Biomarker-based staging of Alzheimer disease: rationale and clinical applications

Nature Reviews Neurology, Journal Year: 2024, Volume and Issue: 20(4), P. 232 - 244

Published: March 1, 2024

Language: Английский

---

Tau follows principal axes of functional and structural brain organization in Alzheimer’s disease

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: June 12, 2024

Abstract Alzheimer’s disease (AD) is a brain network disorder where pathological proteins accumulate through networks and drive cognitive decline. Yet, the role of connectivity in facilitating this accumulation remains unclear. Using in-vivo multimodal imaging, we show that distribution tau reactive microglia humans follows spatial patterns variation, so-called gradients organization. Notably, less distinct (“gradient contraction”) are associated with decline regions greater tau, suggesting an interaction between reduced differentiation on cognition. Furthermore, by modeling subject-specific gradient space, demonstrate frontoparietal temporo-occipital cortices baseline within their functionally structurally connected hubs, respectively. Our work unveils for both functional structural organization pathology AD, supports space as promising tool to map progression.

Language: Английский

---

Dimensional Neuroimaging Endophenotypes: Neurobiological Representations of Disease Heterogeneity Through Machine Learning

Biological Psychiatry, Journal Year: 2024, Volume and Issue: 96(7), P. 564 - 584

Published: May 6, 2024

Language: Английский

---

Atypical clinical variants of Alzheimer’s disease: are they really atypical?

Frontiers in Neuroscience, Journal Year: 2024, Volume and Issue: 18

Published: Feb. 28, 2024

Alzheimer’s disease (AD) is a neuropathological disorder defined by the deposition of proteins, tau and β-amyloid. commonly thought as elderly that associated with episodic memory loss. However, very first patient described AD was in her 50’s impairments multiple cognitive domains. It now clear can present different non-amnestic clinical variants which have been labeled atypical AD. Instead these being considered “atypical,” I propose they provide an excellent model reflect true heterogeneity The usually relatively young age at onset, show striking cortical on molecular PET imaging relates strongly patterns neurodegeneration outcomes. In contrast, patients less PET, neuroimaging outcomes are confounded other age-related pathologies, including TDP-43 vascular pathology. There also considerable anatomical across young-onset amnestic reflects fact causes Future studies should focus careful characterization impairment consider full spectrum AD, design research investigating mechanisms treatment trials, particularly therapeutics targeting tau.

Language: Английский

---

Heterogeneous clinical phenotypes of sporadic early-onset Alzheimer’s disease: a neuropsychological data-driven approach

Alzheimer s Research & Therapy, Journal Year: 2025, Volume and Issue: 17(1)

Published: Feb. 6, 2025

The clinical presentations of early-onset Alzheimer's disease (EOAD) and late-onset are distinct, with EOAD having a more aggressive course greater heterogeneity. Recent publications from the Longitudinal Early-Onset Disease Study (LEADS) described as predominantly amnestic, though this phenotypic description was based solely on judgment. To better understand range presentation, we applied neuropsychological data-driven method to subtype LEADS cohort. Neuropsychological test performance 169 amyloid-positive participants were analyzed. Education-corrected normative comparisons made using sample 98 cognitively normal participants. Comparing relative levels impairment between each cognitive domain, cut-off 1 SD below all other domain scores indicate phenotype "predominant" in given domain. Individuals otherwise considered have multidomain impairment. Whole-cortex general linear modeling cortical atrophy an MRI-based validation these distinct phenotypes. We identified 6 subtypes EOAD: Dysexecutive Predominant (22% sample), Amnestic (11%), Language Visuospatial (15%), Mixed Amnestic/Dysexecutive Multidomain (30%). These phenotypes did not differ by age, sex, or years education. APOE ɛ4 genotype enriched group, who also rated least impaired. Cortical thickness analysis validated dissociations patterns observed groups. In contrast heterogeneity our approach, diagnostic classifications for same judgment indicated that 82% individuals amnestic-predominant, 9% non-amnestic, 4% met criteria Posterior Atrophy, 5% Primary Progressive Aphasia. A uncovered detailed understanding presenting atypical AD compared alone. Clinicians patients may over-report memory dysfunction at expense non-memory symptoms. findings important implications accuracy treatment considerations.

Language: Английский

---

Longitudinal Evolution of Posterior Cortical Atrophy

Neurology, Journal Year: 2025, Volume and Issue: 104(9)

Published: April 8, 2025

Although several large studies have evaluated individuals with posterior cortical atrophy (PCA) cross-sectionally, its longitudinal progression remains poorly characterized. The objectives of this study were to determine the trajectory PCA, encompassing temporal aspects diagnosis, spectrum clinical manifestations, and patient outcomes. This retrospective included participants diagnosed PCA at Mayo Clinic, between 1995 2023. Clinical data (demographics, neurologic evaluations, cognitive tests initial presentation late stage) extracted from medical records. Initial diagnoses during previous including ophthalmologic assessments after onset symptoms, documented. Participants retrospectively classified as PCA-pure if they solely met criteria or PCA-plus exhibited complex phenotypes also meeting for other neurodegenerative syndromes. CSF analyses neuropathology findings cohort 558 (65% female) had a mean age symptom 61 ± 8 years, 68% early-onset (younger than 65 years). duration diagnosis was 3.6 2.5 years. Ophthalmologic/optometric evaluations (49%) completion procedures (16%) common before diagnosis. Psychiatric made in 23% particularly among younger women. Common symptoms misplacement items, difficulties reading driving, concerns pertaining basic visual processing. Notable signs constructional apraxia, dyscalculia, simultanagnosia, space perception deficits. biomarkers consistent Alzheimer disease 139 158 (88%). Superimposed features non-PCA syndromes observed quarter presentation, frequency cases increasing longitudinally. Longitudinal analysis Short Test Mental Status scores predicted an rapid decline function, rate gradually slowing over 0-10 years (time coefficient [SE] = -4.20 [0.29], p < 0.001). highlights protracted time frequent misdiagnoses/misattribution PCA. Ophthalmologic often preceded assessments. more These observations highlight need improve diagnostic processes earlier recognition which may enhance effectiveness emerging disease-modifying therapies.

Language: Английский

---

Default mode network failure and neurodegeneration across aging and amnestic and dysexecutive Alzheimer’s disease

Brain Communications, Journal Year: 2023, Volume and Issue: 5(2)

Published: March 2, 2023

From a complex systems perspective, clinical syndromes emerging from neurodegenerative diseases are thought to result multiscale interactions between aggregates of misfolded proteins and the disequilibrium large-scale networks coordinating functional operations underpinning cognitive phenomena. Across all syndromic presentations Alzheimer's disease, age-related disruption default mode network is accelerated by amyloid deposition. Conversely, variability may reflect selective neurodegeneration modular supporting specific abilities. In this study, we leveraged breadth Human Connectome Project-Aging cohort non-demented individuals (N = 724) as normative assess robustness biomarker dysfunction in failure quotient, across aging spectrum. We then examined capacity quotient focal markers discriminate patients with amnestic 8) or dysexecutive 10) disease at patient level, well phenotypes. Importantly, participants were scanned using protocol, allowing for acquisition high-resolution structural imaging longer resting-state connectivity time. Using regression framework, found that related age, global cortical thickness, hippocampal volume, cognition cohort, replicating previous results Mayo Clinic Study Aging used different scanning protocol. Then, quantile curves group-wise comparisons show commonly distinguished both cohort. contrast, more phenotype-specific, where parieto-frontal areas associated while temporal disease. Capitalizing on large optimized protocols, highlight reflecting shared system-level pathophysiological mechanisms biomarkers distinct pathognomonic processes These findings provide evidence inter-individual impairment relate degeneration disruption. important information advance approaches degeneration, expand armamentarium available aid diagnosis, monitor progression inform trials.

Language: Английский

---

Behavioral and dysexecutive variant of Alzheimer's disease: Insights from structural and molecular imaging studies

Heliyon, Journal Year: 2024, Volume and Issue: 10(8), P. e29420 - e29420

Published: April 1, 2024

Frontal variant Alzheimer's disease (AD) manifests with either behavioral or dysexecutive syndromes. Recent efforts to gain a deeper understanding of this phenotype have led re-conceptualization frontal AD. Behavioral (bAD) and (dAD) phenotypes could be considered subtypes, as suggested by both clinical neuroimaging studies. In review, we focused on imaging studies highlight specific brain patterns in these two uncommon AD phenotypes. Although did not compare directly variants, common epicenter located the cortex inferred. On contrary, 18

Language: Английский

---

Suspecting Non-Alzheimer’s Pathologies and Mixed Pathologies: A Comparative Study Between Brain Metabolism and Tau Images

Journal of Alzheimer s Disease, Journal Year: 2023, Volume and Issue: 97(1), P. 421 - 433

Published: Dec. 12, 2023

Background: Alzheimer’s disease (AD) pathology can be disclosed in vivo using amyloid and tau imaging, unlike non-AD neuropathologies for which no specific markers exist. Objective: We aimed to compare brain hypometabolism tauopathy unveil pathologies. Methods: Sixty-one patients presenting cognitive complaints (age 48–90), including 32 with positive AD biomarkers (52%), performed [18F]-Fluorodeoxyglucose (FDG)-PET (brain metabolism) [18F]-MK-6240-PET (tau). normalized these images data from clinically normal individuals (n = 30), resulting comparable FDG z-scores. computed between-patients correlations evaluate regional associations. For each patient, a predominant biomarker (i.e., Hypometabolism > Tauopathy or Hypometabolism≤Tauopathy) was determined the temporal frontoparietal lobes. within-patient between metabolism investigated their associations demographics, cognition, cardiovascular risk factors (CVRF), CSF biomarkers, white matter hypointensities (WMH). Results: observed negative 37 of 68 cortical regions-of-interest (average Pearson’s r –0.25), mainly lobe. Thirteen (21%) had whereas twenty-five (41%) Hypometabolism≤Tauopathy. Tau-predominant were more frequently females greater burden. Twenty-three (38%) Hypometabolism≤Tauopathy lobe, but This group older higher CVRF than patients. Patients younger, worse WMH burdens. Conclusions: Tau-FDG comparison help suspect pathologies complaints. Stronger are associated younger age,

Language: Английский

---

Atypical forms of Alzheimer's disease: patients not to forget

Current Opinion in Neurology, Journal Year: 2023, Volume and Issue: 36(4), P. 245 - 252

Published: June 22, 2023

Purpose of review The aim this paper is to summarize the latest work on neuroimaging in atypical Alzheimer's disease (AD) patients and emphasize innovative aspects clinic research. will mostly cover language (logopenic variant primary progressive aphasia; lvPPA), visual (posterior cortical atrophy; PCA), behavioral (bvAD) dysexecutive (dAD) variants AD. Recent findings MRI PET can detect differentiate typical AD variants, novel imaging markers like brain iron deposition, white matter hyperintensities (WMH), mean diffusivity, total creatine also contribute. Together, these approaches have helped characterize variant-specific distinct profiles. Even within each variant, various subtypes that capture heterogeneity cases been revealed. Finally, in-vivo pathology led significant advances field. Summary Overall, recent literature contribute increase knowledge lesser-known are key generate clinical trial endpoints, which required for inclusion trials assessing treatments. In return, studying inform neurobiology cognitive functions, such as language, executive, memory, visuospatial abilities.

Language: Английский

---