A digital teleneuropsychology platform for the diagnosis of mild cognitive impairment: from concept to certification as a medical device.

BACKGROUND: Innovative digital solutions are shaping a new concept of dementia care, opening additional venues for prevention, diagnosis, monitoring and treatment. Hereby, we report the development of a tablet-based teleneuropsychology platform (Tenèpsia®), from concept to certification as Medical Device (MD) Class IIA, as per new MD regulation 745/2017. METHODS: The platform was designed for the remote cognitive evaluation and created thanks to the effort of a collaborative working group including experts from three Italian scientific societies and Biogen Italia S.r.l. (hereafter "Biogen"), and developers from Xenia Reply and Inside AI. The development strategy was guided by converting traditional paper-and-pencil tests into digital versions while maintaining comparable neuropsychological features and optimizing patient accessibility and user experience. The experts focused on the choice and adaptation of traditional neuropsychology measures for a 45-min teleneuropsychology assessment. RESULTS: The developers created a web and a mobile interface, respectively, for the professional (neuropsychologist) and non-professional (patient and caregiver) use. Recording of voice, drawing and typing information was enabled. Instant dashboards provide a quick overview of the patient's condition. Simulation activities were performed to obtain MD certification, valid across Europe. CONCLUSION: Neuropsychology services will benefit from the implementation in clinics of harmonized digital tools with adequate scientific and technological standards. The use of digital cognitive testing for the diagnosis of mild cognitive impairment is expected to enhance patient and clinician outcomes through simplified, digital objective data collection, sparing of time and resources, with a positive impact on healthcare costs and access to treatments, reducing inequalities and delays in diagnosis and cure.

Associations between Neuropsychiatric Symptoms and Alzheimer's Disease Biomarkers in People with Mild Cognitive Impairment.

BACKGROUND: Neuropsychiatric symptoms (NPS) are associated with faster decline in mild cognitive impairment (MCI). This study aimed to investigate the association between NPS severity and Alzheimer's disease (AD) biomarkers, i.e., amyloid-ß (Aß), phosphorylated tau protein (p-tau) and hippocampal volume ratio (HR), to characterise in more detail MCI patients with a poor prognosis. METHODS: A total of 506 individuals with MCI and 99 cognitively unimpaired older adults were selected from the ADNI dataset. The patients were divided into three different groups based on their NPI-Q total scores: no NPS (n = 198), mild NPS (n = 160) and severe NPS (n = 148). Regression models were used to assess the association between the severity of NPS and each biomarker level and positivity status. RESULTS: Cerebrospinal fluid Aß levels were positively associated with older age and lower MMSE scores, while higher p-tau levels were associated with female sex and lower MMSE scores. Only patients with severe NPS had a lower HR (ß = -0.18, p = 0.050), i.e., more pronounced medio-temporal atrophy, than those without NPS. DISCUSSION: Only HR was associated with the presence of NPS, partially in line with previous evidence showing that severe NPS may be explained primarily by greater grey matter loss. Future longitudinal studies will be needed to ascertain the relevance of this finding.

Multiancestry analysis of the HLA locus in Alzheimer's and Parkinson's diseases uncovers a shared adaptive immune response mediated by HLA-DRB1*04 subtypes.

Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson's disease (PD) and Alzheimer's disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1*04 subtypes best accounted for the association, strongest with HLA-DRB1*04:04 and HLA-DRB1*04:07, and intermediary with HLA-DRB1*04:01 and HLA-DRB1*04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased Aß42. Protective HLA-DRB1*04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1*04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues.

Individual differences among older adults with mild and moderate dementia in social and emotional loneliness and their associations with cognitive and psychological functioning.

BACKGROUND: Loneliness is a major health issue among older adults. The aim of this study was to assess the relationship between loneliness, in its social and emotional facets, and the cognitive (language), and behavioral/psychological functioning as well as quality of life (QoL) in people with mild and moderate dementia, i.e., considering dementia severity as an individual characteristic. METHODS: This cross-sectional study involved 58 people with mild dementia and 55 people with moderate dementia. Participants completed the Social and Emotional Loneliness scale, along with measures assessing their language skills, the frequency and severity of their behavioral and psychological symptoms, and their QoL. RESULTS: Socio-demographic characteristics and depression, but not loneliness or its social and emotional facets, contributed to explain participants' behavioral and psychological symptoms, regardless of dementia severity. Loneliness explained, though to a small extent (8% of variance), language skills in people with moderate dementia, with social loneliness only accounting for language skills (18% of variance) in this group. Loneliness also modestly accounted for dysphoria symptoms in both the mildly and moderately impaired (6% and 5% of variance, respectively) individuals with social loneliness predicting dysphoric mood in the former group only (7% of variance). Loneliness also explained, to a larger extent, QoL in both the mildly impaired and moderately impaired individuals (27% and 20% of variance, respectively), its social facet predicting QoL in the mildly impaired (30% of variance), and its emotional facet in the moderately impaired (21% of variance) group. CONCLUSION: These findings suggest that loneliness and its facets have a clear impact on perceived QoL, and influence the language skills and dysphoria symptoms of people with dementia, to a degree that depends on dementia severity. The assessment of loneliness and its facets in people with dementia considering dementia severity, and the promotion of social inclusion to reduce it should be considered by professionals.

Dementia-related genetic variants in an Italian population of early-onset Alzheimer's disease.

Early-onset Alzheimer's disease (EOAD) is the most common form of early-onset dementia. Although three major genes have been identified as causative, the genetic contribution to the disease remains unsolved in many patients. Recent studies have identified pathogenic variants in genes representing a risk factor for developing Alzheimer's disease (AD) and in causative genes for other degenerative dementias as responsible for EOAD. To study them further, we investigated a panel of candidate genes in 102 Italian EOAD patients, 45.10% of whom had a positive family history and 21.74% with a strong family history of dementia. We found that 10.78% of patients carried pathogenic or likely pathogenic variants, including a novel variant, in PSEN1, PSEN2, or APP, and 7.84% showed homozygosity for the ε4 APOE allele. Additionally, 7.84% of patients had a moderate risk allele in PSEN1, PSEN2, or TREM2 genes. Besides, we observed that 12.75% of our patients carried only a variant in genes associated with other neurodegenerative diseases. The combination of these variants contributes to explain 46% of cases with a definite familiarity and 32% of sporadic forms. Our results confirm the importance of extensive genetic screening in EOAD for clinical purposes, to select patients for future treatments and to contribute to the definition of overlapping pathogenic mechanisms between AD and other forms of dementia.

Association of Rare APOE Missense Variants V236E and R251G With Risk of Alzheimer Disease.

Importance: The APOE ε2 and APOE ε4 alleles are the strongest protective and risk-increasing, respectively, genetic variants for late-onset Alzheimer disease (AD). However, the mechanisms linking APOE to AD-particularly the apoE protein's role in AD pathogenesis and how this is affected by APOE variants-remain poorly understood. Identifying missense variants in addition to APOE ε2 and APOE ε4 could provide critical new insights, but given the low frequency of additional missense variants, AD genetic cohorts have previously been too small to interrogate this question robustly. Objective: To determine whether rare missense variants on APOE are associated with AD risk. Design, Setting, and Participants: Association with case-control status was tested in a sequenced discovery sample (stage 1) and followed up in several microarray imputed cohorts as well as the UK Biobank whole-exome sequencing resource using a proxy-AD phenotype (stages 2 and 3). This study combined case-control, family-based, population-based, and longitudinal AD-related cohorts that recruited referred and volunteer participants. Stage 1 included 37 409 nonunique participants of European or admixed European ancestry, with 11 868 individuals with AD and 11 934 controls passing analysis inclusion criteria. In stages 2 and 3, 475 473 participants were considered across 8 cohorts, of which 84 513 individuals with AD and proxy-AD and 328 372 controls passed inclusion criteria. Selection criteria were cohort specific, and this study was performed a posteriori on individuals who were genotyped. Among the available genotypes, 76 195 were excluded. All data were retrieved between September 2015 and November 2021 and analyzed between April and November 2021. Main Outcomes and Measures: In primary analyses, the AD risk associated with each missense variant was estimated, as appropriate, with either linear mixed-model regression or logistic regression. In secondary analyses, associations were estimated with age at onset using linear mixed-model regression and risk of conversion to AD using competing-risk regression. Results: A total of 544 384 participants were analyzed in the primary case-control analysis; 312 476 (57.4%) were female, and the mean (SD; range) age was 64.9 (15.2; 40-110) years. Two missense variants were associated with a 2-fold to 3-fold decreased AD risk: APOE ε4 (R251G) (odds ratio, 0.44; 95% CI, 0.33-0.59; P = 4.7 × 10-8) and APOE ε3 (V236E) (odds ratio, 0.37; 95% CI, 0.25-0.56; P = 1.9 × 10-6). Additionally, the cumulative incidence of AD in carriers of these variants was found to grow more slowly with age compared with noncarriers. Conclusions and Relevance: In this genetic association study, a novel variant associated with AD was identified: R251G always coinherited with ε4 on the APOE gene, which mitigates the ε4-associated AD risk. The protective effect of the V236E variant, which is always coinherited with ε3 on the APOE gene, was also confirmed. The location of these variants confirms that the carboxyl-terminal portion of apoE plays an important role in AD pathogenesis. The large risk reductions reported here suggest that protein chemistry and functional assays of these variants should be pursued, as they have the potential to guide drug development targeting APOE.

Distinct brain dysfunctions underlying visuo-constructive deficit in DLB and AD.

Visuo-constructive abilities are a multicomponential process that can be impaired in several neurodegenerative dementias. Among visuo-constructive tasks, the Rey-Osterrieth Complex Figure-copy (ROCF-c) is the most commonly used and it seems influenced by different skills mediated by specific brain regions. This task complexity allows exploring differential mechanisms of impairment in different neurodegenerative disorders. In this study we examined the neuroanatomical substrates of ROCF-c performance in patients with Dementia with Lewy Bodies (DLB) and patients with Alzheimer's disease (AD). We included forty-five patients with probable DLB, and thirty-four patients with probable typical-AD. To identify the ROCF-c scores neural correlates we performed a regression analysis with brain hypometabolism using the ROCF-c scores as independent variable. Then we evaluated the correlation between regional hypometabolism and ROCF-c scores in each group separately, throughout offline Pearson correlation analysis. The DLB and AD groups differed only in visuo-constructive and memory performances. DLB patients performed worse at the visuo-constructive test, while typical-AD patients performed worse at the verbal memory task. In DLB, worse performance at ROCF-c scores (more severe visuo-constructive impairment) correlated with occipital and temporo-parietal hypometabolism. In AD, worse performance at ROCF-c score was associated with brain hypometabolism in the temporo-parietal regions. The inability to correctly perform the ROCF-c derives from distinct brain dysfunctions in DLB and AD. The present results suggest alterations in visuoperceptual processes due to the severe occipital hypometabolism in DLB, and in visuospatial processes related to temporo-parietal hypometabolism in AD.

Effects of Dog-Assisted Therapies on Cognitive Mnemonic Capabilities in People Affected by Alzheimer's Disease.

Alzheimer's disease (AD) is the most common cause of dementia in humans and, currently, a valid treatment is lacking. Our goal is to demonstrate the importance and benefits of the relationship with companion animals (considered as co-therapists), intended as a means of facilitating social relations and promoting evident wellbeing in AD patients. The study involved 30 randomly chosen patients with Alzheimer's disease (group T) and three dogs. The group participated in a total of 24 animal-assisted interventions (AAIs) sessions over a span of 12 weeks, using the Mini-Mental State Examination (MMSE), Wellness and Cognitive Ability Questionnaire (Brief Assessment Cognition or BAC), and Alzheimer's Disease Assessment Scale (ADAS) as assessment tests. A second group (group C), consisting of 10 people with AD, was enrolled as control group and underwent the same assessment tests but did not benefit from the presence of the dogs. Tests were carried out at time T0 (before starting sessions), T1 (end of sessions), and T2 (two months after last session). People belonging to group T achieved an overall improvement in their perceived state of wellbeing, even on a cognitive and mnemonic plane. However, two months after the end of the sessions, the test results in people suffering from AD decreased towards the baseline (T0). The study shows how such progress can be achieved through activities based on the relationship with an animal, as long as the animal is a steady presence in the life of the patient receiving the intervention. Dogs involved in other dog-assisted therapies have been found suitable also for assisting patients with AD.

Being the Family Caregiver of a Patient With Dementia During the Coronavirus Disease 2019 Lockdown.

Background: Family caregivers of patients with dementia are at high risk of stress and burden, and quarantine due to the coronavirus disease 2019 (COVID-19) pandemic may have increased the risk of psychological disturbances in this population. The current study was carried out during the national lockdown declared in March 2020 by the Italian government as a containment measure of the first wave of the coronavirus pandemic and is the first nationwide survey on the impact of COVID-19 lockdown on the mental health of dementia informal caregivers. Methods: Eighty-seven dementia centers evenly distributed on the Italian territory enrolled 4,710 caregiver-patient pairs. Caregivers underwent a telephone interview assessing classical symptoms of caregiver stress and concern for the consequences of COVID-19 infection on patient's health. We calculated prevalence of symptoms and regressed them on various potential stress risk factors: caregivers' sociodemographic characteristics and lifestyle, patients' clinical features, and lockdown-related elements, like discontinuity in medical care. Results: Approximately 90% of caregivers reported at least one symptom of stress, and nearly 30% reported four or more symptoms. The most prevalent symptoms were concern for consequences of COVID-19 on patient's health (75%) and anxiety (46%). The main risk factors for stress were identified as a conflicting relationship with the patient and discontinuity in assistance, but caregiver's female sex, younger age, lower education, and cohabitation with the patient also had an impact. Availability of help from institutions or private individuals showed a protective effect against sense of abandonment but a detrimental effect on concern about the risk for the patient to contract COVID-19. The only protective factor was mild dementia severity, which was associated with a lower risk of feeling isolated and abandoned; type of dementia, on the other hand, did not affect stress risk. Conclusion: Our results demonstrate the large prevalence of stress in family caregivers of patients with dementia during the COVID-19 pandemic and have identified both caregivers and situations at a higher risk of stress, which should be taken into account in the planning of interventions in support of quarantined families and patients.

Enhancing cognitive training effects in Alzheimer's disease: rTMS as an add-on treatment.

The treatment of Alzheimer's disease (AD) in the field of non-pharmacological interventions is a challenging issue, given the limited benefits of the available drugs. Cognitive training (CT) represents a commonly recommended strategy in AD. Recently, repetitive transcranial magnetic stimulation (rTMS) has gained increasing attention as a promising therapeutic tool for the treatment of AD, given its ability of enhancing neuroplasticity. In the present randomized, double-blind, sham-controlled study, we aimed at investigating the add-on effect of a high frequency rTMS protocol applied over the left dorsolateral prefrontal cortex (DLPFC) combined with a face-name associative memory CT in the continuum of AD pathology. Fifty patients from a very early to a moderate phase of dementia were randomly assigned to one of two groups: CT plus real rTMS or CT plus placebo rTMS. The results showed that the improvement in the trained associative memory induced with rTMS was superior to that obtained with CT alone. Interestingly, the extent of the additional improvement was affected by disease severity and levels of education, with less impaired and more educated patients showing a greater benefit. When testing for generalization to non-trained cognitive functions, results indicated that patients in CT-real group showed also a greater improvement in visuospatial reasoning than those in the CT-sham group. Interestingly, this improvement persisted over 12 weeks after treatment beginning. The present study provides important hints on the promising therapeutic use of rTMS in AD.

Behavioral and Psychological Effects of Coronavirus Disease-19 Quarantine in Patients With Dementia.

BACKGROUND: In March 2020, the World Health Organization declared a global pandemic due to the novel coronavirus SARS-CoV-2 and several governments planned a national quarantine in order to control the virus spread. Acute psychological effects of quarantine in frail elderly subjects with special needs, such as patients with dementia, have been poorly investigated. The aim of this study was to assess modifications of neuropsychiatric symptoms during quarantine in patients with dementia and their caregivers. METHODS: This is a sub-study of a multicenter nation-wide survey. A structured telephone interview was delivered to family caregivers of patients with diagnosis of Alzheimer disease (AD), dementia with Lewy bodies (DLB), frontotemporal dementia (FTD), and vascular dementia (VD), followed regularly at 87 Italian memory clinics. Variations in behavioral and psychological symptoms (BPSD) were collected after 1 month since quarantine declaration and associations with disease type, severity, gender, and caregiver's stress burden were analyzed. RESULTS: A total of 4,913 caregivers participated in the survey. Increased BPSD was reported in 59.6% of patients as worsening of preexisting symptoms (51.9%) or as new onset (26%), and requested drug modifications in 27.6% of these cases. Irritability, apathy, agitation, and anxiety were the most frequently reported worsening symptoms and sleep disorder and irritability the most frequent new symptoms. Profile of BPSD varied according to dementia type, disease severity, and patients' gender. Anxiety and depression were associated with a diagnosis of AD (OR 1.35, CI: 1.12-1.62), mild to moderate disease severity and female gender. DLB was significantly associated with a higher risk of worsening hallucinations (OR 5.29, CI 3.66-7.64) and sleep disorder (OR 1.69, CI 1.25-2.29), FTD with wandering (OR 1.62, CI 1.12-2.35), and change of appetite (OR 1.52, CI 1.03-2.25). Stress-related symptoms were experienced by two-thirds of caregivers and were associated with increased patients' neuropsychiatric burden (p<0.0001). CONCLUSION: Quarantine induces a rapid increase of BPSD in approximately 60% of patients and stress-related symptoms in two-thirds of caregivers. Health services need to plan a post-pandemic strategy in order to address these emerging needs.

The Role of Free and Cued Selective Reminding Test in Predicting [18F]Florbetaben PET Results in Mild Cognitive Impairment and Mild Dementia.

BACKGROUND: Free and Cued Selective Reminding Test (FCSRT) is a reliable cognitive marker for Alzheimer's disease (AD), and the identification of neuropsychological tests sensitive to the early signs of AD pathology is crucial both in research and clinical practice. OBJECTIVE: The study aimed to ascertain the ability of FCSRT in predicting the amyloid load as determined from amyloid PET imaging (Amy-PET) in patients with cognitive disorders. METHODS: For our purpose, 79 patients (71 MCI, 8 mild dementia) underwent a complete workup for dementia, including the FCSRT assessment and a [18F]florbetaben PET scan. FCSRT subitem scores were used as predictors in different binomial regression models. RESULTS: Immediate free recall and delayed free recall were the best predictors overall in the whole sample; whereas in patients <76 years, all models further improved with immediate total recall (ITR) and Index of Sensitivity of Cueing (ISC) resulting the most accurate in anticipating Amy-PET results, with a likelihood of being Amy-PET positive greater than 85% for ITR and ISC scores of less than 25 and 0.5, respectively. CONCLUSION: FCSRT proved itself to be a valid tool in dementia diagnosis, also being able to correlate with amyloid pathology. The possibility to predict Amy-PET results through a simple and reliable neuropsychological test might be helpful for clinicians in the dementia field, adding value to a paper and pencil tool compared to most costly biomarkers.

The Impact of COVID-19 Quarantine on Patients With Dementia and Family Caregivers: A Nation-Wide Survey.

INTRODUCTION: Previous studies showed that quarantine for pandemic diseases is associated with several psychological and medical effects. The consequences of quarantine for COVID-19 pandemic in patients with dementia are unknown. We investigated the clinical changes in patients with Alzheimer's disease and other dementias, and evaluated caregivers' distress during COVID-19 quarantine. METHODS: The study involved 87 Italian Dementia Centers. Patients with Alzheimer's Disease (AD), Dementia with Lewy Bodies (DLB), Frontotemporal Dementia (FTD), and Vascular Dementia (VD) were eligible for the study. Family caregivers of patients with dementia were interviewed by phone in April 2020, 45 days after quarantine declaration. Main outcomes were patients' changes in cognitive, behavioral, and motor symptoms. Secondary outcomes were effects on caregivers' psychological features. RESULTS: 4913 patients (2934 females, 1979 males) fulfilled the inclusion criteria. Caregivers reported a worsening in cognitive functions in 55.1% of patients, mainly in subjects with DLB and AD. Aggravation of behavioral symptoms was observed in 51.9% of patients. In logistic regression analysis, previous physical independence was associated with both cognitive and behavioral worsening (odds ratio 1.85 [95% CI 1.42-2.39], 1.84 [95% CI 1.43-2.38], respectively). On the contrary, pandemic awareness was a protective factor for the worsening of cognitive and behavioral symptoms (odds ratio 0.74 [95% CI 0.65-0.85]; and 0.72 [95% CI 0.63-0.82], respectively). Approximately 25.9% of patients showed the onset of new behavioral symptoms. A worsening in motor function was reported by 36.7% of patients. Finally, caregivers reported a high increase in anxiety, depression, and distress. CONCLUSION: Our study shows that quarantine for COVID-19 is associated with an acute worsening of clinical symptoms in patients with dementia as well as increase of caregivers' burden. Our findings emphasize the importance to implement new strategies to mitigate the effects of quarantine in patients with dementia.

Two distinct pathological substrates associated with MMSE-pentagons item deficit in DLB and AD.

INTRODUCTION: Dementia with Lewy Bodies (DLB) is characterized by a prominent deficit in visuospatial abilities. Visuospatial impairment is also detectable in the course of Alzheimer's dementia (AD). However, visuospatial impairment presents some differences in these two conditions, suggesting pathological involvement of distinct brain circuits. Recent studies applied a new method to score the Mini Mental State Examination (MMSE) pentagon copy subtest, namely the Qualitative Scoring Pentagon Test (QSPT), which is a sensitive measure of visuospatial abilities. Using [18F]fluorodeoxy-glucose positron emission tomography (FDG-PET), we assessed the relationship between in vivo brain metabolic dysfunction and visuospatial deficits, in terms of QSPT total value, in DLB and AD. MATERIALS AND METHODS: Sixty Patients were diagnosed as DLB (n = 35) and AD (n = 25) dementia according with the standard research diagnostic criteria. Each patient underwent a FDG-PET scan as support for the final diagnosis. Patients underwent an extended neuropsychological evaluation, including MMSE, language, memory, executive functions and visuospatial abilities tests. The MMSE QSPT scoring was calculated following the methods by Caffarra et al. (2013). Offline voxel-wise correlation analysis between QSPT total scores and FDG-PET brain metabolism was then performed, correcting for MMSE, sex and disease duration. RESULTS: Both groups presented reduced visuospatial performances, as assessed by QSPT scores. DLB compared to AD showed a statistically significant difference in QSPT rotation parameter (p = 0.022). In DLB, worse performance at QSPT total score, i.e. more severe visuospatial impairment, correlated with brain occipital hypometabolism (i.e. lateral occipital cortex, calcarine cortex, fusiform and lingual gyri). In AD, worse performance at QSPT total score correlated with brain hypometabolism in the right parietal cortex (i.e. superior and inferior parietal cortex and angular gyrus). DISCUSSION: These findings reveal that visuospatial deficits may derive from distinct brain alterations in AD and DLB. We propose that the inabilities to perform correctly the QSPT task is related to altered visuoperceptual process in DLB, and visuospatial process in AD. This is consistent with our results showing hypometabolism in brain system related to visuoperceptual processing, namely the occipital cortex in DLB, and visuospatial processing, namely parietal cortex in AD.

ABCA1- and ABCG1-mediated cholesterol efflux capacity of cerebrospinal fluid is impaired in Alzheimer's disease.

HDL-like particles in human cerebrospinal fluid (CSF) promote the efflux of cholesterol from astrocytes toward the neurons that rely on this supply for their functions. We evaluated whether cell cholesterol efflux capacity of CSF (CSF-CEC) is impaired in Alzheimer's disease (AD) by analyzing AD (n = 37) patients, non-AD dementia (non-AD DEM; n = 16) patients, and control subjects (n = 39). As expected, AD patients showed reduced CSF Aß 1-42, increased total and phosphorylated tau, and a higher frequency of the apoε4 genotype. ABCA1- and ABCG1-mediated CSF-CEC was markedly reduced in AD (-73% and -33%, respectively) but not in non-AD DEM patients, in which a reduced passive diffusion CEC (-40%) was observed. Non-AD DEM patients displayed lower CSF apoE concentrations (-24%) compared with controls, while apoA-I levels were similar among groups. No differences in CSF-CEC were found by stratifying subjects for apoε4 status. ABCG1 CSF-CEC positively correlated with Aß 1-42 (r = 0.305, P = 0.025), while ABCA1 CSF-CEC inversely correlated with total and phosphorylated tau (r = -0.348, P = 0.018 and r = -0.294, P = 0.048, respectively). The CSF-CEC impairment and the correlation with the neurobiochemical markers suggest a pathophysiological link between CSF HDL-like particle dysfunction and neurodegeneration in AD.

CSF biomarkers and amyloid PET: concordance and diagnostic accuracy in a MCI cohort.

Brain amyloid deposition is one of the main hallmarks of Alzheimer's disease (AD) and two approaches are available for assessing amyloid pathology in vivo: cerebrospinal fluid (CSF) biomarkers levels and amyloid load visualized by amyloid beta positron emission tomography imaging (Amy-PET) probes. We aimed to investigate the concordance between CSF biomarkers and Amy-PET in a memory clinic cohort. Moreover, using a proper clinical follow-up, we wanted to assess the diagnostic accuracy of CSF and PET biomarkers in predicting the progression of patients with mild cognitive impairment (MCI) to AD dementia. We included 31 MCI patients who underwent [18F]florbetaben PET and CSF sampling (Aß1-42, t-Tau, p-Tau). A semiquantitative visual scan assessment was used to quantify amyloid deposition in 5 brain regions, rating from 1 (negative), to 2 and 3 (positive). CSF biomarkers were considered abnormal if: Aß1-42 < 600 pg/ml, p-Tau/Aß1-42 > 0.08 and t-Tau/Aß1-42 > 0.52. We also applied less lenient cutoffs of 550 pg/ml and 450 pg/ml for Aß1-42. The concordance rate was 77% between Amy-PET and CSF Aß1-42 levels, and 89% between Amy-PET and p-Tau/Aß1-42 and t-Tau/Aß1-42. According to the clinical follow-up, Amy-PET (sensitivity [SE] 93.7%, specificity [SP] 80%) exhibited the best diagnostic accuracy in discriminating AD from non-AD, followed by p-Tau/Aß1-42 ratio and t-Tau/Aß1-42 ratio (SE 93.7%, SP 66.6%), and Aß1-42 levels (SE 81%, SP 60%). The regional uptake of [18F]florbetaben PET in the precuneus and the striatum showed the best SP (86.6%). In discordant cases, the clinical diagnosis was most often in agreement with PET results. In general, concordance between CSF biomarkers and Amy-PET was good, especially when the ratios between CSF amyloid and Tau biomarkers were used. However, Amy-PET proved to be superior to CSF Aß1-42 in terms of diagnostic accuracy for AD, with the possibility to further increase its specificity by focusing the analysis in specific areas such as the precuneus/posterior cingulate cortex and the striatum.

Transethnic meta-analysis of rare coding variants in PLCG2, ABI3, and TREM2 supports their general contribution to Alzheimer's disease.

Rare coding variants in TREM2, PLCG2, and ABI3 were recently associated with the susceptibility to Alzheimer's disease (AD) in Caucasians. Frequencies and AD-associated effects of variants differ across ethnicities. To start filling the gap on AD genetics in South America and assess the impact of these variants across ethnicity, we studied these variants in Argentinian population in association with ancestry. TREM2 (rs143332484 and rs75932628), PLCG2 (rs72824905), and ABI3 (rs616338) were genotyped in 419 AD cases and 486 controls. Meta-analysis with European population was performed. Ancestry was estimated from genome-wide genotyping results. All variants show similar frequencies and odds ratios to those previously reported. Their association with AD reach statistical significance by meta-analysis. Although the Argentinian population is an admixture, variant carriers presented mainly Caucasian ancestry. Rare coding variants in TREM2, PLCG2, and ABI3 also modulate susceptibility to AD in populations from Argentina, and they may have a European heritage.

The Incremental Diagnostic Value of [18F]Florbetaben PET and the Pivotal Role of the Neuropsychological Assessment in Clinical Practice.

BACKGROUND: Amyloid pathology is a key feature of Alzheimer's disease (AD) and can be assessed in vivo with amyloid positron emission tomography (PET) imaging. OBJECTIVE: The objective of this study was to evaluate the incremental value of a PET scan with [18F]florbetaben, in terms of changes of diagnosis, diagnostic confidence, and treatment plan when added to a standardized diagnostic workup for cognitive disorders, with particular focus on the role of the neuropsychological assessment, including the Free and Cued Selective Reminding Test (FCSRT). METHODS: A total of 104 patients (69 mild cognitive impairment, 35 dementia), with diagnostic uncertainty after diagnostic workup, were recruited from our memory clinic. [18F]florbetaben PET scans were interpreted as amyloid negative or positive on the basis of a semi-quantitative visual rating. Clinical diagnosis and diagnostic confidence for AD or non-AD dementia were rated before and after PET result disclosure, as was the impact of PET on the patient management plan. RESULTS: There were 69/104 (66%) [18F]florbetaben positive scans, 51/62 (82%) patients were suspected as having AD before the PET scan and 18/42 (43%) were not. Overall, the data obtained at PET changed 18/104 diagnoses (17%) and increased diagnostic confidence from 69.1±8.1% to 83.5±9.1 (p < 0.001), with the greatest impact on diagnosis and confidence in PET negative patients with an initial diagnosis of AD (p < 0.01) and in early-onset patients (p = 0.01). CONCLUSION: Amyloid PET represents a source of added value in dementia diagnosis, with a significant effect on diagnosis and diagnostic confidence. However, the use of a complete neuropsychological assessment has an add-on value on limiting the amyloid PET influence on change of diagnosis, and the real impact of amyloid PET should always be weighed up together with an accurate standardized diagnostic workup.

Qualitative Evaluation of the Immediate Copy of the Rey-Osterrieth Complex Figure: Comparison Between Vascular and Degenerative MCI Patients.

OBJECTIVE: The immediate copy of the Rey-Osterrieth Complex Figure (ROCF) is considered a visuo-spatial test. However, reproducing this complex structure possibly involves also executive functions, such as planning and organizational strategies. In a previous study, we found a high rate of impaired performances in this test in a sample of subcortical vascular mild cognitive impairment patients. Executive functions contribution in the immediate copy of the ROCF can be assessed with the Boston Qualitative Scoring System (BQSS). We aimed at examining whether BQSS executive scores of ROCF immediate copy: (1) differ between vascular (v-MCI) and degenerative MCI (d-MCI) patients; (2) can at least partly explain the high rate of abnormal ROCF immediate copy performances in v-MCI patients. METHOD: Thirty d-MCI patients (age 75.2 ± 4.4) and 27 v-MCI (age 73.2 ± 6.9) were enrolled. The performances of patients were scored using the BQSS executive scores (Fragmentation, Planning, Organization, Perseveration) during the accomplishment of ROCF immediate copy. RESULTS: Comparing d-MCI and v-MCI performances, d-MCI patients scored worse on ROCF delayed recall (9.9 ± 4.7 vs. 13.4 ± 5.9, p = .020) and MMSE (23.9 ± 2.6 vs. 27.8 ± 2.3, p = .001) while v-MCI patients had more frequently impaired performances in ROCF immediate copy (40% vs. 81%, p = .001) and showed worse scores on Fragmentation (2.4 ± 0.9 vs. 1.8 ± 1.3, p = .035), Planning (2.4 ± 0.8 vs. 1.8 ± 1, p = .039), Organization (4.8 ± 1.3 vs. 3.6 ± 2.1, p = .017), and Perseveration (3.5 ± 0.8 vs. 2.9 ± 1.2, p = .048). CONCLUSIONS: The performance of v-MCI patients in ROCF immediate copy seemed to be more affected by executive dysfunction than the performance obtained by d-MCI. When analyzing ROCF performances, a qualitative approach allows to evaluate patients' strategies during the reproduction, and thus to discriminate between executive and visuo-constructional abilities.