Measuring the morphology of brain sulci has been recently proposed as a novel imaging approach in Alzheimer's disease (AD). We aimed to investigate the relevance of such an approach in AD, by ...exploring its (1) clinical relevance in comparison with traditional imaging methods, (2) relationship with amyloid deposition, (3) association with cognitive functions. Here, 51 patients (n = 32 mild cognitive impairment/mild dementia-AD, n = 19 moderate/severe dementia-AD) diagnosed according to clinical-biological criteria (CSF biomarkers and amyloid-PET) and 29 controls (with negative amyloid-PET) underwent neuropsychological and 3T-MRI examinations. Mean sulcal width (SW) and mean cortical thickness around the sulcus (CT-S) were automatically measured. We found higher SW and lower CT-S in patients with AD than in controls. These differences were more pronounced at later stages of the disease and provided the best diagnostic accuracies among the imaging markers. Correlations were not found between CT-S or SW and amyloid deposition but between specific cognitive functions and regional CT-S/SW in key associated regions. Sulcal morphology is a good supporting diagnosis tool that reflects the main cognitive impairments in AD. It could be considered as a good surrogate marker to evaluate the efficacy of new drugs.
•Examination of sulcal morphology alterations is a good diagnosis tool for Alzheimer's disease.•This imaging marker is more accurate than traditional imaging tools such as hippocampal volume.•Sulcal morphology alterations are correlated to specific cognitive impairment observed.•Sulcal morphology alterations are related to disease severity.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Very-early-onset Alzheimer's disease (young-AD) differentiates from late-onset AD (old-AD) by a predominant involvement of the parietal neocortex leading to atypical presentations. The diagnosis of ...AD is often not the first to be mentioned in such young patients.
We retrospectively reviewed the initial complaint and care pathways of 66 sporadic young-AD (age < 62) and 30 old-AD patients (age > 65) and compared their neuropsychological profiles at the time of diagnosis (based on clinical-biological criteria) with 44 amyloid-negative controls.
The initial complaint of young-AD was non-cognitive and mimicked a burnout in 32% of cases. Their main cognitive complaints were memory (38% vs 87% in old-AD) and language (17% vs 13%) impairment. The referral to a psychiatrist prior to AD diagnosis was more frequent in young-AD than in old-AD (26% vs 0%). At the time of diagnosis, young-AD were at a more severe stage of dementia than old-AD (24% vs 10% with CDR ≥ 1) but had less anosognosia.
Better identifying the initial signs of very-early-onset AD is crucial to improve the early diagnosis and develop new treatments.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
The impact of neuroinflammation on Alzheimer's disease progression is unclear. Hamelin et al. use 18F-DPA-714 PET to evaluate changes in microglial activation in patients. The results support a ...pathophysiological model involving two distinct signatures of microglial activation, which differentially affect disease progression, being either beneficial or detrimental.
Abstract
Although brain neuroinflammation may play an instrumental role in the pathophysiology of Alzheimer's disease, its actual impact on disease progression remains controversial, being reported as either detrimental or protective. This work aimed at investigating the temporal relationship between microglial activation and clinical progression of Alzheimer's disease. First, in a large cohort of patients with Alzheimer's disease we analysed the predictive value of microglial activation assessed by 18F-DPA-714 PET imaging on functional, cognitive and MRI biomarkers outcomes after a 2-year follow-up. Second, we analysed the longitudinal progression of 18F-DPA-714 binding in patients with Alzheimer's disease by comparison with controls, and assessed its influence on clinical progression. At baseline, all participants underwent a clinical assessment, brain MRI, 11C-PiB, 18F-DPA-714 PET imaging and TSPO genotyping. Participants were followed-up annually for 2 years. At the end of the study, subjects were asked to repeat a second 18F-DPA-714-PET imaging. Initial 18F-DPA-714 binding was higher in prodromal (n = 33) and in demented patients with Alzheimer's disease (n = 19) compared to controls (n = 17). After classifying patients into slow and fast decliners according to functional (Clinical Dementia Rating change) or cognitive (Mini-Mental State Examination score decline) outcomes, we found a higher initial 18F-DPA-714 binding in slow than fast decliners. Negative correlations were observed between initial 18F-DPA-714 binding and the Clinical Dementia Rating Sum of Boxes score increase, the MMSE score loss and the progression of hippocampal atrophy. This suggests that higher initial 18F-DPA-714 binding is associated with better clinical prognosis. Twenty-four patients with Alzheimer's disease and 15 control subjects performed a second DPA-PET. We observed an increase of 18F-DPA-714 in patients with Alzheimer's disease as compared with controls (mean 13.2% per year versus 4.2%) both at the prodromal (15.8%) and at the demented stages (8.3%). The positive correlations between change in 18F-DPA-714 binding over time and the three clinical outcome measures (Clinical Dementia Rating, Mini-Mental State Examination, hippocampal atrophy) suggested a detrimental effect on clinical Alzheimer's disease progression of increased neuroinflammation after the initial PET examination, without correlation with PiB-PET uptake at baseline. High initial 18F-DPA-714 binding was correlated with a low subsequent increase of microglial activation and favourable clinical evolution, whereas the opposite profile was observed when initial 18F-DPA-714 binding was low, independently of disease severity at baseline. Taken together, our results support a pathophysiological model involving two distinct profiles of microglial activation signatures with different dynamics, which differentially impact on disease progression and may vary depending on patients rather than disease stages.
Background
While progressive amnesia of the hippocampal type is most often due to Alzheimer’s disease (AD) pathology, other etiologies are not rare during aging, including limbic‐predominant ...age‐related TDP‐43 encephalopathy (LATE) with or without Hippocampal Sclerosis (HS) and Primary age‐related tauopathy (PART). These pathological conditions differ from AD by the lack of cortical amyloid deposition, but the amnestic syndrome mimicking AD can lead to mis‐diagnosis. By coupling amyloid and tau PET imaging in patients with progressive amnesia, we investigated, in vivo, clinical and biological markers that differentiate suspected non‐AD pathophysiology (SNAP) from AD patients.
Method
We included 41 patients with a progressive episodic memory deficit of the hippocampal type (CDR≤ 1), and 30 controls. All patients underwent both PiB‐PET and AV‐1451‐PET. According to their amyloid PET status, we classified patients in SNAP (negative PiB‐PET defined by a GCI<1.45, n=10) and prodromal‐AD (positive PiB‐PET, n=31). Tau‐PET were analyzed individually vs the control group by using Z‐scores in each ROI. Participants were followed up annually for 2 years
Result
SNAP patients were older than AD (77.9+/‐5 vs 70.0+/‐6.8 years) and the proportion of APOE4 carriers was lower (28% vs 62%). No difference in baseline neuropsychological scores was found between SNAP and AD patients regarding MMSE (22.9+/‐2.6 vs 24.2+/‐3.0), verbal or visual episodic memory, or anxiety/depression scales. Volumes of the hippocampus and entorhinal cortex were lower in SNAP and prodromal‐AD than in controls, without any significant difference between both patient groups. As expected, CSF Ab42/Tau and Ab42/Phospho‐tau ratios were lower in SNAP compared to prodromal AD. Tau‐PET imaging was negative in all SNAP patients except one (fronto‐temporal binding), while tau deposition was observed in all AD patients in the temporal +/‐ parietal cortex. Clinical follow‐up at one and two years showed mild dysexecutive syndrome in SNAP and mild parietal cognitive dysfunction in prodromal‐AD.
Conclusion
Amnesia of the hippocampal type not due to AD was observed in 24% of our cohort, with similar severity of amnesia and hippocampal/entorhinal atrophy as in prodromal‐AD, but possibly distinct longitudinal clinical trajectories. Molecular PET imaging suggested a non‐tau pathology in 9 patients and a possible non‐AD tauopathy in one.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Abstract
Background
While progressive amnesia of the hippocampal type is most often due to Alzheimer’s disease (AD) pathology, other etiologies are not rare during aging, including limbic‐predominant ...age‐related TDP‐43 encephalopathy (LATE) with or without Hippocampal Sclerosis (HS) and Primary age‐related tauopathy (PART). These pathological conditions differ from AD by the lack of cortical amyloid deposition, but the amnestic syndrome mimicking AD can lead to mis‐diagnosis. By coupling amyloid and tau PET imaging in patients with progressive amnesia, we investigated, in vivo, clinical and biological markers that differentiate suspected non‐AD pathophysiology (SNAP) from AD patients.
Method
We included 41 patients with a progressive episodic memory deficit of the hippocampal type (CDR≤ 1), and 30 controls. All patients underwent both PiB‐PET and AV‐1451‐PET. According to their amyloid PET status, we classified patients in SNAP (negative PiB‐PET defined by a GCI<1.45, n=10) and prodromal‐AD (positive PiB‐PET, n=31). Tau‐PET were analyzed individually vs the control group by using
Z
‐scores in each ROI. Participants were followed up annually for 2 years
Result
SNAP patients were older than AD (77.9+/‐5 vs 70.0+/‐6.8 years) and the proportion of APOE4 carriers was lower (28% vs 62%). No difference in baseline neuropsychological scores was found between SNAP and AD patients regarding MMSE (22.9+/‐2.6 vs 24.2+/‐3.0), verbal or visual episodic memory, or anxiety/depression scales. Volumes of the hippocampus and entorhinal cortex were lower in SNAP and prodromal‐AD than in controls, without any significant difference between both patient groups. As expected, CSF Ab42/Tau and Ab42/Phospho‐tau ratios were lower in SNAP compared to prodromal AD. Tau‐PET imaging was negative in all SNAP patients except one (fronto‐temporal binding), while tau deposition was observed in all AD patients in the temporal +/‐ parietal cortex. Clinical follow‐up at one and two years showed mild dysexecutive syndrome in SNAP and mild parietal cognitive dysfunction in prodromal‐AD.
Conclusion
Amnesia of the hippocampal type not due to AD was observed in 24% of our cohort, with similar severity of amnesia and hippocampal/entorhinal atrophy as in prodromal‐AD, but possibly distinct longitudinal clinical trajectories. Molecular PET imaging suggested a non‐tau pathology in 9 patients and a possible non‐AD tauopathy in one.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Abstract
Background
Early‐onset Alzheimer’s disease (EOAD) differentiates from late‐onset AD by a predominant and early involvement of the parietal neocortex with hippocampal sparing, leading to ...non‐amnesic cognitive syndromes (deficits in working memory, visuospatial abilities, praxis, or language). The diagnosis of a neurodegenerative disease is often not the first mentioned in such young patients. We aimed to identify the inaugural symptoms and diagnosis in working age EOAD patients.
Methods
We retrospectively reviewed the files of patients younger than 62 years referred to our memory clinic for cognitive dysfunction during the last year. Among 91 patients, 31 were diagnosed with AD based on clinical and biological criteria (cerebrospinal fluid biomarkers). Their mean age was 55±3.8 years.
Results
Eleven EOAD patients (35%) were initially diagnosed with an occupational burnout syndrome, while logopenic aphasia or visuo‐spatial deficit were observed in the remaining 20 patients (65%). In the burnout syndrome subgroup, the delay between the first symptoms and neurological examination was 2.6±1.1 years. The initial Mini‐Mental State Examination score was 19.6±4.6/30. Neuropsychological assessment showed a severe working memory deficit, associated with mild cognitive cortical parietal syndrome. Visual inspection of brain MRI and FDG‐PET showed bilateral parietal atrophy and a severe focal hypometabolism of associative parietal cortices. No patient had family history of EAOD and the molecular genetic testing of AD mutation was negative.
Conclusion
We describe, for the first time, a new clinical presentation of EOAD mimicking an occupational burnout syndrome. The severe inaugural working memory deficit due to the early cortical parietal damage leads to an inability to carry out concurrent professional tasks, a reduction of professional efficacy and a severe anxiety, in the absence of overt aphasia or episodic memory deficit at the time of initial evaluation. The patient stops working and is often referred to psychiatrists, the diagnosis being delayed until the cognitive deficit worsens, and strongly affects the autonomy at a more advanced stage of the disease. It is crucial to consider this clinical phenotype in the definition of EOAD to avoid delayed diagnosis.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Background
Early‐onset Alzheimer’s disease (EOAD) differentiates from late‐onset AD by a predominant and early involvement of the parietal neocortex with hippocampal sparing, leading to non‐amnesic ...cognitive syndromes (deficits in working memory, visuospatial abilities, praxis, or language). The diagnosis of a neurodegenerative disease is often not the first mentioned in such young patients. We aimed to identify the inaugural symptoms and diagnosis in working age EOAD patients.
Methods
We retrospectively reviewed the files of patients younger than 62 years referred to our memory clinic for cognitive dysfunction during the last year. Among 91 patients, 31 were diagnosed with AD based on clinical and biological criteria (cerebrospinal fluid biomarkers). Their mean age was 55±3.8 years.
Results
Eleven EOAD patients (35%) were initially diagnosed with an occupational burnout syndrome, while logopenic aphasia or visuo‐spatial deficit were observed in the remaining 20 patients (65%). In the burnout syndrome subgroup, the delay between the first symptoms and neurological examination was 2.6±1.1 years. The initial Mini‐Mental State Examination score was 19.6±4.6/30. Neuropsychological assessment showed a severe working memory deficit, associated with mild cognitive cortical parietal syndrome. Visual inspection of brain MRI and FDG‐PET showed bilateral parietal atrophy and a severe focal hypometabolism of associative parietal cortices. No patient had family history of EAOD and the molecular genetic testing of AD mutation was negative.
Conclusion
We describe, for the first time, a new clinical presentation of EOAD mimicking an occupational burnout syndrome. The severe inaugural working memory deficit due to the early cortical parietal damage leads to an inability to carry out concurrent professional tasks, a reduction of professional efficacy and a severe anxiety, in the absence of overt aphasia or episodic memory deficit at the time of initial evaluation. The patient stops working and is often referred to psychiatrists, the diagnosis being delayed until the cognitive deficit worsens, and strongly affects the autonomy at a more advanced stage of the disease. It is crucial to consider this clinical phenotype in the definition of EOAD to avoid delayed diagnosis.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Background and objectives: Because myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is a recently identified autoimmune disorder, the natural history of MOGAD is still not well ...described. The objective of this study was to describe the long-term outcomes of adult patients with MOGAD. In addition, we aimed to identify factors affecting relapse risk and neurologic outcomes.Methods: Clinical and biological data were obtained from patients with a first event of MOGAD and included in the French nationwide incident cohort between February 2014 and March 2017. Only patients aged 18 years or older at disease onset and with observation period of at least 3 months were included. Data were collected prospectively until July 2023 and registered in the dedicated French nationwide database. This form includes every relapse with phenotype description during follow-up, date of last assessment, final clinical outcome with Expanded Disability Status Scale score and visual acuity, and maintenance therapy. The probability of recurrence-free survival was assessed using the Kaplan-Meier method.Results: We included 128 patients. The onset phenotype was isolated optic neuritis in 81 patients (63.3%) and isolated myelitis in 25 patients (19.5%). The median follow-up duration was 77.8 months (range 3.2-111.2), with 49 patients (38.3%) experienced at least one relapse. Median times from onset to second and third attacks were 3.2 (1.0-86.2) and 13.0 (2.6-64.4) months, respectively. At the last assessment, Expanded Disability Status Scale Score was ≥3 and ≥6 in 22 (17.2%) and 6 (4.7%) patients, respectively. Eighty patients received at least one maintenance treatment. This treatment was initiated after the first attack in 47 patients (36.7% of the whole cohort) and at the time of a second attack in 25 (19.5%). Multivariate analysis revealed that initiating maintenance treatment after the first attack was associated with a lower relapse risk (OR = 0.26 95% CI 0.11-0.62, p = 0.002). In patients receiving maintenance therapy after first attack, the 2-year, 4-year, 6-year, and 8-year relapse risks were 11%, 15%, 20%, and 20%, respectively. In other patients, the risks were 41%, 46%, 51%, and 56%.Discussion: The highest risk of a relapse in MOGAD occurs early, and initiating maintenance therapy from the first attack substantially reduced the relapse risk.Classification of evidence: This study provides Class III evidence that initiating maintenance therapy from the first attack in patients with MOGAD reduces the relapse risk.
Because myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is a recently identified autoimmune disorder, the natural history of MOGAD is still not well described. The objective ...of this study was to describe the long-term outcomes of adult patients with MOGAD. In addition, we aimed to identify factors affecting relapse risk and neurologic outcomes.BACKGROUND AND OBJECTIVESBecause myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is a recently identified autoimmune disorder, the natural history of MOGAD is still not well described. The objective of this study was to describe the long-term outcomes of adult patients with MOGAD. In addition, we aimed to identify factors affecting relapse risk and neurologic outcomes.Clinical and biological data were obtained from patients with a first event of MOGAD and included in the French nationwide incident cohort between February 2014 and March 2017. Only patients aged 18 years or older at disease onset and with observation period of at least 3 months were included. Data were collected prospectively until July 2023 and registered in the dedicated French nationwide database. This form includes every relapse with phenotype description during follow-up, date of last assessment, final clinical outcome with Expanded Disability Status Scale score and visual acuity, and maintenance therapy. The probability of recurrence-free survival was assessed using the Kaplan-Meier method.METHODSClinical and biological data were obtained from patients with a first event of MOGAD and included in the French nationwide incident cohort between February 2014 and March 2017. Only patients aged 18 years or older at disease onset and with observation period of at least 3 months were included. Data were collected prospectively until July 2023 and registered in the dedicated French nationwide database. This form includes every relapse with phenotype description during follow-up, date of last assessment, final clinical outcome with Expanded Disability Status Scale score and visual acuity, and maintenance therapy. The probability of recurrence-free survival was assessed using the Kaplan-Meier method.We included 128 patients. The onset phenotype was isolated optic neuritis in 81 patients (63.3%) and isolated myelitis in 25 patients (19.5%). The median follow-up duration was 77.8 months (range 3.2-111.2), with 49 patients (38.3%) experienced at least one relapse. Median times from onset to second and third attacks were 3.2 (1.0-86.2) and 13.0 (2.6-64.4) months, respectively. At the last assessment, Expanded Disability Status Scale Score was ≥3 and ≥6 in 22 (17.2%) and 6 (4.7%) patients, respectively. Eighty patients received at least one maintenance treatment. This treatment was initiated after the first attack in 47 patients (36.7% of the whole cohort) and at the time of a second attack in 25 (19.5%). Multivariate analysis revealed that initiating maintenance treatment after the first attack was associated with a lower relapse risk (OR = 0.26 95% CI 0.11-0.62, p = 0.002). In patients receiving maintenance therapy after first attack, the 2-year, 4-year, 6-year, and 8-year relapse risks were 11%, 15%, 20%, and 20%, respectively. In other patients, the risks were 41%, 46%, 51%, and 56%.RESULTSWe included 128 patients. The onset phenotype was isolated optic neuritis in 81 patients (63.3%) and isolated myelitis in 25 patients (19.5%). The median follow-up duration was 77.8 months (range 3.2-111.2), with 49 patients (38.3%) experienced at least one relapse. Median times from onset to second and third attacks were 3.2 (1.0-86.2) and 13.0 (2.6-64.4) months, respectively. At the last assessment, Expanded Disability Status Scale Score was ≥3 and ≥6 in 22 (17.2%) and 6 (4.7%) patients, respectively. Eighty patients received at least one maintenance treatment. This treatment was initiated after the first attack in 47 patients (36.7% of the whole cohort) and at the time of a second attack in 25 (19.5%). Multivariate analysis revealed that initiating maintenance treatment after the first attack was associated with a lower relapse risk (OR = 0.26 95% CI 0.11-0.62, p = 0.002). In patients receiving maintenance therapy after first attack, the 2-year, 4-year, 6-year, and 8-year relapse risks were 11%, 15%, 20%, and 20%, respectively. In other patients, the risks were 41%, 46%, 51%, and 56%.The highest risk of a relapse in MOGAD occurs early, and initiating maintenance therapy from the first attack substantially reduced the relapse risk.DISCUSSIONThe highest risk of a relapse in MOGAD occurs early, and initiating maintenance therapy from the first attack substantially reduced the relapse risk.This study provides Class III evidence that initiating maintenance therapy from the first attack in patients with MOGAD reduces the relapse risk.CLASSIFICATION OF EVIDENCEThis study provides Class III evidence that initiating maintenance therapy from the first attack in patients with MOGAD reduces the relapse risk.
Previous studies analyzed the ability of hippocampal volumes (HV) to differentiate Alzheimer's disease (AD) from frontotemporal dementia (FTD). However, these studies did not include patients ...selected according to clinico-biological criteria, using pathophysiological biomarkers.
To analyze the effectiveness of hippocampal volumetric measures to distinguish AD from behavioral variant FTD (bvFTD), using strict inclusion criteria based on clinical and pathophysiological markers.
Seventy-two participants were included: 31 AD patients with predominant and progressive episodic memory deficits associated with typical AD cerebrospinal fluid (CSF) profile and/or positive amyloid imaging (PET with 11C-labeled Pittsburgh Compound B PiB), 26 bvFTD patients diagnosed according to consensual clinical criteria and with no AD CSF profile, and 15 healthy controls without amyloid retention on PiB-PET exam. HV were segmented with an automated method and were normalized to total intracranial volume (nHV).
Significant reductions in HV were found in both AD and bvFTD patients compared with controls, but there were no significant difference between AD and bvFTD patients. Mean nHV distinguished normal controls from either AD or bvFTD with high sensitivity (80.6% and 76.9%, respectively) and specificity (93.3% for both), but it was inefficient in differentiating AD from bvFTD (9.7% specificity). There was no difference in the clinical and neuropsychological profiles according to HV in bvFTD and AD patients.
When considered alone, measures of HV are not good markers to differentiate AD from bvFTD. Hippocampal sclerosis associated with FTD may explain the high degree of overlap in nHV between both groups.
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