Neuropsychiatric symptoms and cerebrovascular risk in non-demented elders: cross-sectional study using the mild behavioural impairment checklist (MBI-C).

BACKGROUND: Neuropsychiatric symptoms (NPS) may represent early clinical manifestations of evolving brain diseases. Studies underpin the occurrence of NPS in the context of mild cognitive impairment (MCI) and prodromal Alzheimer's disease, where symptoms referred to as 'mild behavioural impairment' (MBI) have been shown to predict conversion to dementia and to hasten cognitive/functional decline. However, the association between NPS and cerebrovascular risk factors has been poorly investigated, despite the high prevalence of the latter among individuals with MCI. The aim of the present study was to investigate the association between MBI and cerebrovascular risk in a clinical sample of non-demented elders. METHODS: Sixty-five MCI and 15 cognitively unimpaired older adults were cross-sectionally assessed with the Mild Behavioural Impairment Checklist (MBI-C), using the cut-off score > 6.5 to define positive screening. Participants were submitted to the Hachinski Ischaemic Score (HIS) to account for cerebrovascular symptoms, vascular risk, and related comorbidities. Neuroimaging scans (magnetic resonance imaging and/or 18F-fluorodeoxyglucose-positron emission tomography) and apolipoprotein E genotype were obtained. RESULTS: Positive associations were found between total MBI-C scores and increasing number of comorbidities present (0-2 comorbidities), but not with three comorbidities. Two domains of the MBI-C-impulse dyscontrol and social inappropriateness-followed the same trend of the MBI-C total score, with higher scores with the increasing numbers of comorbidities. No significant associations were found between MBI symptoms and HIS or cerebrovascular burden in neuroimaging assessment. CONCLUSION: We found weak associations between MBI-C total score and the presence of comorbidities with cerebrovascular risk, but not with structural or functional neuroimaging abnormalities or HIS. This finding may represent that the presence of comorbidities adds limited risk to the occurrence of MBI in this sample of non-demented elders.

AD-Related CSF Biomarkers Across Distinct Levels of Cognitive Impairment: Correlations With Global Cognitive State.

AIM: Associations between cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease (AD) with the severity of cognitive impairment are unclear. We examined the correlations between CSF biomarkers and cognitive performance in the AD continuum. METHODS: We studied 143 elderly patients: cognitively unimpaired (n = 51), mild cognitive impairment (MCI) amnestic (n = 55) and nonamnestic (n = 20), and mild AD (n = 17) assessed with the Cambridge Cognitive Test (CAMCOG). We correlated total CAMCOG and its subdomains with CSF Aß42, T-tau, p-tau levels, and Aß42/p-tau. RESULTS: In the total sample, T-tau and Aß42/p-tau correlated with the total CAMCOG (P < .01); all biomarkers correlated with memory (P < .001); T-tau correlated with language (P < .01). CONCLUSION: Memory and T-tau levels may be the most suitable parameters to reflect cognitive/CSF biomarker correlations. At present, such correlations are of little use in routine clinical practice.

Subcortical Aphasia.

PURPOSE OF REVIEW: Subcortical structures have long been thought to play a role in language processing. Increasingly spirited debates on language studies, arising from as early as the nineteenth century, grew remarkably sophisticated as the years pass. In the context of non-thalamic aphasia, a few theoretical frameworks have been laid out. The disconnection hypothesis postulates that basal ganglia insults result in aphasia due to a rupture of connectivity between Broca and Wernicke's areas. A second viewpoint conjectures that the basal ganglia would more directly partake in language processing, and a third stream proclaims that aphasia would stem from cortical deafferentation. On the other hand, thalamic aphasia is more predominantly deemed as a resultant of diaschisis. This article reviews the above topics with recent findings on deep brain stimulation, neurophysiology, and aphasiology. RECENT FINDINGS: The more recent approach conceptualizes non-thalamic aphasias as the offspring of unpredictable cortical hypoperfusion. Regarding the thalamus, there is mounting evidence now pointing to leading contributions of the pulvinar/lateral posterior nucleus and the anterior/ventral anterior thalamus to language disturbances. While the former appears to relate to lexical-semantic indiscrimination, the latter seems to bring about a severe breakdown in word selection and/or spontaneous top-down lexical-semantic operations. The characterization of subcortical aphasias and the role of the basal ganglia and thalamus in language processing continues to pose a challenge. Neuroimaging studies have pointed a path forward, and we believe that more recent methods such as tractography and connectivity studies will significantly expand our knowledge in this particular area of aphasiology.

Clinical and biological effects of long-term lithium treatment in older adults with amnestic mild cognitive impairment: randomised clinical trial.

BACKGROUND: Experimental studies indicate that lithium may facilitate neurotrophic/protective responses in the brain. Epidemiological and imaging studies in bipolar disorder, in addition to a few trials in Alzheimer's disease support the clinical translation of these findings. Nonetheless, there is limited controlled data about potential use of lithium to treat or prevent dementia. AIMS: To determine the benefits of lithium treatment in patients with amnestic mild cognitive impairment (MCI), a clinical condition associated with high risk for Alzheimer's disease. METHOD: A total of 61 community-dwelling, physically healthy, older adults with MCI were randomised to receive lithium or placebo (1:1) for 2 years (double-blind phase), and followed-up for an additional 24 months (single-blinded phase) (trial registration at clinicaltrials.gov: NCT01055392). Lithium carbonate was prescribed to yield subtherapeutic concentrations (0.25-0.5 mEq/L). Primary outcome variables were the cognitive (Alzheimer's Disease Assessment Scale - cognitive subscale) and functional (Clinical Dementia Rating - Sum of Boxes) parameters obtained at baseline and after 12 and 24 months. Secondary outcomes were neuropsychological test scores; cerebrospinal fluid (CSF) concentrations of Alzheimer's disease-related biomarkers determined at 0, 12 and 36 months; conversion rate from MCI to dementia (0-48 months). RESULTS: Participants in the placebo group displayed cognitive and functional decline, whereas lithium-treated patients remained stable over 2 years. Lithium treatment was associated with better performance on memory and attention tests after 24 months, and with a significant increase in CSF amyloid-beta peptide (Aß1-42) after 36 months. CONCLUSIONS: Long-term lithium attenuates cognitive and functional decline in amnestic MCI, and modifies Alzheimer's disease-related CSF biomarkers. The present data reinforces the disease-modifying properties of lithium in the MCI-Alzheimer's disease continuum. DECLARATION OF INTEREST: None.

An intervention to reduce neuropsychiatric symptoms and caregiver burden in dementia: Preliminary results from a randomized trial of the tailored activity program-outpatient version.

OBJECTIVE: To evaluate the efficacy of the tailored activity program-outpatient version (TAP-O) and to reduce neuropsychiatric symptoms (NPS) in patients with dementia and caregiver burden compared with a control group (psychoeducation intervention). METHODS: Twenty-one persons with dementia and their caregivers were recruited and randomized. The intervention group received TAP-O, designed for outpatients with dementia and their caregivers. TAP-O consisted of eight sessions in which an occupational therapist assessed the patient's abilities and interests; prescribed tailored activities; and educated caregivers about dementia, NPS, and how to implement meaningful activities in the daily routine. The control group received eight sessions of a psychoeducation intervention about dementia and NPS. RESULTS: Compared with controls, patients receiving TAP-O had a significant decrease in hallucination (P = 0.04), agitation (P = 0.03), anxiety (P = 0.02), aggression (P = 0.01), sleep disorder (P = 0.02), aberrant motor behavior (P = 0.02), and in caregiver burden (P = 0.003). CONCLUSIONS: Findings suggest that TAP-O may be an effective nonpharmacological strategy to reduce NPS of outpatients with dementia and to minimize caregiver burden.

Sensitivity and specificity of a briefer version of the Cambridge Cognitive Examination (CAMCog-Short) in the detection of cognitive decline in the elderly: An exploratory study.

OBJECTIVE: To create a reduced and briefer version of the widely used Cambridge Cognitive Examination (CAMCog) battery as a concise cognitive test to be used in primary and secondary levels of health care to detect cognitive decline. Our aim was to reduce the administration time of the original test while maintaining its diagnostic accuracy. METHODS: On the basis of the analysis of 835 CAMCog tests performed by 429 subjects (107 controls, 192 mild cognitive impairment [MCI], and 130 dementia patients), we extracted items that most contributed to intergroup differentiation, according to 2 educational levels (≤8 and >8 y of formal schooling). RESULTS: The final 33-item "low education" and 24-item"high education" CAMCog-Short correspond to 48.5% and 35% of the original version and yielded similar rates of accuracy: area under ROC curves (AUC) > 0.9 in the differentiation between controls × dementia and MCI × dementia (sensitivities > 75%; specificities > 90%); AUC > 0.7 for the differentiation between controls and MCI (sensitivities > 65%; specificities > 75%). CONCLUSIONS: The CAMCog-Short emerges as a promising tool for a brief, yet sufficiently accurate, screening tool for use in clinical settings. Further prospective studies designed to validate its diagnostic accuracy are needed.

Multiple category verbal fluency in mild cognitive impairment and correlation with CSF biomarkers for Alzheimer's disease.

BACKGROUND: Verbal fluency (VF) tasks are widely used in neuropsychological evaluations, as a measure of executive/semantic dysfunction. The revised criteria for Alzheimer's disease (AD) diagnosis (National Institute on Aging and the Alzheimer Association, 2011) incorporating biomarkers has increased the interest in finding algorithms that combine neuropsychological and biomarkers features to better predict conversion from mild cognitive impairment (MCI) to AD. Our aim was to compare the most frequently used VF categories to determine which best discriminated cognitively healthy elderly from MCI patients, and whether cerebrospinal fluid (CSF) biomarkers levels (Aß42, P-tau, T-tau, and Aß42/P-tau) correlated with patient's performance in MCI. METHODS: We studied 37 cognitively healthy elderly and 30 MCI patients in five VF tasks (animal, fruits, means of transportation, FAS-COWA, and verbs); 23 controls and 19 MCI patients had their CSF biomarkers for AD determined. RESULTS: MCI group performed worse than controls in all VF tasks (p < 0.0001). The cut-off scores were: 14 (animals) (AUC = 0.794), 12 (fruits and means of transportation) (AUC = 0.740 and 0.719, respectively), 41 (FAS) (AUC = 0.744), and 11 (verbs) (AUC = 0.700). The model "animal plus FAS-COWA" was the best to discriminate both groups (AUC = 0.833) (all p < 0.05). MCI produced fewer words than controls in the second-half of the task for all categories (p < 0.001). T-tau levels were negatively correlated to animal fluency (r = -0.485, p = 0.035), and showed a trend for negative correlation with fruits fluency (r = -0.4429, p = 0.057). CONCLUSIONS: Animal fluency alone and combined to FAS-COWA was slightly superior in discriminating controls from MCI (p < 0.001), and correlated to T-tau levels.

Apolipoprotein E genotype is not associated with cognitive impairment in older adults with bipolar disorder.

OBJECTIVES: Cognitive decline is part of the long-term outcome for many individuals with bipolar disorder (BD). The ε4 allele (APOE*4) of apolipoprotein E (APOE) is a well-established risk factor for dementia in Alzheimer's disease (AD). However, its contribution to the risk of cognitive deterioration in BD has not yet been determined. Our aim was to analyze the APOE genotype association with cognitive status in a sample of older adults with BD and compare this to the association in individuals with AD, individuals with mild cognitive impairment (MCI), and healthy controls. METHODS: Participants (n = 475) were allocated to four groups: individuals with BD (n = 77), those with AD (n = 211), those with MCI (n = 43), and healthy controls (n = 144) according to clinical and neuropsychological assessment. APOE was genotyped by real-time polymerase chain reaction. Tukey's honest significant difference test and Pearson's chi-squared test were used to compare diagnostic groups. RESULTS: Subjects with BD were similar to controls with respect to the distribution of the APOE genotype (p = 0.636) and allele frequencies (p = 0.481). Significant differences were found when comparing the AD group to the BD group or to controls (APOE genotype: p < 0.0002; allele frequencies: p < 0.001). APOE*4 was significantly increased in the AD group when compared to the BD group (p = 0.031) and controls (p < 0.0001). The cognitively impaired BD subgroup (Mini-Mental State Examination below the cutoff score and/or neuropsychological assessment compatible with MCI) had a statistically significant higher frequency of APOE*2 compared to the AD group (p = 0.003). CONCLUSIONS: APOE*4 is not associated with the diagnosis of BD and does not impact the occurrence of dementia in BD. Given the distinct clinical and biological features of cognitive impairment in BD, we hypothesized that dementia in BD is unrelated to AD pathological mechanisms.

Cognitive impairment in late-life bipolar disorder is not associated with Alzheimer's disease pathological signature in the cerebrospinal fluid.

OBJECTIVES: Cognitive impairment is a common feature of late-life bipolar disorder (BD). Yet, there is limited information on the biological mechanisms associated with this process. It is uncertain whether cognitively impaired patients with BD may present the Alzheimer's disease (AD) bio-signature in the cerebrospinal fluid (CSF), defined as a combination of low concentrations of the amyloid-beta peptide (Aß1-42 ) and high concentrations of total tau (T-tau) and tau phosphorylated at threonine 181 (P-tau). In this study, we sought to determine whether cognitive impairment in elderly patients with BD is associated with the AD CSF bio-signature. METHODS: Seventy-two participants were enrolled in the study. The test group comprised older adults with BD and mild cognitive impairment (BD-MCI; n = 16) and the comparison groups comprised patients with dementia due to AD (n = 17), patients with amnestic MCI (aMCI; n = 14), and cognitively healthy older adults (control group; n = 25). CSF samples were obtained by lumbar puncture and concentrations of Aß1-42 , T-tau and P-tau were determined. RESULTS: CSF concentrations of all biomarkers were significantly different in the AD group compared to all other groups, but did not differentiate BD-MCI subjects from aMCI subjects and controls. BD-MCI patients had a non-significant reduction in CSF Aß1-42 compared to controls, but this was still higher than in the AD group. Concentrations of T-tau and P-tau in BD-MCI patients were similar to those in controls, and significantly lower than those in AD. CONCLUSIONS: Cognitively impaired patients with BD do not display the so-called AD bio-signature in the CSF. We therefore hypothesize that cognitive deterioration in BD is not associated with the classical pathophysiological mechanisms observed in AD, i.e., amyloid deposition and hyperphosphorylation of microtubule-associated tau protein.

Non-invasive sound wave brain stimulation with Transcranial Pulse Stimulation (TPS) improves neuropsychiatric symptoms in Alzheimer's disease.

BACKGROUND: This study explores Transcranial Pulse Stimulation (TPS) as a potential non-invasive treatment for Alzheimer's disease (AD), focusing on its impact on cognitive functions and behavioral symptoms. METHODS: In a prospective, one-arm open-label trial, ten patients with mild to moderate dementia due to AD were assessed using the Alzheimer's Disease Assessment Scale (ADAS-Cog), Neuropsychiatric Inventory (NPI), Pfeffer Functional Activities Questionnaire, and Zarit Caregiver Burden Interview. Assessments occurred at 30- and 90-days post-treatment. The TPS protocol consisted of 10 sessions over five weeks, using the Neurolith® device to deliver 6000 focused shockwave pulses at 0.25 mJ/mm2 and a frequency of 4 Hz. RESULTS: TPS significantly reduced neuropsychiatric symptoms, with NPI scores decreasing by 23.9 points (95% CI: -39.19 to -8.61, p = 0.0042) after 30 days, and by 18.9 points (95% CI: -33.49 to -2.91, p = 0.022) after 90 days. These changes had large effect sizes (Cohen's dz = 1.43 and dz = 0.94, respectively). A decreasing trend was observed in the ADAS-Cog score (-3.6, 95% CI: -7.18 to 0.00, p = 0.05) after 90 days, indicating a potential reduction in cognitive impairment, though not statistically significant. CONCLUSION: The preliminary results indicate that TPS treatment leads to significant improvement in neuropsychiatric symptoms in AD patients, showing promise as a therapeutic approach for AD. Further research is needed to fully establish its effectiveness, especially concerning cognitive functions.

Alzheimer's disease.

Alzheimer's disease (AD) is a chronic neurodegenerative disease with well-defined pathophysiological mechanisms, mostly affecting medial temporal lobe and associative neocortical structures. Neuritic plaques and neurofibrillary tangles represent the pathological hallmarks of AD, and are respectively related to the accumulation of the amyloid-beta peptide (Aß) in brain tissues, and to cytoskeletal changes that arise from the hyperphosphorylation of microtubule-associated Tau protein in neurons. According to the amyloid hypothesis of AD, the overproduction of Aß is a consequence of the disruption of homeostatic processes that regulate the proteolytic cleavage of the amyloid precursor protein (APP). Genetic, age-related and environmental factors contribute to a metabolic shift favoring the amyloidogenic processing of APP in detriment of the physiological, secretory pathway. Aß peptides are generated by the successive cleavage of APP by beta-secretase (BACE-1) and gamma-secretase, which has been recently characterized as part of the presenilin complex. Among several beta-amyloid isoforms that bear subtle differences depending on the number of C-terminal amino acids, Aß (1-42) plays a pivotal role in the pathogenesis of AD. The neurotoxic potential of the Aß peptide results from its biochemical properties that favor aggregation into insoluble oligomers and protofibrils. These further originate fibrillary Aß species that accumulate into senile and neuritic plaques. These processes, along with a reduction of Aß clearance from the brain, leads to the extracellular accumulation of Aß, and the subsequent activation of neurotoxic cascades that ultimately lead to cytoskeletal changes, neuronal dysfunction and cellular death. Intracerebral amyloidosis develops in AD patients in an age-dependent manner, but recent evidence indicate that it may be observed in some subjects as early as in the third or fourth decades of life, with increasing magnitude in late middle age, and highest estimates in old age. According to recent propositions, three clinical phases of Alzheimer's disease may be defined: (i) pre-symptomatic (or pre-clinical) AD, which may last for several years or decades until the overproduction and accumulation of Aß in the brain reaches a critical level that triggers the amyloid cascade; (ii) pre-dementia phase of AD (compatible with the definition of progressive, amnestic mild cognitive impairment), in which early-stage pathology is present, ranging from mild neuronal dystrophy to early-stage Braak pathology, and may last for several years according to individual resilience and brain reserve; (iii) clinically defined dementia phase of AD, in which cognitive and functional impairment is severe enough to surmount the dementia threshold; at this stage there is significant accumulation of neuritic plaques and neurofibrillary tangles in affected brain areas, bearing relationship with the magnitude of global impairment. New technologies based on structural and functional neuroimaging, and on the biochemical analysis of cerebrospinal fluid may depict correlates of intracerebral amyloidosis in individuals with mild, pre-dementia symptoms. These methods are commonly referred to as AD-related biomarkers, and the combination of clinical and biological information yields good diagnostic accuracy to identify individuals at high risk of AD. In other words, the characterization of pathogenic Aß by means of biochemical analysis of biological fluids or by molecular neuroimaging are presented as diagnostic tools to help identify AD cases at the earliest stages of the disease process. The relevance of this early diagnosis of AD relies on the hypothesis that pharmacological interventions with disease-modifying compounds are more likely to produce clinically relevant benefits if started early enough in the continuum towards dementia. Therapies targeting the modification of amyloid-related cascades may be viewed as promising strategies to attenuate or even to prevent dementia. Therefore, the cumulative knowledge on the pathogenesis of AD derived from basic science models will hopefully be translated into clinical practice in the forthcoming years.

Electroconvulsive therapy for treating patients with agitation and related behavioral disorders due to dementia: a systematic review.

Behavioral disturbances are clinically relevant in patients with dementia, and pharmacological regimens to mitigate these symptoms have provided limited results. Proven to be effective in several psychiatric conditions, electroconvulsive therapy is a potentially beneficial strategy for treating severe agitation due to dementia. Objective: This review aimed to examine the publications on the efficacy, safety and tolerability of electroconvulsive therapy in treating patients with agitation due to dementia. Methods: We performed a systematic analysis on the electroconvulsive therapy to treat patients with dementia and coexisting severe agitation. Articles were classified according to the level of evidence based on methodological design. Patients received an acute course of electroconvulsive therapy, often followed by maintenance intervention. Results: We selected 19 studies (156 patients; 64.1% women; 51-98 years old), which met the inclusion criteria: one case-control study by chart analysis (level of evidence 2); one open-label study (level of evidence 3); three historical/retrospective chart analyses (level of evidence 4); and 14 case series/reports (level of evidence 5). No randomized, sham-controlled clinical trials (level of evidence 1) were identified, which represents the main methodological weakness. Some patients had postictal delirium, cardiovascular decompensation and cognitive changes, lasting for a short time. Conclusions: Overall, patients achieved significant improvement in agitation. However, the main finding of the present review was the absence of methodological design based on randomized and sham-controlled clinical trials. Despite methodological limitations and side effects requiring attention, electroconvulsive therapy was considered a safe and effective treatment of patients with severe agitation and related behavioral disorders due to dementia.

Distúrbios comportamentais são clinicamente relevantes em pacientes com demência, e regimes farmacológicos para mitigar esses sintomas têm proporcionado resultados limitados. Comprovadamente eficaz em diversas condições psiquiátricas, a eletroconvulsoterapia é uma estratégia potencialmente benéfica para o tratamento de pacientes com agitação grave na demência. Objetivos: Esta revisão examina as publicações sobre eficácia, segurança e tolerabilidade da eletroconvulsoterapia no tratamento de pacientes com agitação na demência. Métodos: Realizamos uma análise sistemática da eletroconvulsoterapia no tratamento de pacientes com demência e agitação grave. Os artigos foram classificados quanto ao nível de evidência com base no delineamento metodológico. Os pacientes receberam um curso agudo de eletroconvulsoterapia, frequentemente seguido de manutenção. Resultados: Foram selecionados 19 estudos (156 pacientes; 64,1% mulheres; 51­98 anos): um estudo caso-controle desenvolvido com base na análise de prontuários (nível de evidência 2); um estudo aberto (nível de evidência 3); três estudos de análise retrospectiva de prontuários (nível de evidência 4); e 14 séries/relatos de casos (nível de evidência 5). Não foram identificados ensaios clínicos randomizados e controlados com placebo (nível de evidência 1), fator que representa a principal fragilidade metodológica. No entanto, o principal achado da presente revisão consistiu na ausência de desenho metodológico baseado em ensaios clínicos randomizados e controlados com placebo. Em geral, os efeitos colaterais foram transitórios e bem tolerados. Alguns pacientes apresentaram delirium pós-ictal, descompensação cardiovascular e alterações cognitivas por períodos breves. Conclusões: No geral, os pacientes obtiveram melhora significativa na agitação. No entanto, o principal achado da presente revisão foi a ausência de delineamento metodológico baseado em ensaios clínicos randomizados e controlados com placebo. Apesar das limitações metodológicas e dos efeitos adversos, a eletroconvulsoterapia foi considerada um tratamento seguro e eficaz em pacientes com agitação grave e com outros distúrbios comportamentais clinicamente relevantes na demência.

Discourse abilities in euthymic elderly patients with bipolar disorder: a preliminary study.

Cognitive impairment has been well described in euthymic patients with bipolar disorder (BD), as well as in elderly patients. Language disturbances are less studied, and several inconsistencies are reported in the literature. Most language studies focus on verbal fluency and semantic alterations, with a lack of studies addressing discursive abilities in BD. Objective: The aim of this study was to evaluate discourse abilities in euthymic elderly individuals with BD. Methods: We studied 19 euthymic elderly patients with BD and a control group of non-BD, which performed a cognitive assessment of attention, memory, executive functions, and visual abilities. All participants produced a description from the Cookie Theft Picture in oral and written modalities that was analyzed according to micro- and macrolinguistic aspects. Generalized linear models were performed to compare intergroup linguistic performance and to determine whether any cognitive domain was associated with linguistic outcomes. Results: The BD group produced more cohesion errors in the oral and written modalities (p=0.016 and p=0.011, respectively) and fewer thematic units in the oral modality (p=0.027) than the control group. Conclusions: BD patients presented minimal changes in the descriptive discourse task. The BD group produced more cohesion errors than the control group in the oral (p=0.016) and written discourse (p=0.011); also, the BD group produced fewer thematic units than controls in the oral discourse (p=0.027).

Déficits cognitivos têm sido descritos em pacientes com transtorno bipolar (TB) em fase eutímica, bem como em idosos. Alterações linguísticas são menos estudadas, e os achados de literatura são inconsistentes. A maioria dos estudos em linguagem baseia-se em avaliações de fluência verbal e alterações semânticas, havendo escassez de trabalhos que abordem as habilidades discursivas no TB. Objetivo: Avaliar as habilidades discursivas em indivíduos idosos eutímicos com TB. Métodos: Estudamos 19 pacientes idosos eutímicos com TB e um grupo de idosos sem TB e cognitivamente saudáveis, que realizaram avaliação cognitiva da atenção, memória, funções executivas e habilidades visuoespaciais. Todos os participantes produziram uma descrição da Prancha do Roubo dos Biscoitos nas modalidades oral e escrita, que foram analisadas de acordo com aspectos micro e macrolinguísticos. Análises por meio de modelos lineares generalizados foram realizados para comparar o desempenho linguístico entre os grupos e para determinar se algum domínio cognitivo estava associado a esse desempenho. Resultados: O grupo TB produziu mais erros de coesão nas modalidades oral e escrita (p=0,016 e p=0,011, respectivamente) e menos unidades temáticas na modalidade oral (p=0,027) do que o grupo controle. Conclusão: Os pacientes com TB apresentaram alterações leves na tarefa discursiva. O grupo TB produziu maior número de erros de coesão do que o grupo controle no discurso oral (p=0,016) e escrito (p=0,011). Além disso, o grupo TB produziu menor número de unidades temáticas do que os controles na tarefa de discurso oral (p=0,027).

Diagnostic Performance of an Eye-Tracking Assisted Visual Inference Language Test in the Assessment of Cognitive Decline due to Alzheimer's Disease.

BACKGROUND: The assessment of language changes associated with visual search impairment can be an important diagnostic tool in the Alzheimer's disease (AD) continuum. OBJECTIVE: Investigate the performance of an eye-tracking assisted visual inference language task in differentiating subjects with mild cognitive impairment (MCI) or AD dementia from cognitively unimpaired older adults (controls). METHODS: We assessed a group of 95 older adults (49 MCI, 18 mild dementia due to AD, and 28 controls). The subjects performed the same task under multiple experimental conditions which generate correlated responses that need to be taken into account. Thus, we performed a non-parametric repeated measures ANOVA model for verbal answers, and a linear mixed model (LMM) or its generalized version for the analysis of eye tracking variables. RESULTS: Significant differences were found in verbal answers across all diagnostic groups independently of type of inference, i.e., logic or pragmatic. Also, eye-tracking parameters were able to discriminate AD from MCI and controls. AD patients did more visits to challenge stimulus (Control-AD, -0.622, SE = 0.190, p = 0.004; MCI-AD, -0.514, SE = 0.173, p = 0.011), more visits to the correct response stimulus (Control-AD, -1.363, SE = 0.383, p = 0.002; MCI-AD, -0.946, SE = 0.349, p = 0.022), more fixations on distractors (Control-AD, -4.580, SE = 1.172, p = 0.001; MCI-AD, -2.940, SE = 1.070, p = 0.020), and a longer time to first fixation on the correct response stimulus (Control-AD, -0.622, SE = 0.190, p = 0.004; MCI-AD, -0.514, SE = 0.173, p = 0.011). CONCLUSION: The analysis of oculomotor behavior along with language assessment protocols may increase the sensitivity for detection of subtle deficits in the MCI-AD continuum, representing an important diagnostic tool.

Revisiting global cognitive and functional state 13 years after a clinical trial of lithium for mild cognitive impairment.

OBJECTIVES: To re-evaluate a sample of older adults enrolled in a randomized controlled trial of lithium for amnestic mild cognitive impairment (MCI) after 11 to 15 years, re-assessing their current (or last available) global cognitive and functional state. METHODS: We recalled all former participants of the Lithium-MCI trial conducted by our group between 2009 and 2012 to perform a single-blinded, cross-sectional evaluation of their global clinical state to compare the long-term outcome of those who received lithium vs. those who received placebo. RESULTS: Of the original sample (n=61), we were able to reach 36 participants (59% of retention), of whom 22 had previously received lithium (61% of the recall sample) and 14 (39%) had received placebo. Since 30.5% of the recalled sample was deceased, psychometric data were collected only for 69.5% of the participants. We found statistically significant differences in current mean Mini Mental State Examination score according to previous treatment group (25.5 [SD, 5.3] vs. 18.3 [SD, 10.9], p = 0.04). The lithium group also had better performance in the phonemic Verbal Fluency Test than the control group (34.4 [SD, 14.4] vs. 11.6 [SD, 10.10], p < 0.001). Differences in these measures also had large effect sizes, as shown by Cohen's d values of 0.92 and 1.78, respectively. CONCLUSION: This data set suggests that older adults with amnestic MCI who had been treated with lithium during a previous randomized controlled trial had a better long-term global cognitive outcome than those from a matched sample who did not receive the intervention.

Semantic processing and neurobiology in Alzheimer's disease and Mild Cognitive Impairment.

In the present theoretical review we will perform a critical surveillance of linguistic and semantic processing in Mild Cognitive Impairment and Alzheimer's disease, explicitly favouring a neurobiological prism. We conjecture that most linguistic alterations arise from semantic indiscrimination through inhibitory hypofunction. Specifically, a conjoint cluster of cholinergic dysfunction, Aß load and somatostatin-positive cell loss renders the semantic network disinhibited and overly noisy: fine discriminatory processes in temporal and medial-frontal regions cannot differentiate semantic representations from baseline unconscious activity, which leads to failures in faithful retrieval (preferentially idiosyncratic lexical-semantic links, e.g., proper names), verbal fluency anomalies, semantic interference, dampened N400 effects, and various semiological deviances.

Cognitive-communication disorder following right hemisphere damage: Narrative production.

Background: Cognitive-communication disorder (CCD) results from the association of language and cognition impairment that may follow right hemisphere (RH) damage and impair the quality of life of affected persons. Objective: We studied a set of 1,625 narratives produced by a cohort of 125 individuals (50 with a single right vascular lesion in the MCA territory and 75 cognitively healthy controls) using a task of picture-based discourse production. Discourse production was analyzed in its macro-and microlinguistic aspects to characterize better the linguistic mechanisms underlying RH patients' performance. Results: The RH group produced more words and elocutions than controls, with a lower rate of informational content and a higher percentage of global coherence errors (all p-values <0.0001). Conclusion: Individuals with RH lesions showed formal lexical and syntactic aspects of discourse mostly preserved. Alterations in the macrostructure of discourse prevailed over microstructural alterations in our sample, according to most literature studies. The group of individuals with RH lesions produced narratives containing more words and utterances, with a lesser degree of lexical information and more global coherence errors.

Decision tree-based classification as a support to diagnosis in the Alzheimer's disease continuum using cerebrospinal fluid biomarkers: insights from automated analysis.

OBJECTIVE: Cerebrospinal fluid (CSF) biomarkers add accuracy to the diagnostic workup of cognitive impairment by illustrating Alzheimer's disease (AD) pathology. However, there are no universally accepted cutoff values for the interpretation of AD biomarkers. The aim of this study is to determine the viability of a decision-tree method to analyse CSF biomarkers of AD as a support for clinical diagnosis. METHODS: A decision-tree method (automated classification analysis) was applied to concentrations of AD biomarkers in CSF as a support for clinical diagnosis in older adults with or without cognitive impairment in a Brazilian cohort. In brief, 272 older adults (68 with AD, 122 with mild cognitive impairment [MCI], and 82 healthy controls) were assessed for CSF concentrations of Aß1-42, total-tau, and phosphorylated-tau using multiplexed Luminex assays; biomarker values were used to generate decision-tree algorithms (classification and regression tree) in the R statistical software environment. RESULTS: The best decision tree model had an accuracy of 74.65% to differentiate the three groups. Cluster analysis supported the combination of CSF biomarkers to differentiate AD and MCI vs. controls, suggesting the best cutoff values for each clinical condition. CONCLUSION: Automated analyses of AD biomarkers provide valuable information to support the clinical diagnosis of MCI and AD in research settings.

Impact of Cognitive Demand on Eye Movement Pattern in Patients with Alzheimer's Disease.

BACKGROUND: Eye-movement behavior has been used as a reliable tool to identify cognitive and behavioral patterns in individuals with different neuropsychiatric disorders including Alzheimer's disease (AD). Most studies in the field have been dedicated to evaluating eye-movement behavior during cognitive tasks in different protocols using multiple parameters. OBJECTIVE: We aimed to evaluate the differences of eye-movement behavior in healthy subjects, subjects with mild cognitive impairment (MCI), and those with AD in a simple color task with and without cognitive demand. METHODS: 91 subjects: 18 AD, 47 MCI, and 26 healthy controls had their oculomotor parameters assessed during baseline (no cognitive demand involved) and during a simple computational color memory task using an eye-tracker. RESULTS: Baseline showed statistically different and heterogeneous results between normal cognition and MCI groups. Familiarization phase of the task could not discriminate between groups in any of the analyzed parameters. AD subjects made longer fixations and visits on distractors, and more frequent fixations and visits on the target areas than other groups during the response phase. CONCLUSION: Eye-tracking time-related parameters differentiate AD subjects from other groups under cognitive demand even in a simple color memory task.