Final Mini-Mental State Examination Research Articles

Use of medium chain triglyceride (MCT) oil in subjects with Alzheimer's disease: A randomized, double-blind, placebo-controlled, crossover study, with an open-label extension.

IntroductionCerebral glucose and insulin metabolism is impaired in Alzheimer's disease (AD). Ketones provide alternative energy. Will medium chain triglyceride (MCT) oil, a nutritional source of ketones, impact cognition in AD?MethodsThis was a 6‐month randomized, double‐blind, placebo‐controlled, crossover study, with 6‐month open‐label extension in probable AD subjects, on stable medications. MCT dose was 42 g/day, or maximum tolerated. Cognition was assessed with Mini‐Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), and Cognigram®.ResultsTwenty subjects, average age 72.6 years, 45% women, 70% university educated had baseline MMSE 22.6/30 (10–29); MoCA 15.6/30 (4–27); baseline Cognigram® Part 1: 65–106, Part 2: 48–107. Average MCT oil consumption was 1.8 tablespoons/day (25.2 g, 234 kcal). Eighty percent remained stable or improved. Longer MCT exposure and age > 73, resulted in higher final MMSE (P < .001) and Cognigram® 1 scores.DiscussionThis is the longest duration MCT AD study to date. Eighty percent had stabilization or improvement in cognition, and better response with 9‐month continual MCT oil.

Subthreshold amyloid pathology and changes in functional brain networks in patients with delayed cognitive decline after stroke

AbstractBackgroundIn clinical practice, some of the stroke survivors who have normal cognitive function until three to six months after index stroke, develop cognitive decline gradually after then. Although amyloid deposits and advanced small vessel disease are reported to be the possible predictors, pathogenesis for delayed cognitive decline has not been identified yet. Thus, we aimed to explore the brain network characteristics in those with delayed cognitive decline after stroke compared to those without.MethodUsing a prospective stroke registry, we identified patients with ischemic stroke who had undergone the cognitive evaluations including mini‐mental state examination (MMSE) twice or more after index stroke. We included patients whose baseline cognitive evaluation (between 1 and 12 months after stroke) was normal and who had one or more follow‐up evaluations after more than 6 months from the baseline evaluation. Among 222 eligible patients, decliners were defined as having a decline in 3 or more per year or an absolute decline of 5 or more between baseline and follow‐up MMSE, while non‐decliners as having a decline of 1 point per year or less and an absolute decline of less than 3 points. Brain network attributes were analyzed using resting‐state functional MRI, and superimposed amyloid positivity was assessed using 18F‐florbetaben PET.ResultEleven patients (5%, 11/222) met the criteria for decliners, and ten matched non‐decliners were enrolled. For about 5.7 years of follow‐up, the mean change of MMSE scores was ‐9.1 points in the decliners, while ‐0.2 point in the non‐decliners. Ten (10/11) decliners were amyloid‐negative on the amyloid PET, and the APOE e4 allele was identified in one decliner. However, the global SUVR value showed a negative correlation with the final MMSE scores as well as the amount of MMSE change. Normalized transitivity was lower in decliners compared to non‐decliners. Mean connectivity strengths were averaged based on the seven canonical functional networks, and the intra‐network connections within the frontoparietal network showed the considerable differences between groups. (Figure)ConclusionThis study suggests that alteration of brain networks may explain the pathogenesis of the delayed post‐stroke cognitive decline independent of amyloid PET positivity and APOE genotype.

Concomitant LATE‐NC in Alzheimer's disease is not associated with increased tau or amyloid‐β pathological burden

Limbic-predominant age-related TDP-43 encephalopathy neuropathological change (LATE-NC) is present in approximately 50% of Alzheimer's disease (AD) cases and is associated with accelerated cognitive decline. Studies indicate a potential synergistic relationship between LATE-NC and hyperphosphorylated tau. It is unknown if LATE-NC is an independent driver of cognitive impairment or exerts its influence through synergistic relationships with tau. This cliniconeuropathological study investigated the impact of LATE-NC on quantified measures of AD-associated pathology and its impact on clinical measures. A total of 61 AD cases underwent neuropathological assessment for LATE-NC and quantitative assessment [area covered by immunoreactivity (IR)] for early conformational tau (MC-1), late-stage hyperphosphorylated tau (AT8) and amyloid-β in the amygdala and five neocortical regions. Clinical measures included age of disease onset, final Mini-Mental State Examination (MMSE) score and rate of cognitive decline. LATE-NC was present in 41 AD cases (AD/LATE-NC; 67.2%). No significant differences in MC-1-IR, AT8-IR or 4G8-IR were observed in any region between AD/LATE-NC and AD without LATE-NC, indicating no accelerated aggregation or hyperphosphorylation of tau proteins in the AD/LATE-NC cases. Final MMSE was significantly lower in AD/LATE-NC cases and was significantly associated with LATE-NC score even when controlled for the presence of both MC-1-IR and AT8-IR (P=0.009). The presence of LATE-NC in AD is not associated with an increase in the burden of early or late tau or Aβ pathology. LATE-NC is associated with a lower final MMSE score independent of tau pathology.

Cognitive impairment screening using m-health: an android implementation of the mini-mental state examination (MMSE) using speech recognition.

This paper describes an implementation of an Android application that allows cognitive functions to be tested. The application consists of a slightly modified Mini Mental state Examination (MMSE) test that provides examiner assistance in diagnosing cognitive impairments. The application deploys speech recognition techniques to allow easy and automated scoring of the test. The test results and test-related information are stored in a database providing easy access to data for follow-up and analysis, resulting in overall benefits to the examiner workflow. A small-scale pilot study of 5 months duration was conducted in a nursing home where 15 residents were tested with the MMSE app test and with the (paper) MMSE test with the aim of determining the agreement between the two test methods. The final MMSE test scores, with a maximum score of 30, agree; the differences have a mean of 0.1, a standard deviation of 2.1 and fall in a [- 4, + 4] range as is illustrated in a Bland-Altman analysis. From examiner reflections, the motoric skills of the participant are indicated to contribute strongly to the time benefit of the assessment itself. The findings of this study suggest that the mobile digital version of the slightly modified MMSE test has the potential to be used as an attractive alternative for the conventional paper version of the test.

A Quantitative Analysis of Brain Soluble Tau and the Tau Secretion Factor

Neurofibrillary tangles (NFTs) represent products of insoluble tau protein in the brains of patients with Alzheimer disease (AD). The cerebrospinal fluid (CSF) tau level is a biomarker in AD diagnosis. The soluble portion of tau protein in brain parenchyma is presumably the source for CSF tau but this has not previously been quantified. We measured CSF tau and soluble brain tau at autopsy in temporal and frontal brain tissue samples from 7 cognitive normal, 12 mild cognitively impaired, and 19 AD subjects. Based on the measured brain soluble tau, we calculated the whole brain tau load and estimated tau secretion factor. Our results suggest that the increase in NFT in AD is likely attributable to post-translational processes; the increase in CSF tau in AD patients is due to an accelerated carrier-based secretion. Moreover, cognitive dysfunction assessed by final Mini-Mental State Examination scores correlated with the secretion factor but not with the soluble tau.

Zoledronic Acid Use and Risk of Cognitive Decline among Elderly Women and Men with Osteoporosis.

Bisphosphonates are the first line treatment options in the prevention and treatment of osteoporosis among elderly women or men. Age associated cognitive decline may increase due to adverse effects of medications. The aim of the present study was to observe the course of cognitive skills in elderly subjects treated with a bisphosphonate. This prospective study enrolled 120 community-dwelling, non-demented women and men with osteoporosis aged 65 and older who were treated with first-ever zoledronic acid. Mini mental state examination (MMSE) was measured along with geriatric depression scale (GDS) measurement, clock drawing test (CDT), and other clinical and laboratory evaluations that could affect cognition at baseline and 12 months. The primary outcome was at least one point decrease in the final MMSE score at one year. Scores of MMSE (28.29±2.17 and 28.23±2.37, p=0.681), GDS (3.24±2.88 and 2.96±2.88, p=0.062) and CDT (3.69±0.68 and 3.75±0.60, p=0.268) did not change after zoledronic acid infusion at one year. Education in years and presence of newly started medicines with anticholinergic properties was independently associated with at least one point reduction in MMSE score [odds ratio: 3.07 (%95 confidence interval: 1.00-9.44)]. Among elderly woman and men with osteoporosis, cognitive functions remained stable 12 months after the administration of first-ever zoledronic acid.

Hippocampal Sclerosis but Not Normal Aging or Alzheimer Disease Is Associated With TDP-43 Pathology in the Basal Forebrain of Aged Persons.

Transactivating responsive sequence (TAR) DNA-binding protein 43-kDa (TDP-43) pathology has been described in various brain diseases, but the full anatomical distribution and clinical and biological implications of that pathology are incompletely characterized. Here, we describe TDP-43 neuropathology in the basal forebrain, hypothalamus, and adjacent nuclei in 98 individuals (mean age, 86 years; median final mini-mental state examination score, 27). On examination blinded to clinical and pathologic diagnoses, we identified TDP-43 pathology that most frequently involved the ventromedial basal forebrain in 19 individuals (19.4%). As expected, many of these brains had comorbid pathologies including those of Alzheimer disease (AD), Lewy body disease (LBD), and/or hippocampal sclerosis of aging (HS-Aging). The basal forebrain TDP-43 pathology was strongly associated with comorbid HS-Aging (odds ratio = 6.8, p = 0.001), whereas there was no significant association between basal forebrain TDP-43 pathology and either AD or LBD neuropathology. In this sample, there were some cases with apparent preclinical TDP-43 pathology in the basal forebrain that may indicate that this is an early affected area in HS-Aging. We conclude that TDP-43 pathology in the basal forebrain is strongly associated with HS-Aging. These results raise questions about a specific pathogenetic relationship between basal forebrain TDP-43 and non-HS-Aging comorbid diseases (AD and LBD).

Clinicopathologic and 11C-Pittsburgh compound B implications of Thal amyloid phase across the Alzheimer's disease spectrum.

Thal amyloid phase, which describes the pattern of progressive amyloid-β plaque deposition in Alzheimer's disease, was incorporated into the latest National Institute of Ageing - Alzheimer's Association neuropathologic assessment guidelines. Amyloid biomarkers (positron emission tomography and cerebrospinal fluid) were included in clinical diagnostic guidelines for Alzheimer's disease dementia published by the National Institute of Ageing - Alzheimer's Association and the International Work group. Our first goal was to evaluate the correspondence of Thal amyloid phase to Braak tangle stage and ante-mortem clinical characteristics in a large autopsy cohort. Second, we examined the relevance of Thal amyloid phase in a prospectively-followed autopsied cohort who underwent ante-mortem (11)C-Pittsburgh compound B imaging; using the large autopsy cohort to broaden our perspective of (11)C-Pittsburgh compound B results. The Mayo Clinic Jacksonville Brain Bank case series (n = 3618) was selected regardless of ante-mortem clinical diagnosis and neuropathologic co-morbidities, and all assigned Thal amyloid phase and Braak tangle stage using thioflavin-S fluorescent microscopy. (11)C-Pittsburgh compound B studies from Mayo Clinic Rochester were available for 35 participants scanned within 2 years of death. Cortical (11)C-Pittsburgh compound B values were calculated as a standard uptake value ratio normalized to cerebellum grey/white matter. In the high likelihood Alzheimer's disease brain bank cohort (n = 1375), cases with lower Thal amyloid phases were older at death, had a lower Braak tangle stage, and were less frequently APOE-ε4 positive. Regression modelling in these Alzheimer's disease cases, showed that Braak tangle stage, but not Thal amyloid phase predicted age at onset, disease duration, and final Mini-Mental State Examination score. In contrast, Thal amyloid phase, but not Braak tangle stage or cerebral amyloid angiopathy predicted (11)C-Pittsburgh compound B standard uptake value ratio. In the 35 cases with ante-mortem amyloid imaging, a transition between Thal amyloid phases 1 to 2 seemed to correspond to (11)C-Pittsburgh compound B standard uptake value ratio of 1.4, which when using our pipeline is the cut-off point for detection of clear amyloid-positivity regardless of clinical diagnosis. Alzheimer's disease cases who were older and were APOE-ε4 negative tended to have lower amyloid phases. Although Thal amyloid phase predicted clinical characteristics of Alzheimer's disease patients, the pre-mortem clinical status was driven by Braak tangle stage. Thal amyloid phase correlated best with (11)C-Pittsburgh compound B values, but not Braak tangle stage or cerebral amyloid angiopathy. The (11)C-Pittsburgh compound B cut-off point value of 1.4 was approximately equivalent to a Thal amyloid phase of 1-2.

Translation, cultural adaptation and psychometric evaluation of the Leganés cognitive test in a low educated elderly Brazilian population

To validate the Leganés cognitive test (LCT) for cognitive screening in low educated elderly Brazilians. The study sample was composed of 59 elderly residents from the city of Santa Cruz, in Brazil, with low schooling levels. Reliability was analyzed with a two-day interval between assessments, and concurrent validity was assessed using the Mini Mental State Examination (MMSE). According to the LCT, the prevalence of dementia was 11.8%. The scale items showed a moderate to strong correlation between domains (p<0.01), and inter-rater reliability exhibited ICC=0.81, 95%CI=0.72-0.88. The factor analysis resulted in two factors: memory and orientation. Interscale agreement was considered poor (k=-0.02), supporting the hypothesis of an educational impact on final MMSE scores. The results suggest that LCT has acceptable levels of reliability for use in low-educated Brazilian elderly.

Thinking Outside the Box: Alzheimer-Type Neuropathology That Does Not Map Directly Onto Current Consensus Recommendations

The brains of many cognitively impaired patients fall into neuropathologic diagnostic categories that cannot be defined explicitly by guidelines of the National Institute on Aging and Reagan Institute. Here, 2 specific case categories are considered: i) "tangle-intensive" patients with the highest density of neurofibrillary tangles (as graded by the Braak staging system) but only moderate density of neuritic amyloid plaques (as graded by the Consortium to Establish a Registry for Alzheimer's Disease); and ii) "plaque-intensive" patients with intermediate severity neurofibrillary tangles and high density of neuritic amyloid plaques. To understand these technically unclassifiable cases better, we analyzed 1,677 cases with antemortem diagnoses of dementia from the National Alzheimer's Coordinating Center Registry; this registry includes both clinical and pathologic data from the National Institute on Aging-funded Alzheimer Disease Center. To evaluate the diagnostic tendencies of Alzheimer Disease Center neuropathologists, we assessed how the plaque-intensive and tangle-intensive cases were diagnosed. Tangle-intensive cases were more likely to be designated "high likelihood" that the dementia was due to Alzheimer disease, whereas plaque-intensive cases were typically designated as "intermediate likelihood." Only the Braak Stage VI tangle-intensive cases had lower final Mini-Mental State Examination scores than the plaque-intensive cases (p < 0.02). We conclude that more explicit diagnostic categories and a better understanding of the pathology in earlier phases of the disease may be helpful for guiding neuropathologists in the diagnosis of Alzheimer disease.

Apolipoprotein 4 Allele and Problems With Orientation Are Associated With a Persistent Decline in Cognition in Community-Dwelling Elderly Persons

A decline in cognitive test scores in elderly persons can signal the beginning of a descent into dementia or may indicate only a short-term cognitive disturbance. It would be clinically useful to distinguish between the two outcomes and to identify characteristics of each. Four hundred thirty-seven community-dwelling elderly persons were given the Mini-Mental State Examination (MMSE) annually for an average of 7 years. A low score between baseline and final MMSE was identified. A low score 3 or more points lower than baseline score indicated cognitive decline. This decline was called persistent if the final MMSE score was also at least 3 points lower than baseline MMSE score; otherwise, the decline was considered transient. Twenty participants (4.6%) experienced a persistent cognitive decline, 67 participants (15.3%) experienced a transient cognitive decline. Presence of the apolipoprotein epsilon4 allele was significantly associated with persistent cognitive decline (age-adjusted odd ratio [OR] = 11.46, p < .0001) but not with transient cognitive decline (age-adjusted OR = 1.53, p = .219). Incorrect answers on the orientation part of the MMSE at the time of cognitive decline was associated with persistent decline compared to transient decline (age-adjusted OR = 3.58, p = .058). Persistent cognitive decline is an infrequent occurrence in community-dwelling elderly persons. Presence of the epsilon4 allele and errors made by the subject on questions of orientation may be useful in determining whether a cognitive decline is likely to be persistent.

Effect of vascular lesions on cognition in Alzheimer's disease: a community-based study.

To investigate whether clinical and neuropathological differences exist between Alzheimer's disease (AD) cases with and without vascular lesions neuropathologically diagnosed using Consortium to Establish a Registry for Alzheimer's Disease (CERAD) criteria. Descriptive observational study. A community-based registry that identified incident dementia cases. Of the 124 subjects with available clinical and neuropathological assessments, 30 had AD lesions alone, and 18 had AD with vascular lesions. Patients with other neuropathological findings were excluded. Dependent measures included demographic, clinical, and neuropathological characteristics. Neuropathological diagnoses were made using the CERAD criteria and Braak and Braak staging. Of the 124 autopsied cases, 85 cases were diagnosed with neuropathological AD. Of these, 30 had pathology consistent with "pure" AD, whereas 18 had AD pathology with significant vascular lesions (AD/V). There were no differences in age, sex, or education between groups. AD/V cases had higher baseline and final Mini-Mental State Examination (MMSE) scores than pure AD cases, but after adjusting for education, differences in MMSE scores were not statistically significant. The AD/V group had significantly lower Braak staging than the pure AD group, after adjusting for education and final MMSE scores. In this comparison study of AD cases with and without vascular lesions, AD/V cases had less severe AD pathology than those with AD alone, indicating that cerebrovascular disease likely contributes to the severity of cognitive impairment in those with AD. Controlling for vascular risk factors in patients with AD may have a significant effect on severity of dementia.

Cholinergic–serotonergic imbalance contributes to cognitive and behavioral symptoms in Alzheimer’s disease

Neuropsychiatric symptoms seen in Alzheimer’s disease (AD) are not simply a consequence of neurodegeneration, but probably result from differential neurotransmitter alterations, which some patients are more at risk of than others. Therefore, the hypothesis of this study is that an imbalance between the cholinergic and serotonergic systems is related to cognitive symptoms and psychological syndromes of dementia (BPSD) in patients with AD. Cholinergic and serotonergic functions were assessed in post-mortem frontal and temporal cortex from 22 AD patients who had been prospectively assessed with the Mini-Mental State examination (MMSE) for cognitive impairment and with the Present Behavioral Examination (PBE) for BPSD including aggressive behavior, overactivity, depression and psychosis. Not only cholinergic deficits, but also the cholinacetyltransferase/serotonin ratio significantly correlated with final MMSE score both in frontal and temporal cortex. In addition, decreases in cholinergic function correlated with the aggressive behavior factor, supporting a dual role for the cholinergic system in cognitive and non-cognitive disturbances associated to AD. The serotonergic system showed a significant correlation with overactivity and psychosis. The ratio of serotonin to acetylcholinesterase levels was also correlated with the psychotic factor at least in women. It is concluded that an imbalance between cholinergic–serotonergic systems may be responsible for the cognitive impairment associated to AD. Moreover, the major findings of this study are the relationships between neurochemical markers of both cholinergic and serotonergic systems and non-cognitive behavioral disturbances in patients with dementia.

The frequency and clinical course of cognitive impairment in patients with terminal cancer

Cognitive disorders are among the most frequent psychiatric complications of advanced cancer. This study reviews the frequency and clinical course of cognitive failure in patients with advanced cancer admitted to a palliative care unit. In this retrospective study, all 348 patients admitted to the Edmonton General Palliative Care Unit over a period of 26 months were reviewed. The Mini-Mental State Examination (MMSE) was used as a screening tool to assess cognitive functioning and was performed on all patients at the time of admission and once to twice weekly thereafter. In all cases, when cognitive failure was diagnosed, a standardized management protocol was followed. Three hundred and twenty-one patients (92.2%) were evaluable. A total of 1441 MMSEs were performed. Each patient underwent an average of 4.7 +/- 4.26 MMSEs and every patient underwent an MMSE every 4.9 (+/- 3.3) days (median, 3.6 days). The mean age (standard deviation [SD]) of the study group was 64.2 (+/- 12) and the mean +/- SD (median) length of stay was 27 +/- 22 (20.5) days. Two hundred and thirty-one patients (71%) died on the unit. One hundred and forty-two patients (44%) had abnormal MMSE scores (MMSE < 0.8) on admission, whereas 176 patients (55%) had abnormal MMSE scores at the time of death or discharge. Of the 231 patients who died on the unit, 157 (68%) had abnormal MMSE scores prior to death. There was no significant difference in the first MMSE between patients who died and those who were discharged (P = 0.16). Of the 240 patients who underwent 2 or more MMSEs, 99 (41%) had normal initial and final MMSEs, 54 (23%) had normal initial MMSE scores but abnormal final scores, and 62 (26%) had both initial and final abnormal scores. Of the 87 surviving patients with an MMSE score of < 0.8 on admission, 25 (29%) had initial abnormal and final normal scores, indicating an improvement. Twelve of these 25 patients (48%) with abnormal initial scores but normal final scores were discharged versus 52 of 99 patients (53%) with normal initial and final MMSE scores (P > 0.2). Of 124 patients with normal final MMSE scores, 64 (52%) were discharged versus 16 of 116 patients (14%) who had abnormal MMSE final scores (P < 0.0001). These data suggest that cognitive screening should take place in patients with advanced cancer because cognitive failure is highly prevalent in this population, is reversible in a significant proportion of patients, and the presence of sustained cognitive impairment is a poor prognosticator for discharge. However, these results need to be confirmed in prospective studies.