Subtle cognitive impairment as a marker of Alzheimer's pathologies and clinical progression in cognitively normal individuals

Shen, Xue‐Ning; Kuo, Kevin H.M.; Li, Hongqi; Chen, Shi-Dong; Cui, Mei; Tan, Lan; Dong, Qiang; Yu, Jin‐Tai; Initiative, Alzheimer’s Disease Neuroimaging

doi:10.1002/dad2.12198

Cited by 5 publications

(8 citation statements)

References 43 publications

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“…In the present study, we chose to use one set size (i.e. 3) for the sake of comparability of findings along the disease continuum, particularly considering our aim of anticipating the MCI stages [ 9 , 23 , 63 , 83 , 84 ].…”

Section: Discussionmentioning

confidence: 99%

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Memory markers in the continuum of the Alzheimer’s clinical syndrome

et al. 2022

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Background The individual and complementary value of the Visual Short-Term Memory Binding Test (VSTMBT) and the Free and Cued Selective Reminding Test (FCSRT) as markers to trace the AD continuum was investigated. It was hypothesised that the VSTMBT would be an early indicator while the FCSRT would inform on imminent progression. Methods Healthy older adults (n=70) and patients with mild cognitive impairment (MCI) (n=80) were recruited and followed up between 2012 and 2017. Participants with at least two assessment points entered the study. Using baseline and follow-up assessments four groups were defined: Older adults who were healthy (HOA), with very mild cognitive but not functional impairment (eMCI), and with MCI who did and did not convert to dementia (MCI converters and non-converters). Results Only the VSTMBT predicted group membership in the very early stages (HOA vs eMCI). As the disease progressed, the FCSRT became a strong predictor excluding the VSTMB from the models. Their complementary value was high during the mid-prodromal stages and decreased in stages closer to dementia. Discussion The study supports the notion that neuropsychological assessment for AD needs to abandon the notion of one-size-fits-all. A memory toolkit for AD needs to consider tools that are early indicators and tools that suggest imminent progression. The VSTMBT and the FSCRT are such tools.

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Section: Discussionmentioning

confidence: 99%

“…[11,82]). A growing number of studies are reporting cognitive deficits in subthreshold [33,63,75,83,84] and subclinical [71,73,79] stages of the disease continuum. The former evidence comes from studies using Aβ markers in the brain, CSF or blood [5,6].…”

Section: Discussionmentioning

confidence: 99%

Memory markers in the continuum of the Alzheimer’s clinical syndrome

et al. 2022

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“…Subtle cognitive impairment already exists when AD pathology starts accumulating in the brain at detectable thresholds. 5,6,12,41,47,48 Subthreshold levels of -amyloid PET imaging were associated with a decline in FR scores in the A4 study. 20 FR was most sensitive to -amyloidrelated decreases in average cognitive scores, outperforming all tests including logical memory.…”

Section: Discussionmentioning

confidence: 86%

“…4 There is increasing evidence that a subset of cognitively normal individuals has subtle cognitive impairment at baseline. [5][6][7] Not all cognitively normal, biomarker-positive individuals clinically progress to cognitive impairment over the typical duration of a clinical trial, say 18-36 months. 8,9 Because the objective of treatment in many clinical trials is to slow the rate of cognitive decline, inclusion of individuals unlikely to decline, even if randomized to placebo, will attenuate power to identify treatment effects in trials.…”

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confidence: 99%

Association of Stages of Objective Memory Impairment With Incident Symptomatic Cognitive Impairment in Cognitively Normal Individuals

et al. 2023

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BACKGROUND AND OBJECTIVESIncreasing evidence indicates that a subset of cognitively normal individuals has subtle cognitive impairment at baseline. We sought to identify them using the Stages of Objective Memory Impairment (SOMI) system. Symptomatic cognitive impairment was operationalized by a CDR®≥ 0.5. We hypothesized that incident impairment would be higher for participants with subtle retrieval impairment (SOMI-1), higher still for those with moderate retrieval impairment (SOMI-2), and highest for those with storage impairment (SOMI-3/4) after adjusting for demographics and APOE4 status. A secondary objective was to determine whether including biomarkers of β-amyloid, tau pathology, and neurodegeneration in the models affect prediction. We hypothesized that even after adjusting for in-vivo biomarkers, SOMI would remain a significant predictor of time to incident symptomatic cognitive impairment.METHODSAmong 969 cognitively normal participants, defined by a CDR®= 01, from the Knight ADRC, SOMI stage was determined from their baseline Free and Cued Selective Reminding Test (FCSRT) scores, 555 had CSF and structural MRI measures and comprised the biomarker subgroup, and 144 of them were amyloid positive. Cox proportional hazards models tested associations of SOMI stages at baseline and biomarkers with time to incident cognitive impairment defined as the transition to CDR ≥ 0.5.RESULTSAmong all participants, mean age was 69.35 years, 59.6% were female, and mean follow-up was 6.36 years. Participants in SOMI-1-4 had elevated hazard ratios for the transition from normal to impaired cognition in comparison with those who were SOMI-0 (no memory impairment). Individuals in SOMI-1 (mildly impaired retrieval) and SOMI-2 (moderately impaired retrieval) were at nearly double the risk of clinical progression compared to persons with no memory problems. When memory storage impairment emerges (SOMI-3/4), the hazard ratio for clinical progression increased approximately three times. SOMI stage remained an independent predictor of incident cognitive impairment after adjusting for all biomarkers.DISCUSSIONSOMI predicts the transition from normal cognition to incident symptomatic cognitive impairment (CDR ≥ 0.5). The results support the use of SOMI to identify those cognitively normal participants most likely to develop incident cognitive impairment who can then be referred for biomarker screening.

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“…Several studies have already shown that cognitively unimpaired individuals with MNPD, operationalized with differing criteria and cut-offs, have an increased risk of AD biomarker abnormalities [24][25][26] and progression to MCI or dementia [24][25][26][27] as well as increased brain atrophy 27,28 compared with those without MNPD. However, few studies have investigated the effect of MNPD in older individuals with SCD and those that did focused solely on cross-sectional biomarker analyses.…”

Section: Discussionmentioning

confidence: 99%

Relevance of Minor Neuropsychological Deficits in Patients With Subjective Cognitive Decline

Stark,

Wolfsgruber,

Kleineidam

et al. 2023

Neurology

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Background and Objectives:To determine the relevance of minor neuropsychological deficits (MNPD) in patients with subjective cognitive decline (SCD) with regard to CSF levels of Alzheimer’s disease (AD) biomarkers, cognitive decline and clinical progression to mild cognitive impairment (MCI).Methods:This study included clinical SCD patients and SCD free, healthy control (HC) participants with available baseline CSF and/or longitudinal cognitive data from the observationalDZNE Longitudinal Cognitive Impairment and Dementia(DELCODE) study. We defined MNPD as a performance of at least 0.5SD below the mean on a demographically adjusted total score derived from theConsortium to Establish a Registry for Alzheimer’s DiseaseNeuropsychological Assessment Battery. We compared SCD patients with MNPD and those without MNPD with regard to CSF amyloid-β (Aβ)42/Aβ40, phosphorylated tau (p-tau181),total tau and Aβ42/p-tau181levels, longitudinal cognitive composite trajectories and risk of clinical progression to incident MCI (follow-upM±SD: 40.6±23.7 months). Additionally, we explored group differences between SCD and HC in those without MNPD.Results:In our sample (N = 672, mean age: 70.7±5.9 years, 50% female), SCD patients with MNPD (n = 55, 12.5% of SCD group) showed significantly more abnormal CSF biomarker levels, increased cognitive decline and a higher risk of progression to incident MCI (HR: 4.07, 95%CI: 2.46-6.74) compared to SCD patients without MNPD (n = 384). MNPD had a positive predictive value of 57.0% (95%CI: 38.5-75.4) and a negative predictive value of 86.0% (95%CI: 81.9-90.1) for the progression of SCD to MCI within three years. SCD patients without MNPD showed increased cognitive decline and a higher risk of incident MCI compared to HC participants without MNPD (n = 215; HR: 4.09, 95%CI: 2.07-8.09), while AD biomarker levels did not differ significantly between these groups.Discussion:Our results suggest that MNPD are a risk factor for AD related clinical progression in cognitively normal patients seeking medical counseling due to SCD. As such, the assessment of MNPD could be useful for individual clinical prediction and for AD risk stratification in clinical trials. However, SCD remains a risk factor for future cognitive decline even in the absence of MNPD.

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Subtle cognitive impairment as a marker of Alzheimer's pathologies and clinical progression in cognitively normal individuals

Cited by 5 publications

References 43 publications

Memory markers in the continuum of the Alzheimer’s clinical syndrome

Memory markers in the continuum of the Alzheimer’s clinical syndrome

Association of Stages of Objective Memory Impairment With Incident Symptomatic Cognitive Impairment in Cognitively Normal Individuals

Relevance of Minor Neuropsychological Deficits in Patients With Subjective Cognitive Decline

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