Alzheimer's Disease Dementia Research Articles

Recent advances in portable, low-field magnetic resonance imaging in cerebrovascular disease.

This review aims to describe recent advances in low-field (0.064 T) magnetic resonance imaging (LF-MRI) of cerebrovascular disease, including ischemic and hemorrhagic stroke and white matter hyperintensities. Since 2023, several studies have highlighted the rapidly changing landscape of portable, low-field MRI (LF-MRI) and its applications in stroke and cerebrovascular disease. The advantages of using LF-MRI in these settings are multifold: cheaper and dynamic imaging of this patient population confers closer observation during the acute and chronic stages of cerebrovascular disease. Initial deployments of the device span a variety of acute and emergency settings, including imaging around thrombolytic administration, endovascular reperfusion, intracerebral hemorrhage management, and cardiovascular intensive care. LF-MRI also has an important role in cerebrovascular disease monitoring and prevention, namely white matter hyperintensity (WMH) progression and vascular and Alzheimer's dementia. Early studies suggest reliable sensitivity and specificity for these pathologies. With further improvements to LF-MRI hardware, software and postprocessing on the horizon, we anticipate the device's ability to provide inexpensive and flexible neuroimaging to a wide array of healthcare settings that treat, prevent, and manage cerebrovascular disease. Recent studies indicate that LF-MRI promotes rapid, cost-effective, and clinically useful neuroimaging at various clinical timepoints throughout stroke and cerebrovascular disease progression and management.

The Systematic Multi-domain Alzheimer's Risk Reduction Trial (SMARRT) intervention: A personalized approach to dementia risk reduction.

Addressing modifiable risk factors such as physical inactivity and social isolation could reduce risk of Alzheimer's disease and all-cause dementia, but little is known about which factors individuals are most willing to address or how they prefer to address them. To examine and describe behavior change goals set by participants during the Systematic Multi-domain Alzheimer's Risk Reduction Trial (SMARRT). In SMARRT, older adults worked with a health coach and nurse over 2 years to set incremental, personalized goals to reduce dementia risk. We performed quantitative analyses to summarize the numbers of goals per risk factor and qualitative content analyses of health coach and nurse notes to describe types of goals and useful strategies. 82 dementia-free adults (70 to 89 years) with at least two dementia risk factors participated in the SMARRT intervention arm (mean age, 76 ± 5 years; 72% women; 11% Black/African American, 4% Asian, 3% Hispanic, 7% another non-White race). Participants set a median of 12 health coach goals and 1 nurse goals. The risk factors participants chose to work on most frequently were physical activity (95%), hypertension (72%), and cognitive activity (60%). Participants reported that the most useful strategies included support and accountability from the health coach/nurse, setting small goals, and learning to manage setbacks. When given support, older adults at increased risk for dementia set a wide range of goals to reduce dementia risk. A flexible, personalized approach that focuses on setting feasible goals and managing setbacks provides a useful framework for dementia risk reduction.

Classifying cognitive impairment based on FDG-PET and combined T1-MRI and rs-fMRI: An ADNI study.

Mild cognitive impairment (MCI) refers to a memory impairment among non-demented adults. It is a condition that increases the risk of dementia, notably due to Alzheimer's disease (AD). MCI is heterogeneous and there is a need for novel diagnostic approaches. Fluorodeoxyglucose positron emission tomography (FDG-PET) imaging provides robust AD biomarker characteristics, while anatomical and functional magnetic resonance imaging (MRI) offer complementary information. Classify MCI and cognitively normal (CN) adults using FDG-PET images; predict individuals with MCI that convert to AD dementia; determine if MRI can achieve comparable performance to FDG-PET classification. Four ADNI cohorts were created. Cohort 1: 805 participants (MCI n = 455; CN n = 350) that underwent FDG-PET. FDG-PET images were inputs to a one-channel 3-dimensional (3D) DenseNet deep learning model. Cohort 2: 348 participants (MCI n = 174; CN n = 174) with MRI and functional MRI. Cohort 3: overlapping cases from cohorts 1 and 2 (MCI n = 70; CN n = 70). Cohort 4: 336 participants (MCI-converters n = 168; MCI-stable n = 168) with FDG-PET from cohort 1. The one/two-channel models' inputs were T1-weighted MRI and/or amplitude of low-frequency fluctuations images, with classification metrics evaluated through 10-fold cross-validation. The FDG-PET model achieved 88.02%±3.82 accuracy for MCI versus CN classification, with 88.70%±4.70 sensitivity and 87.14%±5.03 specificity. Neither MRI model outperformed the FDG-PET model, as the highest MRI-based accuracy was 76.86%±1.95. The FDG-PET model achieved 63.23%±4.68 accuracy in classifying MCI-converters versus MCI-stable. FDG-PET images produced the highest accuracy in classifying MCI versus CN. While MRI-based approaches were inferior to FDG-PET, multi-contrast MRI still offers value for neurodegeneration classification.

Ten Reasons Why Neurologists Should Refer Patients With Alzheimer Dementia to Music Therapy.

Alzheimer dementia (AD) constitutes a major societal problem with devastating neuropsychiatric involvement. Pharmaceutical interventions carry a heightened risk of side effects; thus, nonpharmacological interventions such as music-based interventions (MBIs), including music therapy, are recommended. The 2023 Neurology release of the Music Based Intervention Toolkit for Brain Disorders of Aging showcased music's emerging role as an intervention to manage symptoms of various brain disorders while defining the building blocks of MBIs to guide research in the exploration of music's therapeutic potential. This study extends beyond the research aspects of the MBI Toolkit to clinical applications by providing neurologists with a summary of MBIs, the MBI Toolkit, how board-certified music therapists (MT-BCs) administered music therapy is a unique MBI, and 10 reasons why they should make referrals to music therapy for their patients with AD.

Utility of Tau PET in the diagnostic work up of neurodegenerative dementia among Indian patients

Background and objectivesTau PET is being increasingly appraised as a novel diagnostic modality for dementia work up. Given limited data among South Asians, we assessed the frequency, patterns, phenotypic associations and incremental value of positive Tau PET scans in clinically diagnosed neurodegenerative dementia. MethodsThis cross-sectional study recruited consecutive patients of Alzheimer's disease (AD) and non-AD syndromes (September 2021 to October 2022, India). Participants underwent clinical interview, cognitive assessment, MRI brain and tau PET scan ([F-18]ML-104). Visual read in a priori regions of interest was used to identify patterns of tau deposition in the brain. ResultsWe recruited 54 participants (mean age: 63.2 ± 9.2 years, 70.4 % men, 77.8 % dementia, 70.4 % early onset cases, 37.8 % APOE4+). The analysis identified abnormal tau uptake in 40/54 (74.1 %) participants; with uptake in AD signature areas in 27/40 (67.5 %) cases [cortical subtype (74.1 %), limbic (14.8 %), combined cortical/limbic (11.1 %)], and patterns not conforming to AD in 13/40 (32.5 %) cases. Tau PET substantiated the diagnosis of AD among 17/19 (89.5 %) cases with clinically diagnosed AD dementia, 8/23 (34.8 %) cases with suspected non-AD cause, and 2/12 (16.7 %) cases with mild cognitive impairment. A trend for increasing proportion of early onset cases, and worsening cognition, behavior and functional ability was seen, from ‘limbic’ to ‘combined cortical/limbic’ to ‘cortical’ subgroups. ConclusionTau PET is a useful modality to differentiate AD dementia from other neurodegenerative causes in the Indian setting where amyloid biomarkers are not widely available. Biological subtypes of AD map well onto clinical phenotypes and need study in larger cohorts.

Neuropsychiatric Symptoms in Dementia

ABSTRACT OBJECTIVE This article discusses the prevalence, pathophysiology, assessment, and management of neuropsychiatric symptoms in patients with dementia. LATEST DEVELOPMENTS There is a growing body of evidence localizing neuropsychiatric symptoms in dementia to frontal circuits in the brain, as well as relating them to pathologic changes seen in different dementias. Although very few medications have been approved by the US Food and Drug Administration (FDA) for the treatment of neuropsychiatric symptoms in dementia, there are more clinical trials showing the benefit of antidepressants, stimulants, and antipsychotics. In line with that trend, in 2023, the FDA approved the use of brexpiprazole, an atypical antipsychotic, for the treatment of agitation in Alzheimer disease dementia. ESSENTIAL POINTS Neuropsychiatric symptoms are a core feature of all dementias and often emerge before cognitive symptoms manifest. They are highly clinically significant symptoms that disrupt the lives of patients and care partners and greatly influence the decision to place patients in long-term care facilities. The first line of treatment for neuropsychiatric symptoms in dementia is nonpharmacologic behavioral modification, but clinicians often must supplement this intervention with medications using an empiric approach.

Baseline-dependent enhancement of working memory by memantine in male rats: Involvement of NMDA receptor subunits and CaMKII signaling

N-methyl-d-aspartate (NMDA) receptors, activated by glutamate, play a crucial role in learning and memory. Memantine (MEM), a non-competitive NMDA receptor antagonist, is currently prescribed for the treatment of Alzheimer's disease or dementia, which meanwhile simultaneously promotes a need to clarify its potential pro-cognitive effects that exist in normal healthy individuals. However, the neurobehavioral mechanisms underlying the cognitive improvement by MEM in normal individuals remain to be elucidated. This study aimed to assess the effects of MEM on working memory, measured by a discrete paired-trial delay alternation task in a T-maze in normal male rats. The impacts of MEM were hypothesized to vary depending on different baseline levels of working memory performance. Neurochemical examination of the levels of calcium/calmodulin-dependent kinase 2 (CaMKII) and NMDA receptor subunits within five targeted brain regions was conducted after behavioral tests. The results showed that acute administration of MEM enhanced working memory performance, with 2.5, 5.0, and 10 mg/kg doses increasing task accuracy compared to the vehicle, particularly in low performers. Neurochemically, the protein expression of CaMKII in the amygdala and that of the glutamate (Glu) N2A subunit in the dorsal striatum were greater in the low-performance group than in the high-performance group. Additionally, the protein expression of the GluN2A subunit in the dorsal striatum was negatively associated with task performance at baseline. The expression of GluN1 and GluN2B in the nucleus accumbens was negatively associated with task performance in the retest three weeks after drug treatment. These findings underscore the baseline-dependent improvement of working memory resulting from MEM administration, with observed drug effects associated with alterations in the levels of NMDA receptor subunits in striatal subareas and CaMKII in the amygdala.

Lecanemab Planning: Blueprint for Safe and Effective Management of Complex Therapies.

Approximately 6.9 million American individuals have Alzheimer dementia and 50% have mild disease. Lecanemab, an approved antiamyloid antibody, is associated with modest reduction in functional decline in patients with mild dementia or mild cognitive impairment. In Clarity-AD, 239 (26.6%) of patients experienced amyloid-related imaging abnormalities (ARIAs) overall (i.e., ARIAs associated with hemorrhages or edema). The complexity of treatment and risks of adverse events necessitate a multidisciplinary collaborative approach. With limited treatment options, lecanemab approval generated significant interest among clinicians, patients, and families. Lecanemab treatment requires biweekly infusions along with ongoing imaging tests, laboratory monitoring, patient assessment, drug interaction screening, and cognitive function monitoring. Processes to support patient selection, access, and safety are important given the monitoring requirements and total cost of care. The planning process for lecanemab can serve as a blueprint to support safe and effective management of therapeutic innovation in neurology and other areas.

Vascular Cognitive Impairment

ABSTRACT OBJECTIVE Vascular cognitive impairment is a major contributor to age-associated cognitive decline, both independently and as a contributor to mixed dementia syndromes. This article reviews the current understanding of how vascular dysfunction contributes to cognitive impairment and dementia risk in older individuals and includes updated diagnostic criteria and treatment recommendations. LATEST DEVELOPMENTS Clinical and research criteria have been evolving to more accurately determine the full prevalence of vascular cognitive impairment. The Boston Criteria version 2.0 for cerebral amyloid angiopathy now includes multiple punctate MRI T2 white matter hyperintensities and MR-visible perivascular spaces in addition to previously described T2* hemorrhagic signatures. MR-visible perivascular spaces are associated with both vascular cognitive impairment and Alzheimer disease, potentially linking cerebrovascular dysfunction to neurodegenerative disorders through its role in brain waste clearance. The American Heart Association’s goal for cardiovascular health promotion, “Life’s Essential 8,” has been updated to include sleep health and acknowledges psychological well-being and social determinants of health as fundamental components necessary to achieve optimal cardiovascular health for all adults. ESSENTIAL POINTS Vascular cognitive impairment is a common and often underrecognized contributor to cognitive impairment in older individuals, with heterogeneous etiologies requiring individualized treatment strategies. Effective cerebrovascular disease risk factor modification starting in midlife is critical to reducing the risk of Alzheimer disease and related dementias, with the goal of preventing vascular brain injury and maintaining cognitive reserve in the presence of nonvascular age-related brain pathologies.

Genetics and Neuropathology of Neurodegenerative Dementias.

This article provides an overview of the current understanding of the genetic and pathologic features of neurodegenerative dementias, with an emphasis on Alzheimer disease and related dementias. In recent years, there has been substantial progress in genetic research, contributing significant knowledge to our understanding of the molecular risk factors involved in neurodegenerative dementia syndromes. Several genes have been linked to monogenic forms of dementia (eg, APP, PSEN1, PSEN2, SNCA, GRN, C9orf72, MAPT) and an even larger number of genetic variants are known to influence susceptibility for developing dementia. As anti-amyloid therapies for patients with early-stage Alzheimer disease have entered the clinical arena, screening for the apolipoprotein E ε4 high-risk allele has come into focus, emphasizing the importance of genetic counseling. Similarly, advances in the pathologic classifications of neurodegenerative dementia syndromes and molecular pathology highlight their heterogeneity and overlapping features and provide insights into the pathogenesis of these conditions. Recent progress in neurogenetics and molecular pathology has improved our understanding of the complex pathogenetic changes associated with neurodegenerative dementias, facilitating improved disease modeling, enhanced diagnostics, and individualized counseling. The hope is that this knowledge will ultimately pave the way for the development of novel therapeutics.

Risk factors for Alzheimer's disease and related dementias in U.S. honor cultures

Risk factors for Alzheimer's disease and related dementias in U.S. honor cultures

Rates and predictors of opioid deprescribing after fracture: A retrospective study of Medicare fee‐for‐service claims

AbstractBackgroundAdults with Alzheimer's disease and Alzheimer's disease related dementias (ADRD) or frailty are susceptible to fractures. Opioid analgesics are frequently prescribed after fractures. Documenting post‐fracture opioid discontinuation rates and predictors of discontinuation among adults with ADRD or frailty can inform clinical practice, identify potential disparities, and improve pain management guidelines. The objective of this paper was to investigate opioid discontinuation in opioid‐naïve older adults who used opioids after an acute fracture.MethodsThis retrospective cohort study included opioid‐naïve Medicare fee‐for‐service beneficiaries (N = 33,027) ≥65 years of age who filled an opioid prescription within 30 days of a vertebral, lower extremity, or upper extremity fracture from 2013 to 2018. Beneficiaries were classified according to ADRD (yes/no) and frailty (yes/no) status using validated claims‐based algorithms. The primary outcome was opioid discontinuation, defined as a 30‐day supply gap. We estimated discontinuation rates with the Kaplan–Meier method and identified predictors of opioid discontinuation using Cox proportional hazards regression.ResultsThe 30‐day opioid discontinuation rate was similar among non‐frail beneficiaries without ADRD (81% [95% CI, 80%–81%]) and those who were non‐frail with ADRD (83% [81%–84%]). Comparatively, 30‐day discontinuation rates were lower among those with frailty and ADRD (76% [75%–77%]) and those with frailty alone (77% [75%–78%]). After adjusting for sociodemographic characteristics, health status, healthcare utilization, and calendar year, beneficiaries with both ADRD and frailty (HR, 0.90 [0.87–0.93]) and those with frailty alone (HR, 0.85 [0.82–0.89]), but not those with ADRD alone (HR, 1.06 [1.01–1.10]), were less likely to discontinue opioids compared with those without ADRD or frailty.Conclusions and RelevanceOur findings suggest that frailty, but not ADRD, was associated with a lower likelihood of opioid discontinuation among older adults who initiated opioids after an acute fracture. Further research is needed to understand how opioid deprescribing practices depend on patient and provider preferences.

Role of Blood P-Tau Isoforms (181, 217, 231) in Predicting Conversion from MCI to Dementia Due to Alzheimer’s Disease: A Review and Meta-Analysis

Blood-based biomarkers are minimally invasive tools to detect the pathological changes of Alzheimer’s Disease (AD). This meta-analysis aims to investigate the use of blood-derived p-tau isoforms (181, 217, 231) to predict conversion from mild cognitive impairment (MCI) to AD dementia (ADD). Studies involving MCI patients with data on blood p-tau isoforms at baseline and clinical diagnosis at follow-up (≥1 year) were included. Twelve studies on p-tau 181 (4340 MCI, conversion rate 20.6%), four on p-tau 217 (913 MCI, conversion rate 33.4%), and one on p-tau 231 (135 MCI, conversion rate 33%) were included. For p-tau 181, the pooled area under the receiver operating characteristic curve (AUC) was 0.73 (95% CI = 0.68–0.78), and for p-tau 217 was 0.85 (95% CI = 0.75–0.91). Plasma levels of p-tau 181 had good discriminatory power to identify MCI patients who will convert to ADD. Although only four studies on p-tau 217 have been included in the meta-analysis, in the last year the predictive power of p-tau 217 is emerging as superior to that of other isoforms. However, given the high heterogeneity detected in the p-tau 217 studies included in this meta-analysis, additional supportive evidence is needed. Insufficient results were available for p-tau 231. These findings support the prognostic utility of p-tau 181 and p-tau 217 measured in blood to predict progression to ADD in MCI and encourage its future implementation in clinical practice.

Life satisfaction and risk of dementia over 18years: an analysis of the National Alzheimer's Coordinating Center dataset.

Life satisfaction predicts lower risk of adverse health outcomes, including morbidity and mortality. Research on life satisfaction and risk of dementia has been limited by a lack of comprehensive clinical assessments of dementia. This study builds on previous research examining life satisfaction and clinically ascertained cognitive impairment and dementia. Participants (N = 23070; Meanage = 71.83, SD = 8.80) from the National Alzheimer's Coordinating Center reported their satisfaction with life at baseline. Incident dementia was ascertained through clinical assessment over up to 18years. Life satisfaction was associated with about 72% lower risk of all-cause of dementia, an association that remained significant accounting for demographic (age, sex, race, ethnicity, education, marital and living status), psychological (depression), clinical (obesity, diabetes, hypertension), behavioral (current and formersmoking), and genetic risk (APOEϵ4) factors. The association was not moderated by demographics, depression, andAPOEε4 status groups. The association was similar when cases occurring in the first five years were excluded, reducing the likelihood of reverse causality. Life satisfaction was also linked to specific causes of dementia, with a reduced risk ranging from about 60% to 90% for Alzheimer's disease and vascular dementia to > 2-fold lower risk of Lewy Body and frontotemporal dementia. Older adults who were satisfied with their lives were also at 61% lower risk of incident mild cognitive impairment and at 22% lower risk of converting from mild cognitive impairment to dementia. Being satisfied with one's life is associated with a lower risk of dementia. Improving life satisfaction could promote better cognitive health and protect against dementia.

The relationship between anxiety and levels of Alzheimer's disease plasma biomarkers.

Anxiety is highly prevalent in Alzheimer's disease (AD), correlating with cerebrospinal fluid/positron emission tomography biomarkers and disease progression. Relationships to plasma biomarkers are unclear. Herein, we compare levels of plasma biomarkers in research participants with and without anxiety at cognitively normal, mild cognitive impairment, and AD dementia stages. We observed significantly higher plasma tau/amyloid-β42 ratio in AD participants with anxiety versus those without, but did not observe differences at other stages or plasma biomarkers. No such relationships were evident with depression. These results support a unique pathophysiological relationship between anxiety and AD that can be reflected in plasma biomarkers, suggestive of heightened neurodegeneration.

Communication Bridge-2 randomized controlled trial: Recruitment and baseline features.

Non-pharmacological interventions may offer significant benefits to the quality of life for persons with primary progressive aphasia (PPA) and their care partners but have lacked efficacy trials. To help fill the efficacy gap, we provide the feasibility of recruitment, enrollment, randomization, and baseline data for the Communication Bridge-2 (CB2) randomized controlled trial (RCT). CB2 is the first international, single enrollment site, Phase 2, Stage 2, parallel-group, active control, RCT delivered via video chat to individuals with PPA and their care partners. Participants were recruited, screened, and randomized into one of two speech-language intervention arms. Ninety-five participant dyads (PPA mean baseline age: 67.1; 48% female) from four countries were enrolled and randomized. Global recruitment, enrollment, and randomization of individuals with PPA into a video chat-delivered non-pharmacologic RCT is feasible. This trial provides a potential model for conducting rigorous non-pharmacologic efficacy trials for Alzheimer's disease and related dementias. Primary progressive aphasia (PPA) negatively impacts communication participation. Communication Bridge-2 (CB2) is a telemedicine-delivered randomized controlled trial. CB2 included global recruitment and randomization of 95 PPA participant dyads. CB2, the first international superiority trial for PPA using video chat shows feasibility. The study provides a model for rigorous non-pharmacologic trials for Alzheimer's disease and related dementias.

The Consortium for Clarity in ADRD Research Through Imaging (CLARiTI).

The presence of multiple pathologies is the largest predictor of dementia. A major gap in the field is the in vivo detection of mixed pathologies and their antecedents. The Alzheimer's Disease Research Centers (ADRCs) are uniquely positioned to address this gap. The ADRCs longitudinally follow ≈ 17,000 participants, ranging from cognitively unimpaired to dementia, arising from Alzheimer's disease (AD) and related dementias (ADRD; e.g., AD, Lewy body disorders, vascular). Motivated by the Alzheimer's Disease Neuroimaging Initiative's (ADNI) impact, the ADRC Consortium for Clarity in ADRD Research Through Imaging (CLARiTI) was formed. Leveraging existing ADRC infrastructure, CLARiTI will integrate standardized imaging and plasma collection to characterize mixed pathologies and use community-engaged research methods to ensure that≥ 25% of the sample is from underrepresented populations (e.g., ethnoculturally minoritized, low education). The resulting ADRD profiles, within a more diverse sample, will provide key resources for ADRCs and an unprecedented, more generalizable publicly available imaging-plasma dataset. HIGHLIGHTS: In vivo detection of mixed pathologies is critical for Alzheimer's disease and related dementias research. The Alzheimer's Disease Research Centers (ADRCs) are uniquely positioned to address gaps related to mixed pathologies. The ADRC Consortium for Clarity in ADRD Research Through Imaging (CLARiTI) will enhance this national program by adding standardized imaging and plasma collection to existing ADRC infrastructure. This effort will provide key resources for ADRCs and an unprecedented publicly available imaging-plasma-neuropath dataset.

Impact of white matter hyperintensity volume on cognition among US Mexican American adults.

Higher white matter hyperintensity (WMH) volume is a marker of cardiovascular disease (CVD) risk. CVD risk factors increase risk for Alzheimer's disease and related dementias (ADRD). Mexican Americans (MA) and individuals of other Hispanic/Latino heritages have higher risk for CVD and ADRD. However, knowledge of associations between WMH volume and cognition in these groups remains limited. We conducted a cross-sectional study of associations between WMH volume and neuropsychological performance (attention/executive functioning, memory) in MA (n = 851) and non-Hispanic White (NHW; n = 747) adults in the Health and Aging Brain Study: Health Disparities. The MA group (mean age = 63.72 ± 7.90 years; 66.3% female) had higher rates of consensus diagnoses of hypertension and diabetes, whereas the NHW group (mean age = 69.18 ± 8.65 years; 55.2% female) had higher rates of diagnosed CVD (ps < .01). WMH volumes were higher among individuals with CVD risk factors/conditions (ps < .01). There were differential associations between WMH and neuropsychological performance across ethnoracial groups (ps < .001), wherein associations were steeper in the NHW group than in the MA group. Lower educational level was associated with higher WMH volume in the NHW group (p < .001), but no association was seen in the MA group (p > .05). Negative effects of pathological changes in the form of WMH on cognition may be less robust or consistent for MA adults than NHW adults. Furthermore, the impact of WMH on cognition in NHW adults may be mitigated by cognitive reserve related to educational attainment.

Clinical and biological underpinnings of longitudinal atrophy pattern progression in Alzheimer's disease.

Magnetic resonance imaging (MRI) has recently enabled to identify four distinct Alzheimer's disease (AD) subtypes: hippocampal sparing (HpSp), typical AD (tAD), limbic predominant (Lp), and minimal atrophy (MinAtr). To date, however, the natural history of these subtypes, especially regarding the presence of subjects switching to other MRI patterns and their clinical and biological differences, remains poorly understood. To investigate the clinical and biological underpinnings of longitudinal atrophy pattern progression in AD. 251 AD patients (16 with significant memory concern, 66 with early mild cognitive impairment (MCI), 125 with late MCI, and 44 with AD dementia) from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database were assigned to their baseline MRI atrophy subtype using Freesurfer-derived cortical:hippocampal volumes ratio. Switching to other MRI patterns was investigated on longitudinal scans, and patients were accordingly classified as "switching" and "stable". Logistic regression models were applied to identify predictors of switching to other MRI patterns. 40% of Lp, 26% of HpSp, and 35% of MinAtr cases switched to other MRI patterns, with tAD representing the destination subtype of all switching HpSp and Lp, and the majority of MinAtr. At baseline significant clinical, cognitive and biomarkers differences were observed across the four subtypes. Only clinical and cognitive variables, however, were significantly associated with switch to other MRI patterns. Our results suggest convergent directions of disease progression across atypical and typical AD forms, at least in a subset of AD subjects, and highlight the importance of deep-phenotyping approaches to understand AD heterogeneity.

Identification and cognitive function prediction of Alzheimer's disease based on multivariate pattern analysis of hippocampal volumes.

Alzheimer's disease (AD) is strongly associated with slowly progressive hippocampal atrophy. Elucidating the relationships between local morphometric changes and disease status for early diagnosis could be aided by machine learning algorithms trained on neuroimaging datasets. This study intended to propose machine learning models for the accurate identification and cognitive function prediction across the AD severity spectrum based on structural magnetic resonance imaging (sMRI) of the bilateral hippocampi. The high-resolution sMRI data of 120 AD dementia patients, 232 amnestic mild cognitive impairment (aMCI) patients, and 206 healthy controls (HCs) were included from the Alzheimer's Disease Neuroimaging Initiative (ADNI). The classification capacity and cognitive predict ability of hippocampal volume was evaluated by multiple pattern analysis using the support vector machine (SVM) and relevance vector regression (RVR) application of the Pattern Recognition for Neuroimaging Toolbox, separately. For validation, the analyses were performed using a biomarker-based regrouping method and another independent local dataset. The SVM application produced a total accuracy of 94.17%, 80.85%, and 70.74% and area under receiver operating characteristic curves of 0.97, 0.87, and 0.72 between HC versus AD dementia, HC versus aMCI, and aMCI versus AD dementia classification, respectively. The RVR application significantly predicted the baseline and mean cognitive function at three years of follow-up. Qualitatively consistent results were obtained using different regrouping method and the local dataset. The machine learning methods based on the bilateral hippocampi distinguished across the AD severity spectrum and predicted the baseline and the longitudinal cognitive function with greater accuracy.