Publications by authors named "Pedro Rosa-Neto"

189 Publications

Artificial intelligence for molecular neuroimaging.

Ann Transl Med 2021 May;9(9):822

Departments of Radiology and Medicine, McMaster University, Hamilton, Ontario, Canada.

In recent years, artificial intelligence (AI) or the study of how computers and machines can gain intelligence, has been increasingly applied to problems in medical imaging, and in particular to molecular imaging of the central nervous system. Many AI innovations in medical imaging include improving image quality, segmentation, and automating classification of disease. These advances have led to an increased availability of supportive AI tools to assist physicians in interpreting images and making decisions affecting patient care. This review focuses on the role of AI in molecular neuroimaging, primarily applied to positron emission tomography (PET) and single photon emission computed tomography (SPECT). We emphasize technical innovations such as AI in computed tomography (CT) generation for the purposes of attenuation correction and disease localization, as well as applications in neuro-oncology and neurodegenerative diseases. Limitations and future prospects for AI in molecular brain imaging are also discussed. Just as new equipment such as SPECT and PET revolutionized the field of medical imaging a few decades ago, AI and its related technologies are now poised to bring on further disruptive changes. An understanding of these new technologies and how they work will help physicians adapt their practices and succeed with these new tools.
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http://dx.doi.org/10.21037/atm-20-6220DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8246223PMC
May 2021

Association of plasma P-tau181 with memory decline in non-demented adults.

Brain Commun 2021 Jul 14;3(3):fcab136. Epub 2021 Jun 14.

Translational Neuroimaging Laboratory, McGill University, Montreal, Canada.

Alzheimer's disease is the leading cause of dementia worldwide and is characterized by a long preclinical phase in which amyloid-β and tau accumulate in the absence of cognitive decline. biomarkers for Alzheimer's disease are expensive, invasive and inaccessible, yet are critical for accurate disease diagnosis and patient management. Recent ultrasensitive methods to measure plasma phosphorylated tau 181 (p-tau181) display strong correlations with tau positron emission tomography, p-tau181 in CSF, and tau pathology at autopsy. The clinical utility of plasma-based p-tau181 biomarkers is unclear. In a longitudinal multicentre observational study, we assessed 1113 non-demented individuals (509 cognitively unimpaired elderly and 604 individuals with mild cognitive impairment) from the Alzheimer's Disease Neuroimaging Initiative who underwent neuropsychological assessments and were evaluated for plasma p-tau181. The primary outcome was a memory composite z-score. Mixed-effect models assessed rates of memory decline in relation to baseline plasma p-tau181, and whether plasma p-tau181 significantly predicted memory decline beyond widely available clinical and genetic data (age, sex, years of education, cardiovascular and metabolic conditions, and ε status). Participants were followed for a median of 4.1 years. Baseline plasma p-tau181 was associated with lower baseline memory (β estimate: -0.49, standard error: 0.06, -value: -7.97), as well as faster rates of memory decline (β estimate: -0.11, standard error: 0.01, -value: -7.37). Moreover, the inclusion of plasma p-tau181 resulted in improved prediction of memory decline beyond clinical and genetic data (marginal of 16.7-23%, χ = 100.81,  < 0.00001). Elevated baseline plasma p-tau181 was associated with higher rates of clinical progression to mild cognitive impairment (hazard ratio = 1.82, 95% confidence interval: 1.2-2.8) and from mild cognitive impairment to dementia (hazard ratio = 2.06, 95% confidence interval: 1.55-2.74). Our results suggest that in elderly individuals without dementia at baseline, plasma p-tau181 biomarkers were associated with greater memory decline and rates of clinical progression to dementia. Plasma p-tau181 improved prediction of memory decline above a model with currently available clinical and genetic data. While the clinical importance of this improvement in the prediction of memory decline is unknown, these results highlight the potential of plasma p-tau181 as a cost-effective and scalable Alzheimer's disease biomarker.
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http://dx.doi.org/10.1093/braincomms/fcab136DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8249102PMC
July 2021

Open science datasets from PREVENT-AD, a longitudinal cohort of pre-symptomatic Alzheimer's disease.

Neuroimage Clin 2021 Jun 17;31:102733. Epub 2021 Jun 17.

StoP-AD Centre, Douglas Mental Health Institute Research Centre, Montréal, QC, Canada; McGill University, Montréal, QC, Canada. Electronic address:

To move Alzheimer Disease (AD) research forward it is essential to collect data from large cohorts, but also make such data available to the global research community. We describe the creation of an open science dataset from the PREVENT-AD (PResymptomatic EValuation of Experimental or Novel Treatments for AD) cohort, composed of cognitively unimpaired older individuals with a parental or multiple-sibling history of AD. From 2011 to 2017, 386 participants were enrolled (mean age 63 years old ± 5) for sustained investigation among whom 349 have retrospectively agreed to share their data openly. Repositories are findable through the unified interface of the Canadian Open Neuroscience Platform and contain up to five years of longitudinal imaging data, cerebral fluid biochemistry, neurosensory capacities, cognitive, genetic, and medical information. Imaging data can be accessed openly at https://openpreventad.loris.ca while most of the other information, sensitive by nature, is accessible by qualified researchers at https://registeredpreventad.loris.ca. In addition to being a living resource for continued data acquisition, PREVENT-AD offers opportunities to facilitate understanding of AD pathogenesis.
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http://dx.doi.org/10.1016/j.nicl.2021.102733DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8254111PMC
June 2021

Interactive rather than independent effect of and sex potentiates tau deposition in women.

Brain Commun 2021 7;3(2):fcab126. Epub 2021 Jun 7.

Translational Neuroimaging Laboratory, The McGill University Research Centre for Studies in Aging, McGill University, Montréal, QC, Canada.

The apolipoprotein E gene () is the most important genetic risk factor for sporadic Alzheimer disease, with the allele being associated with increased cerebral amyloid-β and tau pathologies. Although has been suggested to have a stronger effect in women as compared to men, there is a lack of comprehensive assessment on how the interactive effect of and sex modulates regional vulnerability to tau accumulation. We previously have shown the regional vulnerability to the interactive effect of tau and , yet the sex difference was not specifically addressed. In this study, we leveraged PET imaging data from the Translational Biomarkers in Aging and Dementia cohort at McGill University Research Centre for Studies in Aging to elucidate the by-sex interactive effect on tau burden. We hypothesized sex-dependent regional vulnerability to tau deposition. PET radiopharmaceuticals [F]AZD4694 and [F]MK6240 were used to assess amyloid-β and tau level respectively in 277 subjects from the Translational Biomarkers in Aging and Dementia cohort. We found that the interaction between and sex, rather than their independent main effects, was associated with abnormal tau accumulation in medial temporal regions. Specifically, we found that female carriers showed significantly higher tau burden in early tau deposition regions including the hippocampus, entorhinal and parahippocampal cortices, after accounting for age, educational attainment, clinical diagnosis and neocortical amyloid load. We replicated these findings in 221 subjects from the Alzheimer's Disease Neuroimaging Initiative cohort, in which a different tau-PET radioligand, [F]flortaucipir, was used to assess tau burden. In conclusion, this study provides evidence from two cohort studies that interactive rather than independent effect of and sex potentiates early tau deposition in women. Our results have important implications for clinical trials and practice, which should take into consideration both carriage status and sex for identifying individuals with the highest probability of developing tau accumulation and clinical progression.
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http://dx.doi.org/10.1093/braincomms/fcab126DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8226193PMC
June 2021

A multicentre validation study of the diagnostic value of plasma neurofilament light.

Nat Commun 2021 06 7;12(1):3400. Epub 2021 Jun 7.

Translational Neuroimaging Laboratory, The McGill University Research Centre for Studies in Aging, Montreal, QC, Canada.

Increased cerebrospinal fluid neurofilament light (NfL) is a recognized biomarker for neurodegeneration that can also be assessed in blood. Here, we investigate plasma NfL as a marker of neurodegeneration in 13 neurodegenerative disorders, Down syndrome, depression and cognitively unimpaired controls from two multicenter cohorts: King's College London (n = 805) and the Swedish BioFINDER study (n = 1,464). Plasma NfL was significantly increased in all cortical neurodegenerative disorders, amyotrophic lateral sclerosis and atypical parkinsonian disorders. We demonstrate that plasma NfL is clinically useful in identifying atypical parkinsonian disorders in patients with parkinsonism, dementia in individuals with Down syndrome, dementia among psychiatric disorders, and frontotemporal dementia in patients with cognitive impairment. Data-driven cut-offs highlighted the fundamental importance of age-related clinical cut-offs for disorders with a younger age of onset. Finally, plasma NfL performs best when applied to indicate no underlying neurodegeneration, with low false positives, in all age-related cut-offs.
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http://dx.doi.org/10.1038/s41467-021-23620-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8185001PMC
June 2021

In vivo hippocampal cornu ammonis 1-3 glutamatergic abnormalities are associated with temporal lobe epilepsy surgery outcomes.

Epilepsia 2021 Jul 31;62(7):1559-1568. Epub 2021 May 31.

Department of Neurology and Neurosurgery, Montréal Neurological Institute, McGill University, Montréal, Québec, Canada.

Objective: Previous positron emission tomography (PET) studies using [ C]ABP688 show reduced metabotropic glutamate receptor type 5 (mGluR5) allosteric binding site availability in the epileptogenic hippocampus of mesial temporal lobe epilepsy (MTLE) patients. However, the link between mGluR5 abnormalities and postsurgical outcomes remains unclear. Here, we test whether reduced PET [ C]ABP688 binding in cornu ammonis (CA) sectors more vulnerable to glutamatergic excitotoxicity relates to surgical outcomes.

Methods: We obtained magnetic resonance imaging (MRI) and [ C]ABP688-PET from 31 unilateral MTLE patients and 30 healthy controls. MRI hippocampal subfields were segmented using FreeSurfer. To respect the lower PET special resolution, MRI-derived anatomical subfields were combined into CA1-3, CA4/dentate gyrus, and Subiculum. Partial volume corrected [ C]ABP688 nondisplaceable binding potential (BP ) values were averaged across each subfield, and Z-scores were calculated. Subfield [ C]ABP688-BP was compared between seizure-free and non-seizure-free patients. In addition, we also assessed subfield volumes and [ F]fluorodeoxyglucose (FDG) uptake in each clinical group.

Results: MTLE [ C]ABP688-BP was reduced in ipsilateral (epileptogenic) CA1-3 and CA4/dentate-gyrus (p < .001, 95% confidence interval [CI] = .29-.51) compared to controls, with no difference in Subiculum. [ C]ABP688-BP and subfield volumes were compared between seizure-free (Engel IA, n = 13) and non-seizure-free patients (Engel IC-III, n = 10). In ipsilateral CA1-3 only, [ C]ABP688-BP was lower in seizure-free patients than in non-seizure-free patients (p = .012, 95% CI = 1.46-11.0) independently of volume. A subset analysis of 12 patients with [ C]ABP688-PET+[ F]FDG-PET showed no between-group significant difference in [ F]FDG uptake, whereas CA1-3 [ C]ABP688-BP remained significantly lower in the seven of 12 seizure-free patients (p = .03, 95% CI = -3.13 to -.21).

Significance: Reduced mGluR5 allosteric site availability in hippocampal CA1-3, measured in vivo by [ C]ABP688-PET, is associated with postsurgery seizure freedom independent of atrophy or hypometabolism. Information derived from hippocampal CA1-3 [ C]ABP688-PET is a promising imaging biomarker potentially impactful in surgical decisions for MRI-negative/PET-negative MTLE patients.
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http://dx.doi.org/10.1111/epi.16952DOI Listing
July 2021

A multicenter comparison of [F]flortaucipir, [F]RO948, and [F]MK6240 tau PET tracers to detect a common target ROI for differential diagnosis.

Eur J Nucl Med Mol Imaging 2021 07 27;48(7):2295-2305. Epub 2021 May 27.

Clinical Memory Research Unit, Department of Clinical Sciences, Lund University, Malmö, Sweden.

Purpose: This study aims to determine whether comparable target regions of interest (ROIs) and cut-offs can be used across [F]flortaucipir, [F]RO948, and [F]MK6240 tau positron emission tomography (PET) tracers for differential diagnosis of Alzheimer's disease (AD) dementia vs either cognitively unimpaired (CU) individuals or non-AD neurodegenerative diseases.

Methods: A total of 1755 participants underwent tau PET using either [F]flortaucipir (n = 975), [F]RO948 (n = 493), or [F]MK6240 (n = 287). SUVR values were calculated across four theory-driven ROIs and several tracer-specific data-driven (hierarchical clustering) regions of interest (ROIs). Diagnostic performance and cut-offs for ROIs were determined using receiver operating characteristic analyses and the Youden index, respectively.

Results: Comparable diagnostic performance (area under the receiver operating characteristic curve [AUC]) was observed between theory- and data-driven ROIs. The theory-defined temporal meta-ROI generally performed very well for all three tracers (AUCs: 0.926-0.996). An SUVR value of approximately 1.35 was a common threshold when using this ROI.

Conclusion: The temporal meta-ROI can be used for differential diagnosis of dementia patients with [F]flortaucipir, [F]RO948, and [F]MK6240 tau PET with high accuracy, and that using very similar cut-offs of around 1.35 SUVR. This ROI/SUVR cut-off can also be applied across tracers to define tau positivity.
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http://dx.doi.org/10.1007/s00259-021-05401-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8175317PMC
July 2021

Baseline Neurodegeneration Influences the Longitudinal Effects of Tau on Cognition.

J Alzheimers Dis 2021 ;82(1):159-167

Department of Neurology, National Neuroscience Institute, Singapore, Singapore.

Background: Cerebrospinal fluid t-tau (CSF t-tau) is a measure of neurodegeneration in Alzheimer's disease (AD) and has been increasingly demonstrated to be a non-specific biomarker within the AD continuum.

Objective: We sought to test whether t-tau influences the longitudinal effects of amyloid-β (Aβ) and phospho-tau (p-tau) on memory and executive function (EF) in mild cognitive impairment (MCI).

Methods: 319 MCI individuals from the Alzheimer's Disease Neuroimaging Initiative (ADNI) with baseline and 2-year CSF Aβ, p-tau, t-tau, and neuropsychological assessments were studied. Mediation and moderation analyses evaluated the role of t-tau in the effects of Aβ and p-tau on memory and EF over 2 years.

Results: We found that high baseline p-tau but not Aβ was associated with higher t-tau and lower memory scores at 2 years follow-up. The association between p-tau and memory impairment was partially mediated by t-tau, whereby higher p-tau was indirectly associated with lower memory via higher t-tau. t-tau also moderated the association between p-tau and memory. When t-tau level was relatively lower, higher p-tau was associated with lower memory scores at 2 years. When t-tau level was higher, the memory scores were low regardless of the p-tau level.

Conclusion: Tau-induced neurodegeneration is one key pathway by which AD pathology (p-tau) affects memory impairment. Furthermore, in individuals with lower levels of tau-induced neurodegeneration, higher levels of p-tau were required for memory impairment. Our findings suggest that t-tau plays a significant role in how early AD pathology affects cognitive outcomes.
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http://dx.doi.org/10.3233/JAD-201425DOI Listing
January 2021

Plasma levels of phosphorylated tau 181 are associated with cerebral metabolic dysfunction in cognitively impaired and amyloid-positive individuals.

Brain Commun 2021 15;3(2):fcab073. Epub 2021 Apr 15.

Translational Neuroimaging Laboratory, The McGill University Research Centre for Studies in Aging, Montréal, QC, Canada.

Alzheimer's disease biomarkers are primarily evaluated through MRI, PET and CSF methods in order to diagnose and monitor disease. Recently, advances in the assessment of blood-based biomarkers have shown promise for simple, inexpensive, accessible and minimally invasive tools with diagnostic and prognostic value for Alzheimer's disease. Most recently, plasma phosphorylated tau181 has shown excellent performance. The relationship between plasma phosphorylated tau181 and cerebral metabolic dysfunction assessed by [F]fluorodeoxyglucose PET in Alzheimer's disease is still unknown. This study was performed on 892 older individuals (297 cognitively unimpaired; 595 cognitively impaired) from the Alzheimer's Disease Neuroimaging Initiative cohort. Plasma phosphorylated tau181 was assessed using single molecular array technology and metabolic dysfunction was indexed by [F]fluorodeoxyglucose PET. Cross-sectional associations between plasma and CSF phosphorylated tau181 and [F]fluorodeoxyglucose were assessed using voxelwise linear regression models, with individuals stratified by diagnostic group and by β-amyloid status. Associations between baseline plasma phosphorylated tau181 and longitudinal (24 months) rate of brain metabolic decline were also assessed in 389 individuals with available data using correlations and voxelwise regression models. Plasma phosphorylated tau181 was elevated in β-amyloid positive and cognitively impaired individuals as well as in apolipoprotein E ε4 carriers and was significantly associated with age, worse cognitive performance and CSF phosphorylated tau181. Cross-sectional analyses showed strong associations between plasma phosphorylated tau181 and [F]fluorodeoxyglucose PET in cognitively impaired and β-amyloid positive individuals. Voxelwise longitudinal analyses showed that baseline plasma phosphorylated tau181 concentrations were significantly associated with annual rates of metabolic decline in cognitively impaired individuals, bilaterally in the medial and lateral temporal lobes. The associations between plasma phosphorylated tau181 and reduced brain metabolism, primarily in cognitively impaired and in β-amyloid positive individuals, supports the use of plasma phosphorylated tau181 as a simple, low-cost, minimally invasive and accessible tool to both assess current and predict future metabolic dysfunction associated with Alzheimer's disease, comparatively to PET, MRI and CSF methods.
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http://dx.doi.org/10.1093/braincomms/fcab073DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8088291PMC
April 2021

Astrocyte Biomarkers in Alzheimer Disease: A Systematic Review and Meta-analysis.

Neurology 2021 May 5. Epub 2021 May 5.

Graduate Program in Biological Sciences: Biochemistry, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil;

Objective: To perform a systematic review and meta-analysis to determine whether fluid and imaging astrocyte biomarkers are altered in Alzheimer's disease (AD).

Methods: PubMed and Web of Science databases were searched for articles reporting fluid or imaging astrocyte biomarkers in AD. Pooled effect sizes were determined with mean differences (SMD) using the Hedge's G method with random-effects to determine biomarker performance. Adapted questions from QUADAS-2 were applied for quality assessment. A protocol for this study has been previously registered in PROSPERO (registration number: CRD42020192304).

Results: The initial search identified 1,425 articles. After exclusion criteria were applied, 33 articles (a total of 3,204 individuals) measuring levels of GFAP, S100B, YKL-40 and AQP4 in the blood and cerebrospinal fluid (CSF), as well as MAO-B, indexed by positron emission tomography C-deuterium-L-deprenyl ([C]-DED), were included. GFAP (SMD = 0.94; 95% CI = 0.71-1.18) and YKL-40 (SMD = 0.76; CI 95% = 0.63-0.89) levels in the CSF, S100B levels in the blood (SMD = 2.91; CI 95% = 1.01-4.8) were found significantly increased in AD patients.

Conclusions: Despite significant progress, applications of astrocyte biomarkers in AD remain in their early days. The meta-analysis demonstrated that astrocyte biomarkers are consistently altered in AD and supports further investigation for their inclusion in the AD clinical research framework for observational and interventional studies.
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http://dx.doi.org/10.1212/WNL.0000000000012109DOI Listing
May 2021

Pro-inflammatory interleukin-6 signaling links cognitive impairments and peripheral metabolic alterations in Alzheimer's disease.

Transl Psychiatry 2021 04 28;11(1):251. Epub 2021 Apr 28.

Institute of Medical Biochemistry Leopoldo de Meis, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil.

Alzheimer's disease (AD) is associated with memory impairment and altered peripheral metabolism. Mounting evidence indicates that abnormal signaling in a brain-periphery metabolic axis plays a role in AD pathophysiology. The activation of pro-inflammatory pathways in the brain, including the interleukin-6 (IL-6) pathway, comprises a potential point of convergence between memory dysfunction and metabolic alterations in AD that remains to be better explored. Using T2-weighted magnetic resonance imaging (MRI), we observed signs of probable inflammation in the hypothalamus and in the hippocampus of AD patients when compared to cognitively healthy control subjects. Pathological examination of post-mortem AD hypothalamus revealed the presence of hyperphosphorylated tau and tangle-like structures, as well as parenchymal and vascular amyloid deposits surrounded by astrocytes. T2 hyperintensities on MRI positively correlated with plasma IL-6, and both correlated inversely with cognitive performance and hypothalamic/hippocampal volumes in AD patients. Increased IL-6 and suppressor of cytokine signaling 3 (SOCS3) were observed in post-mortem AD brains. Moreover, activation of the IL-6 pathway was observed in the hypothalamus and hippocampus of AD mice. Neutralization of IL-6 and inhibition of the signal transducer and activator of transcription 3 (STAT3) signaling in the brains of AD mouse models alleviated memory impairment and peripheral glucose intolerance, and normalized plasma IL-6 levels. Collectively, these results point to IL-6 as a link between cognitive impairment and peripheral metabolic alterations in AD. Targeting pro-inflammatory IL-6 signaling may be a strategy to alleviate memory impairment and metabolic alterations in the disease.
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http://dx.doi.org/10.1038/s41398-021-01349-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8080782PMC
April 2021

Mitochondrial complex I abnormalities is associated with tau and clinical symptoms in mild Alzheimer's disease.

Mol Neurodegener 2021 04 26;16(1):28. Epub 2021 Apr 26.

Translational Neuroimaging Laboratory, McGill University Research Centre for Studies in Aging, Douglas Research Institute, Le Centre intégré universitaire de santé et de services sociaux (CIUSSS) de l'Ouest-de-l'Île-de-Montréal; Department of Neurology and Neurosurgery, Psychiatry and Pharmacology and Therapeutics, McGill University, 6875 Boulevard LaSalle, Montreal, H4H 1R3, Canada.

Background: Mitochondrial electron transport chain abnormalities have been reported in postmortem pathological specimens of Alzheimer's disease (AD). However, it remains unclear how amyloid and tau are associated with mitochondrial dysfunction in vivo. The purpose of this study is to assess the local relationships between mitochondrial dysfunction and AD pathophysiology in mild AD using the novel mitochondrial complex I PET imaging agent [F]BCPP-EF.

Methods: Thirty-two amyloid and tau positive mild stage AD dementia patients (mean age ± SD: 71.1 ± 8.3 years) underwent a series of PET measurements with [F]BCPP-EF mitochondrial function, [C]PBB3 for tau deposition, and [C] PiB for amyloid deposition. Age-matched normal control subjects were also recruited. Inter and intrasubject comparisons of levels of mitochondrial complex I activity, amyloid and tau deposition were performed.

Results: The [F]BCPP-EF uptake was significantly lower in the medial temporal area, highlighting the importance of the mitochondrial involvement in AD pathology. [C]PBB3 uptake was greater in the temporo-parietal regions in AD. Region of interest analysis in the Braak stage I-II region showed significant negative correlation between [F]BCPP-EF SUVR and [C]PBB3 BP (R = 0.2679, p = 0.04), but not [C] PiB SUVR.

Conclusions: Our results indicated that mitochondrial complex I is closely associated with tau load evaluated by [C]PBB3, which might suffer in the presence of its off-target binding. The absence of association between mitochondrial complex I dysfunction with amyloid load suggests that mitochondrial dysfunction in the trans-entorhinal and entorhinal region is a reflection of neuronal injury occurring in the brain of mild AD.
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http://dx.doi.org/10.1186/s13024-021-00448-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8074456PMC
April 2021

Association between regional tau pathology and neuropsychiatric symptoms in aging and dementia due to Alzheimer's disease.

Alzheimers Dement (N Y) 2021 31;7(1):e12154. Epub 2021 Mar 31.

McGill University Research Centre for Studies in Aging Verdun Quebec Canada.

Background: Neuropsychiatric symptoms (NPS) are frequent in aging and Alzheimer's disease (AD). Here we study the relationship between NPS and AD pathologies in vivo.

Method: Two hundred and twenty-one individuals from the TRIAD cohort (143 cognitively unimpaired, 52 mild cognitive impairment, and 26 AD) underwent [F]MK6240-tau-positron emission tomography (PET), [F]AZD4694-amyloid-PET, magnetic resonance imaging, and neuropsychological evaluations. Spearman correlations and voxel-based regression models evaluated the relationship between Neuropsychiatric Inventory Questionnaire (NPI-Q) scores, and tau-PET, amyloid-PET, and voxel-based morphometry.

Results: Fifty percent of individuals presented NPS; these correlated with tau, not amyloid beta or neurodegeneration. Associations between NPI-Q score and tau-PET were stronger in the parietal association area, superior frontal, temporal, and medial occipital lobes. NPI-Q domains associated with distinct patterns of tau uptake.

Conclusions: NPS are predominantly related to tau in aging and dementia. Regions affected are part of the behavioral circuits, and vulnerable to early AD pathology. Domain-specific analyses showed NPS are related to the AD pathophysiological processes in a symptom-specific manner.
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http://dx.doi.org/10.1002/trc2.12154DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8012244PMC
March 2021

Associations of AT(N) biomarkers with neuropsychiatric symptoms in preclinical Alzheimer's disease and cognitively unimpaired individuals.

Transl Neurodegener 2021 03 31;10(1):11. Epub 2021 Mar 31.

The McGill University Research Centre for Studies in Aging, Montreal, Canada.

The development of in vivo biomarkers of Alzheimer's disease (AD) has advanced the diagnosis of AD from a clinical syndrome to a biological construct. The preclinical stage of AD continuum is defined by the identification of AD biomarkers crossing the pathological threshold in cognitively unimpaired individuals. While neuropsychiatric symptoms (NPS) are non-cognitive symptoms that are increasingly recognized as early manifestations of AD, the associations of NPS with AD pathophysiology in preclinical AD remain unclear. Here, we review the associations between NPS and AD biomarkers amyloid-β (Aβ), tau and neurodegeneration in preclinical AD and cognitively-unimpaired individuals in 19 eligible English-language publications (8 cross-sectional studies, 10 longitudinal, 1 both cross-sectional and longitudinal). The cross-sectional studies have consistently shown that NPS, particularly depressive and anxiety symptoms, are associated with higher Aβ. The longitudinal studies have suggested that greater NPS are associated with higher Aβ and cognitive decline in cognitively unimpaired subjects over time. However, most of the studies have either cross-sectionally or longitudinally shown no association between NPS and tau pathology. For the association of NPS and neurodegeneration, two studies have shown that the cerebrospinal fluid total-tau is linked to longitudinal increase in NPS and that the NPS may predict longitudinal metabolic decline in preclinical AD, respectively. However, evidence for the association between atrophy and NPS in preclinical AD is less consistent. Therefore, future longitudinal studies with well-designed methodologies and NPS measurements are required not only to determine the relationship among AT(N) biomarkers, NPS and cognitive decline, but also to elucidate the contribution of comorbid pathology to preclinical AD.
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http://dx.doi.org/10.1186/s40035-021-00236-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8011383PMC
March 2021

Plasma pTau181 predicts cortical brain atrophy in aging and Alzheimer's disease.

Alzheimers Res Ther 2021 03 29;13(1):69. Epub 2021 Mar 29.

The McGill University Research Centre for Studies in Aging, Douglas Hospital, McGill University, 875 La Salle Blvd - FBC room 3149, Montreal, QC, H4H 1R3, Canada.

Background: To investigate the association of plasma pTau181, assessed with a new immunoassay, with neurodegeneration of white matter and gray matter cross-sectionally and longitudinally, in aging and Alzheimer's disease.

Methods: Observational data was obtained from the Alzheimer's Disease Neuroimaging Initiative, in which participants underwent plasma assessment and magnetic resonance imaging. Based on their clinical diagnosis, participants were classified as cognitively unimpaired and cognitively impaired. Linear regressions and linear mixed-effect models were used to test the cross-sectional and longitudinal associations between baseline plasma pTau181 and neurodegeneration using voxel-based morphometry.

Results: We observed a negative correlation at baseline between plasma pTau181 and gray matter volume in cognitively unimpaired individuals. In cognitively impaired individuals, we observed a negative association between plasma pTau181 and both gray and white matter volume. In longitudinal analyses conducted in the cognitively unimpaired group, plasma pTau181 was negatively correlated with gray matter volume, starting 36 months after baseline assessments. Finally, in cognitively impaired individuals, plasma pTau181 concentrations were negatively correlated with both gray and white matter volume as early as 12 months after baseline, and neurodegeneration increased in an incremental manner until 48 months.

Conclusions: Higher levels of plasma pTau181 correlate with neurodegeneration and predict further brain atrophy in aging and Alzheimer's disease. Plasma pTau181 may be useful in predicting AD-related neurodegeneration, comparable to positron emission tomography or cerebrospinal fluid assessment with high specificity for AD neurodegeneration.
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http://dx.doi.org/10.1186/s13195-021-00802-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8008680PMC
March 2021

Plasma p-tau231: a new biomarker for incipient Alzheimer's disease pathology.

Acta Neuropathol 2021 05 14;141(5):709-724. Epub 2021 Feb 14.

Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden.

The quantification of phosphorylated tau in biofluids, either cerebrospinal fluid (CSF) or plasma, has shown great promise in detecting Alzheimer's disease (AD) pathophysiology. Tau phosphorylated at threonine 231 (p-tau231) is one such biomarker in CSF but its usefulness as a blood biomarker is currently unknown. Here, we developed an ultrasensitive Single molecule array (Simoa) for the quantification of plasma p-tau231 which was validated in four independent cohorts (n = 588) in different settings, including the full AD continuum and non-AD neurodegenerative disorders. Plasma p-tau231 was able to identify patients with AD and differentiate them from amyloid-β negative cognitively unimpaired (CU) older adults with high accuracy (AUC = 0.92-0.94). Plasma p-tau231 also distinguished AD patients from patients with non-AD neurodegenerative disorders (AUC = 0.93), as well as from amyloid-β negative MCI patients (AUC = 0.89). In a neuropathology cohort, plasma p-tau231 in samples taken on avergae 4.2 years prior to post-mortem very accurately identified AD neuropathology in comparison to non-AD neurodegenerative disorders (AUC = 0.99), this is despite all patients being given an AD dementia diagnosis during life. Plasma p-tau231 was highly correlated with CSF p-tau231, tau pathology as assessed by [F]MK-6240 positron emission tomography (PET), and brain amyloidosis by [F]AZD469 PET. Remarkably, the inflection point of plasma p-tau231, increasing as a function of continuous [F]AZD469 amyloid-β PET standardized uptake value ratio, was shown to be earlier than standard thresholds of amyloid-β PET positivity and the increase of plasma p-tau181. Furthermore, plasma p-tau231 was significantly increased in amyloid-β PET quartiles 2-4, whereas CSF p-tau217 and plasma p-tau181 increased only at quartiles 3-4 and 4, respectively. Finally, plasma p-tau231 differentiated individuals across the entire Braak stage spectrum, including Braak staging from Braak 0 through Braak I-II, which was not observed for plasma p-tau181. To conclude, this novel plasma p-tau231 assay identifies the clinical stages of AD and neuropathology equally well as plasma p-tau181, but increases earlier, already with subtle amyloid-β deposition, prior to the threshold for amyloid-β PET positivity has been attained, and also in response to early brain tau deposition. Thus, plasma p-tau231 is a promising novel biomarker of emerging AD pathology with the potential to facilitate clinical trials to identify vulnerable populations below PET threshold of amyloid-β positivity or apparent entorhinal tau deposition.
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http://dx.doi.org/10.1007/s00401-021-02275-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8043944PMC
May 2021

CCCDTD5: Clinical role of neuroimaging and liquid biomarkers in patients with cognitive impairment.

Alzheimers Dement (N Y) 2020 22;6(1):e12098. Epub 2021 Jan 22.

Centre hospitalier de l'université de Montréal Montreal Canada.

Since 1989, four Canadian Consensus Conferences on the Diagnosis and Treatment of Dementia (CCCDTDs) have provided evidence-based dementia diagnostic and treatment guidelines for Canadian clinicians and researchers. We present the results from the Neuroimaging and Fluid Biomarkers Group of the 5th CCCDTD (CCCDTD5), which addressed topics chosen by the steering committee to reflect advances in the field and build on our previous guidelines. Recommendations on Imaging and Fluid Biomarker Use from this Conference cover a series of different fields. Prior structural imaging recommendations for both computerized tomography (CT) and magnetic resonance imaging (MRI) remain largely unchanged, but MRI is now more central to the evaluation than before, with suggested sequences described here. The use of visual rating scales for both atrophy and white matter anomalies is now included in our recommendations. Molecular imaging with [F]-fluorodeoxyglucose ([18F]-FDG) Positron Emisson Tomography (PET) or [Tc]-hexamethylpropyleneamine oxime/ethylene cysteinate dimer ([Tc]-HMPAO/ECD) Single Photon Emission Tomography (SPECT), should now decidedly favor PET. The value of [F]-FDG PET in the assessment of neurodegenerative conditions has been established with greater certainty since the previous conference, and it has now been recognized as a useful biomarker to establish the presence of neurodegeneration by a number of professional organizations around the world. Furthermore, the role of amyloid PET has been clarified and our recommendations follow those from other groups in multiple countries. SPECT with [I]-ioflupane (DaTscan) is now included as a useful study in differentiating Alzheimer's disease (AD) from Lewy body disease. Finally, liquid biomarkers are in a rapid phase of development and, could lead to a revolution in the assessment AD and other neurodegenerative conditions at a reasonable cost. We hope these guidelines will be useful for clinicians, researchers, policy makers, and the lay public, to inform a current and evidence-based approach to the use of neuroimaging and liquid biomarkers in clinical dementia evaluation and management.
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http://dx.doi.org/10.1002/trc2.12098DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7821956PMC
January 2021

The diagnostic and prognostic capabilities of plasma biomarkers in Alzheimer's disease.

Alzheimers Dement 2021 Jul 25;17(7):1145-1156. Epub 2021 Jan 25.

Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden.

Introduction: This study investigated the diagnostic and disease-monitoring potential of plasma biomarkers in mild cognitive impairment (MCI) and Alzheimer's disease (AD) dementia and cognitively unimpaired (CU) individuals.

Methods: Plasma was analyzed using Simoa assays from 99 CU, 107 MCI, and 103 AD dementia participants.

Results: Phosphorylated-tau181 (P-tau181), neurofilament light, amyloid-β (Aβ42/40), Total-tau and Glial fibrillary acidic protein were altered in AD dementia but P-tau181 significantly outperformed all biomarkers in differentiating AD dementia from CU (area under the curve [AUC] = 0.91). P-tau181 was increased in MCI converters compared to non-converters. Higher P-tau181 was associated with steeper cognitive decline and gray matter loss in temporal regions. Longitudinal change of P-tau181 was strongly associated with gray matter loss in the full sample and with Aβ measures in CU individuals.

Discussion: P-tau181 detected AD at MCI and dementia stages and was strongly associated with cognitive decline and gray matter loss. These findings highlight the potential value of plasma P-tau181 as a non-invasive and cost-effective diagnostic and prognostic biomarker in AD.
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http://dx.doi.org/10.1002/alz.12283DOI Listing
July 2021

Frontotemporal dementia and COVID-19: Hypothesis generation and roadmap for future research.

Alzheimers Dement (N Y) 2020 15;6(1):e12085. Epub 2021 Jan 15.

Department of Neurology National Neuroscience Institute Singapore Singapore.

The COVID-19 pandemic has caused tremendous suffering for patients with dementia and their caregivers. We conducted a survey to study the impact of the pandemic on patients with mild frontotemporal dementia (FTD). Our preliminary findings demonstrate that patients with FTD have significant worsening in behavior and social cognition, as well as suffer greater negative consequences from disruption to health-care services compared to patients with AD. The reduced ability to cope with sudden changes to social environments places patients with FTD at increased vulnerability to COVID-19 infection as well as to poorer clinical and social outcomes. Caregivers of FTD patients also demonstrate high burden during crisis situations. A proportion of patients with FTD benefitted from use of web-based interactive platforms. In this article, we outline the priority areas for research as well as a roadmap for future collaborative research to ensure greatest benefit for patients with FTD and their caregivers.
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http://dx.doi.org/10.1002/trc2.12085DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7810128PMC
January 2021

Frequency of Biologically Defined Alzheimer Disease in Relation to Age, Sex, ε4, and Cognitive Impairment.

Neurology 2021 02 21;96(7):e975-e985. Epub 2020 Dec 21.

From the Translational Neuroimaging Laboratory, The McGill University Research Centre for Studies in Aging, Douglas Hospital (J.T., T.A.P., A.L.B., C.T., M.S., M.C., F.L., M.S.K., G.B., T.W., J.F.-A., S.G., P.R.-N.), and the Departments of Neurology and Neurosurgery (J.T., T.A.P., A.L.B., C.T., M.C., F.L., M.S.K., G.B., T.W., J.F.-A., J.-P.S., P.V., S.G., P.R.-N.), Psychiatry (S.G., P.R.-N.), Radiochemistry (G.M.), and Epidemiology and Biostatistics (P.S.-C.), McGill University, Montreal; and Montreal Neurological Institute (J.T., T.A.P., A.L.B., C.T., F.L., M.S.K., G.B., T.W., J.F.-A., G.M., J.-P.S., P.R.-N.), Canada.

Objective: To assess the frequency of biologically defined Alzheimer disease (AD) in relation to age, sex, ε4, and clinical diagnosis in a prospective cohort study evaluated with amyloid-PET and tau-PET.

Methods: We assessed cognitively unimpaired (CU) elderly (n = 166), patients with amnestic mild cognitive impairment (n = 77), and patients with probable AD dementia (n = 62) who underwent evaluation by dementia specialists and neuropsychologists in addition to amyloid-PET with [F]AZD4694 and tau-PET with [F]MK6240. Individuals were grouped according to their AD biomarker profile. Positive predictive value for biologically defined AD was assessed in relation to clinical diagnosis. Frequency of AD biomarker profiles was assessed using logistic regressions with odds ratios (ORs) and 95% confidence intervals (CIs).

Results: The clinical diagnosis of probable AD dementia demonstrated good agreement with biologically defined AD (positive predictive value 85.2%). A total of 7.88% of CU were positive for both amyloid-PET and tau-PET. Frequency of biologically defined AD increased with age (OR 1.14; < 0.0001) and frequency of ε4 allele carriers (single ε4: OR 3.82; < 0.0001; double ε4: OR 17.55, < 0.0001).

Conclusion: Whereas we observed strong, but not complete, agreement between clinically defined probable AD dementia and biomarker positivity for both β-amyloid and tau, we also observed that biologically defined AD was not rare in CU elderly. Abnormal tau-PET was almost exclusively observed in individuals with abnormal amyloid-PET. Our results highlight that even in tertiary care memory clinics, detailed evaluation by dementia specialists systematically underestimates the frequency of biologically defined AD and related entities.

Classification Of Evidence: This study provides Class I evidence that biologically defined AD (abnormal amyloid PET and tau PET) was observed in 85.2% of people with clinically defined AD and 7.88% of CU elderly.
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http://dx.doi.org/10.1212/WNL.0000000000011416DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8055338PMC
February 2021

Large-scale mGluR5 network abnormalities linked to epilepsy duration in focal cortical dysplasia.

Neuroimage Clin 2021 29;29:102552. Epub 2020 Dec 29.

Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, Canada. Electronic address:

To determine the extent of metabotropic glutamate receptor type 5 (mGluR5) network abnormalities associated with focal cortical dysplasia (FCD), we performed graph theoretical analysis of [C]ABP688 PET binding potentials (BP), which allows for quantification of mGluR5 availability. Undirected graphs were constructed for the entire cortex in 17 FCD patients and 33 healthy controls using inter-regional similarity of [C]ABP688 BP. We assessed group differences in network integration between healthy controls and the ipsilateral and contralateral hemispheres of FCD patients. Compared to healthy controls, FCD patients showed reduced network efficiency and reduced small-world connectivity. The mGluR5 network of FCD patients was also less resilient to targeted removal of high centrality nodes, suggesting a less integrated network organization. In highly efficient hub nodes of FCD patients, we observed a significant negative correlation between local efficiency and duration of epilepsy only in the contralateral hemisphere, suggesting that some nodes may be more vulnerable to persistent epileptic activity. Our study provides the first in vivo evidence for a widespread reduction in cortical mGluR5 network integration in FCD patients. In addition, we find that ongoing epileptic activity may alter chemoarchitectural brain organization resulting in reduced efficiency in distant regions that are essential for network integration.
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http://dx.doi.org/10.1016/j.nicl.2020.102552DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7787952PMC
June 2021

Neuropsychiatric symptoms are early indicators of an upcoming metabolic decline in Alzheimer's disease.

Transl Neurodegener 2021 01 4;10(1). Epub 2021 Jan 4.

Alzheimer's Disease Research Unit, McGill Centre for Studies in Aging, McGill University, Montréal, Québec, Canada.

Background: Neuropsychiatric symptoms (NPS) are increasingly recognized as early non-cognitive manifestations in the Alzheimer's disease (AD) continuum. However, the role of NPS as an early marker of pathophysiological progression in AD remains unclear. Dominantly inherited AD (DIAD) mutation carriers are young individuals who are destined to develop AD in future due to the full penetrance of the genetic mutation. Hence, the study of DIAD mutation carriers enables the evaluation of the associations between pure AD pathophysiology and metabolic correlates of NPS without the confounding effects of co-existing pathologies. In this longitudinal study, we aimed to identify regional brain metabolic dysfunctions associated with NPS in cognitively intact DIAD mutation carriers.

Methods: We stratified 221 cognitively intact participants from the Dominantly Inherited Alzheimer's Network according to their mutation carrier status. The interactions of NPS measured by the Neuropsychiatric Inventory-Questionnaire (NPI-Q), age, and estimated years to symptom onset (EYO) as a function of metabolism measured by [F]flurodeoxyglucose ([F]FDG) positron emission tomography, were evaluated by the mixed-effects regression model with family-level random effects in DIAD mutation carriers and non-carriers. Exploratory factor analysis was performed to identify the neuropsychiatric subsyndromes in DIAD mutation carriers using the NPI-Q sub-components. Then the effects of interactions between specific neuropsychiatric subsyndromes and EYO on metabolism were evaluated with the mixed-effects regression model.

Results: A total of 119 mutation carriers and 102 non-carriers were studied. The interaction of higher NPI-Q and shorter EYO was associated with more rapid declines of global and regional [F]FDG uptake in the posterior cingulate and ventromedial prefrontal cortices, the bilateral parietal lobes and the right insula in DIAD mutation carriers. The neuropsychiatric subsyndromes of agitation, disinhibition, irritability and depression interacted with the EYO to drive the [F]FDG uptake decline in the DIAD mutation carriers. The interaction of NPI and EYO was not associated with [F]FDG uptake in DIAD mutation non-carriers.

Conclusions: The NPS in cognitively intact DIAD mutation carriers may be a clinical indicator of subsequent metabolic decline in brain networks vulnerable to AD, which supports the emerging conceptual framework that NPS represent early manifestations of neuronal injury in AD. Further studies using different methodological approaches to identify NPS in preclinical AD are needed to validate our findings.
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http://dx.doi.org/10.1186/s40035-020-00225-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7780680PMC
January 2021

Lessons Learnt from the Second Generation of Anti-Amyloid Monoclonal Antibodies Clinical Trials.

Dement Geriatr Cogn Disord 2020 15;49(4):334-348. Epub 2020 Dec 15.

Translational Neuroimaging Laboratory, The McGill University Research Centre for Studies in Aging, Douglas Mental Health University Institute, McGill University, Montreal, Québec, Canada,

Background: Alzheimer disease (AD) is a chronic neurodegenerative disorder with complex pathophysiology that affects over 50 million people worldwide. Most drug therapies, to date, have focused on targeting the amyloid-beta (Aβ) pathway, but clinical outcomes of anti-Aβ antibodies have been unsuccessful and unable to meet their primary endpoints. Similar trends have also been observed in treatments that target the tau pathway.

Summary: This paper reviews recent anti-Aβ passive monotherapies, since Bapineuzumab, that have progressed to phase 3 clinical trials. Specifically, we discuss the 4 clinical trial programs of Solanezumab (targets Aβ monomers), Aducanumab (targets Aβ oligomers and plaques), Crenezumab (targets Aβ oligomers), and Gantenerumab (targets Aβ fibrils) which are all exogenous monoclonal antibodies. We conclude with potential reasons for why they have not met their primary endpoints and discuss lessons learnt from these trials. Key Message: Future disease-modifying trials (DMTs) for AD should be conducted in asymptomatic, Aβ-positive individuals. Moreover, potential additive and/or synergistic benefits focusing on anti-Aβ and anti-tau drug combinations merit further investigation.
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http://dx.doi.org/10.1159/000511506DOI Listing
May 2021

Frontal Variant of Alzheimer Disease Differentiated From Frontotemporal Dementia Using in Vivo Amyloid and Tau Imaging.

Cogn Behav Neurol 2020 12;33(4):288-293

Departments of Psychiatry.

The frontal variant of Alzheimer disease (fvAD) is characterized by behavioral and/or dysexecutive impairments that can resemble those of behavioral-variant frontotemporal dementia (bvFTD). This overlap, in addition to the lack of consensus clinical criteria for fvAD, complicates its identification. We provide the first case report of fvAD differentiated in vivo from bvFTD using amyloid-beta and tau PET imaging. The patient, a right-handed woman, presented with forgetfulness at age 60. Cognitive testing at that time revealed mild impairments in memory, attention, and executive functions. Three years later, her family reported that she was displaying socially inappropriate behaviors, inertia, diminished social interest, and altered food preferences-the sum of which met the criteria for possible bvFTD. PET using an amyloid-beta tracer (F-AZD4694) identified diffuse amyloid plaques across the cerebral cortex. PET using a tau tracer specific for neurofibrillary tangles (F-MK6240) identified substantial tau pathology in the brain's frontal lobes. Together with the clinical findings, these images supported the diagnosis of fvAD rather than bvFTD. Considering past and emerging evidence that tau topography in Alzheimer disease (AD) matches the clinical features of AD, we discuss the potential utility of in vivo tau imaging using F-MK6240 for identifying fvAD.
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http://dx.doi.org/10.1097/WNN.0000000000000251DOI Listing
December 2020

Stage-specific links between plasma neurofilament light and imaging biomarkers of Alzheimer's disease.

Brain 2020 12;143(12):3793-3804

Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden.

Neurofilament light (NfL) is a marker of neuroaxonal injury, a prominent feature of Alzheimer's disease. It remains uncertain, however, how it relates to amyloid and tau pathology or neurodegeneration across the Alzheimer's disease continuum. The aim of this study was to investigate how plasma NfL relates to amyloid and tau PET and MRI measures of brain atrophy in participants with and without cognitive impairment. We retrospectively examined the association between plasma NfL and MRI measures of grey/white matter volumes in the Alzheimer's Disease Neuroimaging Initiative [ADNI: n = 1149; 382 cognitively unimpaired control subjects and 767 cognitively impaired participants (mild cognitive impairment n = 420, Alzheimer's disease dementia n = 347)]. Longitudinal plasma NfL was measured using single molecule array (Simoa) technology. Cross-sectional associations between plasma NfL and PET amyloid and tau measures were independently assessed in two cohorts: ADNI [n = 198; 110 cognitively unimpaired, 88 cognitively impaired (MCI n = 67, Alzheimer's disease dementia n = 21), data accessed October 2018]; and Translational Biomarkers in Aging and Dementia [TRIAD, n = 116; 74 cognitively unimpaired, 42 cognitively impaired (MCI n = 16, Alzheimer's disease dementia n = 26), data obtained November 2017 to January 2019]. Associations between plasma NfL and imaging-derived measures were examined voxel-wise using linear regression (cross-sectional) and linear mixed effect models (longitudinal). Cross-sectional analyses in both cohorts showed that plasma NfL was associated with PET findings in brain regions typically affected by Alzheimer's disease; associations were specific to amyloid PET in cognitively unimpaired and tau PET in cognitively impaired (P < 0.05). Longitudinal analyses showed that NfL levels were associated with grey/white matter volume loss; grey matter atrophy in cognitively unimpaired was specific to APOE ε4 carriers (P < 0.05). These findings suggest that plasma NfL increases in response to amyloid-related neuronal injury in preclinical stages of Alzheimer's disease, but is related to tau-mediated neurodegeneration in symptomatic patients. As such, plasma NfL may a useful measure to monitor effects in disease-modifying drug trials.
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http://dx.doi.org/10.1093/brain/awaa342DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7805809PMC
December 2020

Cholinergic dysfunction in the dorsal striatum promotes habit formation and maladaptive eating.

J Clin Invest 2020 12;130(12):6616-6630

Douglas Mental Health University Institute, Department of Psychiatry, McGill University, Montreal, Quebec, Canada.

Dysregulation of habit formation has been recently proposed as pivotal to eating disorders. Here, we report that a subset of patients suffering from restrictive anorexia nervosa have enhanced habit formation compared with healthy controls. Habit formation is modulated by striatal cholinergic interneurons. These interneurons express vesicular transporters for acetylcholine (VAChT) and glutamate (VGLUT3) and use acetylcholine/glutamate cotransmission to regulate striatal functions. Using mice with genetically silenced VAChT (VAChT conditional KO, VAChTcKO) or VGLUT3 (VGLUT3cKO), we investigated the roles that acetylcholine and glutamate released by cholinergic interneurons play in habit formation and maladaptive eating. Silencing glutamate favored goal-directed behaviors and had no impact on eating behavior. In contrast, VAChTcKO mice were more prone to habits and maladaptive eating. Specific deletion of VAChT in the dorsomedial striatum of adult mice was sufficient to phenocopy maladaptive eating behaviors of VAChTcKO mice. Interestingly, VAChTcKO mice had reduced dopamine release in the dorsomedial striatum but not in the dorsolateral striatum. The dysfunctional eating behavior of VAChTcKO mice was alleviated by donepezil and by l-DOPA, confirming an acetylcholine/dopamine deficit. Our study reveals that loss of acetylcholine leads to a dopamine imbalance in striatal compartments, thereby promoting habits and vulnerability to maladaptive eating in mice.
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http://dx.doi.org/10.1172/JCI138532DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7685731PMC
December 2020

Diagnostic performance and prediction of clinical progression of plasma phospho-tau181 in the Alzheimer's Disease Neuroimaging Initiative.

Mol Psychiatry 2021 02 26;26(2):429-442. Epub 2020 Oct 26.

Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Mölndal, Sweden.

Whilst cerebrospinal fluid (CSF) and positron emission tomography (PET) biomarkers for amyloid-β (Aβ) and tau pathologies are accurate for the diagnosis of Alzheimer's disease (AD), their broad implementation in clinical and trial settings are restricted by high cost and limited accessibility. Plasma phosphorylated-tau181 (p-tau181) is a promising blood-based biomarker that is specific for AD, correlates with cerebral Aβ and tau pathology, and predicts future cognitive decline. In this study, we report the performance of p-tau181 in >1000 individuals from the Alzheimer's Disease Neuroimaging Initiative (ADNI), including cognitively unimpaired (CU), mild cognitive impairment (MCI) and AD dementia patients characterized by Aβ PET. We confirmed that plasma p-tau181 is increased at the preclinical stage of Alzheimer and further increases in MCI and AD dementia. Individuals clinically classified as AD dementia but having negative Aβ PET scans show little increase but plasma p-tau181 is increased if CSF Aβ has already changed prior to Aβ PET changes. Despite being a multicenter study, plasma p-tau181 demonstrated high diagnostic accuracy to identify AD dementia (AUC = 85.3%; 95% CI, 81.4-89.2%), as well as to distinguish between Aβ- and Aβ+ individuals along the Alzheimer's continuum (AUC = 76.9%; 95% CI, 74.0-79.8%). Higher baseline concentrations of plasma p-tau181 accurately predicted future dementia and performed comparably to the baseline prediction of CSF p-tau181. Longitudinal measurements of plasma p-tau181 revealed low intra-individual variability, which could be of potential benefit in disease-modifying trials seeking a measurable response to a therapeutic target. This study adds significant weight to the growing body of evidence in the use of plasma p-tau181 as a non-invasive diagnostic and prognostic tool for AD, regardless of clinical stage, which would be of great benefit in clinical practice and a large cost-saving in clinical trial recruitment.
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http://dx.doi.org/10.1038/s41380-020-00923-zDOI Listing
February 2021

Impact of p-tau181 and p-tau217 levels on enrollment for randomized clinical trials and future use of anti-amyloid and anti-tau drugs.

Expert Rev Neurother 2020 12 2;20(12):1211-1213. Epub 2020 Dec 2.

McGill Center for Studies in Aging , Montreal, QC, Canada.

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http://dx.doi.org/10.1080/14737175.2020.1841637DOI Listing
December 2020

Topographic Distribution of Amyloid-β, Tau, and Atrophy in Patients With Behavioral/Dysexecutive Alzheimer Disease.

Neurology 2021 01 22;96(1):e81-e92. Epub 2020 Oct 22.

From the Translational Neuroimaging Laboratory, The McGill University Research Centre for Studies in Aging, Douglas Hospital (J.T., T.A.P., M.S., A.L.B., M.C., C.T., F.L., M.S.K., E.T., T.T., P.V., S.G., P.R.-N.), and Departments of Neurology and Neurosurgery (J.T., T.A.P., A.L.B., M.C., C.T., F.L., M.S.K., E.T., P.V., J.-P.S., S.G., P.R.-N.), Psychiatry (S.R., S.G.), Radiochemistry (G.M.), and Epidemiology and Biostatistics (P.S.-C.), McGill University; Montreal Neurological Institute (J.T., T.A.P., A.L.B., M.C., C.T., F.L., M.S.K., G.M., J.-P.S., P.R.-N.), Canada; Department of Biofunctional Imaging (T.T.), Hamamatsu University School of Medicine, Japan; and MoCA Clinic and Institute (Z.N.), Montreal, Canada.

Objective: To determine the associations between amyloid-PET, tau-PET, and atrophy with the behavioral/dysexecutive presentation of Alzheimer disease (AD), how these differ from amnestic AD, and how they correlate to clinical symptoms.

Methods: We assessed 15 patients with behavioral/dysexecutive AD recruited from a tertiary care memory clinic, all of whom had biologically defined AD. They were compared with 25 patients with disease severity- and age-matched amnestic AD and a group of 131 cognitively unimpaired (CU) elderly individuals. All participants were evaluated with amyloid-PET with [F]AZD4694, tau-PET with [F]MK6240, MRI, and neuropsychological testing.

Results: Voxelwise contrasts identified patterns of frontal cortical tau aggregation in behavioral/dysexecutive AD, with peaks in medial prefrontal, anterior cingulate, and frontal insular cortices in contrast to amnestic AD. No differences were observed in the distribution of amyloid-PET or atrophy as determined by voxel-based morphometry. Voxelwise area under the receiver operating characteristic curve analyses revealed that tau-PET uptake in the medial prefrontal, anterior cingulate, and frontal insular cortices were best able to differentiate between behavioral/dysexecutive and amnestic AD (area under the curve 0.87). Voxelwise regressions demonstrated relationships between frontal cortical tau load and degree of executive dysfunction.

Conclusions: Our results provide evidence of frontal cortical involvement of tau pathology in behavioral/dysexecutive AD and highlight the need for consensus clinical criteria in this syndrome.
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http://dx.doi.org/10.1212/WNL.0000000000011081DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7884976PMC
January 2021

The effects of exercise on sleep quality in persons with Parkinson's disease: A systematic review with meta-analysis.

Sleep Med Rev 2021 Feb 8;55:101384. Epub 2020 Sep 8.

Memory and Motor Rehabilitation Laboratory (MEMORY-LAB), Feil and Oberfeld Research Centre, Jewish Rehabilitation Hospital, Montreal Center for Interdisciplinary Research in Rehabilitation (CRIR), Laval, Quebec, Canada; School of Physical and Occupational Therapy, Faculty of Medicine, McGill University, Montreal, Quebec, Canada. Electronic address: https://memorylab.ca/.

We conducted a systematic review with meta-analysis to determine the evidence in support of exercise to improve sleep quality assessed subjectively and objectively in Parkinson's Disease (PD). Standardized mean differences (SMD) comparing the effects of exercise and control interventions on sleep quality with 95% confidence intervals (CI) were calculated. Data from 10 randomized and 2 non-randomized controlled trials, including a total of 690 persons with PD were included. Exercise had a significant positive effect on sleep quality assessed subjectively (SMD = 0.53; 95% CI = 0.16-0.90; p = 0.005). However, the methodological quality of the studies showing positive effects on sleep quality was significantly poorer than the studies showing no effects. Only one study assessed the impact of exercise on objective sleep quality, showing improvements in sleep efficiency assessed with polysomnography (SMD = 0.94; 95% CI = 0.38-1.50; p = 0.001). Exercise performed at moderate to maximal intensities (SMD = 0.46; 95% CI = 0.05-0.87; p = 0.03) had significant effects on subjective sleep quality. In contrast, exercise performed at mild to moderate intensities showed non-significant effects (SMD = 0.76; 95% CI = -0.24-1.76; p = 0.14). These results support the use of exercise to improve sleep quality in persons with PD and reinforce the importance of achieving vigorous exercise intensities. Biases, limitations, practice points and directions for future research are discussed.
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http://dx.doi.org/10.1016/j.smrv.2020.101384DOI Listing
February 2021
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