Pre-dementia Cognitive Impairment Research Articles

Predicting the Dynamics of Mild Cognitive Impairment According to Immunological Parameters

Background: neuroin flammation is an important link in the pathogenesis of pre-dementia cognitive impairment and the development of dementia in Alzheimer’s disease.The aim of the study was to determine the prognostic value of inflaammatory markers (enzymatic activity of LE and its inhibitor alpha1-PI) at the stage of mild cognitive impairment for subsequent follow-up evaluation.Patients and methods: a total of 103 patients with an amnesic type of mild cognitive impairment (aMCI) aged 50 to 89 years (mean age 68.1 ± 9.4 years) were examined. Mental status of the patients was assessed clinically and by psychometric scales and tests. After 3 years of observation, the patients were divided into two groups depending on the dynamics of cognitive status: the 1st group consisted of 49 patients with progression of cognitive decline to the degree of dementia; the 2nd group included 54 patients with a stable state of cognitive functions. The control group included 61 subjects of the same age and gender. The enzymatic activity of leukocyte elastase (LE) and the functional activity of the α1-proteinase inhibitor (α1-PI) were determined in blood plasma. Cluster analysis was used to isolate immunotypes.Results: the functional activity of α1-PI at the starting point of the study in patients of both follow-up groups exceeded the control values (p = 0.000001, p = 0.000006, respectively). Follow-up groups differed in LE activity at the initial stage. In patients of the 1st group (with an increase in cognitive impairment) LE activity did not differ from the control values (p = 0.144651). Group 2 (with stable cognitive functions) was characterized by a significantly higher LE activity compared to the controls (p = 0.000000). Cluster analysis made it possible to identify two immunotypes that differed in LE activity. In the 1st cluster, LE activity was within the control range and below, it mainly included patients of the 1st follow-up group (68.3%). In the 2nd cluster LE activity exceeded the control values, this cluster mainly consisted of patients of the 2nd follow-up group (85.0%) (χ2 = 27.82, p = 0.0000).Conclusion: the revealed reliable differences in the distribution of follow-up groups for immunological clusters indicate the possibility of using indicators of LE and α1-PI activity for diagnosing and predicting the dynamics of mild cognitive decline.

Substantiated therapy of pre-dementia cognitive impairment with calcium-channel blockers

Pre-dementia cognitive impairments are a significant part of a cognitive impairment range, considered the most perspective in terms of conversion into dementia prevention. At the same time pre-dementia cognitive impairment treatment presents certain difficulties in connection with the absence of precise medicinal strategies with the high evidence level. According to current clinical recommendations, the priority in cognitive pre-dementia treatment lies in the correction of modifiable risk factors of cognitive impairment progression and non-drug therapy methods. Nevertheless, there is a great need in receiving the proofs of pathogenetically justified use of drugs with a potentially effective mechanism of action. Universal and early pathogenetical mechanism of many diseases of central nervous system, leading to the development of cognitive impairments, including Alzheimer’s disease, is Ca2+ dyshomeostasis. In this connection, the use of drugs, regulating Ca2+ metabolism in neurons in treatment of patients with pre-dementia cognitive impairments, especially high brain penetrance drugs, is potentially well-grounded. The article gives the data review of modern researches, studying the efficiency and safety of nimodipin a selective Ca+ channel blocker of the 2 class. The article provides examples of the use of nimodipin in treatment and prevention of pre-dementia syndroms of various genesis: Alzheimer’s disease, chronic brain hypoperfusion damage, post-radiation and postoperative cognitive dysfunction, etc. The article presents experimental data about nimodipin use in the prevention of postoperative delirium in elderly people and in the treatment of non-cognitive neurological disorders. Justification of the perspectives of the application area extension and directions for the further research of nimodipin are as well given in the article.

Long-term results of surgical treatment of patients with cerebral arterial aneurysms

To study the long-term results of surgical treatment of patients operated on for cerebral aneurysms and their impact on functional recovery, independence and cognitive functions in the long-term period. A multivariate regression analysis of long-term results of surgical treatment of 324 patients for cerebral aneurysms was performed (on average after 3.5 years). Upon admission of the patient to the hospital for surgical intervention, a clinical diagnostic examination was performed to confirm the diagnosis and determine the volume, timing and type of intervention. In the late period, a clinical neurological study was performed, which included an assessment of the degree of disability with the Barthel index and a modified Rankin scale, cognitive functions with MMSE, and the mental sphere with HADS. The severity of the condition at admission, corresponding to grade III-IV according to the Hunt-Hess classification, was the risk factor for an unfavorable prognosis for the recovery of patients in the long-term period of cerebral aneurysm surgery. The severe condition of patients at the onset of the disease increases the risk of disability by 1.9 times (p<0.05) and the risk of dementia by 6 times (p<0.05). An independent risk factor for the development of cognitive impairment is the patient's age: with an increase in age by 1 year, the MMSE score decreases by 0.27 (p<0.05). The prevalence of hemorrhage according to the Fisher classification, corresponding to grade III, is a predictor of the development of angiospasm in 91% of cases. In patients with established angiospasm, the risk of developing dementia and pre-dementia cognitive impairment was 57.3% (p<0.05). The best predictions for recovery of cognitive functions in the long-term period were observed in patients who underwent simultaneous aneurysm clipping with extra-intracranial anastomosis (mean MMSE score 25) compared with patients who underwent only aneurysm clipping (mean score 20), endovascular intervention (average score 21) or microsurgical intervention followed by intrathecal fibrinolytic injection (mean MMSE score of 20) (p<0.05). The predictors of unfavorable recovery of cognitive functions and the development of disability in the long-term period of surgical treatment of cerebral aneurysms were the severity of the condition at admission, corresponding to III-IV st. according to the Hunt-Hess classification, the age of the patient at the time of the intervention, the prevalence of hemorrhage according to Fisher, and the choice of surgical technique.

Pre-dementia cognitive impairment

Cognitive disorders are one of the most significant problems of older. Special attention should be paid to the diagnosis of early pre-dementia stages of cognitive impairment (CI): subjective, subtle and mild.The aim of this study was to determine the criteria of pre-mild: subjective and subtle cognitive decline (SCD).Material and methods. The study included 602 patients with pre-mild cognitive impairment with a mean age of 63.24±11.24 years and 515 patients with mild cognitive impairment aged 71.2±8.0 years. The indicators of patients were compared with those of 104 healthy people (average age 64.23±8.14 years) who did not complain of memory impairment and had no deviations during clinical and neuropsychological examination.Results and discussion. Groups of patients with subjective and subtle cognitive decline were distinguished, which differed in most characteristics. At the same time, in both groups of patients, deviations in the results of neuropsychological tests did not exceed one standard deviation from the average results for healthy people, which, in fact, allowed them to be attributed to «pre-mild» cognitive decline. The data obtained confirmed the heterogeneity of the «pre-mild» cognitive decline. The study also shows the allocation limitation of pre-mild cognitive impairment only on the basis of a formal approach based on the quantitative characteristics of neuropsychological research with a difference from control groups necessarily exceeding one standard deviation.Conclusion. The analysis showed the heterogeneity of pre-dementia and pre-mild cognitive impairments that are divided according to the degree of changes in objectively assessed cognitive functions with the similarity of subjective complaints. It is proposed to distinguish subjective cognitive decline with completely normal neuropsychological characteristics and subtle cognitive decline in the event of changes in individual indicators evaluating mainly the control functions and memory.

Structure of the drug treatment adherence in elderly patients with mild cognitive impairment and psychopathological symptoms

Background. The high prevalence of pre-dementia cognitive impairment in the elderly, their poor prognosis with a frequent transition to dementia, polymorbidity with somatic pathology determine the need for adequate correction of all somatic diseases. This increases the importance of treatment adherence.&#x0D; Aim. To assess the structure of drug treatment adherence in elderly patients with mild cognitive impairment (MCI) and psychopathological symptoms.&#x0D; Material and methods. An observational study of 264 patients diagnosed with mild cognitive impairment was conducted. The average age was 68.51.4 years. Of these, 17.6% were men, and 83.3% were women. The patients were divided into two groups: with psychopathological symptoms (main group, n=189) and without psychopathological symptoms (comparison group, n=75). Research methods used: clinical-psychopathological, psychometric, statistical by using Statistica 7 software for Windows OS. The Pearson's chi-squared test, the nonparametric MannWhitney U test, and the correlation analysis with calculation of Spearmans rank correlation coefficient (r) were used.&#x0D; Results. The adherence (compliance) of the study participants in relation to general therapeutic recommendations is represented by social, emotional and behavioural compliance. The total score of general compliance in the main study group was 45.4229.7, in the comparison group 51.0932.3 points (p=0.031). In the main group, half of the participants (49.7%) had a low total score of general compliance, less than half of the participants had an average total score, only 4.8% of the participants showed high compliance with therapeutic recommendations. Increased depression correlates with low overall, social and emotional competence (r=0.512). Severe agitation and aggression correlate with low behavioural and emotional competence (r=0.589). Statistically significant correlations were found between psychotic symptoms and low behavioural compliance (r=0.151 and r=0.145).&#x0D; Conclusion. The overall medication compliance rates are lower in patients with affective and psychotic symptoms; an increase in the number of affective, psychotic, behavioural disorders in patients with mild cognitive impairment correlates with low overall, social, emotional and behavioural compliance.

Awareness and cognitive status of older patients with chronic cardiorenal syndrome in terms of patient-centered approach

Abstract Funding Acknowledgements Type of funding sources: None. A patient-centered approach is the basis for older patients with cardiovascular comorbidity. Collaborative decision making is especially important for older patients with chronic kidney disease (СKD). The aim of the study was to study the possibilities and difficulties of a patient-centered approach in older patients with chronic cardiorenal syndrome. Material and methods. 214 older patients with stable cardiovascular disease (106 males, mean age was 69.5 ± 7.6 years) were studied. CKD was diagnosed and classified according to the KDIGO guidelines (2012). Charlson comorbidity index (CCI) was estimated. Cognitive status was assessed using the Mini-Mental State Examination (MMSE) and the Clinical Dementia Rating scale (CDR). Assessment of socio-demographic characteristics and awareness of patients was determined by questionnaires and interviews. Follow-up period was 12 months. Results. CKD was observed in 144 (67.3%) patients with stable cardiovascular disease. A third of older patients with CKD (48; 33.3%) were informed about impaired renal function (n = 144), and only 23 (16%) older patients with CKD, along with observation by a therapist, consulted a nephrologist . Only half of older patients with cardiovascular pathology, regardless of the presence of CKD, know their cholesterol level and their cardiovascular risk. In 70 (48.6%) older patients with stable cardiovascular pathology and CKD, pre-dementia cognitive impairment was observed, in 28 (19.4%) - mild dementia. A third of older patients with cardiovascular pathology and CKD (47; 32.6%) still have questions about their health. 112 (77.8%) patients would like to be able to remotely communicate with medical personnel in case of health issues. At the same time, only 37 (25.7%) patients with CKD are ready to attend full-time schools for patients. Conclusion. Cognitive impairments and low awareness of older patients with chronic cardiorenal syndrome complicate the implementation of a patient-centered approach.

Evolution of the diagnostic frontiers of Alzheimer's disease and new therapeutic possibilities

Over the past three decades, the definition and diagnostic boundaries of Alzheimer's disease (AD) have been repeatedly revised due to significant progress in understanding of the pathogenesis of neurodegeneration associated with Alzheimer's disease and development of high-tech diagnostic methods. The current approach to diagnosing AD is based on the discovery of biomarkers that reflect the two main neuropathological processes involved in the development of primary neurodegeneration underlying AD-abnormal amyloidogenesis and neuronal degeneration. The currently available diagnostic tools are limited to the detection of cerebrospinal biomarkers and/or assessment of the abnormal amyloid and tau protein burden in the brain via amyloid and tau positron emission tomography ligands. Practical implementation (mostly in the research field) of the biological model of AD diagnosis has led to a significant expansion of its diagnostic boundaries with the inclusion of predementia AD stages: asymptomatic and symptomatic, the latter is clinically corresponding to amnestic mild cognitive impairment (aMCI-amnestic mild cognitive impairment). On the one hand, this approach significantly expands the possibilities to study and use preventive technologies aiming to avert or delay the progression of predementia cognitive impairment to dementia but, on the other, it is associated with a number of negative implications from both the clinical and ethical points of view. A significant limitation of purely biological diagnosis of AD based on biomarker levels is due to the low prognostic value of biomarkers, which can cause diagnostic confusion in certain circumstances. Moreover, since the future evolution of the asymptomatic stage is not yet clear and there are still no reliable ways to prevent the cognitive and behavioral symptoms associated with AD, disclosure of stressful information about this "terrifying" diagnosis to patients can cause irreversible damage by triggering depressive disorder, which is a risk factor of AD itself. The current knowledge about AD prognosis in amyloid-positive cognitively unimpaired patients is insufficient. The most adequate approach to early AD diagnostics appears to be the clinical and biological model, as recommended by the International Working Group (IWG2021), which requires a combination of the clinical AD phenotype and the detection of biomarkers specific to this disease. The article discusses the potential directions for the development of biological diagnostic methods, including those based on the so-called peripheral (plasma) biomarker technologies and promising directions for the development of biological methods of secondary AD prevention.

Vascular cognitive impairment and vascular dementia

Vascular dementia is the second-most-common type of dementia. Vascular cognitive impairment is a term encompassing vascular dementia as well as milder forms of pre-dementia cognitive impairment related to vascular damage that do not meet the criteria for a diagnosis of dementia. Early diagnosis of cerebrovascular disease, including silent infarcts and small vessel disease is difficult, but important, as modification of cardiovascular risk factors is the mainstay of management to decrease further insults and deterioration, and maintain the patient’s independence within their family and social unit.

Use of computer stimulating programs in patients with post-stroke cognitive impairment

Objective: to evaluate the efficiency of using computer stimulation programs (CSPs) for acute ischemic stroke (IS) in patients with cognitive impairment (CI). Patients and methods. 81 patients aged 40 to 79 years with post-stroke CI (PSCI) were examined and randomized into two groups. A study group consisted of 45 people, including 31 and 14 patients with predementia CI and mild dementia, respectively; their median age was 61 [55; 68] years. A comparison group included 36 patients, including 21 and 15 patients with predementia CI and mild dementia; their median age was 64 [57; 70] years. In addition to standard stroke therapy, the study group received a ten-day correction cycle for CI, by using CSPs. Cognitive functions (CF) were evaluated before and after classes, by applying a short mental status questionnaire (SMSQ), a battery of frontal lobe dysfunction tests (BFLDT), a clock drawing test, and a speech activity test. Results. After 10 days of therapy (at 18–20 days of IS), the patients were observed to have statistically significant improvements of cognitive functions in all major neuropsychological scales: SMSQ, BFLDT, a clock drawing test, and a speech activity test (p>0.05). Assessing the total indicators of SMSQ subtests in both groups showed that the study group achieved statistically significant differences in memory, time and place orientation, and concentration. In the study group, the total values of BFTLD subtests were also statistically better in indicators, such as speech fluency (by 33.0%), dynamic praxis (by 23.3%), a simple choice reaction (by 30.0%), and a complicated choice reaction (by 26.7%). At the same time, not only trained functions (attention, memory), but also other cognitive indicators improved. Re-examination demonstrated that the achieved results persisted 6-8 months later. Conclusion. CSPs are a promising area of neurorehabilitation. The method is effective, easy-to-use; the patients can do lessons at hospital and at home after discharge in the presence of relatives or themselves. Further investigations will be able to evaluate the effectiveness of CSPs in patients with PSCI in the later periods of IS.

Cognitive Patterns in Relation to Biomarkers of Cerebrovascular Disease and Vascular Risk Factors

Background: Risk factors for vascular cognitive impairment (VCI) are the same as traditional risk factors for cerebrovascular disease (CVD). Early identification of subjects at higher risk of VCI is important for the development of effective preventive strategies. In addition to traditional vascular risk factors (VRF), circulating biomarkers have emerged as potential tools for early diagnoses, as they could provide in vivo measures of the underlying pathophysiology. While VRF have been consistently linked to a VCI profile (i.e., deficits in executive functions and processing speed), the cognitive correlates of CVD biomarkers remain unclear. In this population-based study, the aim was to study and compare cognitive patterns in relation to VRF and circulating biomarkers of CVD. Methods: The Barcelona-AsIA Neuropsychology Study included 747 subjects older than 50, without a prior history of stroke or coronary disease and with a moderate to high vascular risk (mean age, 66 years; 34.1% women). Three cognitive domains were derived from factoral analysis: visuospatial skills/speed, verbal memory and verbal fluency. Multiple linear regression was used to assess relationships between cognitive performance (multiple domains) and a panel of circulating biomarkers, including indicators of inflammation, C-reactive protein (CRP) and resistin, endothelial dysfunction, asymmetric dimethylarginine (ADMA), thrombosis, plasminogen activator inhibitor 1 (PAI-1), as well as traditional VRF, metabolic syndrome and insulin resistance (homeostatic model assessment for insulin resistance index). Analyses were adjusted for age, gender, years of education and depressive symptoms. Results: Traditional VRF were related to lower performance in verbal fluency, insulin resistance accounted for lower performance in visuospatial skills/speed and the metabolic syndrome predicted lower performance in both cognitive domains. From the biomarkers of CVD, CRP was negatively related to verbal fluency performance and increasing ADMA levels were associated with lower performance in verbal memory. Resistin and PAI-1 did not relate to cognitive function performance. Conclusion: Vascular risk factors, and markers of inflammation and endothelial dysfunction predicted lower performance in several cognitive domains. Specifically, cognitive functions associated with CRP are typically affected in VCI and overlap those related to VRF. ADMA indicated a dissociation in the cognitive profile involving verbal memory. These findings suggest that inflammation and endothelial dysfunction might play a role in the predementia cognitive impairment stages.

Comment: should we diagnose MCI in Parkinson disease?

Both Rektorova and Martinez-Horta, and Kulisevsky agreethat Parkinson disease (PD) patients have frequent cogni-tive impairment already at disease onset, which progressesat a varying rate, terminating in dementia in a substantialnumber of patients. Cognitive deterioration in PD followsan indolent course, like that seen in other neurodegenera-tive diseases, and it is an arbitrary decision to term anysection of this process as mild cognitive impairment (MCI),or by any other name. It will be difficult to justify a‘‘starting point’’ of MCI (since deterioration preceded iteven if not fulfilling criteria), and even the conversion todementia is more complicated to define than in Alzheimerdisease (AD), since activities of daily living are impaired inPD by the motor disability, as well as by apathy, depres-sion, etc. which precludes a clear-cut determination as itapplies, for example, to AD.The term MCI has been coined to denote the prede-mentia cognitive impairment stage of AD and has attractedobjections (Ash and Korczyn 2011). Borrowing it to otherdisorders should not be automatic. Several difficulties arestressed in both papers. In addition, it must be recalled thatmany of the PD patients have a unique premorbid per-sonality, they frequently have depression, apathy andsomnolence, are treated by drugs and of course have motorimpairment—each of which could interfere with the exe-cution and interpretation of neuropsychological tests.The common definition of MCI depends on complaintsby the patient (or a close informant). This is particularlytrue for memory impairment, and it is critical to employthis parameter since a deterioration from a previous func-tional level is implied and there are usually no premorbidscores of cognitive testing in AD. However, accepting thatin PD the first cognitive manifestation may be executivedysfunction, what should be the complaints? Clearly, in PDpatients these cannot be just slowness! At present, thisissue has not been addressed.Both Rektorova and Martinez-Horta, and Kulisevskyemphasize the variability of cognitive deterioration. Atpresent, there are few data on factors influencing the rate ofdecline. One of the important factors may be comorbidities,such as co-existent AD or vascular changes (Korczyn2002). These, of course, will complicate further anyinterpretation of cognitive testing.Another very important issue is why diagnose clinicallyinconspicuous or very mild cognitive impairment in PD?In AD, the reason given is that disease modifying therapiesare being developed which should be used early in thecourse of the disease. Since no such therapies are beingdeveloped against the cognitive deterioration in PD, thebenefits from diagnosing an incipient dementia state are notclear. PD patients know that they face deterioration, par-ticularly motor decline. They will not benefit from beingtold that they have been identified as being more likelythan other PD patients to develop dementia as well.References

Progressive pre-dementia cognitive impairment is predicted by baseline increase of MRI radial diffusion

Progressive pre-dementia cognitive impairment is predicted by baseline increase of MRI radial diffusion

Pre-dementia clinical stages in presenilin 1 E280A familial early-onset Alzheimer's disease: a retrospective cohort study

Mild cognitive impairment (MCI) and pre-MCI have been proposed as stages preceding Alzheimer's disease (AD) dementia. We assessed descendants of individuals with a mutation in presenilin 1 (PSEN1) that causes familial AD, with the aim of identifying distinct stages of clinical progression to AD dementia. We retrospectively studied a cohort of descendants of carriers of the PSEN1 E280A mutation. Pre-dementia cognitive impairment was defined by a score 2 SD away from normal values in objective cognitive tests, and was subdivided as follows: asymptomatic pre-MCI was defined by an absence of memory complaints and no effect on activities of daily living; symptomatic pre-MCI was defined by a score on the subjective memory complaints checklist higher than the mean and no effect on activities of daily living; and MCI was defined by a score on the subjective memory complaints checklist higher than the mean, with no effect on basic activities of daily living and little or no effect on complex daily activities. Dementia was defined according to the diagnostic and statistical manual of mental disorders, fourth edition. Reference mean scores were those of participants who did not carry the PSEN1 E280A mutation. We used the Turnbull survival analysis method to identify ages at onset of each stage of the disease. We measured the time from birth until onset of the three pre-dementia stages, dementia, and death, and assessed decline in cognitive domains for each stage. Follow-up was from Jan 1, 1995, to Jan 27, 2010. 1784 patients were initially identified, 449 of whom were PSEN1 E280A carriers who had complete clinical follow-up. Median age at onset was 35 years (95% CI 30-36) for asymptomatic pre-MCI, 38 years (37-40) for symptomatic pre-MCI, 44 years (43-45) for MCI, and 49 years (49-50) for dementia. The median age at death was 59 years (95% CI 58-61). The median time of progression from asymptomatic to symptomatic pre-MCI was 4 years (95% CI 2-8), from symptomatic pre-MCI to MCI was 6 years (4-7), from MCI to dementia was 5 years (4-6), and from dementia to death was 10 years (9-12). The cognitive profile was predominantly amnestic and was associated with multiple domains. Affected domains showed variability in initial stages, with some transient recovery in symptomatic pre-MCI followed by continuous decline. Clinical deterioration can be detected as measurable cognitive impairment around two decades before dementia onset in PSEN1 E280A carriers. Onset and progression of pre-dementia stages should be considered in the investigation and use of therapeutic interventions for familial AD. Departamento Administrativo de Ciencia, Tecnología e Innovación, COLCIENCIAS, Republic of Colombia.

Defining and describing the pre-dementia stages of familial Alzheimer's disease

With the prospect of prevention trials for familial Alzheimer's disease on the horizon, understanding the natural history of the illness has never been so important. Earlier this year in The Lancet Neurology, Acosta-Baena and colleagues published the results of the largest and longest retrospective study of pre-dementia clinical stages in familial Alzheimer's disease to date. By reviewing serial neuropsychological assessments of individuals from a large Colombian kindred affected by the E280A mutation in the Presenilin 1 gene, they defined three stages of pre-dementia cognitive impairment. Using survival analyses, the authors estimated the median age at onset and rate of progression through each of these stages towards dementia and ultimately death. Their study provides valuable insights into the time course of cognitive decline associated with this mutation. Furthermore, the study highlights some of the challenges of defining pre-dementia clinical stages in familial Alzheimer's disease and the need for the field to develop a consistent terminology.