Contributions of amyloid beta and cerebral small vessel disease in clinical decline.

INTRODUCTION: We assessed whether co-morbid small vessel disease (SVD) has clinical predictive value in preclinical or prodromal Alzheimer's disease. METHODS: In 1090 non-demented participants (65.4 ± 10.7 years) SVD was assessed with magnetic resonance imaging and amyloid beta (Aß) with lumbar puncture and/or positron emission tomography scan (mean follow-up for cognitive function 3.1 ± 2.4 years). RESULTS: Thirty-nine percent had neither Aß nor SVD (A-V-), 21% had SVD only (A-V+), 23% Aß only (A+V-), and 17% had both (A+V+). Pooled cohort linear mixed model analyses demonstrated that compared to A-V- (reference), A+V- had a faster rate of cognitive decline. Co-morbid SVD (A+V+) did not further increase rate of decline. Cox regression showed that dementia risk was modestly increased in A-V+ (hazard ratio [95% confidence interval: 1.8 [1.0-3.2]) and most strongly in A+ groups. Also, mortality risk was increased in A+ groups. DISCUSSION: In non-demented persons Aß was predictive of cognitive decline, dementia, and mortality. SVD modestly predicts dementia in A-, but did not increase deleterious effects in A+. HIGHLIGHTS: Amyloid beta (Aß; A) was predictive for cognitive decline, dementia, and mortality. Small vessel disease (SVD) had no additional deleterious effects in A+. SVD modestly predicted dementia in A-. Aß should be assessed even when magnetic resonance imaging indicates vascular cognitive impairment.

Amyloid PET disclosure in subjective cognitive decline: Patient experiences over time.

INTRODUCTION: We disclosed amyloid positron emission tomography (PET) results in individuals with subjective cognitive decline (SCD) and studied patient experiences and outcomes over a 6-month period. METHODS: Fifty-seven participants from the Subjective Cognitive Impairment Cohort (SCIENCe) (66 ± 8 years, 21 [37%] F, Mini-Mental State Examination 29 ± 1, 15 [26%] amyloid positive [A+]) completed questionnaires 1 week prior (T0), 1 day after (T1), and 6 months after amyloid PET disclosure (T2). Questionnaires addressed patient-reported experiences and outcomes. RESULTS: Independent of amyloid status, participants were satisfied with the consultation (scale 1-10; 7.9 ± 1.7) and information provided (scale 1-4; T1: 3.3 ± 0.9, T2: 3.2 ± 0.8). After 6 months, A+ participants reported more information needs (45% vs. 12%, p = 0.02). Independent of amyloid status, decision regret (scale 1-5; A+: 1.5 ± 0.9, A-: 1.4 ± 0.6, p = 0.53) and negative emotions (negative affect, uncertainty, anxiety) were low (all p > 0.15 and Pinteraction > 0.60). DISCUSSION: Participants with SCD valued amyloid PET disclosure positively, regardless of amyloid status. The need for information after 6 months, which was stronger in A+ individuals, underscores the importance of follow-up. HIGHLIGHTS: Participants with subjective cognitive decline (SCD) positively valued amyloid positron emission tomography (PET) disclosure. Participants with SCD experienced low levels of decision regret. We did not observe an increase in negative emotions. After 6 months, amyloid-positive individuals wanted more information.

Changes in self- and study partner-perceived cognitive functioning in relation to amyloid status and future clinical progression: Findings from the SCIENCe project.

INTRODUCTION: We investigated changes in self- and study partner-reported self-perceived cognitive decline in relation to amyloid pathology and clinical progression, in a sample of cognitively normal individuals. METHODS: A total of 404 participants (63 ± 9 years, 44% female) and their study partners completed the Cognitive Change Index (CCI) yearly (0.7-6.8 follow-up years; n visits = 1436). Baseline and longitudinal associations between (change in) CCI scores, amyloid, and clinical progression were modeled in linear mixed models and Cox regressions. RESULTS: CCI-study partner scores of amyloid-positive individuals increased over time (B = 1.79, 95% confidence interval [CI] = [0.51, 3.06]), while CCI-self scores remained stable (B = -0.45, 95% CI = [-1.77, 0.87]). Ten-point higher baseline CCI-study partner (hazard ratio [HR] = 1.75, 95% CI = [1.30, 2.36]) and CCI-self scores (HR = 1.90, 95% CI = [1.40, 2.58]) were associated with an approximately 2-fold increased risk of progression to mild cognitive impairment or dementia. DISCUSSION: Study partner-reported but not self-perceived complaints increase over time in amyloid-positive individuals, supporting the value of longitudinal study partner report, even in initially cognitively normal individuals.

Recommendations to distinguish behavioural variant frontotemporal dementia from psychiatric disorders.

The behavioural variant of frontotemporal dementia (bvFTD) is a frequent cause of early-onset dementia. The diagnosis of bvFTD remains challenging because of the limited accuracy of neuroimaging in the early disease stages and the absence of molecular biomarkers, and therefore relies predominantly on clinical assessment. BvFTD shows significant symptomatic overlap with non-degenerative primary psychiatric disorders including major depressive disorder, bipolar disorder, schizophrenia, obsessive-compulsive disorder, autism spectrum disorders and even personality disorders. To date, ∼50% of patients with bvFTD receive a prior psychiatric diagnosis, and average diagnostic delay is up to 5-6 years from symptom onset. It is also not uncommon for patients with primary psychiatric disorders to be wrongly diagnosed with bvFTD. The Neuropsychiatric International Consortium for Frontotemporal Dementia was recently established to determine the current best clinical practice and set up an international collaboration to share a common dataset for future research. The goal of the present paper was to review the existing literature on the diagnosis of bvFTD and its differential diagnosis with primary psychiatric disorders to provide consensus recommendations on the clinical assessment. A systematic literature search with a narrative review was performed to determine all bvFTD-related diagnostic evidence for the following topics: bvFTD history taking, psychiatric assessment, clinical scales, physical and neurological examination, bedside cognitive tests, neuropsychological assessment, social cognition, structural neuroimaging, functional neuroimaging, CSF and genetic testing. For each topic, responsible team members proposed a set of minimal requirements, optimal clinical recommendations, and tools requiring further research or those that should be developed. Recommendations were listed if they reached a ≥ 85% expert consensus based on an online survey among all consortium participants. New recommendations include performing at least one formal social cognition test in the standard neuropsychological battery for bvFTD. We emphasize the importance of 3D-T1 brain MRI with a standardized review protocol including validated visual atrophy rating scales, and to consider volumetric analyses if available. We clarify the role of 18F-fluorodeoxyglucose PET for the exclusion of bvFTD when normal, whereas non-specific regional metabolism abnormalities should not be over-interpreted in the case of a psychiatric differential diagnosis. We highlight the potential role of serum or CSF neurofilament light chain to differentiate bvFTD from primary psychiatric disorders. Finally, based on the increasing literature and clinical experience, the consortium determined that screening for C9orf72 mutation should be performed in all possible/probable bvFTD cases or suspected cases with strong psychiatric features.

Effectiveness of Pharmacological Interventions for Symptoms of Behavioral Variant Frontotemporal Dementia: A Systematic Review.

BACKGROUND: Clinical guidance on the symptomatic treatment of behavioral variant frontotemporal dementia (bvFTD) is limited. OBJECTIVE: To provide a systematic review of pharmacological interventions for symptomatic treatment of bvFTD, based on the International bvFTD Criteria Consortium clinical diagnostic criteria: apathy, disinhibition, lack of empathy or sympathy, hyperorality, stereotypical behavior, and executive dysfunction. METHODS: We systematically searched the PubMed, Embase, and PsycINFO databases for reports on pharmacological interventions for individuals with bvFTD, published between 1970 and 2018, using key indicators and relevant terms. Studies were included if the efficacy of the intervention in alleviating bvFTD symptoms was provided as an outcome. Due to the high prevalence of depressive symptoms in individuals with bvFTD, we also evaluated the effect of the interventions on depression. RESULTS: We included 23 studies-11 randomized controlled trials, eight open-label studies, one proof-of-concept study, and three case series-reporting on a total of 573 individuals. Of the 23 studies, 16 used pharmacological interventions that improved bvFTD symptoms. Based on the Neuropsychiatric Inventory, trazodone had the greatest significant reductive effect on the symptoms of bvFTD. Overall, citalopram, rivastigmine, paroxetine, and trazodone all reduced multiple symptoms, including disinhibition, hyperorality, and depression. CONCLUSIONS: This review provides an overview of the pharmacological interventions that can be used to treat the main bvFTD symptoms as well as a guideline for managing bvFTD. More research is needed to investigate the efficacy of pharmacological interventions for bvFTD through use of a validated outcome and a focus on the specific behavioral problems associated with bvFTD.

Peripheral vascular function in stroke: systematic review and meta-analysis.

Peripheral vascular dysfunction, measured as flow-mediated dilation (FMD), is present across all phases of stroke recovery and elevates the risk for recurrent cardiovascular events. The objective of this systematic review and meta-analysis was to characterize baseline FMD in individuals' poststroke, with consideration for each phase of stroke recovery. Three databases (PubMed, CINAHL, and Embase) were searched between January 1, 2000 and October 12, 2023 for studies that examined baseline FMD in stroke. Three reviewers conducted abstract and full-text screening, data extraction, and quality assessment. A random effects model was used to estimate FMD across studies. Meta-regression was used to examine the impact of age and time since stroke (acute, subacute, chronic) on FMD. Twenty-eight studies with ischemic and hemorrhagic stroke were included. Descriptive statistics for the demographics and FMD values of each study are presented. For the meta-analysis, average estimate FMD was 3.9% (95% CI: 2.5-5.3%). We report a large amount of heterogeneity (Cochrane's Q P value <0.001, and I2 = 99.6%). Differences in average age and the time poststroke between studies were not significantly associated with differences in FMD values. Despite the large heterogeneity for FMD values across studies, our primary finding suggests that FMD remains impaired across all phases of stroke.NEW & NOTEWORTHY This systematic review and meta-analysis offers invaluable insight into poststroke vascular function. Despite the inherent heterogeneity among the 28 studies analyzed, we report that peripheral vascular dysfunction, as quantified by flow-mediated dilation, exists across all stages of stroke recovery. This finding underscores the importance for interventions that focus on improving vascular health and secondary stroke prevention.

Alzheimer's Disease and Cognitive Decline in Patients with Cardiovascular Diseases Along the Heart-Brain Axis.

Background: We hypothesize that Alzheimer's disease (AD)-related pathology may accelerate cognitive decline in patients with cardiovascular diseases. Objective: To investigate the association between blood-based biomarkers of AD, astrocyte activation, and neurodegeneration and cognitive decline. Methods: From the multi-center Heart-Brain study, we included 412 patients with heart failure, carotid occlusive disease or vascular cognitive impairment (age:68.6±9.0) and 128 reference participants (65.7±7.5). Baseline amyloid-ß42/40 (Aß42/40), phosphorylated-tau181 (pTau181), glial fibrillary acidic protein (GFAP), and neurofilament light (NfL) were determined using SiMoA (Quanterix). Memory, attention, language, and executive functioning were evaluated (follow-up:2.1±0.3 years). We applied linear mixed models with terms for biomarker, time and biomarker*time interactions, adjusted for age, sex, education, and site, to assess associations between biomarkers and cognitive decline. Results: Among patients, Aß42/40 was not associated with cognitive performance at baseline. However, lower Aß42/40 was associated with steeper decline in global cognition (ß±SE:0.04±0.02). Higher pTau181 was associated with worse baseline performance on global cognition (-0.14±0.04) and memory (-0.31±0.09) and with steeper decline in global cognition (-0.07±0.02), memory (-0.09±0.04), attention (-0.05±0.02), and language (-0.10±0.03). Higher GFAP was associated with worse baseline performance on global cognition (-0.22±0.05), memory (-0.43±0.10), attention (-0.14±0.06), language (-0.15±0.05), and executive functioning (-0.15±0.05) and steeper decline in global cognition (-0.05±0.01). Higher NfL was associated with worse baseline performance on global cognition (-0.16±0.04), memory (-0.28±0.09), attention (-0.20±0.06), and executive functioning (-0.10±0.04), but was not associated with performance over time. In reference participants, no associations were found. Conclusions: Our findings suggest that blood-based biomarkers of AD-related pathology predict cognitive decline in patients with cardiovascular diseases.

Overlap of Neuroanatomical Involvement in Frontotemporal Dementia and Primary Psychiatric Disorders: A Meta-analysis.

BACKGROUND: Despite significant symptomatic overlap between behavioral variant frontotemporal dementia (bvFTD) and primary psychiatric disorders (PPDs), a potential overlap in their structural anatomical changes has not been studied systematically. METHODS: In this magnetic resonance imaging-based meta-analysis, we included studies on bvFTD, schizophrenia, bipolar disorder, and autism spectrum disorder that 1) used voxel-based morphometry analysis to assess regional gray matter volumes (GMVs) and 2) reported the coordinates of the regional GMV. Separate analyses were performed comparing clusters of coordinate-based changes in the GMVs (n = 24,183) between patients and control subjects, and overlapping brain regions between bvFTD and each PPD were examined. RESULTS: We found that GMV alterations in the prefrontal and anterior cingulate cortices, temporal lobe, amygdala, and insula comprise the transdiagnostic brain alterations in bvFTD and PPD. CONCLUSIONS: Our meta-analysis revealed significant anatomical overlap that paves the way for future investigations of shared pathophysiological pathways, and our cross-disorder approach would provide new insights to better understand the relationship between bvFTD and PPD.