Cognitive decline and amyloid accumulation in patients with mild cognitive impairment

Background/Aims: The relationship between baseline (11)C-Pittsburgh compound B ((11)C-PIB) uptake and cognitive decline during a 2-year follow-up was studied in 9 patients with mild cognitive impairment (MCI) who converted to Alzheimer's disease (AD) and 7 who remained with MCI. Methods: (11)C-PIB PET scan was conducted at baseline and cognitive assessment both at baseline and at follow-up. To obtain quantitative regional values of (11)C-PIB uptake, automated region of interest analysis was done using spatially normalized parametric ratio (region-to-cerebellar cortex) images. Results: At baseline, there were statistically significant differences in (11)C-PIB uptake, but not in cognitive test performances between the converters and nonconverters. Memory and executive function declined only in the converters during follow-up. In the converters, lower baseline frontal (11)C-PIB uptake was associated with faster decline in verbal learning. Higher baseline uptake in the caudate nucleus was related to faster decline in memory consolidation, and higher temporal uptake was associated with decline in executive function. Conclusion: Higher (11)C-PIB uptake in the caudate nucleus and temporal lobe was related to decline in memory and executive functions, whereas lower frontal uptake was related to decline in verbal learning. The results indicate that in prodromal AD, frontal amyloid accumulation reaches its maximum in the MCI stage, characterized by memory problems without full-blown dementia.     

Predictors of future cognitive decline in persons with mild cognitive impairment

This study sought first to identify individual items of the Mini-Mental State Examination (MMSE) and demographic variables at baseline that predicted the trajectories of cognitive change among patients with mild cognitive impairment (MCI), and second to quantify the risk of cognitive decline in such patients based on their pattern of failure of MMSE items. 187 MCI patients were evaluated serially with the MMSE for up to 3.5 years. Patients who followed a declining cognitive trajectory differed from the stable reference group in their baseline profile of MMSE test performance. Patient age and performance on delayed recall, constructional praxis, attention, and orientation to time and floor predicted future cognitive decline with good accuracy (79.9%) and specificity (86.4%), and moderate sensitivity (67.2%). These results are presented in the form of a simple clinical tool for quantifying risk of future cognitive decline in MCI.     

Executive function is associated with brain proton magnetic resonance spectroscopy in amnestic mild cognitive impairment

Persons with amnestic mild cognitive impairment (MCI) show deficits on executive function measures, although the neuroanatomic basis of executive function in MCI is unknown. We investigated cognitive correlates of 3-tesla proton magnetic resonance spectroscopy (MRS) of the posterior cingulate gyrus in 26 MCI patients. Posterior cingulate ratio of myo-inositol to creatine (mI/Cr) was negatively correlated (-.51) with spontaneous clock drawing. This relationship was not attenuated after accounting for age, overall cognitive function, or memory performance. This finding suggests a role for the posterior cingulate in executive function in MCI. Proton MRS may offer a means to track neurometabolic changes associated with cognitive impairment in MCI.     

Recollection and familiarity in amnestic mild cognitive impairment: a global decline in recognition memory

Despite memory failures being a central feature of amnestic mild cognitive impairment (a-MCI), there is limited research into the nature of the memory impairment associated with this condition. A further understanding could lead to refinement of criteria needed to qualify for this designation and aid in prediction of who will progress to development of clinical Alzheimer's disease. Dual process models posit that recognition memory is supported by the dissociable processes of recollection and familiarity. The present study sought to evaluate recognition memory in a-MCI in the framework of the dual process model. Patients with a-MCI and age- and education-matched controls were tested on three memory paradigms. Two paradigms were modifications of the process-dissociation procedure in which recollection required either memory of word-pair associations (associative) or the font color of words at study (featural). A final paradigm utilized the task-dissociation methodology comparing performance for item and visual spatial source memory. All three tasks revealed that familiarity was impaired to at least the same extent as recollection. As familiarity is thought to be spared in normal aging, its measurement may provide a relatively specific marker for the early pathological changes of Alzheimer's disease.     

Cognitive training for persons with mild cognitive impairment

Recent randomized control trials and meta-analyses of experimental studies indicate positive effects of non-pharmacological cognitive training on the cognitive function of healthy older adults. Furthermore, a large-scale randomized control trial with older adults, independent at entry, indicated that training delayed their cognitive and functional decline over a five-year follow-up. This supports cognitive training as a potentially efficient method to postpone cognitive decline in persons with mild cognitive impairment (MCI). Most of the research on the effect of cognitive training in MCI has reported increased performance following training on objective measures of memory whereas a minority reported no effect of training on objective cognitive measures. Interestingly, some of the studies that reported a positive effect of cognitive training in persons with MCI have observed large to moderate effect size. However, all of these studies have limited power and few have used long-term follow-ups or functional impact measures. Overall, this review highlights a need for a well-controlled randomized trial to assess the efficacy of cognitive training in MCI. It also raises a number of unresolved issues including proper outcome measures, issues of generalization and choice of intervention format.     

Prediction of AD with MRI-based hippocampal volume in mild cognitive impairment

OBJECTIVE: To test the hypothesis that MRI-based measurements of hippocampal volume are related to the risk of future conversion to Alzheimer's disease (AD) in older patients with a mild cognitive impairment (MCI). BACKGROUND: Patients who develop AD pass through a transitional state, which can be characterized as MCI. In some patients, however, MCI is a more benign condition, which may not progress to AD or may do so slowly. PATIENTS: Eighty consecutive patients who met criteria for the diagnosis of MCI were recruited from the Mayo Clinic Alzheimer's Disease Center/Alzheimer's Disease Patient Registry. METHODS: At entry into the study, each patient received an MRI examination of the head, from which the volumes of both hippocampi were measured. Patients were followed longitudinally with approximately annual clinical/cognitive assessments. The primary endpoint was the crossover of individual MCI patients to the clinical diagnosis of AD during longitudinal clinical follow-up. RESULTS: During the period of longitudinal observation, which averaged 32.6 months, 27 of the 80 MCI patients became demented. Hippocampal atrophy at baseline was associated with crossover from MCI to AD (relative risk [RR], 0.69, p = 0.015). When hippocampal volume was entered into bivariate models-using age, postmenopausal estrogen replacement, standard neuropsychological tests, apolipoprotein E (APOE) genotype, history of ischemic heart disease, and hypertension-the RRs were not substantially different from that found univariately, and the associations between hippocampal volume and crossover remained significant. CONCLUSION: In older patients with MCI, hippocampal atrophy determined by premorbid MRI-based volume measurements is predictive of subsequent conversion to AD.     

Cognitive impairment associated with major depression following mild and moderate traumatic brain injury

Traumatic brain injury (TBI) and major depression are neuropsychiatric conditions that have been associated with cognitive dysfunction. The aim of this study was to explore the relationship between major depression and cognitive impairment following mild and moderate TBI. Seventy-four TBI patients were assessed for the presence of major depression using the Structured Clinical Interview for the DSM-IV and completed a neurocognitive assessment battery. Subjects with major depression (28.4%), compared to those without, were found to have significantly lower scores on measures of working memory, processing speed, verbal memory and executive function. Potential mechanisms and implications for treatment are discussed.     

Perspectives on depression, mild cognitive impairment, and cognitive decline

CONTEXT: The public health implications of depression and cognitive impairment in late life are enormous. Cognitive impairment and late-life depression are associated with increased risk for subsequent dementia; however, investigations of these phenomena appear to be proceeding along separate tracks. OBJECTIVES AND DATA SOURCE: The National Institute of Mental Health organized the conference "Perspectives on Depression, Mild Cognitive Impairment, and Cognitive Decline" to consider how the varied perspectives might be better integrated to examine the associations among depression, mild cognitive impairment, and cognitive decline and to illuminate the common or distinct mechanisms involved in these associations. DATA SYNTHESIS: The following 2 broad questions were addressed: (1) What gaps in our knowledge have the greatest public health significance? (2) Can we more efficiently use our research dollars and participant resources to fill these gaps? Meeting participants included grantees from the National Institute of Mental Health and the National Institute on Aging and program staff from the National Institute of Mental Health, the National Institute on Aging, and the National Institute of Neurological Disorders and Stroke. CONCLUSIONS: One of the most important recommendations to emerge from the meeting discussions is for increased collaboration among clinical and epidemiological investigators whose work focuses in the area of depression with those working primarily in the area of memory disorders. Directions for future research were identified.     

Functional deficits in patients with mild cognitive impairment: prediction of AD

OBJECTIVE: To evaluate the predictive utility of self-reported and informant-reported functional deficits in patients with mild cognitive impairment (MCI) for the follow-up diagnosis of probable AD. METHODS: The Pfeffer Functional Activities Questionnaire (FAQ) and Lawton Instrumental Activities of Daily Living (IADL) Scale were administered at baseline. Patients were followed at 6-month intervals, and matched normal control subjects (NC) were followed annually. RESULTS: Self-reported deficits were higher for patients with MCI than for NC. At baseline, self- and informant-reported functional deficits were significantly greater for patients who converted to AD on follow-up evaluation than for patients who did not convert, even after controlling for age, education, and modified Mini-Mental State Examination scores. While converters showed significantly more informant- than self-reported deficits at baseline, nonconverters showed the reverse pattern. Survival analyses further revealed that informant-reported deficits (but not self-reported deficits) and a discrepancy score indicating greater informant- than self-reported functional deficits significantly predicted the development of AD. The discrepancy index showed high specificity and sensitivity for progression to AD within 2 years. CONCLUSIONS: These findings indicate that in patients with MCI, the patient's lack of awareness of functional deficits identified by informants strongly predicts a future diagnosis of AD. If replicated, these findings suggest that clinicians evaluating MCI patients should obtain both self-reports and informant reports of functional deficits to help in prediction of long-term outcome.     

Mild cognitive impairment is associated with mild parkinsonian signs in a door-to-door study

Mild cognitive impairment (MCI) and healthy aging have been shown to be associated with mild parkinsonian signs (MPS). We performed a door-to-door observational and follow-up study amongst consenting residents of Wadi Ara Arab villages in northern Israel aged ≥65 years (n=687) to examine whether MPS represent a risk factor for MCI and/or conversion from MCI to Alzheimer's disease (AD). In Phase 1, 223 cognitively normal (CN) and 173 MCI subjects were assessed by interview for medical history, neurological examination, motor part of the Unified Parkinson Disease Rating Scale (mUPDRS) (divided into item-clusters: axial, limb bradykinesia, tremor and rigidity) and cognitive tests. MCI subjects (n=111) were re-evaluated in Phase 2 for conversion to AD at least one year after initial assessment. MCI subjects had a higher frequency of axial dysfunction (8.7% vs. 1.3%) and limb bradykinesia (10.4% vs. 1.3%) than CN subjects (p<0.001, both). Stepwise logistic regression analysis estimating the probability of MCI vs. CN revealed higher mUPDRS (OR =1.19, 95% CI, 1.05 to 1.35, p=0.006) and higher limb bradykinesia scores (OR=1.75, 95% CI, 1.2 to 2.56, p=0.003) and not age as explanatory variables. Presence of MPS did not predict conversion to AD after adjustment for age and time-interval. These results suggest that axial and bradykinetic parkinsonian signs represent risk factors for MCI but MPS may not predict conversion from MCI to AD.