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The objective of this study was to examine the diagnostic accuracy of imaging and CSF biomarkers in clinically ambiguous dementia (CAD). 69 patients were prospectively followed. The endpoint was clinical diagnosis at follow-up of 24 months based upon existing criteria. Medial temporal lobe atrophy score on MRI, distinctive patterns on 99 mTc-HMPAO-SPECT, and CSF levels of amyloid-β peptide, total tau protein, and P-tau181P were used together with neuropsychological testing to assess Se (sensitivity) and Sp (specificity) of separate and combined markers. 60 patients reached the endpoint. A definite diagnosis was achieved in 48 patients. CSF biomarkers had a Sp of 71% and a Se of 100% for Alzheimer's disease (AD) diagnosis. Sp increased to 88% and 93% when MRI and MRI + SPECT were combined, at the expense of Se. CSF biomarkers levels also provided clues to frontotemporal (FTD) or vascular dementias (VaD) diagnosis when situated in an intermediate range between normal and pathological values. MRI and SPECT contributed mostly to the diagnosis of VaD (Se 88%, Sp 75%) and FTD (Se 73%, Sp 78%), respectively. Initial neuropsychological testing had a poor diagnostic accuracy, except for a neuropsychiatric inventory score >40 for the diagnosis of FTD (Se 73%, Sp 84%). Independent of the clinical diagnosis, medial temporal lobe atrophy and total-tau were best correlated with cognitive decline at 2 years. In conclusion, CSF biomarkers efficiently predict evolution toward an AD phenotype in CAD. Imaging biomarkers mostly contribute to the differential diagnosis between non-AD dementias. Initial neuropsychological testing was poorly contributive in CAD diagnosis. [ABSTRACT FROM AUTHOR]

A common question in the neuropsychological testing of patients with Alzheimer's Disease is whether or not patients should be tested in the presence of their spouses. We addressed this issue by assessing the neuropsychological performances of Alzheimer's Disease patients in the presence or absence of spouses. Results showed no significant differences between patients' performances in the presence or absence of spouses on tests assessing general cognitive abilities, episodic memory, working memory, inhibition and flexibility. No significant differences were observed regarding either anxiety or depression in patients when tested alone, compared to when spouses were attending. However, patients demonstrated higher verbal fluency when tested alone compared to when spouses attended. Clinicians may carry out neuropsychological assessment in the presence or absence of spouses, except when assessing verbal fluency. In such cases, clinicians should privilege testing patients alone or, if spouses attend the test, take into account this variable when interpreting patients' performances.

Financial decision-making requires trading off between guaranteed and probabilistic outcomes and between immediate and delayed ones. While research has demonstrated that patients with behavioural-variant frontotemporal dementia (bvFTD) prefer immediate rewards at the expense of future ones (i.e. temporal discounting), little is known about how patients choose between smaller, guaranteed and larger, but probabilistic, outcomes (i.e. probabilistic discounting). We thus investigated probabilistic discounting by inviting 18 patients with bvFTD and 20 control participants to choose between fixed smaller monetary amounts and a fixed larger monetary amount with a variated probability of occurrence (e.g. 'Would you rather have 40€ for sure or a 20% chance of winning 100€?'). Results demonstrated lower scores, indicating higher risk tolerance, on the probabilistic discounting task in patients with bvFTD (while impulsively choosing more immediate rewards on the temporal discounting task) compared to control participants. Probabilistic discounting was significantly correlated with a decline in general cognitive performance in patients with bvFTD. When dealing between smaller, guaranteed, and larger, but probabilistic, rewards, patients with bvFTD tend to prefer guaranteed rewards and discount the uncertain ones., (© 2023 The British Psychological Society.)

In this study, we offer a comprehensive assessment of the phenomenological experience of patients with behavioral-variant frontotemporal dementia (bvFTD) upon retrieval of autobiographical memory. We invited patients with bvFTD and control participants to retrieve autobiographical memories and rate, for each memory, its phenomenological characteristics. We also analyzed the retrieved memories regarding specificity (i.e., whether the memory described a general or a detailed event). Results demonstrated that, compared to control participants, patients with bvFTD attributed lower levels of reliving, back in time (feeling as if going back in time), remembering, realness, visual imagery, auditory imagery, language, emotion, rehearsal, importance, spatial recall and temporal recall to their memories. Lower autobiographical specificity was also observed in patients with bvFTD compared to control participants. Autobiographical specificity in patients with bvFTD was associated with verbal fluency and verbal episodic memory, but not with phenomenological experience. Although autobiographical memories of patients with bvFTD show low ratings of phenomenological experience, the patients may still enjoy some limited subjective experience during autobiographical retrieval.

We assessed the aesthetic experience of patients with behavioral variant frontotemporal dementia (bvFTD) to understand their ability to experience feelings of the sublime and to be moved when viewing paintings. We exposed patients with bvFTD and control participants to concrete and abstract paintings and asked them how moved they were by these paintings and whether the latter were beautiful or ugly. Patients with bvFTD declared being less moved than control participants by both abstract and concrete paintings. No significant differences were observed between abstract and concrete paintings in both patients with bvFTD and control participants. Patients with bvFTD provided fewer "beautiful" and more "ugly" responses than controls for both abstract and concrete paintings. No significant differences in terms of "beautiful" and "ugly" responses were observed between abstract and concrete paintings in both patients with bvFTD and control participants. These findings suggest disturbances in the basic affective experience of patients with bvFTD when they are exposed to paintings, as well as a bias in their ability to judge the aesthetic quality of paintings.

Purpose: To assess the likely pathogenic/pathogenic (LP/P) variants rates in Mendelian dementia genes and the moderate-to-strong risk factors rates in patients with Alzheimer disease (AD)., Methods: We included 700 patients in a prospective study and performed exome sequencing. A panel of 28 Mendelian and 6 risk-factor genes was interpreted and returned to patients. We built a framework for risk variant interpretation and risk gradation and assessed the detection rates among early-onset AD (EOAD, age of onset (AOO) ≤65 years, n = 608) depending on AOO and pedigree structure and late-onset AD (66 < AOO < 75, n = 92)., Results: Twenty-one patients carried a LP/P variant in a Mendelian gene (all with EOAD, 3.4%), 20 of 21 affected APP, PSEN1, or PSEN2. LP/P variant detection rates in EOAD ranged from 1.7% to 11.6% based on AOO and pedigree structure. Risk factors were found in 69.5% of the remaining 679 patients, including 83 (12.2%) being heterozygotes for rare risk variants, in decreasing order of frequency, in TREM2, ABCA7, ATP8B4, SORL1, and ABCA1, including 5 heterozygotes for multiple rare risk variants, suggesting non-monogenic inheritance, even in some autosomal-dominant-like pedigrees., Conclusion: We suggest that genetic screening should be proposed to all EOAD patients and should no longer be prioritized based on pedigree structure., Competing Interests: Conflict of Interest The authors have no conflict of interest to declare., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

The decline of autobiographical memory in Alzheimer's disease (AD) is mainly characterized by overgenerality. While there is a large body of research on autobiographical overgenerality in AD, this research has mainly assessed retrieval with a dichotomy between specific vs. general retrieval. To go beyond this dichotomy, we assessed several degrees of autobiographical specificity in patients with AD, namely, we assessed specific vs. categoric vs. extended vs. semantic retrieval. We also assessed sex differences regarding these degrees of autobiographical specificity. We invited patients with mild AD and control participants to complete sentences (e. g., "When I think back to/of…") with autobiographical memories. Memories were categorized into specific, categoric, extended, or semantic memories. Results demonstrated more semantic than specific, categoric or extended memories in men and women with AD. In control participants, analysis demonstrated more specific than categoric, extended, and semantic memories in men and women. Also, no significant differences were observed between women and men with AD, or between control women and men, regarding specific, categoric, extended, and semantic memoires. This study offers not only a nuanced analysis of autobiographical specificity in patients with mild AD, but also an original analysis regarding this specificity by sex., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: The potential of ChatGPT in medical diagnosis has been explored in various medical conditions., Objective: We assessed whether ChatGPT can contribute to the diagnosis of Alzheimer's disease (AD)., Methods: We provided ChatGPT with four generated cases (mild, moderate, or advanced stage AD dementia, or mild cognitive impairment), including descriptions of their complaints, physical examinations, as well as biomarker, neuroimaging, and neuropsychological data., Results: ChatGPT accurately diagnosed the test cases similarly to two blinded specialists., Conclusions: While the use of generated cases can be a limitation to our study, our findings demonstrate that ChatGPT can be a useful tool for symptom assessment and the diagnosis of AD. However, while the use of ChatGPT in AD diagnosis is promising, it should be seen as an adjunct to clinical judgment rather than a replacement., Competing Interests: MEH is an Editorial Board Member of this journal but was not involved in the peer-review process of this article nor had access to any information regarding its peer-review., (© 2024 – The authors. Published by IOS Press.)

Artificial intelligence continues to revolutionize the medical and scientific field, especially with the release of ChatGPT. We assessed whether it provides an accurate interpretation of neuropsychological screening. We provided ChatGPT with the neuropsychological data of a patient with mild Alzheimer's Disease and invited it and two neuropsychologists to interpret the data. While ChatGPT provided an accurate interpretation of scores on each of the neuropsychological tests, it did not use standardized scores and did not specify the cognitive domain that may be most impaired. In contrast, the neuropsychologists used standardized scores to determine that the patient was mainly suffering from memory decline. While ChatGPT may succeed in the general interpretation of neuropsychological testing, at least in patients with Alzheimer's Disease, it still cannot create a pattern of scores across different tests to better specify the nature of cognitive impairment., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: While affective disturbances are a key symptomatic indicator of behavioural variant frontotemporal dementia (bvFTD), little is known about how patients process the emotional load of their autobiographical (i.e. personal) memories., Methods: We assessed the interplay of emotional regulation and autobiographical memory by inviting 18 bvFTD and 20 control participants to remember past personal events. For each memory, participants rated its emotional valence "then" (i.e. when the event has occurred) vs "now" (i.e. when retrieving the event)., Results: Patients with bvFTD described their memories as neutral at both times ( p  = .85), while control participants rated their memories as more positive during "then" than during "now" ( p  = .013). Autobiographical retrieval triggered fewer emotional words ( p  < .001) and less specificity ( p  < .001) in bvFTD patients compared to control participants., Conclusions: The lack of significant differences between the emotional characteristics during "then" than "now" in patients with bvFTD (and the flattening of both) may mirror their hampered ability for emotional generation, which may be associated with difficulties in reframing their past experiences to modify and adapt their meaning. The hampered emotional regulation in bvFTD may also be associated with an avoidance strategy and a passive attitude toward the past.

Pupil dilation is considered an index of cognitive effort, as the pupil typically dilates as the cognitive load increases. In this paper, we evaluated whether older adults demonstrate increased pupil size when performing tasks requiring cognitive inhibition. We invited 44 older and 44 younger adults to perform the Stroop task while their pupil dilation was recorded with eye-tracking glasses. The dependent variables were the number of accurate responses on the Stroop task as well as pupil size in the three conditions of the task (i.e., color naming, word reading, and the interference condition). The results demonstrated less accurate responses in the interference condition than in the color-naming or word-reading conditions, in both older and younger adults. Critically, larger pupil dilation was observed in the interference condition than in the color-naming and word-reading conditions, in both older and younger adults. This study demonstrates that pupil dilation responds to cognitive effort in normal aging, at least in the interference condition of the Stroop task.

While research has shown a distrusted sense of the self in patients with behavioral variant frontotemporal dementia (bvFTD), little is known about how patients describe their self-image. We used the "Who am I?" task to invite patients with bvFTD and control participants to produce statements beginning with "I am…." We distinguished between statements related to physical, social, and psychological self. Analyses showed fewer statements related to physical, social, and psychological self in the patients with bvFTD than in control participants. Another result was the proportionally similar production of statements describing physical, social, and psychological self in both patients with bvFTD and control participants. Finally, the total production of "Who am I?" statements was positively correlated with verbal fluency in both patients with bvTFD and control participants. Our findings demonstrate a diminished ability of patients with bvFTD to process self-images. Our study also paves the way toward the use of the "Who am I" task as a simple and ecologically valid tool allowing for the quantitative and qualitative assessment of the sense of self in patients with bvFTD., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.)

While research has consistently demonstrated how autobiographical memory triggers visual exploration, prior studies did not investigate gender differences in this domain. We thus compared eye movement between women and men while performing an autobiographical retrieval task. We invited 35 women and 35 men to retrieve autobiographical memories while their gaze was monitored by an eye tracker. We further investigated gender differences in eye movement and autobiographical specificity, that is, the ability to retrieve detailed memories. The analysis demonstrated shorter fixations, larger duration and amplitude of saccades, and higher autobiographical specificity in women than in men. The significant gender differences in eye movement disappeared after controlling for autobiographical specificity. When retrieving autobiographical memory, female participants generated a large scan with short fixation and high saccade amplitude, while male participants increased their fixation duration and showed poorer gaze scan. The large saccades in women during autobiographical retrieval may constitute an exploratory gaze behavior enabling better autobiographical memory functioning, which is reflected by the larger number of autobiographical details retrieved compared to men.

Background and Objective: Blood biomarkers for Alzheimer disease (AD) have consistently proven to be associated with CSF or PET biomarkers and effectively discriminate AD from other neurodegenerative diseases. Our aim was to test their utility in clinical practice, from a multicentric unselected prospective cohort where patients presented with a large spectrum of cognitive deficits or complaints., Methods: The MEMENTO cohort enrolled 2,323 outpatients with subjective cognitive complaint (SCC) or mild cognitive impairment (MCI) consulting in 26 French memory clinics. Participants had neuropsychological assessments, MRI, and blood sampling at baseline. CSF sampling and amyloid PET were optional. Baseline blood Aβ42/40 ratio, total tau, p181-tau, and neurofilament light chain (NfL) were measured using a Simoa HD-X analyzer. An expert committee validated incident dementia cases during a 5-year follow-up period., Results: Overall, 2,277 individuals had at least 1 baseline blood biomarker available (n = 357 for CSF subsample, n = 649 for PET subsample), among whom 257 were diagnosed with clinical AD/mixed dementia during follow-up. All blood biomarkers but total tau were mildly correlated with their equivalence in the CSF (r = 0.33 to 0.46, p < 0.0001) and were associated with amyloid-PET status ( p < 0.0001). Blood p181-tau was the best blood biomarker to identify amyloid-PET positivity (area under the curve = 0.74 [95% CI = 0.69; 0.79]). Higher blood and CSF p181-tau and NfL concentrations were associated with accelerated time to AD dementia onset with similar incidence rates, whereas blood Aβ42/40 was less efficient than CSF Aβ42/40. Blood p181-tau alone was the best blood predictor of 5-year AD/mixed dementia risk (c-index = 0.73 [95% CI = 0.69; 0.77]); its accuracy was higher in patients with clinical dementia rating (CDR) = 0 (c-index = 0.83 [95% CI = 0.69; 0.97]) than in patients with CDR = 0.5 (c-index = 0.70 [95% CI = 0.66; 0.74]). A "clinical" reference model (combining demographics and neuropsychological assessment) predicted AD/mixed dementia risk with a c-index = 0.88 [95% CI = 0.86-0.91] and performance increased to 0.90 [95% CI = 0.88; 0.92] when adding blood p181-tau + Aβ42/40. A "research" reference model (clinical model + apolipoprotein E genotype and AD signature on MRI) had a c-index = 0.91 [95% CI = 0.89-0.93] increasing to 0.92 [95% CI = 0.90; 0.93] when adding blood p181-tau + Aβ42/40. Chronic kidney disease and vascular comorbidities did not affect predictive performances., Discussion: In a clinic-based cohort of patients with SCC or MCI, blood biomarkers may be good hallmarks of underlying pathology but add little to 5-year dementia risk prediction models including traditional predictors., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Background and Objectives: GRN variants are a frequent cause of familial frontotemporal dementia (FTD). Monitoring disease progression in asymptomatic carriers of genetic variants is a major challenge in delivering preventative therapies before clinical onset. This study aimed to assess the usefulness of fluorodeoxyglucose (FDG)-PET in identifying metabolic changes in presymptomatic GRN carriers (PS- GRN +) and to trace their longitudinal progression., Methods: Participants were longitudinally evaluated over 5 years in a prospective cohort study focused on GRN disease (Predict-PGRN). They underwent cognitive/behavioral assessment, plasma neurofilament measurement, brain MRI, and FDG-PET. Voxel-wise comparisons of structural and metabolic imaging data between 2 groups were performed for each time point. Longitudinal PET changes were evaluated with voxel-wise comparisons and the metabolic percent annual changes method. The association of regional brain metabolism with plasma neurofilament and cognitive changes was analyzed., Results: Among the 80 individuals enrolled in the study, 58 (27 PS- GRN + and 31 noncarriers) were included in the analyses. Cross-sectional comparisons between PS- GRN + and controls found a significant hypometabolism in the left superior temporal sulcus (STS) region (encompassing the middle and superior temporal gyri), approximately 15 years before the expected disease onset, without significant cortical atrophy. The longitudinal metabolic decline over the following 5 years peaked around the right STS in carriers ( p < 0.001), without significantly greater volume loss compared with that in controls. Their estimated annualized metabolic decrease (-1.37%) was higher than that in controls (-0.21%, p = 0.004). Lower glucose uptake was associated with higher neurofilament increase ( p = 0.003) and lower frontal cognitive scores ( p = 0.014) in PS- GRN +., Discussion: This study detected brain metabolic changes in the STS region, preceding structural and cognitive alterations, thus contributing to the characterization of the pathochronology of preclinical GRN disease. Owing to the STS involvement in the perception of facially communicated cues, it is likely that its dysfunction contributes to social cognition deficits characterizing FTD. Overall, our study highlights brain metabolic changes as an early disease-tracking biomarker and proposes annualized percent decrease as a metric to monitor therapeutic response in forthcoming trials., (© 2022 American Academy of Neurology.)

Idiopathic normal pressure hydrocephalus has a complex multifactorial pathogenesis and is associated with Alzheimer's disease in many patients. To date, it is not well known if a similar association exists with behavioural variant of frontotemporal lobar degeneration. In a first step, we compare the prevalence of idiopathic normal pressure hydrocephalus in two groups of patients, one with behavioural variant of frontotemporal lobar degeneration ( n = 69) and the other with Alzheimer's disease ( n = 178). In the second step, we describe more precisely the phenotype of patients with the association of idiopathic normal pressure hydrocephalus and behavioural variant of frontotemporal lobar degeneration. Firstly, we report that the prevalence of idiopathic normal pressure hydrocephalus was far higher in the group of patients with behavioural variant of frontotemporal lobar degeneration than in the group of patients with Alzheimer's disease (7.25% and 1.1%, respectively, P = 0.02). Secondly, we show that patients with the double diagnosis share common clinical and para-clinical features of both idiopathic normal pressure hydrocephalus and behavioural variant of frontotemporal lobar degeneration patients, including CSF shunting efficacy in real-life experience. Overall, our results suggest a link between these two conditions and should encourage neurologists to look for idiopathic normal pressure hydrocephalus in their behavioural variant of frontotemporal lobar degeneration patients in the event of gait disturbances; the benefit/risk balance could indeed be in favour of shunt surgery for selected patients with this newly described entity., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.)

We evaluated the relationship between eye movements and future thinking. More specifically, we evaluated whether maintained fixation could influence cognitive characteristics of future thinking. We invited participants to imagine future events in two conditions: while freely exploring a white wall and while fixating a cross on the wall. Results demonstrated fewer and longer fixations, as well as fewer and shorter saccades during maintained fixation condition than in the free gaze condition. Shorter total amplitude of saccades was also observed during the maintained fixation condition than during the free-gaze condition. Regarding the cognitive characteristics of future thinking, fewer spatiotemporal details and less visual imagery, slower retrieval time, and shorter descriptions were observed for future thinking during maintained fixation than during free-gaze condition. These results demonstrate that maintaining fixation results in an effortful construction of future scenarios. We suggest that maintained fixation limits the cognitive resources that are required for future thinking., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Diagnosis of Alzheimer disease (AD) can cause substantial psychological distress in patients. We thus assessed how patients with AD remember the announcement of diagnosis., Methods: We recruited 47 participants with mild AD (26 women; M age=68.89 y, SD=7.37; M years of formal education=9.74, SD=3.00). We invited the participants to remember the moment when their clinicians announced their diagnosis, within 6 months of the event, as well as a control memory, over the same period. We analyzed memory retrieval regarding specificity, as well as the subjective experience of retrieval (ie, regarding mental time travel, visual imagery, emotion and importance)., Results: No significant differences were observed between memory of diagnosis and control memory regarding specificity, mental time travel and visual imagery. However, memory of diagnosis triggered a more intense emotional experience and feeling of importance than control memory., Discussion: Retrieval of the diagnosis announcement can activate a strong emotional and personally important experience in patients with AD. When remembering the diagnosis announcement, patients with AD may re-experience some features of that turning point in which they shift from "person" to "patient.", Competing Interests: The authors declare no conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: We present the preliminary study of the 42-item Semantic Memory Test (SMT-42), a test developed to distinguish semantic variant primary progressive aphasia (svPPA) from the other variants: logopenic (lPPA) and nonfluent/agrammatic (naPPA). The test requires the patient to retrieve the conceptual features of items belonging to different lexical categories., Methods: In the first study, we administered the French version of the SMT-42 to a population of healthy subjects and to patients with svPPA matched to a subgroup of the healthy subjects. In the second study, we administered the SMT-42 to four groups of patients (with svPPA, lPPA, naPPA and Alzheimer's disease [AD], respectively) to study its capacity to differentiate patients suffering from svPPA from the other patients., Results: In the first study, 109 healthy subjects were included, 15 of whom were paired with 15 subjects presenting with svPPA. In the second study, designed to compare groups presenting a primary progressive aphasia variant and AD, 12 subjects with svPPA, 6 with naPPA and 9 with lPPA were included, along with 21 subjects with AD. The subjects presenting a semantic deficit were clearly distinguished from the others by their results on the SMT-42 (svPPA: mean = 30.0 (5.9); lPPA: mean = 37.8 (3.3), d = 1.5, p = 0.002; naPPA: mean = 39.8 (1.9), d = 1.89, p = 0.001; AD: mean = 38.5 (2.4), d = 1.63, p < 0.001); (svPPA: median = 31; lPPA: median = 38, U = 9, p = 0.002; naPPA: median = 40.5, U = 1.5, p = 0.001; AD: median = 39, U = 13.5, p < 0.001)., Conclusion: The SMT-42 is simple, rapidly administered (3 minutes on average), easily scored and has good sensitivity, and it appears to be an effective tool for semantic screening in routine clinical practice.

We assessed how Alzheimer's disease (AD) patients would imagine their self in the future. AD patients and healthy controls were asked to generate statements beginning with "I-will-be" to describe how they saw themselves or how they wished to be in the future. These statements were analyzed in terms of four self-dimensions, i.e., physical self, social self, psychological self and self-cessation. The latter was investigated to assess how AD patients processed the idea of their own mortality. Findings demonstrated fewer total "I-will-be" statements in AD participants than in controls, suggesting that the construction of future self-concepts becomes weaker in the disease. Our results also demonstrated fewer statements related to the physical-self, the social-self and the psychological-self, and more statements related to self-cessation in AD participants than in controls. These findings suggest that AD patients are highly preoccupied by the idea of death when thinking about the future of their self., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background and Aims: Autobiographical memory serves to recall past personal experiences and share them with others, promoting social bonding and communication. In this study, we investigated whether encouraging patients with Alzheimer's disease (AD) to share autobiographical memories during formal neuropsychological testing may boost the patient-clinician relationship, and more specifically, the neuropsychologist's level of sympathy as perceived by patients., Methods: We invited patients with mild AD to perform neuropsychological testing in two conditions. In one condition, we invited patients to retrieve and share two autobiographical memories after testing, while in a control condition, the testing session ended without asking patients to retrieve and share any autobiographical memories. After the two conditions, patients were invited to rate the neuropsychologist's level of sympathy towards them., Results: Analysis demonstrated that patients perceived a higher level of sympathy when their neuropsychologist invited them to retrieve and share past personal experiences., Discussion: By inviting patients with AD to retrieve past personal experiences, clinicians can promote a sense of sharing, create a social bond and, consequently, enhance the therapeutic relationship. In other words, by inviting patients with AD to share autobiographical memories, clinicians can promote a "social glue" with their patients, boosting mutual sympathy and patients' well-being., (© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

We investigated whether pupil size can variate with the intensity of cognitive processing in patients with behavioral-variant-Frontotemporal-Dementia (bvFTD). We invited five bvFTD participants and 21 controls to perform forward spans and backward spans, and, in a control condition, to count aloud. We recorded pupil activity using eye-tracking-glasses during the spans and control condition. Analysis demonstrated larger pupil sizes during backward spans than during forward spans, and larger pupil sizes during forward spans than during counting in both bvFTD and control participants. These findings demonstrate how increased cognitive load triggers increased pupil size and how this connection is maintained in bvFTD.

Abstract: While visiting and socialization restrictions during lockdowns were instituted to cope with the Covid-19 spread and to prolong the life of residents of retirement homes, these measures could have been expected to decrease the quality of life of their residents.We assessed longitudinal effects of the two successive lockdowns, as implemented in France, on mental health (i.e., depression, anxiety, and loneliness) in 62 retirement home residents with Alzheimer disease (AD).Analysis demonstrated higher levels of depression, anxiety, and loneliness during the second lockdown than during the first lockdown.The increased levels of depression, anxiety, and loneliness during the second lockdown can be attributed to the longer duration of the restrictive measures, especially the restriction of visits, that were implemented in retirement homes. In addition, the increased workload of geriatric healthcare workers leading to higher levels of burnout and decreased quality of care may help explain the increased loneliness, depression, and anxiety of retirement home residents with AD, which were observed during the second Covid-19 era lockdown., Competing Interests: The authors declare that they have no conflict of interest., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

Temporal discounting refers to the tendency to prefer smaller sooner rewards over larger later rewards. Prior research has reported temporal discounting in Alzheimer's disease (AD). We thus investigated, in this study, the relationship between temporal discounting and future thinking in AD. The study included 40 patients with AD and 42 control participants. We invited participants, on a temporal discounting task, to choose between an immediate but smaller or a delayed but larger amount of money (e.g. "would you prefer 10 dollars today or 50 dollars after one month?"). We also invited the participants to imagine events that may happen in the future, a task known as future thinking. Analysis demonstrated a bias toward immediate rewards (i.e. temporal discounting) as well as difficulties to imagine specific future events in patients with AD. Critically, temporal discounting and future thinking in AD were significantly correlated. Generally speaking, a lack of thinking about the future may lead to impulsive behavior. More specifically, decline in future thinking in AD may limit the ability of patients to project themselves in time to consider outcomes of their decisions, resulting in a tendency to devaluate future rewards in favor of more imminent ones (i.e. temporal discounting).

Background: The objective of this study was twofold. We assessed whether individuals with Alzheimer's disease (AD) demonstrate higher empathy toward people with the same disorder. We also assessed whether empathy may enhance the recognition of these peoples' faces., Method: Twenty-seven mild AD participants and 30 healthy older adults were invited to retain faces depicting either people diagnosed with AD or healthy people. Participants were also invited to rate their empathy toward all faces., Results: Although AD participants reported higher empathy for "AD-labeled" than for "healthy" faces, recognition was similar for both categories of faces. Healthy older adults also reported higher empathy for "AD-labeled" than for "healthy" faces. However, they demonstrated higher recognition for "healthy" than for "AD-labeled" faces., Conclusions: Although our paper shows no effect of empathy on face recognition in AD, it provides a clinically relevant finding: individuals with mild AD can demonstrate significant empathy toward people with the same medical condition.

Platelet-derived growth factor receptor beta (PDGFRB) is one of the genes associated with primary familial brain calcification (PFBC), an inherited neurological disease (OMIM:173410). Genetic analysis of patients and families revealed at least 13 PDGFRB heterozygous missense variants, including two novel ones described in the present report. Limited experimental data published on five of these variants had suggested that they decrease the receptor activity. No functional information was available on the impact of variants located within the receptor extracellular domains. Here, we performed a comprehensive molecular analysis of PDGFRB variants linked to PFBC. Mutated receptors were transfected in various cell lines to monitor receptor expression, signaling, mitogenic activity and ligand binding. Four mutants caused a complete loss of tyrosine kinase activity in multiple assays. One of the novel variants, p.Pro154Ser, decreased the receptor expression and abolished binding of platelet-derived growth factor (PDGF-BB). Others showed a partial loss of function related to reduced expression or signaling. Combining clinical, genetic and molecular data, we consider nine variants as pathogenic or likely pathogenic, three as benign or likely benign and one as a variant of unknown significance. We discuss the possible relationship between the variant residual activity, incomplete penetrance, brain calcification and neurological symptoms. In conclusion, we identified distinct molecular mechanisms whereby PDGFRB variants may result in a receptor loss of function. This work will facilitate genetic counseling in PFBC., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

It is well established that pupil activity indexes cognitive processing. For instance, research has consistently demonstrated that the pupil reacts to working memory span task performance. However, little is known about pupil reaction to cognitive processing in Alzheimer's Disease (AD). We thus investigated whether span tasks can modulate pupil size in patients with AD. We invited 24 patients with AD and 24 healthy older adults to perform backward and forward spans, as well as to count aloud in a control condition, while their pupil activity was recorded with eye tracking glasses. In patients with AD, analysis demonstrated larger pupil size during backward spans ( M = 2.12, SD = .39) than during forward spans ( M = 1.98, SD = .36) [ t (23) = 3.22, p = .004], larger pupil size during forward spans than during counting ( M = 1.67, SD = .33) [ t (23) = 4.75, p < .001], as well as larger pupil size during backward spans than during counting [ t (23) = 10.60, p < .001]. In control participants, analysis demonstrated larger pupil size during backward spans ( M = 3.36, SD = .49) than during forward spans ( M = 2.85, SD = .68) [ t (23) = 5.82, p < .001], larger pupil size during forward spans than during counting ( M = 2.09, SD = .62) [ t (23) = 5.42, < .001], as well as larger pupil size during backward spans than during counting [ t (23) = 9.70, p < .001]. Results also demonstrated a significant interaction effect between groups and conditions [ F (2,92) = 16.63, p < .001]; in other words, patients with AD have shown fewer variations on the pupil size across the conditions compared to the control participants. The larger pupil size during backward spans, compared with forward spans or counting, can be attributed to the high cognitive load of backward spans. The modulation of pupil size, as observed across backward/forward spans and counting, can possibly be attributed to sympathetic/adrenergic and parasympathetic/cholinergic activities. Our study demonstrates the value of pupillometry as a potential biomarker of cognitive processing in AD., (Copyright © 2022 El Haj et al.)

Objective: Neurofilament light chain (NfL) is a promising biomarker in genetic frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). We evaluated plasma neurofilament light chain (pNfL) levels in controls, and their longitudinal trajectories in C9orf72 and GRN cohorts from presymptomatic to clinical stages., Methods: We analysed pNfL using Single Molecule Array (SiMoA) in 668 samples (352 baseline and 316 follow-up) of C9orf72 and GRN patients, presymptomatic carriers (PS) and controls aged between 21 and 83. They were longitudinally evaluated over a period of >2 years, during which four PS became prodromal/symptomatic. Associations between pNfL and clinical-genetic variables, and longitudinal NfL changes, were investigated using generalised and linear mixed-effects models. Optimal cut-offs were determined using the Youden Index., Results: pNfL levels increased with age in controls, from ~5 to~18 pg/mL (p<0.0001), progressing over time (mean annualised rate of change (ARC): +3.9%/year, p<0.0001). Patients displayed higher levels and greater longitudinal progression (ARC: +26.7%, p<0.0001), with gene-specific trajectories. GRN patients had higher levels than C9orf72 (86.21 vs 39.49 pg/mL, p=0.014), and greater progression rates (ARC:+29.3% vs +24.7%; p=0.016). In C9orf72 patients, levels were associated with the phenotype (ALS: 71.76 pg/mL, FTD: 37.16, psychiatric: 15.3; p=0.003) and remarkably lower in slowly progressive patients (24.11, ARC: +2.5%; p=0.05). Mean ARC was +3.2% in PS and +7.3% in prodromal carriers. We proposed gene-specific cut-offs differentiating patients from controls by decades., Conclusions: This study highlights the importance of gene-specific and age-specific references for clinical and therapeutic trials in genetic FTD/ALS. It supports the usefulness of repeating pNfL measurements and considering ARC as a prognostic marker of disease progression., Trial Registration Numbers: NCT02590276 and NCT04014673., Competing Interests: Competing interests: Disclosure of interests unrelated to the present article: ILB served as a member of advisory board for Prevail Therapeutics and of the steering committee for Alector, and received research grants from ANR, DGOS, PHRC, ARSla Association, Fondation Plan Alzheimer outside of the present work., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

C9orf72 repeat expansions are rarely associated with primary progressive aphasias (PPA). In-depth characterization of the linguistic deficits, and the underlying patterns of grey-matter atrophy in PPA associated with the C9orf72 expansions (PPA-C9orf72) are currently lacking. In this study, we comprehensively analyzed a unique series of 16 patients affected by PPA-C9orf72. Eleven patients were issued from two independent French and Finnish cohorts, and five were identified by means of literature review. Voxel-based morphometry (VBM) studies were performed on three of them. This study depicts the spectrum of C9orf72-related aphasic phenotypes, and illustrates their linguistic presentation. The non-fluent/agrammatic variant was the most frequent phenotype in our series (9/16 patients, 56%), with apraxia of speech being the main defining feature. Left frontal lobe atrophy was present in these subjects, peaking in inferior frontal gyrus. Three patients (19%) showed the semantic variant, with progression of atrophy in temporo-polar regions, later involving orbitofrontal cortex. Anterior temporal lobe dysfunction was also particularly relevant in two patients (12.5%) with mixed forms of PPA. Lastly, two patients (12.5%) had unclassifiable PPA with predominating word-finding difficulties. No PPA-C9orf72 patients in our series fulfilled the criteria of the logopenic variant. Importantly, this study underlines the role of C9orf72 mutation in the disruption of the most anterior parts of the language network, including prefrontal and temporo-polar areas. It provides guidelines for C9orf72 testing in PPA patients, with important clinical impact as gene-specific therapies are upcoming., Competing Interests: Declaration of competing interest Disclosure of interests related to the present article: The authors declare no conflicts of interest. Disclosure of interests unrelated to the present article: ILB served as a member of advisory boards for Prevail Therapeutic and Alector, and received research grants from ANR, DGOS, Vaincre Alzheimer Association, ARSla Association, Fondation Plan Alzheimer, JPND outside of the present work., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

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. 18 F-DOPA PET imaging and/or CSF biomarkers were available in some patients. LeSCoD scale was systematically administered and the potential correlation with 18 F-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 18 F-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., (© 2021. Springer-Verlag GmbH Germany, part of Springer Nature.)