brain Atlas https://human.brain‐map.org/) for specific cellular components, was assessed with BrainSMASH package (https://brainsmash.readthedocs.io/en/latest/)ResultHigher NFL, FABP3, and t‐tau CSF values were associated with steeper EC thinning and more HC atrophy (p&lt;.05) over time (Figure 1a). GAMM showed significant non‐linear interactions with Time (except NG): NFL and FABP3 on EC (edf = 3.15, 3.81) and NFL and t‐tau on HC (edf = 3.09, 2.77) (Figure 1b). Aβ+ status (&lt;550 pg/mL) did not significantly moderate the association with any biomarker (all tests p&gt;.08) (Figure 2a). The relationships between CSF NFL with EC thinning (t = ‐3.27, p = 0.001) and HC atrophy (t = ‐2.91, p = 0.004), and FABP3 with EC thinning (t = ‐1.98, p = .05) remained significant, independently of p‐tau. The spatial pattern of cortical atrophy associated with the CSF biomarkers of neurodegeneration (Figure 2b) overlapped with distinct neurogenetic profiles: t‐tau with axonal growth cone (r = ‐.50, punc = .002); NFL with cortical cytoskeleton (r = ‐.61, pfdr&lt;.001) and Ng with the dendritic shaft (r = ‐.40, punc&lt;.009) components.ConclusionCSF NFL and FABP3 predict HC atrophy and EC thinning independently of Aβ/p‐tau. The neurodegenerative biomarkers may improve the accuracy of individual predictions of neurodegenerative changes in OA and identify those with a higher risk of future cognitive decline.

Childhood Disadvantage Moderates Late Midlife Default Mode Network Cortical Microstructure and Visual Memory Association.

Childhood disadvantage is a prominent risk factor for cognitive and brain aging. Childhood disadvantage is associated with poorer episodic memory in late midlife and functional and structural brain abnormalities in the default mode network (DMN). Although age-related changes in DMN are associated with episodic memory declines in older adults, it remains unclear if childhood disadvantage has an enduring impact on this later-life brain-cognition relationship earlier in the aging process. Here, within the DMN, we examined whether its cortical microstructural integrity-an early marker of structural vulnerability that increases the risk for future cognitive decline and neurodegeneration-is associated with episodic memory in adults at ages 56-66, and whether childhood disadvantage moderates this association. Cortical mean diffusivity (MD) obtained from diffusion magnetic resonance imaging was used to measure microstructural integrity in 350 community-dwelling men. We examined both visual and verbal episodic memory in relation to DMN MD and divided participants into disadvantaged and nondisadvantaged groups based on parental education and occupation. Higher DMN MD was associated with poorer visual memory but not verbal memory (β = -0.11, p = .040 vs β = -0.04, p = .535). This association was moderated by childhood disadvantage and was significant only in the disadvantaged group (β = -0.26, p = .002 vs β = -0.00, p = .957). Lower DMN cortical microstructural integrity may reflect visual memory vulnerability in cognitively normal adults earlier in the aging process. Individuals who experienced childhood disadvantage manifested greater vulnerability to cortical microstructure-related visual memory dysfunction than their nondisadvantaged counterparts who exhibited resilience in the face of low cortical microstructural integrity.

Relation of modifiable lifestyle and mood factors to cognitive concerns among participants and their study partners in the A4 screen data.

Subjective cognitive decline (SCD) has been associated with elevated amyloid levels and increased risk of future cognitive decline, as well as modifiable variables, including depression, anxiety, and physical inactivity. Participants generally endorse greater and earlier concerns than their close family and friends (study partners [SPs]), which may reflect subtle changes at the earliest stages of disease among participants with underlying neurodegenerative processes. However, many individuals with subjective concerns are not at risk of Alzheimer's disease (AD) pathology, suggesting that additional factors, such as lifestyle habits, may be contributory. We examined the relation between SCD, amyloid status, lifestyle habits (exercise, sleep), mood/anxiety, and demographic variables among 4481 cognitively unimpaired older adults who are being screened for a multi-site secondary prevention trial (A4 screen data; mean ±SD: age=71.3 ±4.7, education=16.6 ±2.8, 59% women, 96% non-Hispanic or Latino, 92% White]. On the Cognitive Function Index (CFI) participants endorsed higher concerns compared to SPs. Participant concerns were associated with older age, positive amyloid status, worse mood/anxiety, lower education, and lower exercise, whereas SP concerns were associated with older participant age, male gender of participant, positive amyloid status of participant, and worse participant-reported mood/anxiety. Findings suggest that modifiable/lifestyle factors (e.g., exercise, education) may be associated with participant concerns among cognitively unimpaired individuals and highlight the importance of further examining how modifiable factors impact participant- and SP-reported concerns, which may inform trial recruitment and clinical interventions.

Is late-life depression associated with Alzheimer's disease? Evidence from epidemiological, neuropsychological, and neuroimaging perspectives

In 2021, the FDA approved Aducanumab (Aduhelm™), an anti-amyloid antibody intravenous (IV) infusion therapy approved for Alzheimer's disease (AD) that is the first treatment shown to ameliorate neuropathological changes due to AD in the brain. It is well-established that depression increases the risk of future cognitive decline and dementia, but whether depression is specifically associated with AD is unclear, because many of the earlier epidemiological studies employed a relatively short interval (< 5 years) between observation of depression and AD diagnosis. Since neuropathological changes in the brain due to AD may occur years prior to onset of clinical memory symptoms and AD diagnosis, depression that begins late in life may thus represent a non-cognitive prodromal feature of AD. Moreover, the association between depression in older adults and AD biomarkers is also unclear, with some studies suggesting that amyloid-beta, one of the main neuropathological hallmarks of AD, may be reduced in older adults with depression. With the availability of a disease-altering treatment for AD and knowledge that the neuropathological process for AD begins years before onset of clinical memory symptoms, a logical next step in the near future will be to examine whether anti-amyloid therapies can prevent development of AD in high-risk populations. Thus, it is timely to clarify the relationship between depression and dementia. Specifically, is depression an independent risk factor for AD, or is depression associated with dementia more generally? What is the evidence for a distinct form of dementia subtype due to depression?This symposium will address the question of whether major depressive disorder is an independent risk factor for dementia due to AD or other dementia subtypes by presenting evidence from the epidemiological, neuropsychological, and neuroimaging literature. Dr. Linda Mah will begin by presenting an overview of the epidemiological data on the association between depression and AD or dementia subtypes, focusing on differences in the strength of the association as a function of measurement of exposure, follow-up interval, and dementia subtype outcome. Dr. Scott Mackin will present recent work comparing neuropsychological and neuroimaging data including cortico-limbic volume and amyloid-beta burden in older adults with depression versus non-depressed older adults, which provides evidence for late-life depression as having distinct neurodegenerative features independent of AD. Dr. Jennifer Gatchel will present results from a multi-modal neuroimaging study in non-demented older adults with major depressive disorder, which demonstrates a relationship between tau pathology and depression symptoms and decreased interest-motivation-drive, while in contrast, mood symptoms were not associated with either amyloid-beta or medial temporal lobe atrophy. Dr. Benoit Mulsant will serve as discussant for the symposium. Drawing upon the PACt-MD study (“Preventing Alzheimer's dementia with cognitive remediation plus transcranial direct current stimulation in mild cognitive impairment and depression”), Dr. Mulsant will highlight some of the baseline AD biomarker data in the remitted major depressive disorder + mild cognitive impairment group, which suggest that this phenotype may be associated with a distinct dementia subtype. Implications for the clinical management of late-life depression and future research priorities will be discussed.

Arterial spin labelling reveals multi-regional cerebral hypoperfusion in patients with transient ischemic attack that are unrelated to ischemia location: A proof-of-concept study

Patients with transient ischemic attack (TIA) have a substantially increased risk of early dementia. In this exploratory study, we aim to determine whether patients with TIA have 1) measurable regional cerebral hypoperfusion unrelated to the location of ischemia, and 2) determine the relationship of regional cerebral blood flow (rCBF) with their cognitive profiles. Patients with TIA (N=49) and seventy-nine (N=79) age and sex matched controls underwent formal neuropsychological testing and MRI. Quantitative arterial spin labelling rCBF maps (mL/min/100g) were registered to the corresponding high resolution T1-weighted image. Linear regression was used to determine the association between demographic, clinical and cognitive variables and rCBF. Patients with TIA had significantly (p<0.05) lower cognitive scores in the MMSE, MOCA, ACE-R, WAIS-IV DS Coding and Trail Making Tests A and B compared to controls. TIA patients had significantly lower rCBF in the left entorhinal cortex (p=0.03), right posterior cingulate (p=0.04), and right precuneus (p=0.05), after adjusting for age and sex, that were unrelated to the regional anatomical volume and DWI positivity. Regional hypoperfusion in the right posterior cingulate and right precuneus was associated with impaired visual memory (BVMT total, p=0.05 for both regions) and slower processing speed (TMT A, p=0.04 and p=0.01), respectively after adjusting for age and sex. TIA patients have patterns of regional hypoperfusion in multiple cortical regions unrelated to the parcellated regional anatomical volume or the presence of a DWI lesion. Regional hypoperfusion in patients with TIA may be an early marker conferring risk of future cognitive decline that needs to be confirmed by future studies.

In vivo cholinergic system integrity and cognition using [18F]‐FEOBV PET in healthy postmenopausal women: a pilot study

AbstractBackgroundWomen are at a higher risk of developing Alzheimer’s disease (AD), and a possible reason for this may be the effects of estrogen depletion and cholinergic system activity following menopause. The investigational radiotracer [18F]‐fluoroethoxybenzovesamicol (FEOBV) can assess in vivo cholinergic integrity, as the tracer binds to the vesicular cholinergic transporter at the synapse. FEOBV has previously shown cholinergic system decline in AD patients. The present study is an investigation of cholinergic system integrity in a sample of cognitively normal postmenopausal women, aged 50‐70 years that were part of a larger study examining cholinergic compensation following menopause. We predicted that higher FEOBV standardized uptake value ratios (SUVR) would be associated with larger basal forebrain cholinergic volumes, lower levels of amyloid SUVR, and better cognitive performance as measured by the RBANS.MethodsTen postmenopausal women (mean age: 57.3 ± 5.1 years) completed an FEOBV PET scan (6.5 mCi dose), MRI and cognitive assessments. The FEOBV PET images were co‐registered to the participant’s structural MRI data. FEOBV SUVR was normalized in reference to the supraventricular white matter to avoid partial volume effects from ventricular tissue. Preliminary analyses focused on associations between FEOBV SUVR and the key outcome variables.ResultsPreliminary analyses showed a positive relationship between FEOBV SUVR and the gray‐matter volume of the cholinergic basal forebrain of both hemispheres (L: r=0.51, R: r=0.65). Two participants were amyloid positive, and their FEOBV SUVR values were lower compared to the amyloid negative participants. A positive relationship was also seen between FEOBV SUVR and the RBANS total score, with higher SUVR associated with better cognitive performance (r=0.43).ConclusionsIn a small sample of cognitively normal postmenopausal women, greater FEOBV uptake was positively associated with both basal forebrain volume and cognitive performance. The results of this pilot sample show the importance of cholinergic system integrity in cognitive performance following menopause, supporting the idea that cholinergic integrity may be linearly related to performance and amyloid aggregation. Deterioration of cholinergic integrity post‐menopause may increase the risk of future cognitive decline and development of AD.

Subjective cognitive complaints are important in PD-MCI criteria: Associations with CSF markers and cognitive decline

IntroductionAccording to the Movement Disorder Society (MDS), subjective cognitive complaints (SCC) are a diagnostic criterion for PD-mild cognitive impairment (PD-MCI); however, studies often do not incorporate SCC when classifying PD-MCI. This inconsistent use may reflect mixed findings regarding the association between SCC and objective measures of cognitive impairment. Our study aimed to describe the extent that inclusion/exclusion of SCC affects the occurrence of PD-MCI, and if the inclusion of SCC is associated with faster cognitive decline and cerebrospinal fluid markers (CSF) of alpha-synuclein, amyloid beta, total tau, and phophorylated-tau. MethodsIndividuals with PD (N = 358) from the PPMI cohort whom completed measures of neuropsychological performance, subjective cognitive complaints, motor severity, and CSF markers were included. Participants were classified as cognitively normal (CN), PD-MCI with subjective cognitive complaints (PD-MCI + SCC) and PD-MCI without subjective cognitive complaints (PD-MCI –SCC). ResultsPD-MCI rates were consistently higher (16.5–19.1%) across the 5 years when SCC was not included in the diagnostic criteria as opposed to when SCC was included (4.4–11.0%). PD-MCI + SCC experienced greater cognitive decline and had significantly higher levels of tau/ab and p-tau/ab relative to both the CN and PD-MCI - SCC groups. ConclusionsInconsistent implementation of an SCC requirement in PD-MCI classifications may have important implications in terms of the occurrence of PD-MCI and its prognostic value. Classifying PD-MCI only using neuropsychological cut-off criterion, without regard to SCC, may lead to higher rates of PD-MCI. Inclusions of SCC in PD-MCI criteria in newly diagnosed PD participants may strengthen the ability to detect individuals at risk for future cognitive decline, though it is possible that this decline is related to Alzheimer's disease changes rather than worse PD pathology.

Amyloid and tau PET-positive cognitively unimpaired individuals are at high risk for future cognitive decline

A major unanswered question in the dementia field is whether cognitively unimpaired individuals who harbor both Alzheimer’s disease neuropathological hallmarks (that is, amyloid-β plaques and tau neurofibrillary tangles) can preserve their cognition over time or are destined to decline. In this large multicenter amyloid and tau positron emission tomography (PET) study (n = 1,325), we examined the risk for future progression to mild cognitive impairment and the rate of cognitive decline over time among cognitively unimpaired individuals who were amyloid PET-positive (A+) and tau PET-positive (T+) in the medial temporal lobe (A+TMTL+) and/or in the temporal neocortex (A+TNEO-T+) and compared them with A+T− and A−T− groups. Cox proportional-hazards models showed a substantially increased risk for progression to mild cognitive impairment in the A+TNEO-T+ (hazard ratio (HR) = 19.2, 95% confidence interval (CI) = 10.9–33.7), A+TMTL+ (HR = 14.6, 95% CI = 8.1–26.4) and A+T− (HR = 2.4, 95% CI = 1.4–4.3) groups versus the A−T− (reference) group. Both A+TMTL+ (HR = 6.0, 95% CI = 3.4–10.6) and A+TNEO-T+ (HR = 7.9, 95% CI = 4.7–13.5) groups also showed faster clinical progression to mild cognitive impairment than the A+T− group. Linear mixed-effect models indicated that the A+TNEO-T+ (β = −0.056 ± 0.005, T = −11.55, P < 0.001), A+TMTL+ (β = −0.024 ± 0.005, T = −4.72, P < 0.001) and A+T− (β = −0.008 ± 0.002, T = −3.46, P < 0.001) groups showed significantly faster longitudinal global cognitive decline compared to the A−T− (reference) group (all P < 0.001). Both A+TNEO-T+ (P < 0.001) and A+TMTL+ (P = 0.002) groups also progressed faster than the A+T− group. In summary, evidence of advanced Alzheimer’s disease pathological changes provided by a combination of abnormal amyloid and tau PET examinations is strongly associated with short-term (that is, 3–5 years) cognitive decline in cognitively unimpaired individuals and is therefore of high clinical relevance.

Beta amyloid deposition and cognitive decline in Parkinson’s disease: a study of the PPMI cohort

The accumulation of beta amyloid in the brain has a complex and poorly understood impact on the progression of Parkinson’s disease pathology and much controversy remains regarding its role, specifically in cognitive decline symptoms. Some studies have found increased beta amyloid burden is associated with worsening cognitive impairment in Parkinson’s disease, especially in cases where dementia occurs, while other studies failed to replicate this finding. To better understand this relationship, we examined a cohort of 25 idiopathic Parkinson’s disease patients and 30 healthy controls from the Parkinson’s Progression Marker Initiative database. These participants underwent [18F]Florbetaben positron emission tomography scans to quantify beta amyloid deposition in 20 cortical regions. We then analyzed this beta amyloid data alongside the longitudinal Montreal Cognitive Assessment scores across 3 years to see how participant’s baseline beta amyloid levels affected their cognitive scores prospectively. The first analysis we performed with these data was a hierarchical cluster analysis to help identify brain regions that shared similarity. We found that beta amyloid clusters differently in Parkinson’s disease patients compared to healthy controls. In the Parkinson’s disease group, increased beta amyloid burden in cluster 2 was associated with worse cognitive ability, compared to deposition in clusters 1 or 3. We also performed a stepwise linear regression where we found an adjusted R2 of 0.495 (49.5%) in a model explaining the Parkinson’s disease group’s Montreal Cognitive Assessment score 1-year post-scan, encompassing the left gyrus rectus, the left anterior cingulate cortex, and the right parietal cortex. Taken together, these results suggest regional beta amyloid deposition alone has a moderate effect on predicting future cognitive decline in Parkinson’s disease patients. The patchwork effect of beta amyloid deposition on cognitive ability may be part of what separates cognitive impairment from cognitive sparing in Parkinson’s disease. Thus, we suggest it would be more useful to measure beta amyloid burden in specific brain regions rather than using a whole-brain global beta amyloid composite score and use this information as a tool for determining which Parkinson’s disease patients are most at risk for future cognitive decline.

Using the Montreal cognitive assessment to identify individuals with subtle cognitive decline.

Dementia is a devastating neurological disease that may be better managed if diagnosed earlier when subclinical neurodegenerative changes are already present, including subtle cognitive decline and mild cognitive impairment. In this study, we used item-level performance on the Montreal Cognitive Assessment (MoCA) to identify individuals with subtle cognitive decline. Individual MoCA item data from the Alzheimer's Disease Neuroimaging Initiative was grouped using k-modes cluster analysis. These clusters were validated and examined for association with convergent neuropsychological tests. The clusters were then compared and characterized using multinomial logistic regression. A three-cluster solution had 77.3% precision, with Cluster 1 (high performing) displaying no deficits in performance, Cluster 2 (memory deficits) displaying lower memory performance, and Cluster 3 (compound deficits) displaying lower performance on memory and executive function. Age at MoCA (older in compound deficits), gender (more females in memory deficits), and marital status (fewer married in compound deficits) were significantly different among clusters. Age was not associated with increased odds of membership in the high-performing cluster compared to the others. We identified three clusters of individuals classified as cognitively unimpaired using cluster analysis. Individuals in the compound deficits cluster performed lower on the MoCA and were older and less often married than individuals in other clusters. Demographic analyses suggest that cluster identity was due to a combination of both cognitive and clinical factors. Identifying individuals at risk for future cognitive decline using the MoCA could help them receive earlier evidence-based interventions to slow further cognitive decline. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Blood Biomarkers Predict Future Cognitive Decline after Military-Related Traumatic Brain Injury.

Traumatic brain injury (TBI) has been associated with an increased likelihood of late-life dementia; however, the mechanisms driving this relationship are elusive. Bloodbased biomarkers may provide insight into these mechanisms and serve as useful prognostic indicators of cognitive recovery or decline following a TBI. The aim of this study was to examine blood biomarkers within one year of TBI and explore their relationship with cognitive decline. Service members and veterans (n=224) without injury (n=77), or with a history of bodily injury (n=37), uncomplicated mild TBI (n=55), or more severe TBI (n=55), underwent a blood draw and neuropsychological assessment within one year of their injury as part of a case-control study. A subsample (n=87) completed a follow-up cognitive assessment. In the more severe TBI group, baseline glial fibrillary acidic protein (p=.008) and ubiquitin C-terminal hydrolase-L1 (p=.026) were associated with processing speed at baseline, and baseline ubiquitin C-terminal hydrolase-L1 predicted change in immediate (R2Δ=.244, p=.005) and delayed memory (R2Δ=.390, p=.003) over time. In the mild TBI group, higher baseline tau predicted greater negative change in perceptual reasoning (R2Δ=.188, p=.033) and executive functioning (R2Δ=.298, p=.007); higher baseline neurofilament light predicted greater negative change in perceptual reasoning (R2Δ=.211, p=.012). Baseline ubiquitin C-terminal hydrolase-L1 strongly predicted memory decline in the more severe TBI group, while tau and neurofilament light strongly predicted decline in the mild TBI group. A panel including these biomarkers could be particularly helpful in identifying those at risk for future cognitive decline following TBI.

Longitudinal associations between falls and future risk of cognitive decline, the Motoric Cognitive Risk syndrome and dementia: the Einstein Ageing Study.

Backgroundfalls share risk factors with cognitive decline but whether falls predict cognitive decline, pre-dementia syndromes and dementia is poorly understood.Objectivesthis study aimed to examine if falls are associated with cognitive decline in specific domains and the risk of Motoric Cognitive Risk (MCR) syndrome and dementia.Designcross-sectional study.Methodsin older people (age 80.6 ± 5.3 years) free of dementia at baseline, the number of falls (none, one or multiple) during the year before enrolment and the first year of follow-up (exposure) were recorded. Decline in specific cognitive functions (global cognition, episodic verbal memory, verbal fluency, working memory, response inhibition and processing speed-attention), incident MCR and incident dementia were outcome measures. Linear mixed effects models were used to examine the associations between falls and cognitive decline, adjusting for confounders. Cox proportional hazards models were used to determine if falls predicted risk of incident MCR or dementia.Resultsof 522 eligible participants, 140 had a single fall and 70 had multiple falls. Multiple falls were associated with a greater decline in global cognition, episodic memory, verbal fluency and processing speed-attention compared to those with no falls (P < 0.05). Over a median follow-up of 1.0 years 36 participants developed MCR and 43 participants developed dementia. Those with multiple falls had a two-fold increased risk of MCR compared to those with no falls, but no increased risk of developing dementia.Conclusionsmultiple falls may be an important marker to identify older people at greater risk of future cognitive decline and incident MCR.

Arterial Stiffening Moderates the Relationship Between Type-2 Diabetes Mellitus and White Matter Hyperintensity Burden in Older Adults With Mild Cognitive Impairment.

Background: Cerebrovascular dysfunction has been proposed as a possible mechanism underlying cognitive impairment in the context of type 2 diabetes mellitus (DM). Although magnetic resonance imaging (MRI) evidence of cerebrovascular disease, such as white matter hyperintensities (WMH), is often observed in DM, the vascular dynamics underlying this pathology remain unclear. Thus, we assessed the independent and combined effects of DM status and different vascular hemodynamic measures (i.e., systolic, diastolic, and mean arterial blood pressure and pulse pressure index [PPi]) on WMH burden in cognitively unimpaired (CU) older adults and those with mild cognitive impairment (MCI).Methods: 559 older adults (mean age: 72.4 years) from the Alzheimer’s Disease Neuroimaging Initiative were categorized into those with diabetes (DM+; CU = 43, MCI = 34) or without diabetes (DM-; CU = 279; MCI = 203). Participants underwent BP assessment, from which all vascular hemodynamic measures were derived. T2-FLAIR MRI was used to quantify WMH burden. Hierarchical linear regression, adjusting for age, sex, BMI, intracranial volume, CSF amyloid, and APOE ε4 status, examined the independent and interactive effects of DM status and each vascular hemodynamic measure on total WMH burden.Results: The presence of DM (p = 0.046), but not PPi values (p = 0.299), was independently associated with greater WMH burden overall after adjusting for covariates. Analyses stratified by cognitive status revealed a significant DM status x PPi interaction within the MCI group (p = 0.001) such that higher PPi values predicted greater WMH burden in the DM + but not DM- group. No significant interactions were observed in the CU group (all ps > 0.05).Discussion: Results indicate that higher PPi values are positively associated with WMH burden in diabetic older adults with MCI, but not their non-diabetic or CU counterparts. Our findings suggest that arterial stiffening and reduced vascular compliance may have a role in development of cerebrovascular pathology within the context of DM in individuals at risk for future cognitive decline. Given the specificity of these findings to MCI, future exploration of the sensitivity of earlier brain markers of vascular insufficiency (i.e., prior to macrostructural white matter changes) to the effects of DM and arterial stiffness/reduced vascular compliance in CU individuals is warranted.