Agricultural activities and risk of Alzheimer's disease: the TRACTOR project, a nationwide retrospective cohort study.

Data regarding Alzheimer's disease (AD) occurrence in farming populations is lacking. This study aimed to investigate whether, among the entire French farm manager (FM) workforce, certain agricultural activities are more strongly associated with AD than others, using nationwide data from the TRACTOR (Tracking and monitoring occupational risks in agriculture) project. Administrative health insurance data (digital electronic health/medical records and insurance claims) for the entire French agricultural workforce, over the period 2002-2016, on the entire mainland France were used to estimate the risk of AD for 26 agricultural activities with Cox proportional hazards model. For each analysis (one for each activity), the exposed group included all FMs that performed the activity of interest (e.g. crop farming), while the reference group included all FMs who did not carry out the activity of interest (e.g. FMs that never farmed crops between 2002 and 2016). There were 5067 cases among 1,036,069 FMs who worked at least one year between 2002 and 2016. Analyses showed higher risks of AD for crop farming (hazard ratio (HR) = 3.72 [3.47-3.98]), viticulture (HR = 1.29 [1.18-1.42]), and fruit arboriculture (HR = 1.36 [1.15-1.62]). By contrast, lower risks of AD were found for several animal farming types, in particular for poultry and rabbit farming (HR = 0.29 [0.20-0.44]), ovine and caprine farming (HR = 0.50 [0.41-0.61]), mixed dairy and cow farming (HR = 0.46 [0.37-0.57]), dairy farming (HR = 0.67 [0.61-0.73]), and pig farming (HR = 0.30 [0.18-0.52]). This study shed some light on the association between a wide range of agricultural activities and AD in the entire French FMs population.

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.

Hippocampal activity during memory and visual perception: The role of representational content.

The functional organisation of the medial temporal lobe (MTL) has long been described on the basis of cognitive processes such as recollection or familiarity. However, this view has recently been challenged, and researchers have proposed decomposing cognitive phenomena into representations and operations. According to the representational view, representations, such as scenes for the hippocampus and objects for the perirhinal cortex, are critical in understanding the role of MTL regions in cognition. In the present study, 51 healthy young participants underwent functional magnetic resonance imaging (fMRI) while completing a visual-discrimination task. Subsequently, half of the participants performed a patch-cue recognition procedure in which "Rec" responses are believed to reflect the operation of pattern completion, whereas the other half performed a whole-item remember/know procedure. We replicated the previously-reported demonstration that hippocampal involvement in pattern completion is preferential for scenes as compared with objects. In contrast, the perirhinal cortex was more recruited for object processing than for scene processing. We further extended these results to the operations of strength-signal memory and visual discrimination. Finally, the modulation of hippocampal engagement in pattern completion by representational content was found to be specific to its anterior segment. This observation is consistent with the proposal that this segment would process broad/global representations, whereas the posterior hippocampus would perform sharp/local representations. Taken together, these results favour the representational view of MTL functional organisation, but support that this specialisation differs along the hippocampal long-axis.

Prodromal characteristics of dementia with Lewy bodies: baseline results of the MEMENTO memory clinics nationwide cohort.

BACKGROUND: Isolated subjective cognitive impairment (SCI) and mild cognitive impairment (MCI) are the prodromal phases of dementia with Lewy bodies (DLB). MEMENTO is a nationwide study of patients with SCI and MCI with clinic, neuropsychology, biology, and brain imaging data. We aimed to compare SCI and MCI patients with symptoms of prodromal DLB to others in this study at baseline. METHODS: Participants of the French MEMENTO cohort study were recruited for either SCI or MCI. Among them, 892 were included in the Lewy sub-study, designed to search specifically for symptoms of DLB. Probable prodromal DLB diagnosis (pro-DLB group) was done using a two-criteria cutoff score among the four core clinical features of DLB. This Pro-DLB group was compared to two other groups at baseline: one without any core symptoms (NS group) and the one with one core symptom (1S group). A comprehensive cognitive battery, questionnaires on behavior, neurovegetative and neurosensory symptoms, brain 3D volumetric MRI, CSF, FDG PET, and amyloid PET were done. RESULTS: The pro-DLB group comprised 148 patients (16.6%). This group showed more multidomain (59.8%) MCI with slower processing speed and a higher proportion of patients with depression, anxiety, apathy, constipation, rhinorrhea, sicca syndrome, and photophobia, compared to the NS group. The pro-DLB group had isolated lower P-Tau in the CSF (not significant after adjustments for confounders) and on brain MRI widening of sulci including fronto-insular, occipital, and olfactory sulci (FDR corrected), when compared to the NS group. Evolution to dementia was not different between the three groups over a median follow-up of 2.6 years. CONCLUSIONS: Patients with symptoms of prodromal DLB are cognitively slower, with more behavioral disorders, autonomic symptoms, and photophobia. The occipital, fronto-insular, and olfactory bulb involvement on brain MRI was consistent with symptoms and known neuropathology. The next step will be to study the clinical, biological, and imaging evolution of these patients. TRIAL REGISTRATION: Clinicaltrials.gov , NCT01926249.

Early-Onset Cerebral Amyloid Angiopathy and Alzheimer Disease Related to an APP Locus Triplication.

BACKGROUND AND OBJECTIVE: To report a triplication of the amyloid-ß precursor protein (APP) locus along with relative messenger RNA (mRNA) expression in a family with autosomal dominant early-onset cerebral amyloid angiopathy (CAA) and Alzheimer disease (AD). METHODS: Four copies of the APP gene were identified by quantitative multiplex PCR of short fluorescent fragments, fluorescent in situ hybridization (FISH), and array comparative genomic hybridization. APP mRNA levels were assessed using reverse-transcription-digital droplet PCR in the proband's whole blood and compared with 10 controls and 9 APP duplication carriers. RESULTS: Beginning at age 39 years, the proband developed severe episodic memory deficits with a CSF biomarker profile typical of AD and multiple lobar microbleeds in the posterior regions on brain MRI. His father had seizures and recurrent cerebral hemorrhage since the age of 37 years. His cerebral biopsy showed abundant perivascular amyloid deposits, leading to a diagnosis of CAA. In the proband, we identified 4 copies of a 506-kb region located on chromosome 21q21.3 and encompassing the whole APP gene without any other gene. FISH suggested that the genotype of the proband was 3 copies/1 copy corresponding to an APP locus triplication, which was consistent with the presence of 2 APP copies in the healthy mother and with the paternal medical history. Analysis of the APP mRNA level showed a 2-fold increase in the proband and a 1.8 fold increase in APP duplication carriers compared with controls. DISCUSSION: Increased copy number of APP is sufficient to cause AD and CAA, with likely earlier onset in case of triplication compared with duplication.

Daily life activities in patients with Alzheimer's disease or semantic dementia: Multitasking assessment.

The aim of the present study was to compare patients with mild to moderate Alzheimer's disease (AD) or semantic dementia (SD) on their cognitive processes and the severity of their daily life activity impairments. Three types of tasks were administered to patients (SD = 15; AD = 31) and 30 healthy controls (HC): 1) informant-based scales and questionnaires, 2) a neuropsychological assessment exploring executive functions, episodic and semantic memory, and 3) a new original test featuring multi-step naturalistic actions and multitasking: the Sequential Daily Life Multitasking (SDLM). We predicted that patients with AD would mainly exhibit task perplexity, associated with episodic and executive deficits on the SDLM, while the behavior of patients with SD would mostly be characterized by object perplexity, associated with semantic memory deficits. Results showed that patients with AD or SD were impaired across all neuropsychological tests, particularly episodic memory in AD and semantic memory in SD. General performance on the SDLM also appeared dramatically impaired in both patient groups, and correlated with results of questionnaires about instrumental activities and memory impairments. However, specific qualitative measurements on the SDLM did not allow us to pinpoint different patterns of errors and behavior in patients with AD versus SD. We suggest that the inability of patients in both groups to perform the SDLM may derive from a constellation of disorders or else from more subtle impairment of cognitive and conative processes that requires further exploration.

Impact of emotionally negative information on attentional processes in normal aging and Alzheimer's disease.

Impairments of emotional processing have been reported in Alzheimer's disease (AD), consistently with the existence of early amygdala atrophy in the pathology. In this study, we hypothesized that patients with AD might show a deficit of orientation toward emotional information under conditions of visual search. Eighteen patients with AD, 24 age-matched controls, and 35 young controls were eye-tracked while they performed a visual search task on a computer screen. The target was a vehicle with implicit (negative or neutral) emotional content, presented concurrently with one, three, or five non-vehicle neutral distractors. The task was to find the target and to report whether a break in the target frame was on the left or on the right side. Both control groups detected negative targets more efficiently than they detected neutral targets, showing facilitated engagement toward negative information. In contrast, patients with AD showed no influence of emotional information on engagement delays. However, all groups reported the frame break location more slowly for negative than for neutral targets (after accounting for the last fixation delay), showing a more difficult disengagement from negative information. These findings are the first to highlight a selective lack of emotional influence on engagement processes in patients with AD. The involvement of amygdala alterations in this behavioral impairment remains to be investigated.

Brain Volume Predicts Behavioral and Psychological Symptoms in Alzheimer's Disease.

BACKGROUND: Behavioral and psychological symptoms of dementia (BPSD) are frequent and troublesome for patients and caregivers. Considering possible preventive approaches, a better understanding of underlying neural correlates of BPSD is crucial. OBJECTIVE: The aim is to assess whether brain regional volume predicts behavioral changes in mild AD. METHODS: This work took part from the PACO study, a multicenter and prospective study that included 252 patients with mild AD from 2009 to 2014. Fifty-three patients were retained. Forty healthy matched control subjects from the ADNI cohort were included as controls. Voxel-based morphometry analysis was conducted to assess regional brain volume using baseline MRI scans as a predictor of future behavioral changes over a period of 18 months. Behavior was assessed at baseline and longitudinally at 6-month intervals using the shortened form of the Neuropsychiatric Inventory (NPI). RESULTS: The volume of 23 brain structures in frontal, temporal, parietal, occipital, subcortical regions and cerebellum predicted the evolution of NPI scores. Frontal volume was the most powerful predictor with frontal gyri, anterior cingulate cortex, and orbital gyri being particularly involved. CONCLUSION: To our knowledge, this is the first study assessing regional brain volumes as predictors of behavioral changes considered at earlier stages of AD. Up to 23 brain structures were associated with an increased risk of developing BPSD. Frontal lobe volume was the strongest predictor of future evolution of NPI. The involvement of multiple structures in the prediction of behavior suggests a role of the main large-scale networks involved in cognition.

The - weak - role of memory in tool use: Evidence from neurodegenerative diseases.

OBJECTIVE: Although tool use disorders are frequent in neurodegenerative diseases, the question of which cognitive mechanisms are at stake is still under debate. Memory-based hypotheses (i.e., the semantic knowledge hypothesis and the manipulation knowledge hypothesis) posit that tool use relies solely on stored information about either tools or gestures whereas a reasoning-based hypothesis (i.e., the technical-semantic hypothesis) suggests that loss of semantic knowledge can be partially compensated by technical reasoning about the physical properties of tools and objects. METHOD: These three hypotheses were tested by comparing performance of 30 healthy controls, 30 patients with Alzheimer's disease and 13 patients with semantic dementia in gesture production tasks (i.e., pantomime of tool use, single tool use, real tool use) and tool or gesture recognition tasks (i.e., functional and contextual matching, recognition of tool manipulation). Individual, item-based patterns of performance were analyzed to answer the following question: Could participants demonstrate the use of tools about which they had lost knowledge? With this aim in mind, "validation" and "rebuttal" frequencies were calculated based on each prediction. RESULTS: Predictions from the technical-semantic hypothesis were more frequently observed than memory-based predictions. A number of patients were able to use and demonstrate the use of tools for which they had lost either semantic or manipulation knowledge (or both). CONCLUSIONS: These data lead to question the role of different types of memory in tool use. The hypothesis of stored, tool-specific knowledge does not predict accurately clinical performances at the individual level. This may lead to explore the influence of either additional memory systems (e.g., personal/impersonal memory) or other modes of reasoning (e.g., theory of mind) on tool use skills.

Study protocol on Alzheimer's disease and related disorders: focus on clinical and imaging predictive markers in co-existing lesions.

BACKGROUND: One of the crucial challenges for the future of therapeutic approaches to Alzheimer's disease (AD) is to target the main pathological processes responsible for disability and dependency. However, a progressive cognitive impairment occurring after the age of 70, the main population affected by dementia, is often related to mixed lesions of neurodegenerative and vascular origins. Whereas young patients are mostly affected by pure lesions, ageing favours the occurrence of co-lesions of AD, cerebrovascular disease (CVD) and Lewy body dementia (LBD). Most of clinical studies report on functional and clinical disabilities in patients with presumed pure pathologies. But, the weight of co-morbid processes involved in the transition from an independent functional status to disability in the elderly with co-lesions still remains to be elucidated. Neuropathological examination often performed at late stages cannot answer this question at mild or moderate stages of cognitive disorders. Brain MRI, Single Photon Emission Computed Tomography (SPECT) with DaTscan®, amyloid Positron Emission Tomography (PET) and CerebroSpinal Fluid (CSF) AD biomarkers routinely help in performing the diagnosis of underlying lesions. The combination of these measures seems to be of incremental value for the diagnosis of mixed profiles of AD, CVD and LBD. The aim is to determine the clinical, neuropsychological, neuroradiological and biological features the most predictive of cognitive, behavioral and functional impairment at 2 years in patients with co-existing lesions. METHODS: A multicentre and prospective cohort study with clinical, neuro-imaging and biological markers assessment will recruit 214 patients over 70 years old with a cognitive disorder of AD, cerebrovascular and Lewy body type or with coexisting lesions of two or three of these pathologies and fulfilling the diagnostic criteria for dementia at a mild to moderate stage. Patients will be followed every 6 months (clinical, neuropsychological and imaging examination and collection of cognitive, behavioural and functional impairment) for 24 months. DISCUSSION: This study aims at identifying the best combination of markers (clinical, neuropsychological, MRI, SPECT-DaTscan®, PET and CSF) to predict disability progression in elderly patients presenting coexisting patterns. TRIAL REGISTRATION: NCT02052947 .

Structural, Microstructural, and Metabolic Alterations in Primary Progressive Aphasia Variants.

Neuroimaging studies have described the brain alterations in primary progressive aphasia (PPA) variants (semantic, logopenic, nonfluent/agrammatic). However, few studies combined T1, FDG-PET, and diffusion MRI techniques to study atrophy, hypometabolism, and tract alterations across the three PPA main variants. We therefore explored a large early-stage cohort of semantic, logopenic and nonfluent/agrammatic variants (N = 86) and of 23 matched healthy controls with anatomical MRI (cortical thickness), FDG PET (metabolism) and diffusion MRI (white matter tracts analyses), aiming at identifying cortical and sub-cortical brain alterations, and confronting these alterations across imaging modalities and aphasia variants. In the semantic variant, there was cortical thinning and hypometabolism in anterior temporal cortices, with left-hemisphere predominance, extending toward posterior temporal regions, and affecting tracts projecting to the anterior temporal lobes (inferior longitudinal fasciculus, uncinate fasciculus) and tracts projecting to or running nearby posterior temporal cortices: (superior longitudinal fasciculus, inferior frontal-occipital fasciculus). In the logopenic variant metabolic alterations were more extensive than atrophy affecting mainly the left temporal-parietal junction and extending toward more anterior temporal cortices. Metabolic and tract data were coherent given the alterations of the left superior and inferior longitudinal fasciculus and the left inferior frontal-occipital fasciculus. In the nonfluent/agrammatic variant cortical thinning and hypometabolism were located in the left frontal cortex but Broca's area was only affected on metabolic measures. Metabolic and tract alterations were coherent as reflected by damage to the left uncinate fasciculus connecting with Broca's area. Our findings provide a full-blown statistically robust picture of brain alterations in early-stage variants of primary progressive aphasia which has implications for diagnosis, classification and future therapeutic strategies. They demonstrate that in logopenic and semantic variants patterns of brain damage display a non-negligible overlap in temporal regions whereas they are substantially distinct in the nonfluent/agrammatic variant (frontal regions). These results also indicate that frontal networks (combinatorial syntax/phonology) and temporal networks (lexical/semantic representations) constitute distinct anatomo-functional entities with differential vulnerability to degenerative processes in aphasia variants. Finally, the identification of the specific damage patterns could open an avenue for trans-cranial stimulation approaches by indicating the appropriate target-entry into the damaged language system.

Early Emotional Attention is Impacted in Alzheimer's Disease: An Eye-Tracking Study.

Emotional deficits have been repetitively reported in Alzheimer's disease (AD) without clearly identifying how emotional processing is impaired in this pathology. This paper describes an investigation of early emotional processing, as measured by the effects of emotional visual stimuli on a saccadic task involving both pro (PS) and anti (AS) saccades. Sixteen patients with AD and 25 age-matched healthy controls were eye-tracked while they had to quickly move their gaze toward a positive, negative, or neutral image presented on a computer screen (in the PS condition) or away from the image (in the AS condition). The age-matched controls made more AS mistakes for negative stimuli than for other stimuli, and triggered PSs toward negative stimuli more quickly than toward other stimuli. In contrast, patients with AD showed no difference with regard to the emotional category in any of the tasks. The present study is the first to highlight a lack of early emotional attention in patients with AD. These results should be taken into account in the care provided to patients with AD, since this early impairment might seriously degrade their overall emotional functioning.

Cerebral microbleeds and CSF Alzheimer biomarkers in primary progressive aphasias.

OBJECTIVE: To reveal the prevalence and localization of cerebral microbleeds (CMBs) in the 3 main variants of primary progressive aphasia (PPA) (logopenic, semantic, and nonfluent/agrammatic), to identify the relationship with underlying Alzheimer pathology, and to explore whether CMBs contribute to language breakdown. METHODS: We used a cross-sectional design in a multicenter cohort of 82 patients with PPA and 19 similarly aged healthy controls. MRI allowed for rating CMBs (2-dimensional gradient recalled echo T2*, susceptibility weighted imaging sequences) and white matter hyperintensities. CSF Alzheimer disease biomarker analyses available in 63 of the 82 patients provided the stratification of PPA into subgroups with patients who had or did not have probable underlying Alzheimer pathology. RESULTS: The prevalence of CMBs was higher in patients with PPA (28%) than in controls (16%). They were more prevalent in logopenic PPA (50%) than in semantic PPA (18%) and nonfluent/agrammatic PPA (17%). The localization of CMBs was mainly lobar (81%) with no difference between the PPA variants. CMBs were more frequent in PPA patients with positive than with negative CSF Alzheimer disease biomarkers (67% vs 20%). Patients with and without lobar CMBs had similar volumes of white matter hyperintensities. Language and general cognitive impairment in PPA was unrelated to CMB rates. CONCLUSIONS: CMB prevalence in PPA is higher than in healthy controls. CMBs were most prevalent in the logopenic variant, were related to underlying Alzheimer pathology, and did not affect the language/cognitive impairment. Our findings also suggest that CMB detection with MRI contributes to PPA variant diagnosis, especially of logopenic PPA, and provides an estimator of the underlying neuropathology.

Cognitive and imaging markers in non-demented subjects attending a memory clinic: study design and baseline findings of the MEMENTO cohort.

BACKGROUND: The natural history and disease mechanisms of Alzheimer's disease and related disorders (ADRD) are still poorly understood. Very few resources are available to scrutinise patients as early as needed and to use integrative approaches combining standardised, repeated clinical investigations and cutting-edge biomarker measurements. METHODS: In the nationwide French MEMENTO cohort study, participants were recruited in memory clinics and screened for either isolated subjective cognitive complaints (SCCs) or mild cognitive impairment (MCI; defined as test performance 1.5 SD below age, sex and education-level norms) while not demented (Clinical Dementia Rating [CDR] <1). Baseline data collection included neurological and physical examinations as well as extensive neuropsychological testing. To be included in the MEMENTO cohort, participants had to agree to undergo both brain magnetic resonance imaging (MRI) and blood sampling. Cerebral 18F-fluorodeoxyglucose positon emission tomography and lumbar puncture were optional. Automated analyses of cerebral MRI included assessments of volumes of whole-brain, hippocampal and white matter lesions. RESULTS: The 2323 participants, recruited from April 2011 to June 2014, were aged 71 years, on average (SD 8.7), and 62% were women. CDR was 0 in 40% of participants, and 30% carried at least one apolipoprotein E ε4 allele. We observed that more than half (52%) of participants had amnestic mild cognitive impairment (17% single-domain aMCI), 32% had non-amnestic mild cognitive impairment (16.9% single-domain naMCI) and 16% had isolated SCCs. Multivariable analyses of neuroimaging markers associations with cognitive categories showed that participants with aMCI had worse levels of imaging biomarkers than the others, whereas participants with naMCI had markers at intermediate levels between SCC and aMCI. The burden of white matter lesions tended to be larger in participants with aMCI. Independently of CDR, all neuroimaging and neuropsychological markers worsened with age, whereas differences were not consistent according to sex. CONCLUSIONS: MEMENTO is a large cohort with extensive clinical, neuropsychological and neuroimaging data and represents a platform for studying the natural history of ADRD in a large group of participants with different subtypes of MCI (amnestic or not amnestic) or isolated SCCs. TRIAL REGISTRATION: Clinicaltrials.gov, NCT01926249 . Registered on 16 August 2013.

Rethinking the Cognitive Mechanisms Underlying Pantomime of Tool Use: Evidence from Alzheimer's Disease and Semantic Dementia.

OBJECTIVES: Pantomiming the use of familiar tools is a central test in the assessment of apraxia. However, surprisingly, the nature of the underlying cognitive mechanisms remains an unresolved issue. The aim of this study is to shed a new light on this issue by exploring the role of functional, mechanical, and manipulation knowledge in patients with Alzheimer's disease and semantic dementia and apraxia of tool use. METHODS: We performed multiple regression analyses with the global performance and the nature of errors (i.e., production and conception) made during a pantomime of tool use task in patients and control participants as dependent variables and tasks investigating functional, mechanical, and manipulation knowledge as predictors. RESULTS: We found that mechanical problem solving, assessing mechanical knowledge, was a good predictor of the global performance of pantomime of tool use. We also found that occurrence of conception errors was robustly predicted by the task assessing functional knowledge whereas that of production errors was not explained by only one predictor. CONCLUSIONS: Our results suggest that both functional and mechanical knowledge are important to pantomime the use of tools. To our knowledge, this is the first demonstration that mechanical knowledge plays a role in pantomime of tool use. Although impairment in pantomime of tool use tasks (i.e., apraxia) is widely explained by the disruption of manipulation knowledge, we propose that pantomime of tool use is a complex problem-solving task. (JINS, 2017, 23, 128-138).

Tool use disorders in neurodegenerative diseases: Roles of semantic memory and technical reasoning.

In the field of apraxia, it has been suggested that the ability to use tools and objects in daily life depends not only on semantic knowledge about tool function and context of use but also on technical reasoning about mechanical properties of tools and objects. The aim of the present work was to assess tool use abilities regarding these hypotheses in patients with neurodegenerative diseases and reduced autonomy. Performance of patients with Alzheimer's disease (AD) (n = 31), semantic dementia (SD) (n = 16) and corticobasal syndrome (CBS) (n = 7) was compared to that of healthy control participants (n = 31) in familiar tool use tasks, functional/contextual associations and mechanical problem solving (MPS). A conversion method was applied to data in order to avoid ceiling effects. Tool use disorders were found in all patient groups but the underlying reasons were different. Patients with SD had difficulties in imagining and selecting familiar tools due to the semantic loss but they performed in normal range in MPS tasks. Interestingly, they performed better with only one tool and its corresponding object, which is interpreted as a partial compensation of semantic loss by spared technical reasoning. Patients with CBS exhibited the reverse pattern, that is, MPS deficits without semantic loss. However, additional qualitative research is needed to disentangle the relative contributions of motor and technical reasoning deficits to this pattern. Both of these profiles were found in patients with AD. For all that, these patients did not commit the same errors as stroke patients with left brain-damage documented in previous works. Several hypotheses are proposed to account for the specificity of tool use disorders in neurodegenerative diseases, and recommendations are provided to caregivers.

Morphologic and neuropsychological patterns in patients suffering from Alzheimer's disease.

INTRODUCTION: We conducted a retrospective study to identify morphological subgroups of patients referred for AD or aMCI and to seek for differences across neuropsychological performances. METHODS: One hundred forty-five patients (mean age = 76.01, 88 women and 57 men) referred for AD, either at the stage of dementia or aMCI, were examined using structural MRI. Five observers reviewed blindly twice all examinations. We rated microangiopathy, hippocampal, parietal atrophies, including a gradient of fronto-parietal atrophy (GFPA). A multiple component analysis (MCA) followed by a hierarchical ascending classification was conducted to identify morphologically distinct subgroups. Among these, 76 patients completed all the neuropsychological tests. Univariate and multivariate analyses were further conducted on these data across morphological subgroups. The institutional review board approved the research protocol. RESULTS: Inter- and intra-raters' agreements were excellent and very good for microangiopathy and hippocampal atrophy ratings. They were higher for GFPA than for the parietal atrophy scale. MCA without priors identified three groups: group 1 was characterized by no/discrete microangiopathy, severe hippocampal, and predominant parietal atrophy; group 2 had significant microangiopathy, severe hippocampal atrophy, and no predominant parietal atrophy; group 3 had a mild hippocampal atrophy and parietal atrophies. In group 1, working memory profile was less impaired than in group 2 (p = 0.01). Neuropsychological performances of group 3 were higher in most domains. CONCLUSION: Combined characterization of microangiopathy, hippocampal, parietal, and GFPA allows identifying morphological subgroups among patients referred for AD and at risk. These groups have some neuropsychological differences, suggesting different pathophysiological mechanisms or co-existing conditions.

Screening of dementia genes by whole-exome sequencing in early-onset Alzheimer disease: input and lessons.

Causative variants in APP, PSEN1 or PSEN2 account for a majority of cases of autosomal dominant early-onset Alzheimer disease (ADEOAD, onset before 65 years). Variant detection rates in other EOAD patients, that is, with family history of late-onset AD (LOAD) (and no incidence of EOAD) and sporadic cases might be much lower. We analyzed the genomes from 264 patients using whole-exome sequencing (WES) with high depth of coverage: 90 EOAD patients with family history of LOAD and no incidence of EOAD in the family and 174 patients with sporadic AD starting between 51 and 65 years. We found three PSEN1 and one PSEN2 causative, probably or possibly causative variants in four patients (1.5%). Given the absence of PSEN1, PSEN2 and APP causative variants, we investigated whether these 260 patients might be burdened with protein-modifying variants in 20 genes that were previously shown to cause other types of dementia when mutated. For this analysis, we included an additional set of 160 patients who were previously shown to be free of causative variants in PSEN1, PSEN2 and APP: 107 ADEOAD patients and 53 sporadic EOAD patients with an age of onset before 51 years. In these 420 patients, we detected no variant that might modify the function of the 20 dementia-causing genes. We conclude that EOAD patients with family history of LOAD and no incidence of EOAD in the family or patients with sporadic AD starting between 51 and 65 years have a low variant-detection rate in AD genes.

Mechanical problem-solving strategies in Alzheimer's disease and semantic dementia.

OBJECTIVE: The goal of this study was to explore whether the tool-use disorders observed in Alzheimer's disease (AD) and semantic dementia (SD) are of the same nature as those observed in left brain-damaged (LBD) patients. Recent evidence indicates that LBD patients with apraxia of tool use encounter difficulties in solving mechanical problems, characterized by the absence of specific strategies. This pattern may show the presence of impaired mechanical knowledge, critical for both familiar and novel tool use. So, we explored the strategies followed by AD and SD patients in mechanical problem-solving tasks in order to determine whether mechanical knowledge is also impaired in these patients. METHOD: We used a mechanical problem-solving task in both choice (i.e., several tools were proposed) and no-choice (i.e., only 1 tool was proposed) conditions. We analyzed quantitative data and strategy profiles. RESULTS: AD patients but not SD patients met difficulties in solving mechanical problem-solving tasks. However, the key finding is that AD patients, despite their difficulties, showed strategy profiles that are similar to that of SD patients or controls. Moreover, AD patients exhibited a strategy profile distinct from the one previously observed in LBD patients. CONCLUSIONS: Those observations lead us to consider that difficulties met by AD patients to solve mechanical problems or even to use familiar tools may not be caused by mechanical knowledge impairment per se. In broad terms, what we call apraxia of tool use in AD is certainly not the same as apraxia of tool use observed in LBD patients. (PsycINFO Database Record