This expert working group report proposes an updated approach to subtype definition of vascular parkinsonism (VaP) based on a review of the existing literature. The persistent lack of consensus on ...clear terminology and inconsistent conceptual definition of VaP formed the impetus for the current expert recommendation report. The updated diagnostic approach intends to provide a comprehensive tool for clinical practice. The preamble for this initiative is that VaP can be diagnosed in individual patients with possible prognostic and therapeutic consequences and therefore should be recognized as a clinical entity. The diagnosis of VaP is based on the presence of clinical parkinsonism, with variable motor and non-motor signs that are corroborated by clinical, anatomic or imaging findings of cerebrovascular disease. Three VaP subtypes are presented: (1) The acute or subacute post-stroke VaP subtype presents with acute or subacute onset of parkinsonism, which is typically asymmetric and responds to dopaminergic drugs; (2) The more frequent insidious onset VaP subtype presents with progressive parkinsonism with prominent postural instability, gait impairment, corticospinal, cerebellar, pseudobulbar, cognitive and urinary symptoms and poor responsiveness to dopaminergic drugs. A higher-level gait disorder occurs frequently as a dominant manifestation in the clinical spectrum of insidious onset VaP, and (3) With the emergence of molecular imaging biomarkers in clinical practice, our diagnostic approach also allows for the recognition of mixed or overlapping syndromes of VaP with Parkinson's disease or other neurodegenerative parkinsonisms. Directions for future research are also discussed.
•The diagnosis of VaP is based on convergence of parkinsonism with findings consistent with cerebrovascular disease.
In a multicenter cohort of probable dementia with Lewy bodies (DLB), we tested the hypothesis that β-amyloid and tau biomarker positivity increases with age, which is modified by
genotype and sex, ...and that there are isolated and synergistic associations with the clinical phenotype.
We included 417 patients with DLB (age 45-93 years, 31% women). Positivity on β-amyloid (A+) and tau (T+) biomarkers was determined by CSF β-amyloid
and phosphorylated tau in the European cohort and by Pittsburgh compound B and AV-1451 PET in the Mayo Clinic cohort. Patients were stratified into 4 groups: A-T-, A+T-, A-T+, and A+T+.
A-T- was the largest group (39%), followed by A+T- (32%), A+T+ (15%), and A-T+ (13%). The percentage of A-T- decreased with age, and A+ and T+ increased with age in both women and men. A+ increased more in
ε4 carriers with age than in noncarriers. A+ was the main predictor of lower cognitive performance when considered together with T+. T+ was associated with a lower frequency of parkinsonism and probable REM sleep behavior disorder. There were no significant interactions between A+ and T+ in relation to the clinical phenotype.
Alzheimer disease pathologic changes are common in DLB and are associated with the clinical phenotype. β-Amyloid is associated with cognitive impairment, and tau pathology is associated with lower frequency of clinical features of DLB. These findings have important implications for diagnosis, prognosis, and disease monitoring, as well as for clinical trials targeting disease-specific proteins in DLB.
This study provides Class II evidence that in patients with probable DLB, β-amyloid is associated with lower cognitive performance and tau pathology is associated with lower frequency of clinical features of DLB.
Previous research on associations between cardiovascular health, measured at a single timepoint, and rate of age-related cognitive decline shows divergent findings dependent on the participants' age ...and the health metric studied. The aim of this study was to add to the knowledge in this field by investigating whether change in cardiovascular health, assessed with Life's Simple 7 (LS7) score, is associated with rate of cognitive change in young-old and old-old adults.
The study included 1022 participants aged ≥ 60 years from the Swedish National Study on Aging and Care-Kungsholmen (SNAC-K), who underwent repeated neuropsychological testing (episodic memory, semantic memory, verbal fluency, and perceptual speed) across up to 15 years. LS7, composed of seven cardiovascular health metrics (smoking, diet, physical activity, body mass index, plasma glucose, total serum cholesterol, and blood pressure), was assessed at baseline and at the 6-year follow-up. Change in LS7 was calculated as the difference between baseline and 6 years (range - 5 to 8 points) and categorised into worse (-5 to -2 points), stable (-1 to 1 points), and improved (2 to 8 points). Change in cognitive performance as a function of LS7 change categories was estimated using linear mixed-effects models.
Participants were classified as stable (67.1%), improved (21.0%), or worse (11.8%) according to changes in LS7 score. Both the worse and improved categories were associated with faster cognitive decline. Age-stratified analyses revealed that worsening of LS7 was clearly associated with faster cognitive decline in the old-old (≥ 78 years), whereas improvement tended be associated with faster cognitive decline in the young-old (< 78 years) group.
Change in cardiovascular health in old age may lead to accelerated cognitive decline, particularly in late senescence. These results suggest that it is important to monitor and maintain cardiovascular health status in very old adults.
IMPORTANCE: Plasma phosphorylated tau (p-tau) has proven to be an accurate biomarker for Alzheimer disease (AD) pathologic characteristics, offering a less expensive and less invasive alternative to ...cerebrospinal fluid (CSF) and positron emission tomography biomarkers for amyloid-β and tau. Alzheimer disease comorbid pathologic characteristics are common and are associated with more rapid cognitive decline in patients with dementia with Lewy bodies (DLB); therefore, it is anticipated that plasma p-tau concentrations may have utility in assessing cognitive impairment in individuals with this disorder. OBJECTIVE: To measure the concentrations of plasma p-tau (p-tau181 and p-tau231) and evaluate their associations with cognitive decline in individuals with probable DLB. DESIGN, SETTING, AND PARTICIPANTS: This multicenter longitudinal cohort study included participants from the European-DLB (E-DLB) Consortium cohort enrolled at 10 centers with harmonized diagnostic procedures from January 1, 2002, to December 31, 2020, with up to 5 years of follow-up. A total of 1122 participants with plasma samples were available. Participants with acute delirium or terminal illness and patients with other previous major psychiatric or neurologic disorders were excluded, leaving a cohort of 987 clinically diagnosed participants with probable DLB (n = 371), Parkinson disease (n = 204), AD (n = 207), as well as healthy controls (HCs) (n = 205). MAIN OUTCOMES AND MEASURES: The main outcome was plasma p-tau181 and p-tau231 levels measured with in-house single molecule array assays. The Mini-Mental State Examination (MMSE) was used to measure cognition. RESULTS: Among this cohort of 987 patients (512 men 51.9%; mean SD age, 70.0 8.8 years), patients with DLB did not differ significantly regarding age, sex, or years of education from those in the AD group, but the DLB group was older than the HC group and included more men than the AD and HC groups. Baseline concentrations of plasma p-tau181 and p-tau231 in patients with DLB were significantly higher than those in the HC group but lower than in the AD group and similar to the Parkinson disease group. Higher plasma concentrations of both p-tau markers were found in a subgroup of patients with DLB with abnormal CSF amyloid-β42 levels compared with those with normal levels (difference in the groups in p-tau181, −3.61 pg/mL; 95% CI, −5.43 to −1.79 pg/mL; P = .049; difference in the groups in p-tau231, −2.51 pg/mL; 95% CI, −3.63 to −1.39 pg/mL; P = .02). There was no difference between p-tau181 level and p-tau231 level across confirmed AD pathologic characteristcs based on reduced Aβ42 level in CSF in individuals with DLB. In DLB, a significant association was found between higher plasma p-tau181 and p-tau231 levels and lower MMSE scores at baseline (for p-tau181, −0.092 MMSE points; 95% CI, −0.12 to −0.06 MMSE points; P = .001; for p-tau231, −0.16 MMSE points; 95% CI, −0.21 to −0.12 MMSE points; P < .001), as well as more rapid MMSE decline over time. Plasma p-tau181 level was associated with a decrease of −0.094 MMSE points per year (95% CI, −0.144 to −0.052 MMSE points; P = .02), whereas plasma p-tau231 level was associated with an annual decrease of −0.130 MMSE points (95% CI, −0.201 to −0.071 MMSE points; P = .02), after adjusting for sex and age. CONCLUSIONS AND RELEVANCE: This study suggests that plasma p-tau181 and p-tau231 levels may be used as cost-effective and accessible biomarkers to assess cognitive decline in individuals with DLB.
Purpose
The purpose of this study is to develop and validate a 3D deep learning model that predicts the final clinical diagnosis of Alzheimer’s disease (AD), dementia with Lewy bodies (DLB), mild ...cognitive impairment due to Alzheimer’s disease (MCI-AD), and cognitively normal (CN) using fluorine 18 fluorodeoxyglucose PET (18F-FDG PET) and compare model’s performance to that of multiple expert nuclear medicine physicians’ readers.
Materials and methods
Retrospective 18F-FDG PET scans for AD, MCI-AD, and CN were collected from Alzheimer’s disease neuroimaging initiative (556 patients from 2005 to 2020), and CN and DLB cases were from European DLB Consortium (201 patients from 2005 to 2018). The introduced 3D convolutional neural network was trained using 90% of the data and externally tested using 10% as well as comparison to human readers on the same independent test set. The model’s performance was analyzed with sensitivity, specificity, precision, F1 score, receiver operating characteristic (ROC). The regional metabolic changes driving classification were visualized using uniform manifold approximation and projection (UMAP) and network attention.
Results
The proposed model achieved area under the ROC curve of 96.2% (95% confidence interval: 90.6–100) on predicting the final diagnosis of DLB in the independent test set, 96.4% (92.7–100) in AD, 71.4% (51.6–91.2) in MCI-AD, and 94.7% (90–99.5) in CN, which in ROC space outperformed human readers performance. The network attention depicted the posterior cingulate cortex is important for each neurodegenerative disease, and the UMAP visualization of the extracted features by the proposed model demonstrates the reality of development of the given disorders.
Conclusion
Using only 18F-FDG PET of the brain, a 3D deep learning model could predict the final diagnosis of the most common neurodegenerative disorders which achieved a competitive performance compared to the human readers as well as their consensus.
Neurodegenerative diseases are one of the most important contributors to morbidity and mortality in the elderly. In Europe, over 14 million people are currently living with dementia, at a cost of ...over 400 billion EUR annually. Recent advances in diagnostics and approval for new pharmaceutical treatments for Alzheimer’s disease (AD), the most common etiology of dementia, heralds the beginning of precision medicine in this field. However, their implementation will challenge an already over-burdened healthcare systems. There is a need for innovative digital solutions that can drive the related clinical pathways and optimize and personalize care delivery. Public-private partnerships are ideal vehicles to tackle these challenges. Here we describe the Innovative Health Initiative (IHI) public-private partnership project PROMINENT that has been initiated by connecting leading dementia researchers, medical professionals, dementia patients and their care partners with the latest innovative health technologies using a precision medicine based digital platform. The project builds upon the knowledge and already implemented digital tools from several collaborative initiatives that address new models for early detection, diagnosis, and monitoring of AD and other neurodegenerative disorders. The project aims to provide support to improvement efforts to each aspect of the care pathway including diagnosis, prognosis, treatment, and data collection for real world evidence and cost effectiveness studies. Ultimately the PROMINENT project is expected to lead to cost-effective care and improved health outcomes.
Modifiable vascular risk factors have been associated with late-life cognitive impairment. The Life Simple 7 (LS7) score comprises seven cardiovascular health metrics: smoking, diet, physical ...activity, body mass index, plasma glucose, total serum cholesterol, and blood pressure.
To investigate the association between individual and composite LS7 metrics and rate of cognitive decline, and potential differences in these associations between young-old and old-old individuals.
This cohort study included 1,950 participants aged≥60 years (M = 70.7 years) from the Swedish National Study on Aging and Care-Kungsholmen (SNAC-K), who underwent repeated neuropsychological testing (episodic and semantic memory, verbal fluency, processing speed, global cognition) across 12 years. The LS7 score was assessed at baseline and categorized as poor, intermediate, or optimal. Level and change in cognitive performance as a function of LS7 categories were estimated using linear mixed-effects models.
Having an optimal LS7 total score was associated with better performance (expressed in standard deviation units) at baseline for perceptual speed (β= 0.21, 95%CI 0.12-0.29), verbal fluency (β= 0.08, 0.00-0.16), and global cognition (β= 0.06, 0.00-0.12) compared to the poor group. Age-stratified analyses revealed associations for cognitive level and change only in the young-old (< 78 years) group. For the specific metrics, diverging patterns were observed for young-old and old-old individuals.
Meeting the LS7 criteria for ideal cardiovascular health in younger old age is associated with slower rate of cognitive decline. However, the LS7 criteria may have a different meaning for cognitive function in very old adults.
Objective: We investigated whether vascular risk factors (VRFs), assessed with Life's Simple 7 (LS7), are associated with the rate of cognitive decline in the years preceding a dementia diagnosis. ...Method: This study included 1,449 stroke-free participants aged ≥60 years from the Swedish National Study on Aging and Care in Kungsholmen, who underwent repeated neuropsychological testing (episodic memory, semantic memory, verbal fluency, perceptual speed) across 12 years. The LS7 score, assessed at baseline, included smoking, diet, physical activity, body mass index, plasma glucose, total cholesterol, and blood pressure. Preclinical dementia was defined as being dementia-free at baseline and diagnosed with dementia during follow-up. Level and change in cognitive performance as a function of LS7 category (poor vs. intermediate to optimal) and future dementia status were estimated using linear mixed-effect models. Results: Participants who later developed dementia had, on average, a poorer LS7 score compared to those who remained dementia-free. For individuals aged 60-72 years, poor diet was associated with accelerated decline in perceptual speed (β = −0.05, 95% CI −0.08, −0.02), and a poor glucose score was associated with faster rates of verbal fluency (β = −0.019, 95% CI −0.09, −0.01) and global cognitive (β = −0.028, 95% CI −0.06, 0.00) decline in the preclinical dementia group. Conclusions: VRFs exacerbate rate of cognitive decline in the years preceding a dementia diagnosis. This effect was most pronounced in young-old age and primarily driven by diet and glucose. The effect of VRFs may be especially detrimental for cognitive decline trajectories of individuals with impending dementia.
Key Points
Question: This study investigated whether vascular risk factors (smoking, diet, physical activity, body mass index, plasma glucose, total serum cholesterol, and blood pressure) are associated with accelerated cognitive decline in the preclinical dementia phase. Findings: The results indicated that poor cardiovascular health might be associated with further acceleration of cognitive decline in the years preceding a dementia diagnosis. Importance: The preclinical dementia stage could be the last opportunity to influence the rate of cognitive decline by altering vascular risk factors. Next Steps: Future studies should investigate the extent to which management of VRFs in individuals at increased risk of dementia may slow down cognitive decline.
IMPORTANCE: Cerebral amyloid-β aggregation is an early event in Alzheimer disease (AD). Understanding the association between amyloid aggregation and cognitive manifestation in persons without ...dementia is important for a better understanding of the course of AD and for the design of prevention trials. OBJECTIVE: To investigate whether amyloid-β aggregation is associated with cognitive functioning in persons without dementia. DESIGN, SETTING, AND PARTICIPANTS: This cross-sectional study included 2908 participants with normal cognition and 4133 with mild cognitive impairment (MCI) from 53 studies in the multicenter Amyloid Biomarker Study. Normal cognition was defined as having no cognitive concerns for which medical help was sought and scores within the normal range on cognitive tests. Mild cognitive impairment was diagnosed according to published criteria. Study inclusion began in 2013 and is ongoing. Data analysis was performed in January 2017. MAIN OUTCOMES AND MEASURES: Global cognitive performance as assessed by the Mini-Mental State Examination (MMSE) and episodic memory performance as assessed by a verbal word learning test. Amyloid aggregation was measured with positron emission tomography or cerebrospinal fluid biomarkers and dichotomized as negative (normal) or positive (abnormal) according to study-specific cutoffs. Generalized estimating equations were used to examine the association between amyloid aggregation and low cognitive scores (MMSE score ≤27 or memory z score≤−1.28) and to assess whether this association was moderated by age, sex, educational level, or apolipoprotein E genotype. RESULTS: Among 2908 persons with normal cognition (mean SD age, 67.4 12.8 years), amyloid positivity was associated with low memory scores after age 70 years (mean difference in amyloid positive vs negative, 4% 95% CI, 0%-7% at 72 years and 21% 95% CI, 10%-33% at 90 years) but was not associated with low MMSE scores (mean difference, 3% 95% CI, −1% to 6%, P = .16). Among 4133 patients with MCI (mean SD age, 70.2 8.5 years), amyloid positivity was associated with low memory (mean difference, 16% 95% CI, 12%-20%, P < .001) and low MMSE (mean difference, 14% 95% CI, 12%-17%, P < .001) scores, and this association decreased with age. Low cognitive scores had limited utility for screening of amyloid positivity in persons with normal cognition and those with MCI. In persons with normal cognition, the age-related increase in low memory score paralleled the age-related increase in amyloid positivity with an intervening period of 10 to 15 years. CONCLUSIONS AND RELEVANCE: Although low memory scores are an early marker of amyloid positivity, their value as a screening measure for early AD among persons without dementia is limited.
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