Abstract Introduction The International Working Group recommended the Free and Cued Selective Reminding Test (FCSRT) as a sensitive detector of the amnesic syndrome of the hippocampal type in typical ...Alzheimer's disease (AD). But does it differentiate AD from other neurodegenerative diseases? Methods We assessed the FCSRT and cerebrospinal fluid (CSF) AD biomarkers in 992 cases. Experts, blinded to biomarker data, attributed in 650 cases a diagnosis of typical AD, frontotemporal dementia, posterior cortical atrophy, Lewy body disease, progressive supranuclear palsy, corticobasal syndrome, primary progressive aphasias, “subjective cognitive decline,” or depression. Results The FCSRT distinguished typical AD from all other conditions with a sensitivity of 100% and a specificity of 75%. Non-AD neurodegenerative diseases with positive AD CSF biomarkers (“atypical AD”) did not have lower FCSRT scores than those with negative biomarkers. Discussion The FCSRT is a reliable tool for diagnosing typical AD among various neurodegenerative diseases. At an individual level, however, its specificity is not absolute. Our findings also widen the spectrum of atypical AD to multiple neurodegenerative conditions.
The SORL1 protein plays a protective role against the secretion of the amyloid β peptide, a key event in the pathogeny of Alzheimer's disease. We assessed the impact of SORL1 rare variants in ...early-onset Alzheimer's disease (EOAD) in a case-control setting. We conducted a whole exome analysis among 484 French EOAD patients and 498 ethnically matched controls. After collapsing rare variants (minor allele frequency ≤1%), we detected an enrichment of disruptive and predicted damaging missense SORL1 variants in cases (odds radio (OR)=5.03, 95% confidence interval (CI)=(2.02-14.99), P=7.49.10(-5)). This enrichment was even stronger when restricting the analysis to the 205 cases with a positive family history (OR=8.86, 95% CI=(3.35-27.31), P=3.82.10(-7)). We conclude that predicted damaging rare SORL1 variants are a strong risk factor for EOAD and that the association signal is mainly driven by cases with positive family history.
To determine the prevalence of early-onset Alzheimer disease (EOAD) and of autosomal dominant forms of EOAD (ADEOAD), we performed a population-based study in the city of Rouen (426,710 residents). ...EOAD was defined as onset of disease at age <61 years, and ADEOAD was defined as the occurrence of at least three EOAD cases in three generations. Using these stringent criteria, we calculated that the EOAD and ADEOAD prevalences per 100,000 persons at risk were 41.2 and 5.3, respectively. We then performed a mutational analysis of the genes for amyloid precursor protein (
APP), presenilin 1 (
PSEN1), and presenilin 2 (
PSEN2) in 34 families with ADEOAD ascertained in France. In 19 (56%) of these families, we identified 16 distinct
PSEN1 missense mutations, including 4 (Thr147Ile, Trp165Cys, Leu173Trp, and Ser390Ile) not reported elsewhere.
APP mutations, including a novel mutation located at codon 715, were identified in 5 (15%) of the families. In the 10 remaining ADEOAD families and in 9 additional autosomal dominant Alzheimer disease families that did not fulfill the strict criteria for ADEOAD, no
PSEN1, PSEN2, or
APP mutation was identified. These results show that (1)
PSEN1 and
APP mutations account for 71% of ADEOAD families and (2) nonpenetrance at age <61 years is probably infrequent for
PSEN1 or
APP mutations.
Recent studies have indicated that gamma band oscillations participate in the temporal binding needed for the synchronization of cortical networks involved in short-term memory and attentional ...processes. To date, no study has explored the temporal dynamics of gamma band in the early stages of dementia. At baseline, gamma band analysis was performed in 29 cases with mild cognitive impairment (MCI) during the
n
-back task. Based on phase diagrams, multiple linear regression models were built to explore the relationship between the cognitive status and gamma oscillation changes over time. Individual measures of phase diagram complexity were made using fractal dimension values. After 1 year, all cases were assessed neuropsychologically using the same battery. A total of 16 MCI patients showed progressive cognitive decline (PMCI) and 13 remained stable (SMCI). When adjusted for gamma values at lag −2, and −3 ms, PMCI cases displayed significantly lower average changes in gamma values than SMCI cases both in detection and 2-back tasks. Gamma fractal dimension of PMCI cases displayed significantly higher gamma fractal dimension values compared to SMCI cases. This variable explained 11.8% of the cognitive variability in this series. Our data indicate that the progression of cognitive decline in MCI is associated with early deficits in temporal binding that occur during the activation of selective attention processes.
Self-report is the "gold standard" for pain assessment, however, observational pain scales, such as Doloplus-2 must be used for patients who cannot communicate. In this follow-up study, we report the ...psychometric properties of the observational Doloplus-2 scale using the visual analog scale (VAS) pain score as a gold standard and evaluate its performance.
Prospective clinical study of 180 hospitalized older patients who demonstrated good comprehension and reliable use of the VAS: 131 participants with dementia and 49 without. All participants assessed their chronic pain using the VAS. Doloplus-2 was independently completed by the nursing team.
Mean age of patients (133 women, 47 men) was 83.7+/-6.5. Median mini-mental state examination of patients with diagnosis of dementia was 18.0+/-7.7. Nearly half of the patients (49%) reported that they experienced pain in response to a direct question. The administration of Doloplus-2 was possible in all 180 patients. Doloplus-2 correlated moderately with self-assessment (Spearman coefficient: 0.46). In a multiple regression model, Doloplus-2 predicted 41% of the variability in pain intensity measured by VAS. The somatic dimension alone explained 36% of the variance, the psychosocial bloc 5% with no better contribution of the psychomotor bloc. To shorten Doloplus-2, we constructed a version with only the 5 items that were significantly associated with the VAS score in the multiple regression models.
The observational Doloplus-2 scale correlates moderately with self-assessment pain score and has adequate internal consistency. Our data also suggest that Doloplus-2 could be substantially shortened as the brief version performed similarly to the complete Doloplus-2.
Posterior cortical atrophy (PCA) induces progressive dysfunction of ventral and dorsal visual networks. Little is known, however, about corresponding changes in functional connectivity (FC).
To ...investigate FC changes in the visual networks, their relationship with cortical atrophy, and the association with Alzheimer's disease (AD) pathology.
Ten PCA patients and 28 age-matched controls participated in the study. Using resting state fMRI, we measured FC in ventral and dorsal cortical visual networks, defined on the basis of a priori knowledge of long-range white matter connections. To assess the relationships with AD, we determined AD biomarkers in cerebrospinal fluid and FC in the default mode network (DMN), which is vulnerable to AD pathology. Voxel-based morphometry analysis assessed the pattern of grey matter (GM) atrophy.
PCA patients showed GM atrophy in bilateral occipital and inferior parietal regions. PCA patients had lower FC levels in a ventral network than controls, but higher FC in inferior components of the dorsal network. In particular, the increased connectivity correlated with greater GM atrophy in occipital regions. All PCA patients had positive cerebrospinal fluid biomarkers for AD; however, FC in global DMN did not differ from controls.
FC in PCA reflects brain structure in a non-univocal way. Hyperconnectivity of dorsal networks may indicate aberrant communication in response to posterior brain atrophy or processes of neural resilience during the initial stage of brain dysfunction. The lack of difference from controls in global DMN FC highlights the atypical nature of PCA with respect to typical AD.
To compare the administration of neuropsychological tests by teleneuropsychology (TeleNP) and face to face (F-F) in order to determine the feasibility and reliability of TeleNP.
At the inclusion ...visit, all participants underwent a traditional F-F neuropsychological assessment as part of their standard care. Four months after inclusion, they were randomized to undergo an additional neuropsychological assessment either by F-F administration or by TeleNP.
A total of 150 adults with cognitive complaints, but with no major cognitive or sensorial impairment were included. At 4 months, 69 participants were randomized in the F-F arm and 71 in TeleNP arm (10 lost in the follow-up). The overall satisfaction was high: 87.1% in the TeleNP arm were "very satisfied", and 82.9% indicated no preference between F-F and TeleNP. In agreement with previous data from the literature, neuropsychological assessments gave similar results across both administration conditions for a large majority of tests Mini-Mental State Examination (MMSE), Free and Cued Selective Reminding Test (FCSRT) French version, Mahieux gestural praxis battery, Frontal Assessment Battery (FAB), time of completion of the Trail making Test (TMT) A and B, number of errors of the TMT B, Rey complex figure test, categorical et phonological verbal fluency tests and minor differences for others 80-picture naming test (DO-80), FAB, Digit Span forward and backward and number of errors in the TMT A.
TeleNP is a promising method to be able to test patients as an alternative to F-F condition. Before this procedure can be generalized, it is now necessary to standardize the adaptation of certain tests and to test them in populations with more significant cognitive disorders.
Background. The conversion of mild cognitive impairment (MCI) to Alzheimer's disease is associated with substantial compromise of neocortical circuits subserving rapid cognitive functions such as ...working memory. Event-related potential (ERP) analysis is a powerful tool to identify early impairment of these circuits, yet research for an electrophysiological marker of cognitive deterioration in MCI is scarce. Using a “2-back” activation paradigm, we recently described an electrophysiological correlate of working memory activation (positive-negative working memory PNwm component) over parietal electrodes. Methods. Ours was a longitudinal study of 24 MCI patients with ERP analysis at inclusion and neuropsychological follow-up after 1 year. We used ERP waveform subtraction analysis between the n-back and control tasks. Analysis of variance (ANOVA) was used to compare electroencephalograph latencies between progressive MCI (PMCI) and stable MCI (SMCI), and univariate regression was used to assess the relationship between neuropsychological measures at baseline and clinical outcome. Results. Thirteen (54%) MCI patients showed PMCI, and 11 (46%) remained stable (SMCI). In SMCI, a PNwm component with significantly larger density compared to baseline was identified when subtracting the detection task for both the 1- and 2-back tasks. In contrast, in PMCI, the PNwm component was absent in both 1-back and 2-back conditions. Neuropsychological variables and n-back test performance at inclusion did not predict cognitive deterioration 1 year later. Conclusions. In conjunction with recent functional imaging data, the present results support the notion of an early dysfunction of neural generators within the parietal cortex in MCI. They also reveal that the absence of the PNwm component may provide an easily applicable qualitative predictive marker of rapid cognitive deterioration in MCI.
Aims
A large interindividual variability in plasma concentrations has been reported in patients treated with donepezil, the most frequently prescribed antidementia drug. We aimed to evaluate clinical ...and genetic factors influencing donepezil disposition in a patient population recruited from a naturalistic setting.
Methods
A population pharmacokinetic study was performed including data from 129 older patients treated with donepezil. The patients were genotyped for common polymorphisms in the metabolic enzymes CYP2D6 and CYP3A, in the electron transferring protein POR and the nuclear factor NR1I2 involved in CYP activity and expression, and in the drug transporter ABCB1.
Results
The average donepezil clearance was 7.3 l h−1 with a 30% interindividual variability. Gender markedly influenced donepezil clearance (P < 0.01). Functional alleles of CYP2D6 were identified as unique significant genetic covariate for donepezil clearance (P < 0.01), with poor metabolizers and ultrarapid metabolizers demonstrating, respectively, a 32% slower and a 67% faster donepezil elimination compared with extensive metabolizers.
Conclusion
The pharmacokinetic parameters of donepezil were well described by the developed population model. Functional alleles of CYP2D6 significantly contributed to the variability in donepezil disposition in the patient population and should be further investigated in the context of individual dose optimization to improve clinical outcome and tolerability of the treatment.
In vivo clinical, anatomical and metabolic differences between posterior cortical atrophy (PCA) patients presenting with different Alzheimer's disease (AD) cerebrospinal fluid (CSF) biomarkers ...profiles are still unknown.
Twenty-seven PCA patients underwent CSF examination and were classified as 1) PCA with a typical CSF AD profile (PCA-tAD; abnormal amyloid and T-tau/P-tau biomarkers, n = 13); 2) PCA with an atypical AD CSF profile (PCA-aAD; abnormal amyloid biomarker only, n = 9); and 3) PCA not associated with AD (PCA-nonAD; normal biomarkers, n = 5). All patients underwent clinical and cognitive assessment, structural MRI, and a subset of them underwent brain 18F-FDG PET.
All patients' groups showed a common pattern of posterior GM atrophy and hypometabolism typical of PCA, as well as equivalent demographics and clinical/cognitive profiles. PCA-tAD patients showed a group-specific pattern of hypometabolism in the left fusiform gyrus and inferior temporal gyrus. PCA-aAD did not present a group-specific atrophy pattern. Finally, group-specific gray matter atrophy in the right dorsolateral prefrontal cortex, left caudate nucleus and right medial temporal regions and hypometabolism in the right supplementary motor area and paracentral lobule were observed in PCA-nonAD patients.
Our findings suggest that both PCA-tAD and PCA-aAD patients are on the AD continuum, in agreement with the recently suggested A/T/N model. Furthermore, in PCA, the underlying pathology has an impact at least on the anatomo-functional presentation. Brain damage observed in PCA-tAD and PCA-aAD was mostly consistent with the well-described presentation of the disease, although it was more widespread in PCA-tAD group, especially in the left temporal lobe. Additional fronto-temporal (especially dorsolateral prefrontal) damage seems to be a clue to underlying non-AD pathology in PCA, which warrants the need for longitudinal follow-ups to investigate frontal symptoms in these patients.
•In our sample, approximately 80% PCA patients presented with an AD CSF profile.•In 20% PCA cases, CSF investigations suggested a non-AD pathology.•PCA-AD and PCA-nonAD patients were not clinically different on general measures.•All PCA patients presented the neurodegeneration profile commonly reported in PCA.•PCA-nonAD patients presented additional group-specific neurodegeneration in more anterior fronto-temporal regions.
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