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Several studies showed that transcranial direct current stimulation (tDCS) enhances cognition in patients with mild cognitive impairment (MCI), however, whether tDCS leads to additional gains when combined with cognitive training remains unclear. This study aims to compare the effects of a concurrent tDCS-cognitive training intervention with either tDCS or cognitive training alone on a group of patients with MCI.
The study was a 3-parallel-arm study. The intervention consisted of 20 daily sessions of 20 minutes each. Patients (n = 62) received anodal tDCS to the left dorsolateral prefrontal cortex, cognitive training on 5 cognitive domains (orientation, attention, memory, language, and executive functions), or both. To examine intervention gains, we examined global cognitive functioning, verbal short-term memory, visuospatial memory, and verbal fluency pre- and post-intervention.
All outcome measures improved after the intervention in the 3 groups. The improvement in global cognitive functioning and verbal fluency was significantly larger in patients who received the combined intervention. Instead, the intervention gain in verbal short-term memory and visuospatial memory was similar across the 3 groups.
tDCS, regardless of the practicalities, could be an efficacious treatment in combination with cognitive training given the increased effectiveness of the combined treatment.
Future studies will need to consider individual differences at baseline, including genetic factors and anatomical differences that impact the electric field generated by tDCS and should also consider the feasibility of at-home treatments consisting of the application of tDCS with cognitive training.
Cognitive impairment is one of the most common symptoms of anti-leucine rich glioma inactivated 1 (anti-LGI-1) encephalitis, but little is known about the cognitive profile of these patients. This study characterized the cognitive profile of patients with anti-LGI-1 encephalitis and compared patterns of impairment to healthy controls and other patient groups with known temporal lobe/limbic involvement.
A retrospective analysis of adult patients with anti-LGI-1 encephalitis who underwent neuropsychological assessment was conducted. Performance patterns of anti-LGI-1 patients were compared to patients deemed cognitively healthy (HC), as well as patients with amnestic mild cognitive impairment (aMCI) and temporal lobe epilepsy (TLE).
Among 10 anti-LGI encephalitis patients (60% male, median age 67.5 years) who underwent neuropsychological testing (median = 38.5 months from symptom onset), cognitive deficits were common, with 100% of patients showing impairment (≤1.5 SD below mean) on 1+ measures and 80% on 2+ measures. Patients with anti-LGI-1 encephalitis performed worse than controls on measures of basic attention, vigilance, psychomotor speed, complex figure copy, and aspects of learning/memory. Of measures which differed from controls, there were no differences between the anti-LGI-1 and TLE patients, while the anti-LGI-1 patients exhibited higher rates of impairment in basic attention and lower rates of delayed verbal memory impairment compared to the aMCI patients.
Long-term cognitive deficits are common in patients with anti-LGI-1 encephalitis and involve multiple domains. Future research in larger samples is needed to confirm these findings.
While decreased alpha-band functional connectivity (FC) and changes in network topology have been reported in Alzheimer’s disease, it is not yet entirely known whether these differences mark cognitive decline in the early stages of the disease.
Our study aimed to analyze EEG FC and network differences in the alpha frequency band during visuospatial memory maintenance between Mild Cognitive Impairment (MCI) patients and healthy elderly with subjective memory complaints.
FC and network structure of 17 MCI patients and 20 control participants were studied with 128-channel EEG during a visuospatial memory task. FC was measured by amplitude envelope correlation with leakage correction (AEC-c), while network analysis was performed by applying the Minimum Spanning Tree approach.
Increasing memory load enhanced the mean alpha-band FC in the control group. In contrast to that, after an initial increase, the MCI group showed significantly (p<0.05) diminished FC in the highest memory load condition. Mean alpha AEC-c correlated significantly with the size and mean diffusivity of medial temporal lobe structures in the entire sample. The network analysis revealed a rerouted network in the MCI group with a more centralized topology and a more unequal traffic load distribution compared to the control group.
Alpha-band FC correlates with cognitive load-related modulation, with medial temporal lobe atrophy, and with the disruption of hippocampal fiber integrity in the earliest stages of cognitive decline. The more integrated network topology of the MCI group is in line with the “hub overload and failure” framework and might be part of a compensatory mechanism.
SARS-Co-V2 neuroinvasive ability might be the basis for the onset of delirium and neuropsychiatric outcomes.
We hypothesized that some infected patients with preexisting cognitive dysfunction may present delirium as unique manifestation of COVID-19 infection or as a prodrome of a new episode consistent with the psychiatric history.
We conducted a PubMed literature search to verify whether cognitive impairment might predispose to COVID-19. We included three patients with mild cognitive impairment and delirium at admission for SARS-Co-V2 suspected infection. Delirium was diagnosed according to DSM-5 criteria‚ Cognitive Assessment Method and Coma Glasgow Scale.
Literature analysis evidenced patients presenting delirium or delirium-like symptoms as clinical manifestation of COVID-19, plus a cognitive impairment‚ from mild to severe‚ which preexisted or was evidenced during the acute phase or after the infection. Most studies described delirium in patients with a past neurological/psychiatric history. Contrasting data emerged on the potential link between COVID-19 and delirium in patients with cognitive impairment and without a past neuropsychiatric history. Our patients had no history of other medical complications. Our first patient had no psychiatric history‚ the second reported only a depressive episode‚ and the third had story of bipolar disorder. Delirium resolved completely after 2 days in the first patient. The other patients required 4 and 14 days to resolve: delirium appeared as the prodrome of a new psychiatric episode in line with their past history.
Clinicians should acknowledge the possibility that COVID-19 infection may appear as delirium and acute psychiatric sequelae as unique manifestation.
Subjective cognitive difficulties (SCDs) are associated with factors commonly reported in older adults and former contact sport athletes, regardless of objective cognitive decline. We investigated the relative contribution of these factors to SCD in former National Football League (NFL)-players with and without a diagnosis of mild cognitive impairment (MCI).
Former NFL players (n = 907) aged ≥ 50 years (mean = 64.7 ± 8.9), with (n = 165) and without (n = 742) a diagnosis of MCI completed health questionnaires. Multivariable regression and dominance analyses determined the relative importance of SCD factors on SCD: 1) depression, 2) anxiety, 3) sleep disturbance, 4) pain interference, 5) ability to participate in social roles and activities, 6) stress-related events, 7) fatigue, 8) concussion history, and 9) education. SCD outcomes included Neuro-QoL Emotional-Behavioral Dyscontrol and the PROMIS Cognitive Function. Fisher’s z-transformation compared comorbid contributing factors to SCD across MCI and non-MCI groups.
Complete dominance of anxiety was established over most comorbid factors across the MCI and non-MCI groups. Fatigue also exhibited complete dominance over most comorbid factors, though its influence in the MCI group was less robust (general dominance). Average contributions to variance accounted for by comorbid factors to ratings of SCD across MCI and non-MCI groups did not statistically differ (Z-statistics <1.96, ps>.05).
Anxiety and fatigue are the most robust factors associated with SCD in former professional football players across various combinations of clinical presentations (different combinations of comorbid factors), regardless of documented cognitive impairment. Self-reported deficits may be less reliable in detecting objective impairment in the presence of these factors, with multidimensional assessment being ideal.
This study examines whether memory intervention programs can mitigate health care costs. Research suggests these programs translate to a decreased intention of older adults who are worried about age-normal memory changes to seek traditional outlets for medical/psychiatric help. We employed a cost-benefit analysis approach to analyze the effectiveness of a memory intervention program within Ontario. We leveraged estimates of decreased intentionality to seek physician care following a community-based memory intervention with physician billing profiles to calculate the potential cost savings to the province’s health care system. The intervention studied was found to reduce provincial health care spending by $6,094 per program group. This amount exceeds $121.25 in direct costs per attendee associated with administering five program sessions. This analysis justifies further research on how community-based memory and aging programs can offer low-cost solutions to help individuals cope with subjective memory complaints and assist the health care system in prioritizing care for aging patients.
The current study examined the effects of a 16-week creative expression program on brain activity during a story creating task and resting-state functional network connectivity in mild cognitive impairment (MCI) adults.
Thirty-six MCI adults were allocated to either the creative expression program (CrExp, n = 18) or control group (CG,n = 18). Before and after intervention, all participants were scanned with functional magnetic resonance imaging (fMRI) during story creating task performance and a resting state. The two-group comparison was calculated between the blood oxygenation level-dependent (BOLD) signal changes for each cluster to investigate the differences in fMRI activation and functional connectivity (FC) between two groups.
Task activation analyses showed an increase in the right anterior cingulate gyrus (ACG), right medial frontal gyrus (MFG), right lentiform nucleus (LN), left hippocampus (HIP), left middle occipital gyrus (MOG), and left cerebellum posterior lobe (CPL) (p < 0.05). Story creating performance improvements were associated with greater activation in the left HIP region. Resting-state functional connectivity (FC) between left HIP and certain other brain areas shown a significant interaction of creative expression group versus control group. Moreover, connectivity between the right angular gyrus (ANG), right inferior temporal gyrus (ITG), right superior occipital gyrus (SOG), left ANG, and left MFG were related to improved cognitive performance (p < 0.05).
These data extend current knowledge by indicating that the creative expression program can improve cognitive activation in MCI, and these enhancements may be related to the neurocognitive network plasticity changes induced by creative expression training.
There is now evidence to suggest that there may be an interaction between B vitamins and n-3 PUFA, with suggestions that increasing intake of both nutrients simultaneously may benefit cognition in older adults. The aim of this systematic review was to investigate whether supplementation with a combination of n-3 PUFA and B vitamins can prevent cognitive decline in older adults. Randomised controlled trials conducted in older adults that measured cognitive function were retrieved. The included trials provided a combination of n-3 PUFA and B vitamins alone, or in combination with other nutrients. Trials that provided n-3 PUFA alone and also measured B vitamin status or provided B vitamin supplementation alone and measured n-3 PUFA status were also included. The databases searched were The Cochrane Library, EMBASE, CINAHL, Scopus and MEDLINE. A total of 14 papers were included in the analysis (n 4913; age: 60–70 years; follow-up 24 weeks to 4 years). The meta-analysis results found a significant benefit of nutrient formulas, which included both n-3 PUFA and B vitamins alongside other nutrients, v. placebo on global cognition assessed using composite scores from a neuropsychological test battery (G = 0·23, P = 0·002), global cognition using single measures of cognition (G = 0·28, P = 0·004) and episodic memory (G = 0·32, P = 0·001). The results indicate that providing a combination of n-3 PUFA and B vitamins as part of a multi-nutrient formula benefits cognition in older adults v. a placebo, and the potential for an interaction between these key nutrients should be considered in future experimental work.
Depression is common in persons experiencing mild cognitive impairment (MCI), with 32% (95% Cl 27, 37) overall experiencing depression. Persons with MCI who have depression have more cognitive changes compared to those without depression. To understand how we can detect depressive symptoms in persons with MCI, we undertook a systematic review to identify tools that were validated compared with a reference standard.
We searched MEDLINE, EMBASE, PsycINFO, and Cochrane from inception to April 25, 2021, and conducted a gray literature search. Title/abstract and full-text screening were completed in duplicate. Demographic information, reference standards, prevalence, and diagnostic accuracy measures were then extracted from included articles (PROSPERO CRD: CRD42016052120).
Across databases, 8,748 abstracts were generated after removing duplicates. Six hundred and sixty-five records underwent full-text screening, with six articles included for data extraction. Nine tools were identified compared to a reference standard, with multiple demonstrating a sensitivity of 100% (Brief Assessment Schedule Depression Cards, Beck Depression Inventory-II, Cornell Scale for Depression in Dementia, Zung Self-Rated Depression Scale, and the Neuropsychiatric Inventory). The second highest sensitivity reported was 89% (Patient Health Questionnaire-9). Too few studies were available for a meta-analysis.
Multiple depression detection tools have been examined amongst MCI outpatients, with several showing high sensitivity. However, this evidence is only present in single studies, with little demonstration of how differing MCI types affect accuracy. More research is needed to confirm the accuracy of these tools amongst persons with MCI. At this time, several tools could be suitable for use in cognitive clinics.
Drug repositioning refers to the development of a drug for an indication other that in the marketing authorisation and drug repurposing is the use of known drugs for new indications. Both repositioning and repurposing are opportunities to complement traditional drug development and may shorten the time for a drug to reach the patient. This chapter provides a detailed overview of the pharmacological, preclinical, clinical and epidemiological evidence for four drugs or drug classes currently considered as the highest priority candidates for repurposing in Alzheimer’s disease: fasudil, phenserine, antiviral drugs and glucagon-like peptide 1 (GLP-1) analogs. In addition, key considerations on the future of repurposing are provided, including the role of transcriptional approaches and targeting risk genes and growth factors.
Most recordings of verbal fluency tasks include substantial amounts of task-irrelevant content that could provide clinically valuable information for the detection of mild cognitive impairment (MCI). We developed a method for the analysis of verbal fluency, focusing not on the task-relevant words but on the silent segments, the hesitations, and the irrelevant utterances found in the voice recordings.
Phonemic (‘k’, ‘t’, ‘a’) and semantic (animals, food items, actions) verbal fluency data were collected from healthy control (HC; n = 25; Mage = 67.32) and MCI (n = 25; Mage = 71.72) participants. After manual annotation of the voice samples, 10 temporal parameters were computed based on the silent and the task-irrelevant segments. Traditional fluency measures, based on word count (correct words, errors, repetitions) were also employed in order to compare the outcome of the two methods.
Two silence-based parameters (the number of silent pauses and the average length of silent pauses) and the average word transition time differed significantly between the two groups in the case of all three semantic fluency tasks. Subsequent receiver operating characteristic (ROC) analysis showed that these three temporal parameters had classification abilities similar to the traditional measure of counting correct words.
In our approach for verbal fluency analysis, silence-related parameters displayed classification ability similar to the most widely used traditional fluency measure. Based on these results, an automated tool using voiced-unvoiced segmentation may be developed enabling swift and cost-effective verbal fluency-based MCI screening.
Previous research has indicated that attention-deficit/hyperactivity disorder (ADHD) is associated with an increased risk for dementia, but studies are scarce and inconclusive. We aimed to investigate the association between ADHD, and dementia and mild cognitive impairment (MCI). Additionally, we aimed to investigate the impact of comorbid conditions, educational attainment, head injuries, other developmental disorders, and sex on the association.
The study population consisted of 3,591,689 individuals born between 1932 and 1963, identified from Swedish population-based registers. Cases of ADHD, dementia and MCI were defined according to ICD diagnostic codes and ATC codes for medication prescriptions. A Cox proportional hazards model was used to test the associations between ADHD, and dementia and MCI.
Individuals with ADHD had an increased risk for dementia and MCI. After adjusting for sex and birth year, a hazard ratio (HR) was 2.92 (95% confidence interval 2.40–3.57) for dementia, and 6.21 (5.25–7.35) for MCI. Additional adjustment for psychiatric disorders (depression, anxiety, substance use disorder, and bipolar disorder) substantially attenuated the associations, HR = 1.62 (1.32–1.98) for dementia, and 2.54 (2.14–3.01) for MCI. Common metabolic disorders (hypertension, type 2 diabetes, and obesity), sleep disorders, head injuries, educational attainment, and other developmental disorders, had a limited impact on the association. The association between ADHD and dementia was stronger in men.
ADHD is a potential risk factor for dementia and MCI, although the risk significantly attenuates after controlling for psychiatric disorders. Further research is needed to confirm these findings and to explore underlying mechanisms of the associations.
The aim of this study was to identify any relationship between hearing loss and mild cognitive impairment.
This was a systematic review and meta-analysis of randomised controlled trials conducted using Medline and the Cochrane Library up to 24 June 2020. Prospective, cohort and cross-sectional, and observational studies that reported on the relationship between mild cognitive impairment and hearing loss were included.
A total of 34 studies reporting data on 48 017 participants were included. Twenty-three studies observed a significant association between hearing loss and mild cognitive impairment. The pooled risk ratio across all studies of prevalence of mild cognitive impairment in people with hearing loss was 1.44 (random-effects; 95 per cent CI = 1.27–1.64; p < 0.00001; I2 = 0 per cent). Significantly more people with mild cognitive impairment had peripheral hearing loss compared with those without (risk ratio, 1.40 random-effects; 95 per cent CI = 1.10–1.77; p = 0.005; I2 = 0 per cent). When the incidence was studied, significantly more people with peripheral hearing loss had mild cognitive impairment compared with those without (risk ratio = 2.06 random-effects; 95 per cent CI = 1.35–3.15; p = 0.0008; I2 = 97 per cent); however; a high level of statistical heterogeneity was evident.
Most of the studies included in this systematic review observed a significant association between hearing loss and mild cognitive impairment.
This study aims to establish reference data for nondemented adults between 80 and 84 years of age based on the German version of the Consortium to Establish a Registry for Alzheimer’s disease Neuropsychological (CERAD-NP) test battery and to assess the possible influence of hearing and vision impairments on CERAD-NP performance.
Two hundred one volunteers were examined with the German CERAD-NP test battery, and 18 test scores were calculated from the data. The sample included 99 men (49%), the mean age was 81.8 years (SD = 1.3), and the mean years of education were 13.9 (SD = 3.1). Percentiles for continuous and percentile ranks for discrete test scores were calculated separately for four norm groups. The groups were classified according to gender and education. Multiple regression analysis was used to predict cognitive performance from visual acuity and hearing ability.
The normative data obtained were consistent with other findings from younger and older age groups. Worse visual acuity predicted slower performance in the Trail Making Test (TMT). None of the other CERAD-NP tests were correlated to sensory functions.
Using age-appropriate reference data, such as that established here for the 80–84 year age group can help to improve the detection of cognitive decline and prevent biases that arise when old-old adults are compared to younger old adults. Visual acuity should be considered an influencing factor on TMT performance.
We examined the association between bilingualism, executive function (EF), and brain volume in older monolinguals and bilinguals who spoke English, Spanish, or both, and were cognitively normal (CN) or diagnosed with Mild Cognitive Impairment (MCI) or dementia. Gray matter volume (GMV) was higher in language and EF brain regions among bilinguals, but no differences were found in memory regions. Neuropsychological performance did not vary across language groups over time; however, bilinguals exhibited reduced Stroop interference and lower scores on Digit Span Backwards and category fluency. Higher scores on Digit Span Backwards were associated with a younger age of English acquisition, and a greater degree of balanced bilingualism was associated with lower scores in category fluency. The initial age of cognitive decline did not differ between language groups. The influence of bilingualism appears to be reflected in increased GMV in language and EF regions, and to a lesser degree, in EF.
Cognitive impairment or dementia is increasing in prevalence worldwide and may be an unrecognised and early complication of a number of endocrine conditions, including diabetes mellitus and thyroid disease. In addition, these conditions may be predisposing factors towards developing dementia. In this chapter, we will discuss these issues with reference to diabetes in particular, being the endocrine disorder with the strongest association with cognitive impairment. Identifying cognitive impairments among people with endocrine disorders is important, as is identifying endocrine conditions in people living with dementia, as this may require adjustment of therapeutic targets and of treatment. There are particular challenges in certain clinical groups, including depressive pseudodementia, behavioural and psychological symptoms of dementia, frailty and mild cognitive impairment. Targets for glycaemic control may need to be relaxed in this group of patients, and this is supported by international best practice guidelines.
Impaired olfaction may be a biomarker for early Lewy body disease, but its value in mild cognitive impairment with Lewy bodies (MCI-LB) is unknown. We compared olfaction in MCI-LB with MCI due to Alzheimer’s disease (MCI-AD) and healthy older adults. We hypothesized that olfactory function would be worse in probable MCI-LB than in both MCI-AD and healthy comparison subjects (HC).
Cross-sectional study assessing olfaction using Sniffin’ Sticks 16 (SS-16) in MCI-LB, MCI-AD, and HC with longitudinal follow-up. Differences were adjusted for age, and receiver operating characteristic (ROC) curves were used for discriminating MCI-LB from MCI-AD and HC.
Participants were recruited from Memory Services in the North East of England.
Thirty-eight probable MCI-LB, 33 MCI-AD, 19 possible MCI-LB, and 32HC.
Olfaction was assessed using SS-16 and a questionnaire.
Participants with probable MCI-LB had worse olfaction than both MCI-AD (age-adjusted mean difference (B) = 2.05, 95% CI: 0.62–3.49, p = 0.005) and HC (B = 3.96, 95% CI: 2.51–5.40, p < 0.001). The previously identified cutoff score for the SS-16 of ≤ 10 had 84% sensitivity for probable MCI-LB (95% CI: 69–94%), but 30% specificity versus MCI-AD. ROC analysis found a lower cutoff of ≤ 7 was better (63% sensitivity for MCI-LB, with 73% specificity vs MCI-AD and 97% vs HC). Asking about olfactory impairments was not useful in identifying them.
MCI-LB had worse olfaction than MCI-AD and normal aging. A lower cutoff score of ≤ 7 is required when using SS-16 in such patients. Olfactory testing may have value in identifying early LB disease in memory services.
To test the hypothesis that higher level of purpose in life is associated with lower likelihood of dementia and mild cognitive impairment (MCI) in older Brazilians.
As part of the Pathology, Alzheimer’s and Related Dementias Study (PARDoS), informants of 1,514 older deceased Brazilians underwent a uniform structured interview. The informant interview included demographic data, the Clinical Dementia Rating scale to diagnose dementia and MCI, the National Institute of Mental Health Diagnostic Interview Schedule for depression, and a 6-item measure of purpose in life, a component of well-being.
Purpose scores ranged from 1.5 to 5.0 with higher values indicating higher levels of purpose. On the Clinical Dementia Rating Scale, 940 persons (62.1%) had no cognitive impairment, 121 (8.0%) had MCI, and 453 (29.9%) had dementia. In logistic regression models adjusted for age at death, sex, education, and race, higher purpose was associated with lower likelihood of MCI (odds ratio = .58; 95% confidence interval [CI]: .43, .79) and dementia (odds ratio = .49, 95% CI: .41, .59). Results were comparable after adjusting for depression (identified in 161 [10.6%]). Neither race nor education modified the association of purpose with cognitive diagnoses.
Higher purpose in life is associated with lower likelihood of MCI and dementia in older black and white Brazilians.
Alzheimer’s disease (AD) is the most common major neurocognitive disorder of ageing. Although largely ignored until about a decade ago, accumulating evidence suggests that deteriorating brain energy metabolism plays a key role in the development and/or progression of AD-associated cognitive decline. Brain glucose hypometabolism is a well-established biomarker in AD but was mostly assumed to be a consequence of neuronal dysfunction and death. However, its presence in cognitively asymptomatic populations at higher risk of AD strongly suggests that it is actually a pre-symptomatic component in the development of AD. The question then arises as to whether progressive AD-related cognitive decline could be prevented or slowed down by correcting or bypassing this progressive ‘brain energy gap’. In this review, we provide an overview of research on brain glucose and ketone metabolism in AD and its prodromal condition – mild cognitive impairment (MCI) – to provide a clearer basis for proposing keto-therapeutics as a strategy for brain energy rescue in AD. We also discuss studies using ketogenic interventions and their impact on plasma ketone levels, brain energetics and cognitive performance in MCI and AD. Given that exercise has several overlapping metabolic effects with ketones, we propose that in combination these two approaches might be synergistic for brain health during ageing. As cause-and-effect relationships between the different hallmarks of AD are emerging, further research efforts should focus on optimising the efficacy, acceptability and accessibility of keto-therapeutics in AD and populations at risk of AD.
Electroencephalographic (EEG) abnormalities are greater in mild cognitive impairment (MCI) with Lewy bodies (MCI-LB) than in MCI due to Alzheimer’s disease (MCI-AD) and may anticipate the onset of dementia. We aimed to assess whether quantitative EEG (qEEG) slowing would predict a higher annual hazard of dementia in MCI across these etiologies. MCI patients (n = 92) and healthy comparators (n = 31) provided qEEG recording and underwent longitudinal clinical and cognitive follow-up. Associations between qEEG slowing, measured by increased theta/alpha ratio, and clinical progression from MCI to dementia were estimated with a multistate transition model to account for death as a competing risk, while controlling for age, cognitive function, and etiology classified by an expert consensus panel.
Over a mean follow-up of 1.5 years (SD = 0.5), 14 cases of incident dementia and 5 deaths were observed. Increased theta/alpha ratio on qEEG was associated with increased annual hazard of dementia (hazard ratio = 1.84, 95% CI: 1.01–3.35). This extends previous findings that MCI-LB features early functional changes, showing that qEEG slowing may anticipate the onset of dementia in prospectively identified MCI.