Association of Blood MicroRNA Expression and Polymorphisms with Cognitive and Biomarker Changes in Older Adults.

BACKGROUND: Identifying individuals before the onset of overt symptoms is key in the prevention of Alzheimer's disease (AD). OBJECTIVES: Investigate the use of miRNA as early blood-biomarker of cognitive decline in older adults. DESIGN: Cross-sectional. SETTING: Two observational cohorts (CHARIOT-PRO, Alzheimer's Disease Neuroimaging Initiative (ADNI)). PARTICIPANTS: 830 individuals without overt clinical symptoms from CHARIOT-PRO and 812 individuals from ADNI. MEASUREMENTS: qPCR analysis of a prioritised set of 38 miRNAs in the blood of individuals from CHARIOT-PRO, followed by a brain-specific functional enrichment analysis for the significant miRNAs. In ADNI, genetic association analysis for polymorphisms within the significant miRNAs' genes and CSF levels of phosphorylated-tau, total-tau, amyloid-ß42, soluble-TREM2 and BACE1 activity using whole genome sequencing data. Post-hoc analysis using multi-omics datasets. RESULTS: Six miRNAs (hsa-miR-128-3p, hsa-miR-144-5p, hsa-miR-146a-5p, hsa-miR-26a-5p, hsa-miR-29c-3p and hsa-miR-363-3p) were downregulated in the blood of individuals with low cognitive performance on the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). The pathway enrichment analysis indicated involvement of apoptosis and inflammation, relevant in early AD stages. Polymorphisms within genes encoding for hsa-miR-29c-3p and hsa-miR-146a-5p were associated with CSF levels of amyloid-ß42, soluble-TREM2 and BACE1 activity, and 21 variants were eQTL for hippocampal MIR29C expression. CONCLUSIONS: six miRNAs may serve as potential blood biomarker of subclinical cognitive deficits in AD. Polymorphisms within these miRNAs suggest a possible interplay between the amyloid cascade and microglial activation at preclinical stages of AD.

Hot spot identification method based on Andrews curves: an application on the COVID-19 crisis effects on caregiver distress in neurocognitive disorder.

Identifying and locating areas - hot spots - that present high concentration of observations in a high-dimensional data set is crucial in many data processing and analysis methods and techniques, since observations that belong to the same hot spot share information and behave in a similar way. A useful tool towards that aim is the reduction of the data dimensionality and the graphical representation of them. In the present paper, a new method to identify and locate hot spots is proposed, based on the Andrews curves. Simulations results demonstrate the performance of the proposed method, which is also applied to a high-dimensional data set, regarding caregiver distress related to symptoms of people with neurocognitive disorder and to the mental effects of the recent outbreak of the COVID-19 pandemic.

Old age mental health services in Southern Balkans: Features, geospatial distribution, current needs, and future perspectives.

BACKGROUND: Healthcare services are increasingly confronted with challenges related to old age mental disorders. The survey aimed to provide an overview of existing psychogeriatric services in Albania, Bulgaria, Greece, and North Macedonia. METHODS: After identification of psychogeriatric units across the four countries, their head physicians were asked to provide data on their clinical, teaching, and research activity, as well as staff composition. Moreover, the attitudes of head physicians to current needs and future service development were explored. RESULTS: A total of 15 psychogeriatric units were identified (3 in Bulgaria, 8 in Greece, and 4 in North Macedonia). Results show wide variation regarding the location, team size and composition, service availability, numbers of patients attending, and inpatient treatment length. Most head physicians underscored the urgent need for breakthroughs in the graduate and postgraduate education in psychogeriatrics of medical and nonmedical professionals, as well as in the interconnection of their units with community primary healthcare services and long-term care facilities for seniors via telemedicine. They would welcome the development of national standards for psychogeriatric units, potentially embodying clear pointers for action. A number of head physicians advocated the development of nationwide old age mental health registries. CONCLUSIONS: Regional disparities in resources and services for seniors' mental health services were unveiled. These data may enrich the dialogue on optimizing psychogeriatric services through planning future cross-border collaborations mainly based on telemedicine services, especially in the era of the novel coronavirus pandemic, and training/education in psychogeriatrics of mental health professionals.

Combined assessment of DYRK1A, BDNF and homocysteine levels as diagnostic marker for Alzheimer's disease.

Early identification of Alzheimer's disease (AD) risk factors would aid development of interventions to delay the onset of dementia, but current biomarkers are invasive and/or costly to assess. Validated plasma biomarkers would circumvent these challenges. We previously identified the kinase DYRK1A in plasma. To validate DYRK1A as a biomarker for AD diagnosis, we assessed the levels of DYRK1A and the related markers brain-derived neurotrophic factor (BDNF) and homocysteine in two unrelated AD patient cohorts with age-matched controls. Receiver-operating characteristic curves and logistic regression analyses showed that combined assessment of DYRK1A, BDNF and homocysteine has a sensitivity of 0.952, a specificity of 0.889 and an accuracy of 0.933 in testing for AD. The blood levels of these markers provide a diagnosis assessment profile. Combined assessment of these three markers outperforms most of the previous markers and could become a useful substitute to the current panel of AD biomarkers. These results associate a decreased level of DYRK1A with AD and challenge the use of DYRK1A inhibitors in peripheral tissues as treatment. These measures will be useful for diagnosis purposes.

Soluble amyloid precursor protein ß as blood-based biomarker of Alzheimer's disease.

The aim of this study was to explore concentrations differences of soluble amyloid precursor protein (sAPP) α and ß in blood plasma in patients with probable Alzheimer's disease (AD) and cognitively healthy age-matched control subjects, as well as patients with behavioural variant frontotemporal dementia (bvFTD). Concentrations of sAPPα and ß were measured using enzyme-linked immunosorbent assay technology in 80 patients with probable AD, 37 age-matched control subjects and 14 patients with bvFTD. Concentration differences were explored using parametric tests. Significantly decreased plasma concentrations in the AD group compared with both the control group and the bvFTD group were detected for sAPPß (P = 0.03 for both group comparisons), but not for sAPPα. The study provides a further piece of evidence in support of sAPPß as a promising new biomarker of AD, which may potentially improve the diagnostic accuracy of existing markers and also enable a less invasive diagnostic workup. Further research is required to establish normal ranges and to replicate the results in independent cohorts including larger numbers of participants covering a wider spectrum of cognitive impairment.

Head circumference, apolipoprotein E genotype and cognition in the Bavarian School Sisters Study.

BACKGROUND: The apolipoprotein E (APOE) ɛ4 allele is correlated with an earlier onset of Alzheimer's disease symptoms; larger head circumference has been associated with an individual resilience against cognitive impairment. METHODS: We explored if larger head circumference attenuates the effect of the APOE ɛ4 allele on cognition in 380 Catholic sisters covering the spectrum from normal cognitive performance to severe dementia. RESULTS: Linear regression analysis, adjusting for risk factors for cognitive decline, revealed that APOE ɛ4 was correlated with worse cognition and that larger head circumference attenuated the negative effect of the ɛ4 allele on cognitive performance. CONCLUSION: Larger head circumference (i.e. larger brain size) seems to be associated with greater resilience against genetic determinants of cognitive impairment, possibly due to enhanced brain or cognitive reserve.

CSF soluble amyloid precursor proteins in the diagnosis of incipient Alzheimer disease.

OBJECTIVE: To explore if soluble amyloid precursor proteins (sAPP) in CSF improve the identification of patients with incipient Alzheimer disease (AD) in a group of patients with mild cognitive impairment (MCI). METHODS: A cohort study with follow-up assessments of 58 patients with MCI with baseline CSF sampling was conducted: 21 patients had progressed to probable AD (MCI-AD), 27 still had MCI, 8 had reverted to normal (MCI-NAD), and 2 patients with frontotemporal dementia (FTD) were excluded. Sixteen additional patients with FTD were included to explore the specificity of the CSF markers. CSF concentrations of sAPPα, sAPPß, tau, and Aß(1-42) were measured with sensitive and specific ELISAs. Associations between diagnostic status, CSF protein concentrations, and other patient characteristics were explored using multiple logistic regression analyses with stepwise variable selection. The optimal sensitivity and specificity of the best models were derived from receiver operating characteristic curves. RESULTS: The MCI-AD group had significantly higher sAPPß concentrations than the MCI-NAD and the FTD groups. A combination of sAPPß, tau, and age differentiated the MCI-AD and the MCI-NAD groups with a sensitivity of 80.00% and a specificity of 81.00%. The best model for the differentiation of the MCI-AD and the FTD groups included sAPPß and tau, and showed a sensitivity of 95.20% and a specificity of 81.20%. Aß(1-42) and sAPPα did not significantly contribute to the models. CONCLUSION: These findings suggest that sAPPß may be clinically useful, and superior to Aß(1-42), in the early and differential diagnosis of incipient AD.

[Cognitive reserve and its relevance for the prevention and diagnosis of dementia]. / Kognitive Reservekapazität und ihre Bedeutung für Auftreten und Verlauf der Demenz.

Progressive brain damage is undoubtedly the main cause of clinical symptoms of dementia in neurodegenerative disorders such as Alzheimer's disease. However, the association between brain damage and cognitive symptoms is not linear. Certain interindividual differences such as a good school education or a greater brain volume are associated with a higher resilience against brain damage that is usually referred to as cognitive reserve (CR). Individuals with high CR have a diminished risk for dementia and both active and passive concepts for this phenomenon are discussed. In the concept of passive CR, peculiarities of brain structure such as higher synapse or neuron counts are regarded as buffers against brain damage. Symptoms of dementia do not occur until a certain threshold of damage is passed. In addition to the passive concepts, active mechanisms are also discussed that are associated with the ability to maintain a certain level of cognitive performance in the face of progressive neurodegeneration for a longer period. In subjects with healthy cognitive function, these active mechanisms contribute to the adaptation of brain activity when task difficulty level is increased. Confronted with progressive neurodegeneration, these active mechanisms help to compensate for brain damage. Individuals with higher CR show more efficient activation for solving the same task, which helps them to preserve normal levels of cognitive performance for a longer period.

Validation of the German revised Addenbrooke's cognitive examination for detecting mild cognitive impairment, mild dementia in alzheimer's disease and frontotemporal lobar degeneration.

BACKGROUND/AIMS: The diagnostic accuracy of the German version of the revised Addenbrooke's Cognitive Examination (ACE-R) in identifying mild cognitive impairment (MCI), mild dementia in Alzheimer's disease (AD) and mild dementia in frontotemporal lobar degeneration (FTLD) in comparison with the conventional Mini Mental State Examination (MMSE) was assessed. METHODS: The study encompasses 76 cognitively healthy elderly individuals, 75 patients with MCI, 56 with AD and 22 with FTLD. ACE-R and MMSE were validated against an expert diagnosis based on a comprehensive diagnostic procedure. Statistical analysis was performed using the receiver operating characteristic method and regression analyses. RESULTS: The optimal cut-off score for the ACE-R for detecting MCI, AD, and FTLD was 86/87, 82/83 and 83/84, respectively. ACE-R was superior to MMSE only in the detection of patients with FTLD [area under the curve (AUC): 0.97 vs. 0.92], whilst the accuracy of the two instruments did not differ in identifying MCI and AD. The ratio of the scores of the memory ACE-R subtest to verbal fluency subtest contributed significantly to the discrimination between AD and FTLD (optimal cut-off score: 2.30/2.31, AUC: 0.77), whereas the MMSE and ACE-R total scores did not. CONCLUSION: The German ACE-R is superior to the most commonly employed MMSE in detecting mild dementia in FTLD and in the differential diagnosis between AD and FTLD. Thus it might serve as a valuable instrument as part of a comprehensive diagnostic workup in specialist centres/clinics contributing to the diagnosis and differential diagnosis of the cause of dementia.

Short-term influence of elevation of plasma homocysteine levels on cognitive function in young healthy adults.

BACKGROUND: Acute homocysteine elevation has been shown to have a significant impact on cognitive function in animal models. OBJECTIVES: Investigation of the short-term impact of elevation of plasma homocysteine levels through a dietary intervention on cognitive abilities of young healthy adults. PARTICIPANTS: 100 healthy medical students of both genders were enrolled in the study. DESIGN AND MEASUREMENTS: Homocysteine levels and cognitive abilities were measured at 08:30 (before breakfast) and at 15:00 (two hours after lunch and six hours after breakfast). Food intake was restricted to specified comestibles. The cognitive assessment comprised a version of the Short Test for General Intelligence, three subtests of the Syndrome Short Test and the Stroop test. RESULTS: At 15:00 plasma homocysteine was significantly elevated in 56 participants (P < 0.00001), whilst in 44 it was decreased (P < 0.00001) in comparison to baseline (08:30). The decrease was however of limited clinical significance. The differences in the changes in cognitive performance between the two groups did not attain statistical significance (P > 0.05) and the direction of the changes did not differ between them. Accordingly, the multiple linear regression analysis did not reveal an important influence of homocysteine elevation on cognitive performance variations. CONCLUSIONS: Significant increase of plasma homocysteine is not associated with a straightforward inhibitory or facilitatory short-term effect on physiological cognitive parameters in young healthy adults.

Homocysteine and cognitive function in geriatric depression.

BACKGROUND/OBJECTIVES: Cognitive dysfunction is a common aspect of the spectrum of symptoms of geriatric depression. High homocysteine levels have been linked to cognitive decline in neuropsychiatric disorders. The present study investigated possible associations between cognitive impairment observed in geriatric depression and homocysteine levels. METHODS: The performance of 25 mentally healthy individuals and 40 patients with geriatric depression in terms of language processing, processing speed, concentration and attention was assessed with the Stroop Test and the d2 Test of Attention. Serum homocysteine was determined with an enzyme immunoassay. RESULTS: The performance of depressed patients was significantly worse in language processing (p = 0.001) and processing speed (p < 0.0001). Depressed patients with high levels of homocysteine performed better than patients with homocysteine concentrations

[Usage of drugs with potential adverse effects on cognition in a memory-clinic]. / Verwendung von Medikamenten mit ungünstigen Wirkungen auf die Kognition in einer Gedächtnissprechstunde.

Cognitive decline is a frequent clinical symptom in elderly patients. In particular, memory disturbances are an early sign and a risk factor for subsequent development of neurodegenerative dementia. At the same time, elderly patients often receive multiple medications due to an increasing number of acquired diseases. Certain drugs have adverse side effects on cognition due to interference with the cholinergic or GABA-ergic system. This could lead to underestimation of the actual cognitive status at initial clinical presentation. In the present study we included 221 patients (mean age 68,5 years) who presented for the first time in a specialized memory-clinic and who had or developed dementia during follow up. Most patients had mixed vascular-degenerative dementia (57 %). On average, patients took 2.1 drugs. 19.9 % of the patients had medications with potential adverse effects on cognition. Patients with medication affecting cognition had a worse cognitive performance than patients with a medication not influencing cognitive functioning (Mini-Mental vs. 18.8. 22.01, p = 0.01) in univariate analysis. Psychotropic drugs were used less frequently (38 %) than primary non-CNS medication. The results remained unchanged even after performing a case-control study with the mixed dementia population with age and gender matched patients. However, in multivariate analysis, only the absolute number of medication taken remained as an independent factor. Our data highlight the clinical importance of medication history in the diagnostic work-up of cognitive impairment. The absolute number of medication taken seems to be more important than medication with possible adverse side effects on cognition.

[Comparison of patient therapy adherence of two structural different memory clinics]. / Vergleich der Therapietreue von zwei regional benachbarten Gedächtnissprechstunden mit unterschiedlicher Struktur.

There are more than 100 memory clinics established in Germany, Austria and German-speaking Switzerland. We compared the impact of the structure of two German memory clinics (Erlangen and Nuremberg) on therapeutic outcome. 483 patients suffering from dementia with indication for antidementive therapy were included in this study. The data ascertainment included patient-related data, the mini mental score, comorbidity as well as psychiatric drug therapy. After a mean follow-up of 3.7 years, we performed a single cross-sectional survey covering over 90 % of patients to assess clinical course and adherence to therapy. The patients of the Erlangen University Memory Clinic were significantly younger (69.8 +/- 9.49 vs. 74.6 +/- 10.7 years; p = 0.01) and had a better mini mental score at their first presentation (20.9 +/- 9.4 vs. 19.5 +/- 5.9; p = 0.02). They showed a non-significantly faster disease progression (as measured by mini mental decline per year), than the patients from Nuremberg. Concerning the allocation of diagnosis, more late onset-dementias and dementias of a mixed type were treated at the Nuremberg clinic. At the university clinic, more dementias were of unclassified origin. Concomitant drug therapies, death rates and therapy adherence (53 %) were not different between the two clinics. The two memory clinics under investigation differed in patient age, disease severity and diagnostic assessment. Still, parameters of therapeutic outcome showed converging results.

[Validation of a short test (3MS-R) for detecting Alzheimer's disease]. / Validierung eines kurzen Testverfahrens (3MS-R) für die Erkennung der Alzheimer-Demenz.

BACKGROUND: The Modified Mini-Mental State Examination-revised (3MS-R) is a brief cognitive test designed to detect cognitive impairment, which is often used in Canada and USA. OBJECTIVE: To assess the accuracy of the 3MS-R in identifying Alzheimer's disease (AD) in comparison with the conventional Mini-Mental State Examination (MMSE) in a German-speaking population. SUBJECTS: The study refers to 31 patients with early AD and 5 patients with moderate dementia of AD etiology, as well as to 46 age-matched cognitively normal participants. METHOD: The 3MS-R and the MMSE were validated against an expert diagnosis based on a comprehensive diagnostic workup. The 3MS scores were adjusted for educational attainment. Statistical analysis was performed using the Receiver Operating Characteristics (ROC). RESULTS: ROC curves demonstrated the superiority of the ACE over the MMSE in identifying AD (Area under the Curve: 3MS-R vs. MMSE: 0.995 vs.0.953). The optimal cut-off score for the 3MS for detecting AD was 88 and had a sensitivity of 98% and a specificity of 94%. The German version of the 3MS-R is a short and practical but accurate test battery for the identification of AD. The effectiveness of the German version of the test in detecting other forms of dementias or mild cognitive impairment could be a task for future studies.

Validation of the Addenbrooke's cognitive examination for detecting early Alzheimer's disease and mild vascular dementia in a German population.

We assessed the diagnostic accuracy of the German version of the Addenbrooke's Cognitive Examination (ACE) in identifying early Alzheimer's disease (AD) and mild vascular dementia (VaD) in comparison with the conventional Mini-Mental State Examination (MMSE). The study refers to 50 patients with mild dementia of AD, 26 patients with mild dementia of vascular etiology and to 54 cognitively normal subjects. The ACE and MMSE were validated against an expert diagnosis based on a comprehensive diagnostic workup. Statistical analysis was performed using the receiver operator characteristics method. The optimal cut-off score for the ACE for detecting dementia in patients with early AD was 85/86, which had a sensitivity of 93% and a specificity of 86%. The optimal cut-off for the ACE for the identification of dementia in patients with mild VaD was also 85/86 and it had a sensitivity of 93% and a specificity of 100%. The kappa values imply a substantial agreement between the diagnoses made by the ACE and the MMSE. The German version of the ACE is a short and practical but accurate test battery for the identification of AD and VaD, assessing a broad range of cognitive functions and providing a wide profile of cognitive functions/dysfunctions.

[Validation of a Short Telephone Test (T3MS) for the Diagnosis of Cognitive Impairment]. / Validierung eines kurzen telefonischen Tests (T3MS) für die Erkennung kognitiver Störungen.

The identification of cognitive impairment in general practice requires short but accurate tests. For epidemiologic surveys and genetic family studies cognitive tests are desirable which can be administered over the telephone. We assessed the ability of a telephone version of the Modified Mini Mental State Examination (T3MS) to identify mild cognitive impairment (MCI) and mild dementia in Alzheimer's disease (AD) and compared it with the diagnostic accuracy of the conventional Mini Mental State Examination (MMSE). The study refers to 34 patients of the outpatient clinic for cognitive disorders of the technical university of Munich of whom 18 had MCI and 16 had mild dementia in AD, respectively. The study also included 14 cognitively unimpaired age-matched probands. The T3MS and MMST were validated against an expert diagnosis base on a comprehensive diagnostic workup. Statistical analysis was performed using the receiver-operator-characteristics (ROC) method. The T3MS outperformed the MMST in the distinction between MCI patients and cognitively unimpaired individuals. In the separation between cognitively unimpaired probands and patients with mild AD the T3MS achieved a sensitivity and specificity of 100 %. The T3MS is a short and practical but accurate telephone test for the identification of mild dementia in AD for use in epidemiological surveys and genetic family studies. The interview achieves higher diagnostic precision than the MMSE and contributes to a valid assessment of cognitive performance. For the identification of mild cognitive impairment, however, the T3MS was less appropriate.

Progression to dementia in clinical subtypes of mild cognitive impairment.

OBJECTIVE: To examine the outcome among patients diagnosed with different types of mild cognitive impairment (MCI). PATIENTS: A follow-up examination (average follow-up period: 3.49 +/- 2.2 years) was performed in 81 cognitively impaired, non-demented patients aged >55 years at baseline. RESULTS: 8 of 32 patients with amnestic MCI (25%), 22 of 41 patients with multiple-domain MCI (54%), and 3 of 8 patients with single non-memory MCI (37.5%) progressed to dementia. The clinical type of MCI is significantly associated with the likelihood of conversion to dementia. DISCUSSION: When the clinical syndrome of MCI evolves on a neurodegenerative basis, the multiple-domain type of MCI has a less favorable prognosis than the amnestic type and may represent a more advanced prodromal stage of dementia.

[Mild cognitive impairment]. / Grossvater wird immer vergesslicher--Schon krankhaft oder noch normal?

From today's point of view, patients with a mild cognitive impairment (MCI) are at risk for developing a dementia. This clinical picture occurs frequently in the population and is easily recognized through simple tests and interviews conducted in the general and neurological medical practice. A goal of the diagnostics is to detect potentially redressable causes, above all depressive disorders, and to introduce a therapy. In many cases, however, MCI is an early stage of Alzheimer's disease or other neurodegenerative processes. When such a cause is suspected, the most important medical measure is to monitor the progression of the disease so that when deterioration occurs, therapy with antidementia drugs can promptly begin. In the future, patients with MCI will play an increasingly important role as the target group for the prevention of dementia.

Efficacy and cognitive effects of right unilateral electroconvulsive therapy.

The efficacy, memory, and cognitive effects of right unilateral (RUL) electroconvulsive therapy (ECT) at 2.5 times threshold in 32 inpatients with moderate to severe major depressive disorder were evaluated at baseline, during the course of treatment, and 1 month after treatment. Neuropsychological assessment included the Randt Memory Test, Personal Memory Test, short-version Wechsler Adult Intelligence Scale-Revised, and Self-Rating Scale of Memory Functions. At the treatment end point, although the Hamilton Depression Rating Scale mean score was decreased by 54.2%. the response rate of 2.5 times threshold RUL ECT using stringent criteria was only 31.2%. Treatment was associated with significant anterograde memory impairment in the short term. Mean total scores of the Randt Memory Test and Personal Memory Test were decreased from baseline by 14.8% and 32.5%, respectively, after six sessions of ECT. These memory deficits were significantly improved by the 1 month follow-up examination. Subjective memory scores increased consistently during treatment, correlating with improvements in mood. No adverse effects on nonmemory cognition were found. Although RUL ECT at 2.5 times threshold is not associated with marked or persistent cognitive disturbances, its efficacy may be insufficient in clinical practice.