The application of artificial intelligence (AI) in neurology is a growing field offering opportunities to improve accuracy of diagnosis and treatment of complicated neuronal disorders, plus fostering a deeper understanding of the aetiologies of these diseases through AI-based analyses of large omics data. The most common neurodegenerative disease, Alzheimer's disease (AD), is characterized by brain accumulation of specific pathological proteins, accompanied by cognitive impairment. In this review, we summarize the latest progress on the use of AI in different AD-related fields, such as analysis of neuroimaging data enabling early and accurate AD diagnosis; prediction of AD progression, identification of patients at higher risk and evaluation of new treatments; improvement of the evaluation of drug response using AI algorithms to analyze patient clinical and neuroimaging data; the development of personalized AD therapies; and the use of AI-based techniques to improve the quality of daily life of AD patients and their caregivers.
- MeSH
- Alzheimer Disease * diagnosis drug therapy metabolism MeSH
- Clinical Trials as Topic MeSH
- Humans MeSH
- Neuroimaging methods MeSH
- Artificial Intelligence * MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Review MeSH
BACKGROUND: Mild behavioral impairment (MBI) has been commonly reported in early Alzheimer's disease (AD) but rarely using biomarker-defined samples. It is also unclear whether genetic polymorphisms influence MBI in such individuals. We thus aimed to examine the association between the cognitive status of participants (amnestic mild cognitive impairment (aMCI-AD) vs cognitively normal (CN) older adults) and MBI severity. Within aMCI-AD, we further examined the association between APOE and BDNF risk genetic polymorphisms and MBI severity. METHODS: We included 62 aMCI-AD participants and 50 CN older adults from the Czech Brain Aging Study. The participants underwent neurological, comprehensive neuropsychological examination, APOE and BDNF genotyping, and magnetic resonance imaging. MBI was diagnosed with the Mild Behavioral Impairment Checklist (MBI-C), and the diagnosis was based on the MBI-C total score ≥ 7. Additionally, self-report instruments for anxiety (the Beck Anxiety Inventory) and depressive symptoms (the Geriatric Depression Scale-15) were administered. The participants were stratified based on the presence of at least one risk allele in genes for APOE (i.e., e4 carriers and non-carriers) and BDNF (i.e., Met carriers and non-carriers). We used linear regressions to examine the associations. RESULTS: MBI was present in 48.4% of the aMCI-AD individuals. Compared to the CN, aMCI-AD was associated with more affective, apathy, and impulse dyscontrol but not social inappropriateness or psychotic symptoms. Furthermore, aMCI-AD was related to more depressive but not anxiety symptoms on self-report measures. Within the aMCI-AD, there were no associations between APOE e4 and BDNF Met and MBI-C severity. However, a positive association between Met carriership and self-reported anxiety appeared. CONCLUSIONS: MBI is frequent in aMCI-AD and related to more severe affective, apathy, and impulse dyscontrol symptoms. APOE and BDNF polymorphisms were not associated with MBI severity separately; however, their combined effect warrants further investigation.
- MeSH
- Alzheimer Disease * diagnostic imaging epidemiology genetics MeSH
- Apolipoproteins E genetics MeSH
- Genotype MeSH
- Cognitive Dysfunction * diagnostic imaging epidemiology genetics MeSH
- Humans MeSH
- Brain-Derived Neurotrophic Factor genetics MeSH
- Neuropsychological Tests MeSH
- Polymorphism, Genetic genetics MeSH
- Aged MeSH
- Check Tag
- Humans MeSH
- Aged MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
INTRODUCTION: The evidence for characteristics of persons with subjective cognitive decline (SCD) associated with amyloid positivity is limited. METHODS: In 1640 persons with SCD from 20 Amyloid Biomarker Study cohort, we investigated the associations of SCD-specific characteristics (informant confirmation, domain-specific complaints, concerns, feelings of worse performance) demographics, setting, apolipoprotein E gene (APOE) ε4 carriership, and neuropsychiatric symptoms with amyloid positivity. RESULTS: Between cohorts, amyloid positivity in 70-year-olds varied from 10% to 76%. Only older age, clinical setting, and APOE ε4 carriership showed univariate associations with increased amyloid positivity. After adjusting for these, lower education was also associated with increased amyloid positivity. Only within a research setting, informant-confirmed complaints, memory complaints, attention/concentration complaints, and no depressive symptoms were associated with increased amyloid positivity. Feelings of worse performance were associated with less amyloid positivity at younger ages and more at older ages. DISCUSSION: Next to age, setting, and APOE ε4 carriership, SCD-specific characteristics may facilitate the identification of amyloid-positive individuals.
IMPORTANCE: One characteristic histopathological event in Alzheimer disease (AD) is cerebral amyloid aggregation, which can be detected by biomarkers in cerebrospinal fluid (CSF) and on positron emission tomography (PET) scans. Prevalence estimates of amyloid pathology are important for health care planning and clinical trial design. OBJECTIVE: To estimate the prevalence of amyloid abnormality in persons with normal cognition, subjective cognitive decline, mild cognitive impairment, or clinical AD dementia and to examine the potential implications of cutoff methods, biomarker modality (CSF or PET), age, sex, APOE genotype, educational level, geographical region, and dementia severity for these estimates. DESIGN, SETTING, AND PARTICIPANTS: This cross-sectional, individual-participant pooled study included participants from 85 Amyloid Biomarker Study cohorts. Data collection was performed from January 1, 2013, to December 31, 2020. Participants had normal cognition, subjective cognitive decline, mild cognitive impairment, or clinical AD dementia. Normal cognition and subjective cognitive decline were defined by normal scores on cognitive tests, with the presence of cognitive complaints defining subjective cognitive decline. Mild cognitive impairment and clinical AD dementia were diagnosed according to published criteria. EXPOSURES: Alzheimer disease biomarkers detected on PET or in CSF. MAIN OUTCOMES AND MEASURES: Amyloid measurements were dichotomized as normal or abnormal using cohort-provided cutoffs for CSF or PET or by visual reading for PET. Adjusted data-driven cutoffs for abnormal amyloid were calculated using gaussian mixture modeling. Prevalence of amyloid abnormality was estimated according to age, sex, cognitive status, biomarker modality, APOE carrier status, educational level, geographical location, and dementia severity using generalized estimating equations. RESULTS: Among the 19 097 participants (mean [SD] age, 69.1 [9.8] years; 10 148 women [53.1%]) included, 10 139 (53.1%) underwent an amyloid PET scan and 8958 (46.9%) had an amyloid CSF measurement. Using cohort-provided cutoffs, amyloid abnormality prevalences were similar to 2015 estimates for individuals without dementia and were similar across PET- and CSF-based estimates (24%; 95% CI, 21%-28%) in participants with normal cognition, 27% (95% CI, 21%-33%) in participants with subjective cognitive decline, and 51% (95% CI, 46%-56%) in participants with mild cognitive impairment, whereas for clinical AD dementia the estimates were higher for PET than CSF (87% vs 79%; mean difference, 8%; 95% CI, 0%-16%; P = .04). Gaussian mixture modeling-based cutoffs for amyloid measures on PET scans were similar to cohort-provided cutoffs and were not adjusted. Adjusted CSF cutoffs resulted in a 10% higher amyloid abnormality prevalence than PET-based estimates in persons with normal cognition (mean difference, 9%; 95% CI, 3%-15%; P = .004), subjective cognitive decline (9%; 95% CI, 3%-15%; P = .005), and mild cognitive impairment (10%; 95% CI, 3%-17%; P = .004), whereas the estimates were comparable in persons with clinical AD dementia (mean difference, 4%; 95% CI, -2% to 9%; P = .18). CONCLUSIONS AND RELEVANCE: This study found that CSF-based estimates using adjusted data-driven cutoffs were up to 10% higher than PET-based estimates in people without dementia, whereas the results were similar among people with dementia. This finding suggests that preclinical and prodromal AD may be more prevalent than previously estimated, which has important implications for clinical trial recruitment strategies and health care planning policies.
- MeSH
- Alzheimer Disease * cerebrospinal fluid diagnostic imaging epidemiology MeSH
- Amyloid beta-Peptides cerebrospinal fluid MeSH
- Amyloidogenic Proteins MeSH
- Amyloidosis * MeSH
- Apolipoproteins E genetics MeSH
- Biomarkers cerebrospinal fluid MeSH
- Cognitive Dysfunction * diagnostic imaging epidemiology MeSH
- Middle Aged MeSH
- Humans MeSH
- Peptide Fragments cerebrospinal fluid MeSH
- Positron-Emission Tomography MeSH
- Prevalence MeSH
- tau Proteins cerebrospinal fluid MeSH
- Cross-Sectional Studies MeSH
- Aged MeSH
- Check Tag
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
Pozvolna, ale jistě nastává nová éra inovativních léčebných možností Alzheimerovy nemoci. Objevují se nové cíle léčby a vznikají různé monoklonální protilátky zasahující cíleně molekuly uplatňující se v patogenezi Alzheimerovy nemoci. Cílem přehledové práce je seznámit čtenáře s novými potenciálními léčivy, přičemž většina uvedených v tomto přehledovém článku je právě ve 3. fázi klinické studie.
A new era of innovative treatment options for Alzheimer‘s disease is emerging. New goals of treatment are being developed with various monoclonal antibodies targeting potentially pathological molecules involved in the pathogenesis of Alzheimer‘s disease. The aim of this review is to acquaint the reader with new potential drugs, while most of those mentioned in this review are in the third phase of clinical trials.
- Keywords
- aducanumab,
- MeSH
- Alzheimer Disease * drug therapy MeSH
- Antibodies, Monoclonal, Humanized pharmacology therapeutic use MeSH
- Clinical Trials, Phase III as Topic MeSH
- Humans MeSH
- Antibodies, Monoclonal pharmacology therapeutic use MeSH
- Drug Approval MeSH
- Check Tag
- Humans MeSH
- Publication type
- Research Support, Non-U.S. Gov't MeSH
- Review MeSH
PURPOSE: To evaluate cerebral amyloid-β(Aβ) pathology in older adults with cognitive complaints, visual assessment of PET images is approved as the routine method for image interpretation. In research studies however, Aβ-PET semi-quantitative measures are associated with greater risk of progression to dementia; but until recently, these measures lacked standardization. Therefore, the Centiloid scale, providing standardized Aβ-PET semi-quantitation, was recently validated. We aimed to determine the predictive values of visual assessments and Centiloids in non-demented patients, using long-term progression to dementia as our standard of truth. METHODS: One hundred sixty non-demented participants (age, 54-86) were enrolled in a monocentric [18F] flutemetamol Aβ-PET study. Flutemetamol images were interpreted visually following the manufacturers recommendations. SUVr values were converted to the Centiloid scale using the GAAIN guidelines. Ninety-eight persons were followed until dementia diagnosis or were clinically stable for a median of 6 years (min = 4.0; max = 8.0). Twenty-five patients with short follow-up (median = 2.0 years; min = 0.8; max = 3.9) and 37 patients with no follow-up were excluded. We computed ROC curves predicting subsequent dementia using baseline PET data and calculated negative (NPV) and positive (PPV) predictive values. RESULTS: In the 98 participants with long follow-up, Centiloid = 26 provided the highest overall predictive value = 87% (NPV = 85%, PPV = 88%). Visual assessment corresponded to Centiloid = 40, which predicted dementia with an overall predictive value = 86% (NPV = 81%, PPV = 92%). Inclusion of the 25 patients who only had a 2-year follow-up decreased the PPV = 67% (NPV = 88%), reflecting the many positive cases that did not progress to dementia after short follow-ups. CONCLUSION: A Centiloid threshold = 26 optimally predicts progression to dementia 6 years after PET. Visual assessment provides similar predictive value, with higher specificity and lower sensitivity. TRIAL REGISTRATION: Eudra-CT number: 2011-001756-12.
- MeSH
- Alzheimer Disease * MeSH
- Amyloid beta-Peptides metabolism MeSH
- Aniline Compounds MeSH
- Benzothiazoles MeSH
- Dementia * diagnostic imaging MeSH
- Cognitive Dysfunction * diagnostic imaging MeSH
- Middle Aged MeSH
- Humans MeSH
- Brain metabolism MeSH
- Positron-Emission Tomography MeSH
- Aged, 80 and over MeSH
- Aged MeSH
- Check Tag
- Middle Aged MeSH
- Humans MeSH
- Aged, 80 and over MeSH
- Aged MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
Cíl: Současná diagnostická kritéria Alzheimerovy nemoci zdůrazňují vedle klinické diagnózy také vyšetření metabolických biomarkerů. V ČR je dostupné vyšetření pomocí amyloidové PET a vyšetření biomarkerů v likvoru (hladiny beta amyloidu Aβ 1-42, celkového tau a fosforylovaného tau 181). Cílem této studie bylo zhodnotit konkordanci amyloidové PET a biomarkerů v likvoru v klinických podmínkách a navrhnout způsob interpretace výsledků likvoru ke zlepšení predikce výsledku amyloidové PET především u rozporných případů. Metodika: Celkem 103 pacientů podstoupilo neuropsychologické vyšetření, MR mozku, vyšetření biomarkerů v likvoru a vizuálně hodnocenou PET s flutemetamolem. Následně byly srovnány konkordance výsledků biomarkerů likvoru a PET a byla vypočítána optimální hraniční hodnota pro poměr beta amyloidu 1-42 a fosforylovaného tau proteinu. Výsledky: Výsledek PET byl konkordantní s vyšetřením beta amyloidu 1-42 v likvoru v 79 %, s výsledkem fosforylovaného tau v 72 %. Ve 40 % byl rozporný výsledek mezi biomarkery v likvoru vzájemně. Mezi PET pozitivními a negativními pacienty nejlépe rozlišoval poměr beta amyloidu 1-42 a fosforylovaného tau (AUC = 0,938, 95% CI = 0,890–0,986; p < 0,001), kdy hraniční hodnota 9,47 měla senzitivitu 91 % a specificitu 91,3 %. Závěr: Obě metody vykazují dobrou vzájemnou diagnostickou shodu. V případě rozporných nálezů v likvoru doporučujeme využít poměrné hodnoty beta amyloidu 1-42 a fosforylovaného tau.
Aim: Current diagnostic criteria for Alzheimer's disease shift the focus from clinical findings to metabolic biomarkers. Most widely used metabolic biomarkers in the Czech Republic are cerebrospinal fluid levels of beta amyloid 1-42, total tau, and phosphorylated tau 181, as well as amyloid PET. Our aim was to investigate the concordance of amyloid PET and cerebrospinal fluid biomarkers in clinical settings and propose a way of interpreting cerebrospinal fluid biomarker results in order to better predict the amyloid PET status in contradictory cases. Methods: A total of 103 patients underwent neuropsychological assessment, brain MRI, visually evaluated flutemetamol amyloid PET and examination of biomarkers in the cerebrospinal fluid. Concordance of amyloid PET and cerebrospinal fluid biomarkers was compared and subsequent optimal cut-off for the beta amyloid 1-42 and phosphorylated tau protein ratio was calculated. Results: Concordance between amyloid PET and beta amyloid 1-42 was 79%, followed by phosphorylated tau protein (72%). In 40% of cases, the results of cerebrospinal fluid biomarkers was contradictory. Beta amyloid 1-42 and phosphorylated tau protein ratio was found to best discriminate between amyloid PET positive and negative patients (AUC = 0.938, 95% CI = 0.890 - 0.986; P < 0.001). Ratio of 9.47 provided 91.0% sensitivity and 91.3% specificity. Conclusion: Both methods show good diagnostic concordance. In case of contradictory cerebrospinal fluid biomarkers, we encourage using the beta amyloid 1-42 and phosphorylated tau protein ratio. requirements” for biomedical papers.
- Keywords
- amyloidová PET,
- MeSH
- Alzheimer Disease * diagnosis MeSH
- Amyloid beta-Peptides analysis cerebrospinal fluid MeSH
- Biomarkers MeSH
- Clinical Studies as Topic MeSH
- Middle Aged MeSH
- Humans MeSH
- Cerebrospinal Fluid MeSH
- Positron Emission Tomography Computed Tomography methods MeSH
- tau Proteins analysis cerebrospinal fluid MeSH
- Aged, 80 and over MeSH
- Aged MeSH
- Check Tag
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Aged, 80 and over MeSH
- Aged MeSH
- Female MeSH
PURPOSE: Identification of demographic, physical/physiological, lifestyle and genetic factors contributing to the onset of dementia, specifically Alzheimer disease (AD), and implementation of novel methods for early diagnosis are important to alleviate prevalence of dementia globally. The Czech Brain Aging Study (CBAS) is the first large, prospective study to address these issues in Central/Eastern Europe by enrolling non-demented adults aged 55+ years, collecting a variety of personal and biological measures and tracking cognitive function over time. PARTICIPANTS: The CBAS recruitment was initiated in 2011 from memory clinics at Brno and Prague University Hospitals, and by the end of 2018, the study included 1228 participants. Annual follow-ups include collection of socioeconomic, lifestyle and personal history information, neurology, neuropsychology, laboratory, vital sign and brain MRI data. In a subset, biomarker assessment (cerebrospinal fluid (CSF) and amyloid positron emission tomography) and spatial navigation were performed. Participants were 69.7±8.1 years old and had 14.6±3.3 years of education at baseline, and 59% were women. By the end of 2018, 31% finished three and more years of follow-up; 9% converted to dementia. Apolipoprotein E status is available from 95% of the participants. The biological sample bank linked to CBAS database contained CSF, serum and DNA. FINDINGS TO DATE: Overall, the findings, mainly from cross-sectional analyses, indicate that spatial navigation is a promising marker of early AD and that it can be distinguished from other cognitive functions. Specificity of several standard memory tests for early AD pathology was assessed with implications for clinical practice. The relationship of various lifestyle factors to cognition and brain atrophy was reported. FUTURE PLANS: Recruitment is ongoing with secured funding. Longitudinal data analyses are currently being conducted. Proposals for collaboration on specific data from the database or biospecimen, as well as collaborations with similar cohort studies to increase sample size, are welcome. Study details are available online (www.cbas.cz).
- MeSH
- Alzheimer Disease epidemiology MeSH
- Dementia epidemiology MeSH
- Risk Assessment MeSH
- Cohort Studies MeSH
- Middle Aged MeSH
- Humans MeSH
- Protective Factors MeSH
- Prospective Studies MeSH
- Aged MeSH
- Check Tag
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Multicenter Study MeSH
- Research Support, Non-U.S. Gov't MeSH
- Geographicals
- Czech Republic MeSH
BACKGROUND: Great effort has been put into developing simple and feasible tools capable to detect Alzheimer's disease (AD) in its early clinical stage. Spatial navigation impairment occurs very early in AD and is detectable even in the stage of mild cognitive impairment (MCI). OBJECTIVE: The aim was to describe the frequency of self-reported spatial navigation complaints in patients with subjective cognitive decline (SCD), amnestic and non-amnestic MCI (aMCI, naMCI) and AD dementia and to assess whether a simple questionnaire based on these complaints may be used to detect early AD. METHOD: In total 184 subjects: patients with aMCI (n=61), naMCI (n=27), SCD (n=63), dementia due to AD (n=20) and normal controls (n=13) were recruited. The subjects underwent neuropsychological examination and were administered a questionnaire addressing spatial navigation complaints. Responses to the 15 items questionnaire were scaled into four categories (no, minor, moderate and major complaints). RESULTS: 55% of patients with aMCI, 64% with naMCI, 68% with SCD and 72% with AD complained about their spatial navigation. 38-61% of these complaints were moderate or major. Only 33% normal controls expressed complaints and none was ranked as moderate or major. The SCD, aMCI and AD dementia patients were more likely to express complaints than normal controls (p's<0.050) after adjusting for age, education, sex, depressive symptoms (OR for SCD=4.00, aMCI=3.90, AD dementia=7.02) or anxiety (OR for SCD=3.59, aMCI=3.64, AD dementia=6.41). CONCLUSION: Spatial navigation complaints are a frequent symptom not only in AD, but also in SCD and aMCI and can potentially be detected by a simple and inexpensive questionnaire.
- MeSH
- Alzheimer Disease epidemiology physiopathology MeSH
- Cognitive Dysfunction epidemiology physiopathology MeSH
- Cohort Studies MeSH
- Middle Aged MeSH
- Humans MeSH
- Statistics, Nonparametric MeSH
- Neuropsychological Tests MeSH
- Spatial Navigation physiology MeSH
- Surveys and Questionnaires MeSH
- Aged, 80 and over MeSH
- Aged MeSH
- Space Perception physiology MeSH
- Check Tag
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Aged, 80 and over MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Geographicals
- Czech Republic MeSH
RATIONALE: Development of new drugs for treatment of Alzheimer's disease (AD) requires valid paradigms for testing their efficacy and sensitive tests validated in translational research. OBJECTIVES: We present validation of a place-navigation task, a Hidden Goal Task (HGT) based on the Morris water maze (MWM), in comparable animal and human protocols. METHODS: We used scopolamine to model cognitive dysfunction similar to that seen in AD and donepezil, a symptomatic medication for AD, to assess its potential reversible effect on this scopolamine-induced cognitive dysfunction. We tested the effects of scopolamine and the combination of scopolamine and donepezil on place navigation and compared their effects in human and rat versions of the HGT. Place navigation testing consisted of 4 sessions of HGT performed at baseline, 2, 4, and 8 h after dosing in humans or 1, 2.5, and 5 h in rats. RESULTS: Scopolamine worsened performance in both animals and humans. In the animal experiment, co-administration of donepezil alleviated the negative effect of scopolamine. In the human experiment, subjects co-administered with scopolamine and donepezil performed similarly to subjects on placebo and scopolamine, indicating a partial ameliorative effect of donepezil. CONCLUSIONS: In the task based on the MWM, scopolamine impaired place navigation, while co-administration of donepezil alleviated this effect in comparable animal and human protocols. Using scopolamine and donepezil to challenge place navigation testing can be studied concurrently in animals and humans and may be a valid and reliable model for translational research, as well as for preclinical and clinical phases of drug trials.
- MeSH
- Muscarinic Antagonists pharmacology MeSH
- Maze Learning drug effects MeSH
- Cholinesterase Inhibitors pharmacology MeSH
- Adult MeSH
- Double-Blind Method MeSH
- Indans pharmacology MeSH
- Rats MeSH
- Humans MeSH
- Young Adult MeSH
- Piperidines pharmacology MeSH
- Rats, Wistar MeSH
- Spatial Navigation drug effects MeSH
- Scopolamine pharmacology MeSH
- Animals MeSH
- Check Tag
- Adult MeSH
- Rats MeSH
- Humans MeSH
- Young Adult MeSH
- Male MeSH
- Female MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Randomized Controlled Trial MeSH
