Combined in vivo MRI assessment of locus coeruleus and nucleus basalis of Meynert integrity in amnestic Alzheimer's disease, suspected-LATE and frontotemporal dementia.

BACKGROUND: The locus coeruleus (LC) and the nucleus basalis of Meynert (NBM) are altered in early stages of Alzheimer's disease (AD). Little is known about LC and NBM alteration in limbic-predominant age-related TDP-43 encephalopathy (LATE) and frontotemporal dementia (FTD). The aim of the present study is to investigate in vivo LC and NBM integrity in patients with suspected-LATE, early-amnestic AD and FTD in comparison with controls. METHODS: Seventy-two participants (23 early amnestic-AD patients, 17 suspected-LATE, 17 FTD patients, defined by a clinical-biological diagnosis reinforced by amyloid and tau PET imaging, and 15 controls) underwent neuropsychological assessment and 3T brain MRI. We analyzed the locus coeruleus signal intensity (LC-I) and the NBM volume as well as their relation with cognition and with medial temporal/cortical atrophy. RESULTS: We found significantly lower LC-I and NBM volume in amnestic-AD and suspected-LATE in comparison with controls. In FTD, we also observed lower NBM volume but a slightly less marked alteration of the LC-I, independently of the temporal or frontal phenotype. NBM volume was correlated with the global cognitive efficiency in AD patients. Strong correlations were found between NBM volume and that of medial temporal structures, particularly the amygdala in both AD and FTD patients. CONCLUSIONS: The alteration of LC and NBM in amnestic-AD, presumed-LATE and FTD suggests a common vulnerability of these structures to different proteinopathies. Targeting the noradrenergic and cholinergic systems could be effective therapeutic strategies in LATE and FTD.

Phenotype and imaging features associated with APP duplications.

BACKGROUND: APP duplication is a rare genetic cause of Alzheimer disease and cerebral amyloid angiopathy (CAA). We aimed to evaluate the phenotypes of APP duplications carriers. METHODS: Clinical, radiological, and neuropathological features of 43 APP duplication carriers from 24 French families were retrospectively analyzed, and MRI features and cerebrospinal fluid (CSF) biomarkers were compared to 40 APP-negative CAA controls. RESULTS: Major neurocognitive disorders were found in 90.2% symptomatic APP duplication carriers, with prominent behavioral impairment in 9.7%. Symptomatic intracerebral hemorrhages were reported in 29.2% and seizures in 51.2%. CSF Aß42 levels were abnormal in 18/19 patients and 14/19 patients fulfilled MRI radiological criteria for CAA, while only 5 displayed no hemorrhagic features. We found no correlation between CAA radiological signs and duplication size. Compared to CAA controls, APP duplication carriers showed less disseminated cortical superficial siderosis (0% vs 37.5%, p = 0.004 adjusted for the delay between symptoms onset and MRI). Deep microbleeds were found in two APP duplication carriers. In addition to neurofibrillary tangles and senile plaques, CAA was diffuse and severe with thickening of leptomeningeal vessels in all 9 autopsies. Lewy bodies were found in substantia nigra, locus coeruleus, and cortical structures of 2/9 patients, and one presented vascular amyloid deposits in basal ganglia. DISCUSSION: Phenotypes associated with APP duplications were heterogeneous with different clinical presentations including dementia, hemorrhage, and seizure and different radiological presentations, even within families. No apparent correlation with duplication size was found. Amyloid burden was severe and widely extended to cerebral vessels as suggested by hemorrhagic features on MRI and neuropathological data, making APP duplication an interesting model of CAA.

Could tau-PET imaging contribute to a better understanding of the different patterns of clinical progression in Alzheimer's disease? A 2-year longitudinal study.

BACKGROUND: Monitoring the progression of Tau pathology makes it possible to study the clinical diversity of Alzheimer's disease. In this 2-year longitudinal PET study, we aimed to determine the progression of [18F]-flortaucipir binding and of cortical atrophy, and their relationships with cognitive decline. METHODS: Twenty-seven AD patients at the mild cognitive impairment/mild dementia stages and twelve amyloid-negative controls underwent a neuropsychological assessment, 3 T brain MRI, and [18F]-flortaucipir PET imaging (Tau1) and were monitored annually over 2 years with a second brain MRI and tau-PET imaging after 2 years (Tau2). We analyzed the progression of tau standardized uptake value ratio (SUVr) and grey matter atrophy both at the regional and voxelwise levels. We used mixed effects models to explore the relations between the progression of SUVr values, cortical atrophy, and cognitive decline. RESULTS: We found an average longitudinal increase in tau SUVr values, except for the lateral temporoparietal cortex where the average SUVr values decreased. Individual analyses revealed distinct profiles of SUVr progression according to temporoparietal Tau1 uptake: high-Tau1 patients demonstrated an increase in SUVr values over time in the frontal lobe, but a decrease in the temporoparietal cortex and a rapid clinical decline, while low-Tau1 patients displayed an increase in SUVr values in all cortical regions and a slower clinical decline. Cognitive decline was strongly associated with the progression of regional cortical atrophy, but only weakly associated with SUVr progression. CONCLUSIONS: Despite a relatively small sample size, our results suggest that tau-PET imaging could identify patients with a potentially "more aggressive" clinical course characterized by high temporoparietal Tau1 SUVr values and a rapid clinical progression. In these patients, the paradoxical decrease in temporoparietal SUVr values over time could be due to the rapid transition to ghost tangles, for which the affinity of the radiotracer is lower. They could particularly benefit from future therapeutic trials, the neuroimaging outcome measures of which deserve to be discussed.

Tau-PET imaging predicts cognitive decline and brain atrophy progression in early Alzheimer's disease.

OBJECTIVES: To explore whether regional tau binding measured at baseline is associated with the rapidity of Alzheimer's disease (AD) progression over 2 years, as assessed by the decline in specified cognitive domains, and the progression of regional brain atrophy, in comparison with amyloid-positron emission tomography (PET), MRI and cerebrospinal fluid (CSF) biomarkers. METHODS: Thirty-six patients with AD (positive CSF biomarkers and amyloid-PET) and 15 controls underwent a complete neuropsychological assessment, 3T brain MRI, [11C]-PiB and [18F]-flortaucipir PET imaging, and were monitored annually over 2 years, with a second brain MRI after 2 years. We used mixed effects models to explore the relations between tau-PET, amyloid-PET, CSF biomarkers and MRI at baseline and cognitive decline and the progression of brain atrophy over 2 years in patients with AD. RESULTS: Baseline tau-PET was strongly associated with the subsequent cognitive decline in regions that are usually associated with each cognitive domain. No significant relationship was observed between the cognitive decline and initial amyloid load, regional cortical atrophy or CSF biomarkers. Baseline tau tracer binding in the superior temporal gyrus was associated with subsequent atrophy in an inferomedial temporal volume of interest, as was the voxelwise tau tracer binding with subsequent cortical atrophy in the superior temporal, parietal and frontal association cortices. CONCLUSIONS: These results suggest that tau tracer binding is predictive of cognitive decline in AD in domain-specific brain areas, which provides important insights into the interaction between tau burden and neurodegeneration, and is of the utmost importance to develop new prognostic markers that will help improve the design of therapeutic trials.

Telemedicine in French Memory Clinics During the COVID-19 Pandemic.

This multicenter study was conducted in French memory clinics during the first COVID-2019 lockdown (March-May 2020). The objective was to evaluate the effect of a telemedicine consultation on treatment modification in dementia care. Among 874 patients who had a telemedicine consultation, 103 (10.7%) had treatment modifications, in particular those living with a relative or diagnosed with Alzheimer's disease. A control group of patients referred March-May 2019 was also included. Treatment modification rate was similar between periods with an adjusted percentage difference of -4% (p = 0.27). Telemedicine consultations allowed treatment modifications with only a minor short-term negative impact on therapeutic strategies.

Distinct amyloid and tau PET signatures are associated with diverging clinical and imaging trajectories in patients with amnestic syndrome of the hippocampal type.

We aimed to investigate the amyloid and tau PET imaging signatures of patients with amnestic syndrome of the hippocampal type (ASHT) and study their clinical and imaging progression according to their initial PET imaging status. Thirty-six patients with a progressive ASHT and 30 controls underwent a complete neuropsychological assessment, 3 T brain MRI, [11C]-PiB and [18F]-Flortaucipir PET imaging. Subjects were clinically followed-up annually over 2 years, with a second 3 T MRI (n = 27 ASHT patients, n = 28 controls) and tau-PET (n = 20 ASHT patients) at the last visit. At baseline, in accordance with the recent biological definition of Alzheimer's disease (AD), the AD PET signature was defined as the combination of (i) positive cortical amyloid load, and (ii) increased tau tracer binding in the entorhinal cortices and at least one of the following regions: amygdala, parahippocampal gyri, fusiform gyri. Patients who did not meet these criteria were considered to have a non-AD pathology (SNAP). Twenty-one patients were classified as AD and 15 as SNAP. We found a circumscribed tau tracer retention in the entorhinal cortices and/or amygdala in 5 amyloid-negative SNAP patients. At baseline, the SNAP patients were older and had lower ApoE ε4 allele frequency than the AD patients, but both groups did not differ regarding the neuropsychological testing and medial temporal lobe atrophy. During the 2-year follow-up, the episodic memory and language decline, as well as the temporo-parietal atrophy progression, were more pronounced in the AD sub-group, while the SNAP patients had a more pronounced progression of atrophy in the frontal lobes. Longitudinal tau tracer binding increased in AD patients but remained stable in SNAP patients. At baseline, distinct amyloid and tau PET signatures differentiated early AD and SNAP patients despite identical cognitive profiles characterized by an isolated ASHT and a similar degree of medial temporal atrophy. During the longitudinal follow-up, AD and SNAP patients diverged regarding clinical and imaging progression. Among SNAP patients, tau PET imaging could detect a tauopathy restricted to the medial temporal lobes, which was possibly explained by primary age-related tauopathy.

Characterization of the initial complaint and care pathways prior to diagnosis in very young sporadic Alzheimer's disease.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: Better identifying the initial signs of very-early-onset AD is crucial to improve the early diagnosis and develop new treatments.

LeSCoD: a new clinical scale for the detection of Lewy body disease in neurocognitive disorders.

BACKGROUND: Dementia with Lewy bodies remains underdiagnosed in clinical practice mainly because of the low sensitivity of existing diagnostic criteria and a strong overlap with Alzheimer's pathology that can mask the Lewy phenotype. OBJECTIVE: The objective of this study was therefore to develop and validate a new clinical scale designed to detect signs of Lewy body disease, called LeSCoD for Lewy body Screening scale in Cognitive Disorders. METHODS: 128 patients who fulfilled the clinical criteria of dementia with Lewy bodies (DLB; n = 32), Alzheimer's disease (AD; n = 77) or both (n = 19) was prospectively enrolled. 18F-DOPA PET imaging and/or CSF biomarkers were available in some patients. LeSCoD scale was systematically administered and the potential correlation with 18F-DOPA PET imaging was evaluated in a subgroup of patients. RESULTS: LeSCoD scale showed robust internal and external validity. We determined a cut-off of 10 above which the sensitivity and specificity for Lewy body disease diagnosis were 86% and 95%, respectively. The LeSCoD scale correlated with striatal dopamine uptake in 18F-DOPA PET. CONCLUSION: LeSCoD scale is a simple and reliable tool for the evaluation of Lewy body disease in routine clinical practice, with a higher sensitivity and specificity than the existing criteria. It might be an alternative to the use of dopamine-specific imaging.

[18F]-AV-1451 tau PET imaging in Alzheimer's disease and suspected non-AD tauopathies using a late acquisition time window.

The utility of tau PET imaging in non-Alzheimer's disease (AD) tauopathies like behavioural frontotemporal dementia (bvFTD), which is mainly underlain by TDP-43 or tau pathology, remains debated. We aim to test the hypothesis that [18F]-AV-1451 tau PET using later than usual acquisition times, which have previously been shown in AD to allow to get closer to tracer equilibrium between the reference region and high-binding structures, and could be better suited to the lower affinity of this tracer for the straight tau filaments present in non-AD tauopathies, would allow to detect cortical tau pathology in a fraction of bvFTD patients and in patients with non-fluent primary progressive aphasia (nfPPA, most often underlain by tau pathology). Sixteen AD patients, 11 controls, 7 bvFTD patients (including a carrier of a GRN mutation leading to TDP-43 pathology) and 2 nfPPA patients were included. We compared SUVr obtained at the usual early time window for [18F]-AV-1451 PET acquisition (ET: 80-100 min) to a later acquisition window (LT: 190-210 min) between groups. Compared with ET, [18F]-AV-1451 LT uptake in AD patients was significantly higher in the temporo-parietal cortex, and lower in subcortical regions. The LT window allowed to detect significantly increased tau binding in the frontal or temporal cortex in 3 bvFTD patients and in the 2 nfPPA patients that was not detectable with ET. The GRN mutation carrier showed no significant increase of tracer binding. [18F]-AV-1451 late acquisition window could allow cortical binding to abnormal tau deposits to be revealed in a subset of bvFTD patients, which may distinguish them from the TDP-43 subtype.

Early alteration of the locus coeruleus in phenotypic variants of Alzheimer's disease.

Neuropathological studies showed early locus coeruleus (LC) neuronal loss associated with tauopathy in Alzheimer's Disease (AD). We used the LC signal intensity (LC-I) on 3T MRI to assess the LC integrity in AD (n = 37) and controls (n = 17). The LC-I was decreased in AD regardless of typical (amnesic) and atypical presentation (logopenic aphasia/visuo-spatial deficit), from the prodromal stage, and independently of the amyloid load measured by PiB-PET. The LC-I was correlated with memory performance of typical AD. This supports the pathophysiological model in which the LC plays a critical role in AD and may thus be a potential therapeutic target.