Sarcopenia screening in elderly with Alzheimer's disease: performances of the SARC-F-3 and MSRA-5 questionnaires.

BACKGROUND: The 3-item SARC-F (SARC-F-3) and the 5-item Mini Sarcopenia Risk Assessment (MSRA-5) questionnaires have been recently proposed to screen elderly people regarding the risk of sarcopenia. However, no studies have investigated their performances in Alzheimer's disease (AD). METHODS: We conducted a single-center observational study, including 130 consecutive AD patients (mean age: 70.71 ± 8.50 y, 54.6% women) who attended a center for neurodegenerative diseases. Sarcopenia was diagnosed using the European Working Group on Sarcopenia in Older People of 2010 (EWGSOP1) and of 2018 (EWGSOP2) criteria. Sensitivity, specificity, positive and negative likelihood ratio, and the area under the receiver operating characteristic curve (AUC) were used to assess the diagnostic performance of SARC-F-3 and MSRA-5. RESULTS: SARC-F-3 showed a sensitivity of 9.7%, a specificity of 82.8% and an AUC of 0.41 using EWGSOP1, whereas the sensitivity was of 16.7%, specificity of 84.7% and AUC of 0.58 using EWGSOP2. The MSRA-5 displayed a sensitivity of 3.2%, a specificity of 89.9% and an AUC of 0.41 using EWGSOP1, whereas sensitivity was of 0%, specificity of 91.1% and the AUC of 0.55 using EWGSOP2 criteria. The questionnaires showed a moderate agreement (Cohen's k = 0.53). CONCLUSIONS: In our sample of AD patients, a sizable number of sarcopenic individuals were misidentified by SARC-F-3 and MSRA-5, making those questionnaires unsuitable for sarcopenia screening. Considering that sarcopenia has a high prevalence in dementia and that its correct and timely identification is paramount for optimal management of patients, the development and validation of an ad-hoc sarcopenia screening tool for AD patients is highly desirable.

The diagnostic accuracy of late-life depression is influenced by subjective memory complaints and educational level in an older population in Southern Italy.

The prevalence of late-life depression (LLD) depends on the study sample, measurements, and diagnostic approaches. We estimated the 30 item-Geriatric Depression Scale (GDS-30) accuracy against the gold standard LLD diagnosis made with the Semi-structured Clinical Diagnostic Interview for DSM-IV-TR Axis I Disorders, focusing on the prevalence of a late-life major depressive disorder (MDD), in a population-based sample of 843 subjects aged>65 years, subdivided into three groups: normal cognition, subjective memory complaints, and mild cognitive impairment. At the optimal cut-off score (≥4), the GDS-30 showed 65.1% sensitivity and 68.4% specificity for LLD (63% and 66% for late-life MDD, respectively). Using the standard cut-off score (≥10), the GDS-30 specificity reached 91.2%, while sensitivity dropped to 37.7%, indicating a lower screening accuracy [area under the curve(AUC):0.728, 95% confidence interval(CI):0.67-0-78]. The GDS-30 performance was associated with educational level, but not with age, gender, cognition, apathy, and somatic/psychiatric multimorbidity. For subjective memory complaints subjects, at the optimal cut-off score (≥7), the GDS-30 showed better discrimination performances (AUC=0.792,95%CI:0.60-0.98), but again the educational level affected the diagnostic performance. In subjective memory complaints subjects, symptom-based scales like the GDS-30 may feature a better performance for diagnosing depression in older age, but the GDS-30 seems to require adjustment to the patient's educational level.

The Role of Age on Beta-Amyloid1-42 Plasma Levels in Healthy Subjects.

Beta-amyloid (Aß) plaques have been observed in the brain of healthy elderlies with frequencies strongly influenced by age. The aim of the study is to evaluate the role of age and other biochemical and hematological parameters on Aß1-42 plasma levels in cognitively and neurologically normal individuals. Two-hundred and seventy-five normal subjects stratified by age groups (<35 years, 35-65 years, and >65 years) were included in the study. Aß1-42 plasma levels significantly correlated with age (rs = 0.27; p < 0.0001) in the whole sample, inversely correlated with age in the first age group (rs = -0.25, p = 0.01), positively correlated in the second group (rs = 0.22, p = 0.03), while there was no significant correlation in the older group (rs = 0.02, p = 0.86). Both age (ß-estimate = 0.08; p < 0.001) and cholesterol (ß-estimate = 0.03; p = 0.009) were significantly associated with Aß1-42 plasma level in multivariable analysis. However, only the association with age survived post hoc adjustment for multiple comparisons. The different effects of age on the Aß level across age groups should be explored in further studies to better understand the age-dependent variability. This could better define the value of plasma Aß as a biomarker of the Alzheimer neuropathology.

A New Presenilin 1 (Psen1) Mutation (p.Cys263Trp) as a Cause of Both Early and Late-Onset Alzheimer's Disease in a Large Italian Family.

Mutations in the PSEN1 gene are the most common cause of autosomal dominant Alzheimer's disease, and are characterized by a high phenotype variability. This study describes a five-generation family, with a prevalent late-onset of the disease and a high frequency of depression, in which a new missense mutation (c.789T > G, p.Cys263Trp) in exon 8 of the PSEN1 gene was found. Only the proband presented an early onset at the age of 45 with attention deficit, followed by spatial disorientation, psychiatric symptoms and parkinsonian signs. The other two cases had a late onset of the disease and a typical presentation with memory loss. Both were characterized by a high level of anxiety and depression. The disease course was different with signs of Lewy body dementia for the proband's mother, and pyramidal involvement and a shorter disease duration for the proband's maternal aunt. The other eight cases with late-onset dementia and three cases with a long history of depression have been reported in the family pedigree, underlying the high phenotype variability of PSEN1 mutations.

Brain Structural Covariance Networks in Behavioral Variant of Frontotemporal Dementia.

Recent research on behavioral variant frontotemporal dementia (bvFTD) has shown that personality changes and executive dysfunctions are accompanied by a disease-specific anatomical pattern of cortical and subcortical atrophy. We investigated the structural topological network changes in patients with bvFTD in comparison to healthy controls. In particular, 25 bvFTD patients and 20 healthy controls underwent structural 3T MRI. Next, bilaterally averaged values of 34 cortical surface areas, 34 cortical thickness values, and six subcortical volumes were used to capture single-subject anatomical connectivity and investigate network organization using a graph theory approach. Relative to controls, bvFTD patients showed altered small-world properties and decreased global efficiency, suggesting a reduced ability to combine specialized information from distributed brain regions. At a local level, patients with bvFTD displayed lower values of local efficiency in the cortical thickness of the caudal and rostral middle frontal gyrus, rostral anterior cingulate, and precuneus, cuneus, and transverse temporal gyrus. A significant correlation was also found between the efficiency of caudal anterior cingulate thickness and Mini-Mental State Examination (MMSE) scores in bvFTD patients. Taken together, these findings confirm the selective disruption in structural brain networks of bvFTD patients, providing new insights on the association between cognitive decline and graph properties.

Plasma Inflammatory Cytokines Are Elevated in ALS.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease which leads to death in a median time of 2-3 years. Inflammation has been claimed important to the ALS pathogenesis, but its role is still not well-characterized. In the present study, a panel of five cytokines (IL-2, IL-6, IL-10, IFN-gamma, and TNF-alpha) measured in plasma has been investigated in ALS. These biomarkers of inflammation were measured in a population-based cohort of 79 patients with ALS and 79 age- and sex-matched healthy controls using the Bio-Plex technology (Bio-Rad). All the five cytokines were significantly increased in plasma samples of patients compared with controls (p < 0.0001), with IL-6 having the highest median concentration (10.11 pg/ml) in the ALS group. Furthermore, IL-6 was the plasma cytokine with the highest discrimination ability between patients and controls according to the receiver operating characteristic analysis (area under the curve = 0.93). At a cut-off point of 5.71 pg/ml, it was able to classify patients and controls with 91% of sensitivity and 87% of specificity. In the ALS group, plasma IL-6 concentration correlated with demographic (age: rs = 0.25, p = 0.025) and clinical (revised ALS Functional Rating Scale at evaluation: rs = -0.32, p = 0.007; Manual Muscle Testing: rs = -0.33, p = 0.004; progression: rs = 0.29, p = 0.0395) parameters. In line with previous studies, our results confirm that inflammatory cytokines are elevated in ALS, supporting a possible role of inflammation in disease mechanism and progression. However, the precise role of inflammation in ALS needs to be further investigated on larger samples and with more mechanistic studies.

Telemedicine for Delivery of Care in Frontotemporal Lobar Degeneration During COVID-19 Pandemic: Results from Southern Italy.

BACKGROUND: The COVID-19 pandemic is changing clinical practice in neurology, after the governments decided the introduction of social distancing and interruption of medical non-emergency services in many countries. Teleneurology is an effective tool for the remote evaluation of patients but its adoption for frontotemporal lobar dementia (FTD) is in a preliminary stage. OBJECTIVE: We evaluated multidisciplinary assessment of patients with FTD using telehealth during the COVID-19 pandemic. METHODS: All patients received a diagnosis of FTD during 2018-2019 according to international criteria. A structured questionnaire and Clinical Dementia Rating Scale (CDR)-FTD were used by the neurologist with patients and/or caregivers. Index symptoms of COVID-19 infection were searched. RESULTS: Twenty-eight clinical interviews were completed with caregivers and four with both patients/caregivers. Most patients and caregivers were satisfied with the neurological interview and expressed their willingness to continue to be included in remote evaluation programs (90%). Fifty percent of patients experienced significant worsening of clinical picture and quality of life since the start of social distancing. The CDR-FTD scale revealed a significant worsening of behavior (p = 0.01) and language functions (p = 0.009), compared to the last in-person evaluation at the center. One patient presented index symptoms of COVID-19 infection and was confirmed to be positive for COVID-19 with pharyngeal swab. CONCLUSION: The study was conducted in Italy, one of the countries hit particularly hard by the COVID-19 pandemic, with interruption of all non-emergency medical services. Our study indicates that telemedicine is a valid tool to triage patients with FTD to increase practice outreach and efficiency.

The Italian Version of the Test Your Memory (TYM-I): A Tool to Detect Mild Cognitive Impairment in the Clinical Setting.

The Test Your Memory (TYM) is a brief self-administered, cognitive screening test, currently used in several settings. It requires minimal administrator supervision and the computation of the final test score takes approximately 2 min. We assessed the discrimination ability of the Italian version of the TYM (TYM-I) in detecting Mild Cognitive Impairment (MCI) in clinical setting. TYM-I was administered to 94 MCI patients and 134 healthy controls. The clinical diagnosis of MCI was considered as the gold standard. An extended formal neuropsychological test battery was used to define MCI subtypes. Receiver Operating Characteristic (ROC) analyses were conducted to find the optimal cut-off and measure discrimination ability of TYM-I in detecting MCI. TYM-I had a similar area under the curve (AUC = 0.85) point estimate as Mini Mental State Examination (MMSE) (AUC = 0.83). A TYM-I score lower or equal to 36 was found to be optimal cut off to detect MCI. The TYM-I showed the highest discrimination ability among individuals aged more than 70 and high educational level (AUC = 0.89). The amnestic MCI subtype patients, compared to non-amnestic MCI patients, had worse performance in recall, orientation and visuospatial abilities TYM-I subscores. The TYM-I is a valid screening test in detecting cognitive dysfunction, easily carried out in clinical practice. The TYM-I subscores may allow to identify amnestic and non-amnestic MCI subtypes.

Associations of Cognitive Function and Education Level With All-Cause Mortality in Adults on Hemodialysis: Findings From the COGNITIVE-HD Study.

RATIONALE & OBJECTIVE: In the general population, cognitive impairment is associated with increased mortality, and higher levels of education are associated with lower risks for cognitive impairment and mortality. These associations are not well studied in patients receiving long-term hemodialysis and were the focus of the current investigation. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: Adult hemodialysis patients treated in 20 Italian dialysis clinics. EXPOSURES: Patients' cognitive function across 5 domains (memory, attention, executive function, language, and perceptual-motor function), measured using a neuropsychological assessment comprising 10 tests; and patients' self-reported years of education. OUTCOME: All-cause mortality. ANALYTICAL APPROACH: Nested multivariable Cox regression models were used to examine associations of cognition (any domain impaired, number of domains impaired, and global function score from principal components analysis of unadjusted test scores) and education with mortality and whether there were interactions between them. RESULTS: 676 (70.6%) patients participated, with a median age of 70.9 years and including 38.8% women. Cognitive impairment was present in 79.4% (527/664; 95% CI, 76.3%-82.5%). During a median follow-up of 3.3 years (1,874 person-years), 206 deaths occurred. Compared to no cognitive impairment, adjusted HRs for mortality were 1.77 (95% CI, 1.07-2.93) for any impairment, 1.48 (95% CI, 0.82-2.68) for 1 domain impaired, 1.88 (95% CI, 1.01-3.53) for 2 domains, and 2.01 (95% CI, 1.14-3.55) for 3 to 5 domains. The adjusted HR was 0.68 (95% CI, 0.51-0.92) per standard deviation increase in global cognitive function score. Compared with primary or lower education, adjusted HRs were 0.79 (95% CI, 0.53-1.20) for lower secondary and 1.13 (95% CI, 0.80-1.59) for upper secondary or higher. The cognition-by-education interaction was not significant (P=0.7). LIMITATIONS: Potential selection bias from nonparticipation and missing data; no data for cognitive decline; associations with education were not adjusted for other socioeconomic factors. CONCLUSIONS: Cognitive impairment is associated with premature mortality in hemodialysis patients. Education does not appear to be associated with mortality.

Comparative evaluation of two immunoassays for cerebrospinal fluid ß-Amyloid1-42 measurement.

AIM OF THE STUDY: Beta-Amyloid 1-42 peptide (ßA42) is a cerebro-spinal fluid (CSF) biomarker, key element of the NIA Alzheimer's disease diagnostic criteria. The enzyme-linked immunosorbent assay (ELISA) has been the mainstay method for ßA42 measurement on cerebrospinal fluid (CSF). Recently, a new ßA42 measurement method in chemiluminescence enzyme immunoassay (CLEIA) is available on Lumipulse G 600 II automatic platform. The aim of the work was to evaluate the concordance of the ELISA and the new method (CLEIA) in the CSF ßA42 levels measurement. MATERIALS AND METHODS: CSF ßA42 levels were assayed in 49 samples using the ELISA method (Innotest ß- amyloid 1-42, Fujirebio Europe N.V., Gent, Belgium) and CLEIA method on Lumipulse G600II fully automatic platform (Lumipulse G ß- amyloid 1-42, Fujirebio Europe N.V., Gent, Belgium). We compared values of the two methods using acceptability interval based on Inherent Combined Imprecision (ICI), the Passing-Bablok regression analysis, the Pearson correlation coefficient (r) and the Bland-Altman plot. RESULTS: The analysis of the ICI showed that the two methods differ substantially. The regression equation (y = -103.04 + 1.52×) highlighted the presence of proportional systematic difference, without significant deviation from linearity (p = .42). The Pearson correlation coefficient was 0.826. The Bland-Altman plot analysis showed a significant systematic difference in the two methods: ELISA measurements were in average -27.06% (95% CI -31.89 to -22.23%) lower compared to CLEIA ones. CONCLUSIONS: Our study highlighted a difference between the two methods. Therefore, the cut-off for the normal levels of ßA42 should be reviewed in the laboratory report.

Loss of Swallow Tail Sign on Susceptibility-Weighted Imaging in Dementia with Lewy Bodies.

We assessed nigral dorsolateral hyperintensity (swallow tail sign) at susceptibility-weighted imaging using 3T-MRI in 15 dementia with Lewy bodies (DLB), 11 Alzheimer's disease (AD), and 8 frontotemporal dementia (FTD) patients and 10 subjects with subjective memory complaint (SMC). More DLB patients lacked nigral hyperintesity (p < 0.05). Sensitivity, specificity, and accuracy of DLB diagnosis were, respectively: 80%, 64%, and 73% versus AD; 80%, 75%, and 78% versus FTD; and 80%, 90%, and 84% versus SMC. Considering bilateral loss, sensitivity decreased (53%) but specificity increased (82-100%). Swallow tail sign loss, especially if bilateral, can be useful for DLB diagnosis.

Social Dysfunction in Older Age and Relationships with Cognition, Depression, and Apathy: The GreatAGE Study.

BACKGROUND: Most studies focused on only one measure of social dysfunction in older age, without proper validation and distinction across different dimensions including subjectivity, structural, and functional aspects. OBJECTIVE: We sought to validate the Social Dysfunction Rating Scale (SDRS) and its factorial structure, also determining the association of SDRS with cognitive functions, global psychopathology, and social deprivation. METHODS: The SDRS was administered to 484 Italian community-dwelling elderly, recruited in the GreatAGE study, a population-based study on aging conducted in Castellana Grotte, Bari, Southern Italy. We determined objective and subjective psychometric properties of SDRS against the gold standard evaluation of social dysfunction according to the Semi-structured Clinical Diagnostic Interview for DSM-IV-TR Axis I Disorders (SCID-I) criterion. RESULTS: The SDRS showed a moderate accuracy with an optimal cut-off of 26 maximized with higher sensitivity (0.74,95% CI:0.63-0.84) than specificity (0.57,95% CI:0.50-0.64). A five-factor structure was carried out and five dimensions of SDRS were identified (loneliness; social isolation; feeling of contribution/uselessness; lack of leisure activities; anxiety for the health). Education and global cognitive functions were inversely correlated to SDRS, while a direct association with global psychopathology, depression, and apathy was found. The prevalence of higher SDRS scores was major in subjects with current psychiatric disorders versus other subjects.∥Conclusion: The SDRS could be a valid instrument to capture both size and quality of social dysfunction, both in subjects with psychiatric disorders and in normal subjects. Several categories of social dysfunction differed only in the degree of health deprivation, not in social or material deprivation.

Plasma ß-amyloid1-42 reference values in cognitively normal subjects.

BACKGROUND: In clinical practice, the use of plasma ß-Amyloid1-42 (Aß1-42) as biomarker for Alzheimer's disease is largely limited by the absence of reference values. The aim of this study was to evaluate Aß1-42 plasma concentrations in cognitively normal subjects and to propose reference values. METHODS: Plasma samples were obtained from 245 subjects, with a wide age-range (19-89 years), enrolled at the Unit of Laboratory Medicine of the "Azienda Ospedaliera Cardinale G. Panico" (younger subjects) and from a population-based study on aging (GreatAGE study) (older subjects). Three different age-groups were established: young (≤ 34), adult (35 ≤ age ≤ 64) and old (>64). The Innogenetics Elisa kit for plasma Aß1-42 was used for the analysis. RESULTS: The mean (SD) concentration of plasma Aß1-42 was 17.65 (5.71) pg/mL. A positive trend was found in Aß1-42 levels across the three age groups (p < .0001): young subjects showed values of Aß1-42 significantly lower than the adult group (p < .0001) and than the old one (p < .0001 overall); no significant differences were found between the adult and the old groups (p = 1.0000). For the entire cohort the lower limit of 90% Reference Interval, double-sided, was 8.12 pg/mL (95% CI 6.77-9.45) and the upper limit was 29.00 pg/mL (95% CI 27.01-31.00). CONCLUSION: The present study proposes reference values for plasma Aß1-42. Nevertheless, further studies are needed to confirm these results and corroborate the use of these reference values in clinical practice.

Clinical features and genetic characterization of two dizygotic twins with C9orf72 expansion.

The objective of the study was to present a detailed clinical, genetic, and epigenetic characterization of 2 amyotrophic lateral sclerosis (ALS) concordant dizygotic twins. The described cases underwent clinical and paraclinical examinations according to the motor neuron disease protocol of our referral center. Mutation analysis of the major causative genes related to ALS was performed. The methylation profile of the CpG island located in the promoter region of C9orf72 and in the repeat region itself was investigated by bisulfite sequencing of C9orf72 expansion carriers. The described cases presented an overlapping phenotype. Genetic analysis revealed the presence of an abnormal (>50 repeats) G4C2-repeat expansion in C9orf72. Both the direct bisulfite sequencing-sensitive and the methylation-sensitive HhaI assays did not reveal any DNA methylation at the CpG island 5' of the G4C2 repeat in C9orf72. The (G4C2)n methylation assay indicated that also the expansion itself was not methylated in both twins, suggesting a probably intermediate allele expansion. This is the first report of ALS-concordant dizygotic twins carrying a C9orf72 expansion probably of intermediate length, and with a detailed clinical and genetic characterization. Twin studies add significant information about the mechanisms of C9orf72 expansion pleiotropism, probably driven by genetic, epigenetic, and environmental factors.

An Old Challenge with New Promises: A Systematic Review on Comprehensive Geriatric Assessment in Long-Term Care Facilities.

Comprehensive geriatric assessment (CGA) is a multidimensional and multidisciplinary diagnostic process focused on determining the clinical profile, pathological risk, residual skills, short- and long-term prognosis, and personalized therapeutic and care plan of the functionally compromised and frail older subjects. Previous evidence suggested that the effectiveness of CGA programs may be influenced by settings where the CGA is performed [i.e., hospital, posthospital discharge/long-term care facilities (LTCFs), or community/home] as well as the specific clinical conditions of older frail individuals. In this scenario, CGA and quality of care in LTCFs have been a challenge for decades. In the present article, we systematically reviewed evidence from the last three decades of clinical research devoted to systematic implementation of CGA programs in LTCFs, that is, nursing homes, care homes, residential homes, and rehabilitation facilities. In the United States, all LTC residents must undergo a CGA on a regular basis on admission to a facility, prompting the development of the Resident Assessment Instrument (RAI) Minimum Data Set, a specific CGA-based assessment tool in this population. In the LTCF setting, the present reviewed evidence suggested that most complex older subjects may benefit from a CGA in terms of improved quality of care and reduced hospitalization events and that CGA must be standardized across healthcare settings to promote greater health system integration and coordination. In the LTCF setting, particularly in nursing homes, other new and promising CGA programs have also been proposed to develop rapid screening CGA-based tools to enhance in the future the ability of primary care physicians to recognize and treat geriatric syndromes in this setting. However, at present, the interRAI suite of instruments represented an integrated health information system that has the potential to provide person-centered information transcending healthcare settings.

Prevalence and patterns of cognitive impairment in adult hemodialysis patients: the COGNITIVE-HD study.

Background: Mounting evidence indicates an increased risk of cognitive impairment in adults with end-stage kidney disease on dialysis, but the extent and pattern of deficits across the spectrum of cognitive domains are uncertain. Methods: We conducted a cross-sectional study of 676 adult hemodialysis patients from 20 centers in Italy, aiming to evaluate the prevalence and patterns of cognitive impairment across five domains of learning and memory, complex attention, executive function, language and perceptual-motor function. We assessed cognitive function using a neuropsychological battery of 10 tests and calculated test and domain z-scores using population norms (age or age/education). We defined cognitive impairment as a z-score ≤ -1.5. Results: Participants' median age was 70.9 years (range 21.6-94.1) and 262 (38.8%) were women. Proportions of impairment on each domain were as follows: perceptual-motor function 31.5% (150/476), language 41.2% (273/662), executive function 41.7% (281/674), learning and memory 42.2% (269/638), complex attention 48.8% (329/674). Among 474 participants with data for all domains, only 28.9% (n = 137) were not impaired on any domain, with 25.9% impaired on a single domain (n = 123), 17.3% on two (n = 82), 13.9% on three (n = 66), 9.1% on four (n = 43) and 4.9% (n = 23) on all five. Across patients, patterns of impairment combinations were diverse. Conclusions: In conclusion, cognitive impairment is extremely common in hemodialysis patients, across numerous domains, and patients often experience multiple deficits simultaneously. Clinical care should be tailored to meet the needs of patients with different types of cognitive impairment and future research should focus on identifying risk factors for cognitive decline.

The potential of solanezumab and gantenerumab to prevent Alzheimer's disease in people with inherited mutations that cause its early onset.

INTRODUCTION: The recent failure of several clinical trials on anti-ß-amyloid (Aß) drugs in Alzheimer's disease (AD) suggested earlier intervention in the disease course. Secondary prevention trials have been started in autosomal-dominant AD (ADAD) individuals without cognitive dysfunction and in cognitively healthy subjects at risk of developing sporadic AD (SAD). AREAS COVERED: Herein, the authors discuss prevention trials in ADAD and SAD, with a focus on the anti-Aß monoclonal antibodies solanezumab and gantenerumab presently in Phase III clinical development. These therapies are also being tested in the Dominantly Inherited Alzheimer's Network Trials Unit (DIAN-TU). EXPERT OPINION: Anti-Aß monoclonal antibodies are being tested in subjects at the preclinical stage of ADAD and even in symptom-free subjects at risk of developing SAD. The subsequent DIAN-TU Adaptive Prevention Trial is a 4-year study that will assess whether such biomarker effects may stop the progress of the AD process, preventing cognitive symptoms. The hope is to interfere in the disease course when it is not too late. A clinical success of these prevention trials would represent the proof of the Aß hypothesis of AD.

Midlife Metabolic Profile and the Risk of Late-Life Cognitive Decline.

Among metabolic syndrome components, the effects of higher plasma glucose levels on cognitive decline (CD) have been considered in few studies. We evaluated the associations among midlife glycemia, total cholesterol, high-density lipoprotein cholesterol, triglycerides, midlife insulin resistance [homeostasis model assessment for insulin resistance (HOMA-index)], and CD in the older subjects of the population-based MICOL Study (Castellana Grotte, Italy) at baseline (M1) and at follow-ups seven (M2) and twenty years later (M3). At M1, a dementia risk score and a composite cardiovascular risk score for dementia were calculated. For 797 subjects out of 833, we obtained a Mini-Mental State Examination (MMSE) score at M3, subdividing these subjects in three cognitive functioning subgroups: normal cognition, mild CD, and moderate-severe CD. Mean fasting glycemia at baseline was significantly higher in moderate-severe CD subgroup (114.6±71.4 mg/dl) than in the normal cognition subgroup (101.2±20.6). Adjusting for gender, age, and other metabolic components, higher fasting glycemia values both at M1 [odds ratio (OR) = 1.31; 95% confidence interval (CI): 1.08-1.59] and M2 (OR = 1.26; 95% CI: 1.01-1.57) were associated with an increased risk of moderate-severe CD. Mean HOMA index value was significantly higher in the moderate-severe CD subgroup (5.7±9.4) compared to the normal cognition subgroup (2.9±1.4) at M1. The dementia risk probability (MMSE < 24) increased moving through higher categories of the dementia risk score and decreased as long as the cardiovascular score increased. The present findings highlighted the indication to control blood glucose levels, regardless of a diagnosis of diabetes mellitus, as early as midlife for prevention of late-life dementia.

Bipolar Disorder and Frontotemporal Dementia: An Intriguing Association.

Bipolar disorder (BD) could represent a prodromal state of frontotemporal dementia (FTD). Two patients affected by lifelong BD with a progressive decline of cognitive functions, behavioral, and neurological signs, reached the early diagnosis of FTD before the age of 60. They were diagnosed as affected by primary progressive aphasia and FTD with parkinsonism, respectively. A diagnosis of FTD should therefore be taken into account, in case of unexpected cognitive and behavioral decline in patients with a long history of BD. Follow-up studies with genetic, neuropsychological, and neuroimaging markers of these BD/FTD patients could further explore some of the underlying association, opening new viable therapeutic options.

Prefrontal Activity and Connectivity with the Basal Ganglia during Performance of Complex Cognitive Tasks Is Associated with Apathy in Healthy Subjects.

OBJECTIVE: Convergent evidence indicates that apathy affects cognitive behavior in different neurological and psychiatric conditions. Studies of clinical populations have also suggested the primary involvement of the prefrontal cortex and the basal ganglia in apathy. These brain regions are interconnected at both the structural and functional levels and are deeply involved in cognitive processes, such as working memory and attention. However, it is unclear how apathy modulates brain processing during cognition and whether such a modulation occurs in healthy young subjects. To address this issue, we investigated the link between apathy and prefrontal and basal ganglia function in healthy young individuals. We hypothesized that apathy may be related to sub-optimal activity and connectivity in these brain regions. METHODS: Three hundred eleven healthy subjects completed an apathy assessment using the Starkstein's Apathy Scale and underwent fMRI during working memory and attentional performance tasks. Using an ROI approach, we investigated the association of apathy with activity and connectivity in the DLPFC and the basal ganglia. RESULTS: Apathy scores correlated positively with prefrontal activity and negatively with prefrontal-basal ganglia connectivity during both working memory and attention tasks. Furthermore, prefrontal activity was inversely related to attentional behavior. CONCLUSIONS: These results suggest that in healthy young subjects, apathy is a trait associated with inefficient cognitive-related prefrontal activity, i.e., it increases the need for prefrontal resources to process cognitive stimuli. Furthermore, apathy may alter the functional relationship between the prefrontal cortex and the basal ganglia during cognition.