Detection and Prediction of Mild Cognitive Impairment in Alzheimer’s Disease Mice

Background: The recent failure of clinical trials to treat Alzheimer’s disease (AD) indicates that the current approach of modifying disease is either wrong or is too late to be efficient. Mild cognitive impairment (MCI) denotes the phase between the preclinical phase and clinical overt dementia. AD mouse models that overexpress human amyloid-β (Aβ) are used to study disease pathogenesis and to conduct drug development/testing. However, there is no direct correlation between the Aβ deposition, the age of onset, and the severity of cognitive dysfunction. Objective: To detect and predict MCI when Aβ plaques start to appear in the hippocampus of an AD mouse. Methods: We trained wild-type and AD mice in a Morris water maze (WM) task with different inter-trial intervals (ITI) at 3 months of age and assessed their WM performance. Additionally, we used a classification algorithm to predict the genotype (APPtg versus wild-type) of an individual mouse from their respective WM data. Results: MCI can be empirically detected using a short-ITI protocol. We show that the ITI modulates the spatial learning of AD mice without affecting the formation of spatial memory. Finally, a simple classification algorithm such as logistic regression on WM data can give an accurate prediction of the cognitive dysfunction of a specific mouse. Conclusion: MCI can be detected as well as predicted simultaneously with the onset of Aβ deposition in the hippocampus in AD mouse model. The mild cognitive impairment prediction can be used for assessing the efficacy of a treatment.

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Heterogeneity of Amyloid Binding in Cognitively Impaired Patients Consecutively Recruited from a Memory Clinic: Evaluating the Utility of Quantitative 18F-Flutemetamol PET-CT in Discrimination of Mild Cognitive Impairment from Alzheimer’s Disease and Other Dementias

Journal of Alzheimer s Disease ◽

10.3233/jad-200890 ◽

2020 ◽

pp. 1-14

Author(s):

Yi-Wen Bao ◽

Anson C.M. Chau ◽

Patrick Ka-Chun Chiu ◽

Yat Fung Shea ◽

Joseph S.K. Kwan ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Impairment ◽

Mild Cognitive Impairment ◽

Amyloid Β ◽

Standardized Uptake Value ◽

Subjective Cognitive Decline ◽

Cognitively Impaired ◽

Memory Clinic ◽

Pet Ct

Background: With the more widespread use of 18F-radioligand-based amyloid-β (Aβ) PET-CT imaging, we evaluated Aβ binding and the utility of neocortical 18F-Flutemetamol standardized uptake value ratio (SUVR) as a biomarker. Objective: 18F-Flutemetamol SUVR was used to differentiate 1) mild cognitive impairment (MCI) from Alzheimer’s disease (AD), and 2) MCI from other non-AD dementias (OD). Methods: 109 patients consecutively recruited from a University memory clinic underwent clinical evaluation, neuropsychological test, MRI and 18F-Flutemetamol PET-CT. The diagnosis was made by consensus of a panel consisting of 1 neuroradiologist and 2 geriatricians. The final cohort included 13 subjective cognitive decline (SCD), 22 AD, 39 MCI, and 35 OD. Quantitative analysis of 16 region-of-interests made by Cortex ID software (GE Healthcare). Results: The global mean 18F-Flutemetamol SUVR in SCD, MCI, AD, and OD were 0.50 (SD-0.08), 0.53 (SD-0.16), 0.76 (SD-0.10), and 0.56 (SD-0.16), respectively, with SUVR in SCD and MCI and OD being significantly lower than AD. Aβ binding in SCD, MCI, and OD was heterogeneous, being 23%, 38.5%, and 42.9% respectively, as compared to 100% amyloid positivity in AD. Using global SUVR, ROC analysis showed AUC of 0.868 and 0.588 in differentiating MCI from AD and MCI from OD respectively. Conclusion: 18F-Flutemetamol SUVR differentiated MCI from AD with high efficacy (high negative predictive value), but much lower efficacy from OD. The major benefit of the test was to differentiate cognitively impaired patients (either SCD, MCI, or OD) without AD-related-amyloid-pathology from AD in the clinical setting, which was under-emphasized in the current guidelines proposed by Amyloid Imaging Task Force.

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Association of brain amyloid-β with cerebral perfusion and structure in Alzheimer’s disease and mild cognitive impairment

Brain ◽

10.1093/brain/awu043 ◽

2014 ◽

Vol 137 (5) ◽

pp. 1550-1561 ◽

Cited By ~ 79

Author(s):

Niklas Mattsson ◽

Duygu Tosun ◽

Philip S. Insel ◽

Alix Simonson ◽

Clifford R Jack ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Impairment ◽

Mild Cognitive Impairment ◽

Cerebral Perfusion ◽

Amyloid Β

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The Role of Apolipoprotein E ε4 in Early and Late Mild Cognitive Impairment

European Neurology ◽

10.1159/000516774 ◽

2021 ◽

Vol 84 (6) ◽

pp. 472-480

Author(s):

Yulin Luo ◽

Li Tan ◽

Joseph Therriault ◽

Hua Zhang ◽

Ying Gao ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Impairment ◽

Mild Cognitive Impairment ◽

Apolipoprotein E ◽

Amyloid Β ◽

Disease Assessment ◽

Tau Pathology ◽

Ε4 Allele ◽

State Examination

Background: Apolipoprotein E (APOE) ε4 is highly associated with mild cognitive impairment (MCI). However, the specific influence of APOE ε4 status on tau pathology and cognitive decline in early MCI (EMCI) and late MCI (LMCI) is poorly understood. Our goal was to evaluate the association of APOE ε4 with cerebrospinal fluid (CSF) tau levels and cognition in EMCI and LMCI patients in the Alzheimer’s Disease Neuroimaging Initiative database, and whether this association was mediated by amyloid-β (Aβ). Methods: Participants were 269 cognitively normal (CN), 262 EMCI, and 344 LMCI patients. They underwent CSF Aβ42 and tau detection, APOE ε4 genotyping, Mini-Mental State Examination, (MMSE), and Alzheimer’s disease assessment scale (ADAS)-cog assessments. Linear regressions were used to examine the relation of APOE ε4 and CSF tau levels and cognitive scores in persons with and without Aβ deposition (Aβ+ and Aβ−). Results: The prevalence of APOE ε4 is higher in EMCI and LMCI than in CN (p < 0.001 for both), and in LMCI than in EMCI (p = 0.001). APOE ε4 allele was significantly higher in Aβ+ subjects than in Aβ− subjects (p < 0.001). Subjects who had a lower CSF Aβ42 level and were APOE ε4-positive experienced higher levels of CSF tau and cognitive scores in EMCI and/or LMCI. Conclusions: An APOE ε4 allele is associated with increased CSF tau and worse cognition in both EMCI and LMCI, and this association may be mediated by Aβ. We conclude that APOE ε4 may be an important mediator of tau pathology and cognition in the early stages of AD.

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Interactions between Amyloid-β and Tau in Cerebrospinal Fluid of People with Mild Cognitive Impairment and Alzheimer's Disease

Journal of Alzheimer s Disease ◽

10.3233/jad-132393 ◽

2014 ◽

Vol 42 (s3) ◽

pp. S91-S98 ◽

Cited By ~ 7

Author(s):

Zdena Kristofikova ◽

Jan Ricny ◽

Michaela Kolarova ◽

Martin Vyhnalek ◽

Jakub Hort ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cerebrospinal Fluid ◽

Cognitive Impairment ◽

Mild Cognitive Impairment ◽

Amyloid Β

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Longitudinal plasma p-tau217 is increased in early stages of Alzheimer’s disease

Brain ◽

10.1093/brain/awaa286 ◽

2020 ◽

Vol 143 (11) ◽

pp. 3234-3241 ◽

Cited By ~ 2

Author(s):

Niklas Mattsson-Carlgren ◽

Shorena Janelidze ◽

Sebastian Palmqvist ◽

Nicholas Cullen ◽

Anna L Svenningsson ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Impairment ◽

Mild Cognitive Impairment ◽

Amyloid Β ◽

Linear Mixed Effects ◽

Three Samples ◽

Longitudinal Plasma ◽

Early Alzheimer’S Disease ◽

Alzheimer’S Disease Dementia

Abstract Plasma levels of tau phosphorylated at threonine-217 (p-tau217) is a candidate tool to monitor Alzheimer’s disease. We studied 150 cognitively unimpaired participants and 100 patients with mild cognitive impairment in the Swedish BioFINDER study. P-tau217 was measured repeatedly for up to 6 years (median three samples per person, median time from first to last sample, 4.3 years). Preclinical (amyloid-β-positive cognitively unimpaired, n = 62) and prodromal (amyloid-β-positive mild cognitive impairment, n = 49) Alzheimer’s disease had accelerated p-tau217 compared to amyloid-β-negative cognitively unimpaired (β = 0.56, P < 0.001, using linear mixed effects models) and amyloid-β-negative mild cognitive impairment patients (β = 0.67, P < 0.001), respectively. Mild cognitive impairment patients who later converted to Alzheimer’s disease dementia (n = 40) had accelerated p-tau217 compared to other mild cognitive impairment patients (β = 0.79, P < 0.001). P-tau217 did not change in amyloid-β-negative participants, or in patients with mild cognitive impairment who did not convert to Alzheimer’s disease dementia. For 80% power, 109 participants per arm were required to observe a slope reduction in amyloid-β-positive cognitively unimpaired (71 participants per arm in amyloid-β-positive mild cognitive impairment). Longitudinal increases in p-tau217 correlated with longitudinal worsening of cognition and brain atrophy. In summary, plasma p-tau217 increases during early Alzheimer’s disease and can be used to monitor disease progression.

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18F-MK-6240 PET for early and late detection of neurofibrillary tangles

Brain ◽

10.1093/brain/awaa180 ◽

2020 ◽

Vol 143 (9) ◽

pp. 2818-2830 ◽

Cited By ~ 6

Author(s):

Tharick A Pascoal ◽

Joseph Therriault ◽

Andrea L Benedet ◽

Melissa Savard ◽

Firoza Z Lussier ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Impairment ◽

Mild Cognitive Impairment ◽

Amyloid Β ◽

Standardized Uptake Value ◽

Braak Staging ◽

High Affinity ◽

Tau Pet ◽

Transentorhinal Cortex

Abstract Braak stages of tau neurofibrillary tangle accumulation have been incorporated in the criteria for the neuropathological diagnosis of Alzheimer’s disease. It is expected that Braak staging using brain imaging can stratify living individuals according to their individual patterns of tau deposition, which may prove crucial for clinical trials and practice. However, previous studies using the first-generation tau PET agents have shown a low sensitivity to detect tau pathology in areas corresponding to early Braak histopathological stages (∼20% of cognitively unimpaired elderly with tau deposition in regions corresponding to Braak I–II), in contrast to ∼80–90% reported in post-mortem cohorts. Here, we tested whether the novel high affinity tau tangles tracer 18F-MK-6240 can better identify individuals in the early stages of tau accumulation. To this end, we studied 301 individuals (30 cognitively unimpaired young, 138 cognitively unimpaired elderly, 67 with mild cognitive impairment, 54 with Alzheimer’s disease dementia, and 12 with frontotemporal dementia) with amyloid-β 18F-NAV4694, tau 18F-MK-6240, MRI, and clinical assessments. 18F-MK-6240 standardized uptake value ratio images were acquired at 90–110 min after the tracer injection. 18F-MK-6240 discriminated Alzheimer’s disease dementia from mild cognitive impairment and frontotemporal dementia with high accuracy (∼85–100%). 18F-MK-6240 recapitulated topographical patterns consistent with the six hierarchical stages proposed by Braak in 98% of our population. Cognition and amyloid-β status explained most of the Braak stages variance (P < 0.0001, R2 = 0.75). No single region of interest standardized uptake value ratio accurately segregated individuals into the six topographic Braak stages. Sixty-eight per cent of the cognitively unimpaired elderly amyloid-β-positive and 37% of the cognitively unimpaired elderly amyloid-β-negative subjects displayed tau deposition, at least in the transentorhinal cortex (Braak I). Tau deposition solely in the transentorhinal cortex was associated with an elevated prevalence of amyloid-β, neurodegeneration, and cognitive impairment (P < 0.0001). 18F-MK-6240 deposition in regions corresponding to Braak IV–VI was associated with the highest prevalence of neurodegeneration, whereas in Braak V–VI regions with the highest prevalence of cognitive impairment. Our results suggest that the hierarchical six-stage Braak model using 18F-MK-6240 imaging provides an index of early and late tau accumulation as well as disease stage in preclinical and symptomatic individuals. Tau PET Braak staging using high affinity tracers has the potential to be incorporated in the diagnosis of living patients with Alzheimer’s disease in the near future.

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P3-175: Relationships between global cognitive dysfunction and PET biomarkers in normal aging, mild cognitive impairment and Alzheimer's disease

Alzheimer s & Dementia ◽

10.1016/j.jalz.2012.05.1395 ◽

2012 ◽

Vol 8 (4S_Part_14) ◽

pp. P514-P514

Author(s):

Eun Hyun Seo ◽

Dong Young Lee ◽

IL Han Choo ◽

Bo Kyung Sohn ◽

Jee Wook Kim ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Impairment ◽

Mild Cognitive Impairment ◽

Cognitive Dysfunction ◽

Normal Aging

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Relationship between Amyloid-β Deposition and the Coupling between Structural and Functional Brain Networks in Patients with Mild Cognitive Impairment and Alzheimer’s Disease

Brain Sciences ◽

10.3390/brainsci11111535 ◽

2021 ◽

Vol 11 (11) ◽

pp. 1535

Author(s):

Hui Zhang ◽

Edward S. Hui ◽

Peng Cao ◽

Henry K. F. Mak

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Impairment ◽

Mild Cognitive Impairment ◽

Brain Networks ◽

Amyloid Β ◽

Potential Candidate ◽

Functional Brain ◽

Specific Effects ◽

Functional Brain Networks

Previous studies have demonstrated that the accumulation of amyloid-β (Aβ) pathologies has distinctive stage-specific effects on the structural and functional brain networks along the Alzheimer’s disease (AD) continuum. A more comprehensive account of both types of brain network may provide a better characterization of the stage-specific effects of Aβ pathologies. A potential candidate for this joint characterization is the coupling between the structural and functional brain networks (SC-FC coupling). We therefore investigated the effect of Aβ accumulation on global SC-FC coupling in patients with mild cognitive impairment (MCI), AD, and healthy controls. Patients with MCI were dichotomized according to their level of Aβ pathology seen in 18F-flutemetamol PET-CT scans—namely, Aβ-negative and Aβ-positive. Our results show that there was no difference in global SC-FC coupling between different cohorts. During the prodromal AD stage, there was a significant negative correlation between the level of Aβ pathology and the global SC-FC coupling of MCI patients with positive Aβ, but no significant correlation for MCI patients with negative Aβ. During the AD dementia stage, the correlation between Aβ pathology and global SC-FC coupling in patients with AD was positive. Our results suggest that Aβ pathology has distinctive stage-specific effects on global coupling between the structural and functional brain networks along the AD continuum.

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Citicoline in the Treatment of Mild Cognitive Impairment in Blood Relatives of Patients with Alzheimer’s Disease: Immediate and Long-Term Effects of Course Therapy

Psychiatry ◽

10.30629/2618-6667-2021-19-4-42-51 ◽

2021 ◽

Vol 19 (4) ◽

pp. 42-51

Author(s):

N. D. Seleznеva ◽

I. F. Roshchina ◽

E. V. Ponomareva ◽

S. Iv. Gavrilova

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Impairment ◽

Mild Cognitive Impairment ◽

Cognitive Functioning ◽

Cognitive Dysfunction ◽

Therapeutic Effects ◽

Long Term Effects ◽

Voluntary Attention

The aim was to study immediate and long-term (post-therapeutic) effects of a three-month course of therapy with citicoline in 1st-degree relatives of patients with Alzheimer’s disease (AD). All the included relatives of patients with AD revealed signs of minimal cognitive dysfunction (MCD) and mild cognitive decline syndrome (MCI — Mild Cognitive Impairment, ICD-10 code F06.7). Study participants: the study involved 90 first-degree relatives: 24 with MCI and 66 with MCD. Study design: an open-label comparative multidisciplinary study of the six-month dynamics of cognitive functioning of two groups of relatives who received a three-month course of citicoline therapy. The baseline indicators of the cognitive functioning of relatives with MCI syndrome and MKD were compared with the indicators at the end of the three-month course of therapy with citicoline at a daily dose of 1000 mg as well as 3 months after the end of the course of treatment. Methods: clinical, psychopathological, neuropsychological, psychometric, genetic, statistical ones. Results: а significant positive effect of the course therapy with citicoline on the cognitive impairment of 1st degree AD-patients’ relatives with minimal cognitive dysfunction and more pronounced cognitive impairments met the diagnostic criteria for MCI syndrome has been found. A significantly greater value of both immediate and long-term therapeutic effect of MKD compared with MCI in relatives was established by psychometric and neuropsychological indicators characterizing voluntary memorization of verbal and visual stimuli, optical and spatial activity, voluntary attention, and associative verbal thinking. Conclusion: the results of the study can be used as the basis for a model of prevention of the progression of cognitive deficit and the development of dementia in persons with a high risk of developing AD, i.e. in individuals with both genetic risk and signs of cognitive impairment.

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