Understanding the Episodic Memory and Executive Functioning Axis Impairment in MCI Patients: A Multicenter Study in Comparison with CSF Biomarkers.

BACKGROUND: This study aimed to explore the association between a verbal learning task that evaluates the potential mutual dependency between memory and executive functions (i.e., the Test of Memory Strategies, TMS) and cerebrospinal fluid (CSF) Alzheimer's Disease (AD) biomarkers. METHODS: A sample of 47 mild cognitive impairment (MCI) participants from Poland and Spain were classified according to the Erlangen Score Diagnostic Algorithm (ESA) into CSF- (n = 16) and CSF+ (n = 31) groups. Correlation analyses between TMS word-list conditions and CSF biomarkers were conducted. Additionally, an analysis of covariance was performed to define the effect on ESA classification in the sample, using as a covariable the country of origin of the participants. RESULTS: Significant associations between the TMS-3 condition and Aß42, t-tau, and p-tau were observed for the whole sample. In addition, the CSF- participants obtained higher cognitive performance in TMS-3 compared to the CSF+ group. This outcome persisted if the groups were based on Aß42 scores, but not t-tau or p-tau values. CONCLUSIONS: These findings could indicate that poor performance on verbal learning tests may be affected by executive dysfunctions. Therefore, future intervention plans focused on training executive functions would be of interest to improve the ability of MCI patients to encode and organize information.

The validity and reliability of the Test of Memory Strategies among Italian healthy adults.

Background: Previous literature has shown that executive functions (EF) are related to performance in memory (M) tasks. Nevertheless, there is a shortage of psychometric tests that examine these two constructs simultaneously. The Test of Memory Strategies (TMS; previously validated in Spain and Portugal) could be a useful verbal learning task that evaluates these two constructs at once. In this study, we aimed to evaluate the psychometric properties of the TMS in an Italian adult sample. Method: One hundred twenty-one healthy volunteers (74 F, Mean age = 45.9 years old, SD = 20.4) who underwent a neuropsychological examination participated in this study. We conducted a Confirmatory factor analysis (CFA) to evaluate the structural validity of the TMS. We conducted a latent variable analysis to examine convergent and discriminant validity of the TMS sub-scale scores reflecting executive functions and memory. We also examined the TMS reliability in terms of internal consistency through the McDonald's omega. Results: The CFA confirmed the expectation that the TMS-1 and TMS-2 subtests reflect a factor and that the TMS-3, TMS-4, and TMS-5 subtests reflect a different factor. This result is in line with the prediction that TMS-1 and TMS-2 require the use of executive functions and memory simultaneously, and therefore we called this factor executive functions (EF); whereas the TMS-3, TMS-4, and TMS-5 subtests require less involvement of executive functions, thus reflecting a construct that we named memory (M). The TMS subtests for EF and M showed convergent validity with the test scores using a traditional neuropsychological battery, assessing memory and executive functions separately. Finally, the reliability of the subtests was good. Conclusions: These preliminary findings suggest that TMS is a valid and reliable scale to simultaneously assess M and EF while among Italian healthy adults.

Directional DBS of the Fornix in Alzheimer's Disease Achieves Long-Term Benefits: A Case Report.

Background: Current treatments for Alzheimer's disease (AD) modulate global neurotransmission but are neither specific nor anatomically directed. Tailored stimulation of target nuclei will increase treatment efficacy while reducing side effects. We report the results of the first directional deep brain stimulation (dDBS) surgery and treatment of a patient with AD in an attempt to slow the progression of the disease in a woman with multi-domain, amnestic cognitive status. Methods: We aimed to assess the safety of dDBS in patients with AD using the fornix as stimulation target (primary objective) and the clinical impact of the stimulation (secondary objective). In a registered clinical trial, a female patient aged 81 years with a 2-year history of cognitive decline and diagnoses of AD underwent a bilateral dDBS surgery targeting the fornix. Stimulation parameters were set between 3.9 and 7.5 mA, 90 µs, 130 Hz for 24 months, controlling stimulation effects by 18F-fluoro-2-deoxy-D-glucose (18F-FDG) scans (baseline, 12 and 24 months), magnetoencephalography (MEG) and clinical/neuropsychological assessment (baseline, 6, 12, 18, and 24 months). Results: There were no important complications related to the procedure. In general terms, the patient showed cognitive fluctuations over the period, related to attention and executive function patterns, with no meaningful changes in any other cognitive functions, as is shown in the clinical dementia rating scale (CDR = 1) scores over the 24 months. Such stability in neuropsychological scores corresponds to the stability of the brain metabolic function, seen in PET scans. The MEG studies described low functional connectivity at baseline and a subsequent increase in the number of significant connections, mainly in the theta band, at 12 months. Conclusion: The dDBS stimulation in the fornix seems to be a safe treatment for patients in the first stage of AD. Effects on cognition seem to be mild to moderate during the first months of stimulation and return to baseline levels after 24 months, except for verbal fluency. Clinical Trial Registration: [https://clinicaltrials.gov/ct2/show/NCT03290274], identifier [NCT03290274].

Executive Functions Influence on Memory Process in Patients with Paranoid Schizophrenia and Bipolar Disorders with and without Psychotic Symptoms. A Pilot Study.

The objective of the present study was to evaluate whether declarative memory deficits are related to executive function deficits (EF), since they could be a consequence of a poor organization of the material to memorize. This interaction between both cognitive processes can be studied simultaneously in a single task such as the Test of Memory Strategies (TSM). 23 patients with paranoid schizophrenic disorder, 11 with bipolar disorder with psychotic symptoms, 13 with bipolar disorder without psychotic symptoms and 15 healthy subjects were evaluated with the TSM; with the memory test Texts A and B (subtest of the Barcelona neuropsychological assessment battery), which assesses short-term and immediate recall without the influence of EF; and with the Trail Making Test (TMT): Part A (sustained attention) and Part B (executive control). The patients groups and the control group showed an improvement in memory performance across each of the TSM conditions. However, this facilitating effect of the strategies differed among the groups (the patients with higher EF deficits showed less improvement). Regarding these results, we conclude that this cognitive process cannot be independent of EF. However, due to the pilot nature of this study, it would be recommended to replicate these findings in new studies.

Executive Control on Memory Test Performance across Life: Test of Memory Strategies.

The ability to generate memory strategies is a key factor in performance of episodic memory tests. There is evidence about the inefficient use of memory strategies in old adults. However, a question remains unresolved: Worse performance on memory test in the older people is due to an inability to mobilize cognitive strategies or to an episodic memory deficit? In this study we tried to answer it by using the Test of Memory Strategies (TMS), which parametrically reduces the need of executive functions on memory tests. The test consists of five experimental conditions (TMS1-5) where a progressive external organization of the material reduces the need to mobilize memory strategies. TMS was applied to a sample of 180 participants (n = 180) divided into three age groups (25-45; 46-65; 66-85). The results showed an increased performance in all groups groups (F(2, 177) = 14.79, p < .001) across conditions (F(3.88,674.04) = 292.48, p < .001), without group differences in those conditions with a maximum reduction of the need of executive functions (F(7.61,674.04) = 1.95, p = .053). However, middle age and older adults showed more difficulties in establishing cognitive strategies, in the initial conditions. These results lead to the conclusion that the typical pattern of low performance on episodic memory tasks in the older population may be due to the deterioration of executive functions and not mainly to a primary decline of memory process.

Spatial analysis of thickness changes in ten retinal layers of Alzheimer's disease patients based on optical coherence tomography.

The retina is an attractive source of biomarkers since it shares many features with the brain. Thickness differences in 10 retinal layers between 19 patients with mild Alzheimer's disease (AD) and a control group of 24 volunteers were investigated. Retinal layers were automatically segmented and their thickness at each scanned point was measured, corrected for tilt and spatially normalized. When the mean thickness of entire layers was compared between patients and controls, only the outer segment layer of patients showed statistically significant thinning. However, when the layers were compared point-by point, patients showed statistically significant thinning in irregular regions of total retina and nerve fiber, ganglion cell, inner plexiform, inner nuclear and outer segment layers. Our method, based on random field theory, provides a precise delimitation of regions where total retina and each of its layers show a statistically significant thinning in AD patients. All layers, except inner nuclear and outer segments, showed thickened regions. New analytic methods have shown that thinned regions are interspersed with thickened ones in all layers, except inner nuclear and outer segments. Across different layers we found a statistically significant trend of the thinned regions to overlap and of the thickened ones to avoid overlapping.

Changes in visual function and retinal structure in the progression of Alzheimer's disease.

BACKGROUND: Alzheimer's Disease (AD) can cause degeneration in the retina and optic nerve either directly, as a result of amyloid beta deposits, or secondarily, as a result of the degradation of the visual cortex. These effects raise the possibility that tracking ophthalmologic changes in the retina can be used to assess neurodegeneration in AD. This study aimed to detect retinal changes and associated functional changes in three groups of patients consisting of AD patients with mild disease, AD patients with moderate disease and healthy controls by using non-invasive psychophysical ophthalmological tests and optical coherence tomography (OCT). METHODS: We included 39 patients with mild AD, 21 patients with moderate AD and 40 age-matched healthy controls. Both patients and controls were ophthalmologically healthy. Visual acuity, contrast sensitivity, colour perception, visual integration, and choroidal thicknesses were measured. In addition, OCT and OCT angiography (OCTA) were applied. FINDINGS: Visual acuity, contrast sensitivity, colour perception, and visual integration were significantly lower in AD patients than in healthy controls. Compared to healthy controls, macular thinning in the central region was significant in the mild AD patients, while macular thickening in the central region was found in the moderate AD group. The analysis of macular layers revealed significant thinning of the retinal nerve fibre layer, the ganglion cell layer and the outer plexiform layer in AD patients relative to controls. Conversely, significant thickening was observed in the outer nuclear layer of the patients. However, mild AD was associated with significant thinning of the subfovea and the nasal and inferior sectors of the choroid. Significant superonasal and inferotemporal peripapillary thinning was observed in patients with moderate disease. CONCLUSIONS: The first changes in the mild AD patients appear in the psychophysical tests and in the central macula with a decrease in the central retinal thickness. When there was a disease progression to moderate AD, psychophysical tests remained stable with respect to the decrease in mild AD, but significant thinning in the peripapillary retina and thickening in the central retina appeared. The presence of AD is best indicated based on contrast sensitivity.

Effects of aging on memory strategies: a validation of the Portuguese version of the Test of Memory Strategies.

OBJECTIVE: Previous literature has shown that executive functions (EF) are related to performance in memory tasks. The fact that there are no psychometric tests that evaluate these two constructs simultaneously led a group of researchers to develop the Test of Memory Strategies (TSM). Given the potential importance of this instrument for neuropsychological evaluation, in this study, we aimed to evaluate the psychometric properties of the TMS in Portuguese sample. We also examined the effect of aging by exploring profiles of performance on the TMS, comparing young and elderly healthy subjects. METHOD: Total of 135 healthy participants were submitted to a neuropsychological assessment and were divided into four age groups: a group of young adults (25-35 years) and three groups of older individuals (aged 60-69 years, 70-79 years, and 80 or more years). RESULTS: Findings supported the reliability of the TMS scores, based on analyses of internal consistency. As expected, factor analysis of the TMS scores revealed that the test yielded two factors, one capturing EF and the other memory. Correlations with classic neuropsychological tests supported convergent and discriminant validity of the TMS scores. The elderly groups presented more difficulties in creating and mobilizing memory strategies when compared with a younger group, after controlling for the influence of education, although both groups presented increases in performance throughout the five TMS subscales. CONCLUSIONS: The findings suggest that the TMS is an adequate measure to assess memory and EF, simultaneously, presenting adequate psychometric properties for a Portuguese sample.

[Non-pharmacological treatment of cognitive impairment]. / Tratamiento no farmacológico del deterioro cognitivo.

This article reviews the effect of non-pharmacological therapies in persons with cognitive impairment, especially treatments aimed at brain stimulation and functional maintenance, since both pharmacological and non-pharmacological therapies affecting the cognitive and psychoaffective domains are reviewed in another article in this supplement. The article also discusses the close and reciprocal relationship between cognitive impairment, diet and nutritional status and describes the main nutritional risk factors and protective factors in cognitive decline.

Ophthalmologic Psychophysical Tests Support OCT Findings in Mild Alzheimer's Disease.

Purpose. To analyze in mild Alzheimer's disease (MAD) patients, GDS-4 (Reisberg Scale), whether or not some psychophysical tests (PTs) support OCT macular findings in the same group of MAD patients reported previously. Methods. Twenty-three MAD patients and 28 age-matched control subjects with mean Mini Mental State Examination of 23.3 and 28.2, respectively, with no ocular disease or systemic disorders affecting vision were included. Best-corrected visual acuity (VA), contrast sensitivity (CS) (3, 6, 12, and 18 cpds), color perception (CP), and perception digital test (PDT) were tested in one eye of each patient. Results. In comparison with the controls, MAD patients presented (i) a significant decrease in VA, PDT, and CS for all spatial frequencies analyzed, especially the higher ones, and (ii) a significant increase in unspecific errors on the blue axis (P < 0.05 in all instances). In MAD patients, a wide aROC curve was plotted in all PTs. Conclusions. In MAD, CS, VA, and the tritan axis in CP were impaired. The PTs with the greatest predictive value are the higher spatial frequencies in CS and tritan unspecific errors in CP. PT abnormalities are consistent with the structural findings reported in the same MAD patients using OCT.

Analysis of Retinal Peripapillary Segmentation in Early Alzheimer's Disease Patients.

Decreased thickness of the retinal nerve fiber layer (RNFL) may reflect retinal neuronal-ganglion cell death. A decrease in the RNFL has been demonstrated in Alzheimer's disease (AD) in addition to aging by optical coherence tomography (OCT). Twenty-three mild-AD patients and 28 age-matched control subjects with mean Mini-Mental State Examination 23.3 and 28.2, respectively, with no ocular disease or systemic disorders affecting vision, were considered for study. OCT peripapillary and macular segmentation thickness were examined in the right eye of each patient. Compared to controls, eyes of patients with mild-AD patients showed no statistical difference in peripapillary RNFL thickness (P > 0.05); however, sectors 2, 3, 4, 8, 9, and 11 of the papilla showed thinning, while in sectors 1, 5, 6, 7, and 10 there was thickening. Total macular volume and RNFL thickness of the fovea in all four inner quadrants and in the outer temporal quadrants proved to be significantly decreased (P < 0.01). Despite the fact that peripapillary RNFL thickness did not statistically differ in comparison to control eyes, the increase in peripapillary thickness in our mild-AD patients could correspond to an early neurodegeneration stage and may entail the existence of an inflammatory process that could lead to progressive peripapillary fiber damage.

Association of perceived health and depression with older adults' subjective memory complaints: contrasting a specific questionnaire with general complaints questions.

The objectives of this paper were to evaluate the association of subjective memory complaints (SMC) with perceived state of health, mood and episodic memory (associative and everyday memory). We studied these areas using two different complaint assessment methods (three general questions and a validated scale). The study included 269 older adults (aged 65-87) with age-related memory changes, but without cognitive impairment. They were evaluated with Mini-cognitive Exam, Rivermead Behavioural Memory Test (a test of everyday memory), Paired Associates Learning Test, Memory Failures of Everyday Questionnaire, three memory complaints questions, Nottingham Health Profile and Geriatric Depression Scale. The results indicated that memory for everyday performance, mood and perceived health were independent predictors of SMC, with mood and perceived health being stronger predictors than actual memory performance. Age was not associated with subjective memory and, with regard to level of education, only the illiterate level was associated with SMC. A specific questionnaire on subjective memory was found to be preferable to an aggregate of complaints questions on self-reported memory; only health profile was found to predict the outcomes on memory complaints questions. Our conclusion is that a group of underlying factors other than everyday memory were playing a role in SMC; these SMC of subjects with age-related memory changes were mainly associated with subjective evaluations of their health.

Synchronization during an internally directed cognitive state in healthy aging and mild cognitive impairment: a MEG study.

Mild cognitive impairment (MCI) is a stage between healthy aging and dementia. It is known that in this condition the connectivity patterns are altered in the resting state and during cognitive tasks, where an extra effort seems to be necessary to overcome cognitive decline. We aimed to determine the functional connectivity pattern required to deal with an internally directed cognitive state (IDICS) in healthy aging and MCI. This task differs from the most commonly employed ones in neurophysiology, since inhibition from external stimuli is needed, allowing the study of this control mechanism. To this end, magnetoencephalographic (MEG) signals were acquired from 32 healthy individuals and 38 MCI patients, both in resting state and while performing a subtraction task of two levels of difficulty. Functional connectivity was assessed with phase locking value (PLV) in five frequency bands. Compared to controls, MCIs showed higher PLV values in delta, theta, and gamma bands and an opposite pattern in alpha, beta, and gamma bands in resting state. These changes were associated with poorer neuropsychological performance. During the task, this group exhibited a hypersynchronization in delta, theta, beta, and gamma bands, which was also related to a lower cognitive performance, suggesting an abnormal functioning in this group. Contrary to controls, MCIs presented a lack of synchronization in the alpha band which may denote an inhibition deficit. Additionally, the magnitude of connectivity changes rose with the task difficulty in controls but not in MCIs, in line with the compensation-related utilization of neural circuits hypothesis (CRUNCH) model.

Early dysfunction of functional connectivity in healthy elderly with subjective memory complaints.

It is still an open question whether subjective memory complaints (SMC) can actually be considered to be clinically relevant predictors for the development of an objective memory impairment and even dementia. There is growing evidence that suggests that SMC are associated with an increased risk of dementia and with the presence of biological correlates of early Alzheimer's disease. In this paper, in order to shed some light on this issue, we try to discern whether subjects with SMC showed a different profile of functional connectivity compared with subjects with mild cognitive impairment (MCI) and healthy elderly subjects. In the present study, we compare the degree of synchronization of brain signals recorded with magnetoencephalography between three groups of subjects (56 in total): 19 with MCI, 12 with SMC and 25 healthy controls during a memory task. Synchronization likelihood, an index based on the theory of nonlinear dynamical systems, was used to measure functional connectivity. Briefly, results show that subjects with SMC have a very similar pattern of connectivity to control group, but on average, they present a lower synchronization value. These results could indicate that SMC are representing an initial stage with a hypo-synchronization (in comparison with the control group) where the brain system is still not compensating for the failing memory networks, but behaving as controls when compared with the MCI subjects.

[Neuropsychological characteristics and diagnostic approach to Parkinsons disease dementia and Lewy body dementia]. / Características Neuropsicológicas y Aproximación Diagnóstica a la Demencia Parkinson y a la Demencia por Cuerpos de Lewy.

When approaching the neurophysiological characteristics and diagnostic approach to Parkinson's disease dementia (PDD) and Lewy body dementia (LBD), the first idea that comes to mind is that both types of dementia fall within the group of subcortical dementias, with the practical implications that this observation entails. We should therefore leave our knowledge of Alzheimer's dementia and other cortical dementias to one side as, in most cases, these forms of dementia do not correspond clinically or diagnostically to subcortical dementias. Therefore, the clinical and therapeutic approach of PDD and LBD differs from that of cortical dementias in form, if not in essence.

Brain activity patterns in stable and progressive mild cognitive impairment during working memory as evidenced by magnetoencephalography.

It has been reported that mild cognitive impairment (MCI) patients, when compared with controls, show increased activity in different brain regions within the ventral pathway during memory tasks. A key question is whether this profile of increased activity could be useful to predict which patients will develop dementia. Herein, we present profiles of brain magnetic activity during a memory task recorded with magnetoencephalography from MCI patients (N = 10), Alzheimer's disease (AD) patients (N = 10), and healthy volunteers (N = 17). After 2½ years of follow-up, five of the MCI patients developed AD. Patients who progressed to AD (PMCI) showed higher activity than those who remained stable (SMCI), AD patients and controls. This increased activity in PMCI patients involves regions within the ventral and dorsal pathways. In contrast, SMCI patients showed higher activation than controls only along the ventral pathway. This increase in both the ventral and dorsal pathways in PMCI patients may reflect a compensatory mechanism for the loss in efficiency in memory networks, which would be absent in AD patients as they showed lower activity levels than the rest of the groups.

Increased biomagnetic activity in healthy elderly with subjective memory complaints.

OBJECTIVE: Subjective memory complaints (SMCs) are frequently reported by elderly people with or without objective cognitive impairment (OMI) as assessed by neuropsychological tests. We investigate whether SMCs are associated with altered brain biomagnetic patterns even in the absence of OMI. METHODS: We report spatio-temporal patterns of brain magnetic activity recorded with magnetoencephalography during a memory task in 51 elderly participants divided into the following groups: patients with mild cognitive impairment (MCI) with SMC and OMI, individuals with SMC but not OMI, and healthy controls without neither SMC nor OMI. Exclusion criteria for all three groups included a diagnosis of depression or any other psychiatric condition. RESULTS: No statistically significant differences were found between MCI patients and participants with SMC. However, the SMC showed higher activation, between 200 and 900 ms after stimulus onset, than the control group in posterior ventral regions and in the dorsal pathway. MCI patients showed higher activation than the control group in the posterior part of the ventral pathway. CONCLUSIONS: These findings suggest that similar physiological mechanisms may underlie SMC and MCI, which could be two stages in a cognitive continuum. SIGNIFICANCE: MEG provide different neurophysiological profiles between SMC and control subjects.