Nicole A. Kochan

A multifactorial approach to understanding fall risk in older people

OBJECTIVE: To identify the interrelationships and discriminatory value of a broad range of objectively measured explanatory risk factors for falls.

The Sydney Memory and Ageing Study (MAS): methodology and baseline medical and neuropsychiatric characteristics of an elderly epidemiological non-demented cohort of Australians aged 70-90 years.

BACKGROUND The Sydney Memory and Ageing Study (Sydney MAS) was initiated in 2005 to examine the clinical characteristics and prevalence of mild cognitive impairment (MCI) and related syndromes, and to determine the rate of change in cognitive function over time. METHODS Non-demented community-dwelling individuals (N = 1037) aged 70-90 were recruited from two areas of Sydney, following a random approach to 8914 individuals on the electoral roll. They underwent detailed neuropsychiatric and medical assessments and donated a blood sample for clinical chemistry, proteomics and genomics. A knowledgeable informant was also interviewed. Structural MRI scans were performed on 554 individuals, and subgroups participated in studies of falls and balance, metabolic and inflammatory markers, functional MRI and prospective memory. The cohort is to be followed up with brief telephone reviews annually, and detailed assessments biannually. RESULTS This is a generally well-functioning cohort mostly living in private homes and rating their health as being better than average, although vascular risk factors are common. Most (95.5%) participants or their informants identified a cognitive difficulty, and 43.5% had impairment on at least one neuropsychological test. MCI criteria were met by 34.8%; with 19.3% qualifying for amnestic MCI, whereas 15.5% had non-amnestic MCI; 1.6% had impairment on neuropsychological test performance but no subjective complaints; and 5.8% could not be classified. The rate of MCI was 30.9% in the youngest (70-75) and 39.1% in the oldest (85-90) age bands. Rates of depression and anxiety were 7.1% and 6.9% respectively. CONCLUSIONS Cognitive complaints are common in the elderly, and nearly one in three meet criteria for MCI. Longitudinal follow-up of this cohort will delineate the progression of complaints and objective cognitive impairment, and the determinants of such change.

Discrete Neuroanatomical Networks Are Associated with Specific Cognitive Abilities in Old Age

There have been many attempts at explaining age-related cognitive decline on the basis of regional brain changes, with the usual but inconsistent findings being that smaller gray matter volumes in certain brain regions predict worse cognitive performance in specific domains. Additionally, compromised white matter integrity, as suggested by white matter hyperintensities or decreased regional white matter fractional anisotropy, has an adverse impact on cognitive functions. The human brain is, however, a network and it may be more appropriate to relate cognitive functions to properties of the network rather than specific brain regions. We report on graph theory-based analyses of diffusion tensor imaging tract-derived connectivity in a sample of 342 healthy individuals aged 72–92 years. The cognitive domains included processing speed, memory, language, visuospatial, and executive functions. We examined the association of these cognitive assessments with both the connectivity of the whole brain network and individual cortical regions. We found that the efficiency of the whole brain network of cortical fiber connections had an influence on processing speed and visuospatial and executive functions. Correlations between connectivity of specific regions and cognitive assessments were also observed, e.g., stronger connectivity in regions such as superior frontal gyrus and posterior cingulate cortex were associated with better executive function. Similar to the relationship between regional connectivity efficiency and age, greater processing speed was significantly correlated with better connectivity of nearly all the cortical regions. For the first time, regional anatomical connectivity maps related to processing speed and visuospatial and executive functions in the elderly are identified.

White matter integrity in mild cognitive impairment: A tract-based spatial statistics study

Mild cognitive impairment (MCI) as a clinical diagnosis has limited specificity, and identifying imaging biomarkers may improve its predictive validity as a pre-dementia syndrome. This study used diffusion tensor imaging (DTI) to detect white matter (WM) structural alterations in MCI and its subtypes, and aimed to examine if DTI can serve as a potential imaging marker of MCI. We studied 96 amnestic MCI (aMCI), 69 non-amnestic MCI (naMCI), and 252 cognitively normal (CN) controls. DTI was performed to measure fractional anisotropy (FA), and tract-based spatial statistics (TBSS) were applied to investigate the characteristics of WM changes in aMCI and naMCI. The diagnostic utility of DTI in distinguishing MCI from CN was further evaluated by using a binary logistic regression model. We found that FA was significantly reduced in aMCI and naMCI when compared with CN. For aMCI subjects, decreased FA was seen in the frontal, temporal, parietal, and occipital WM, together with several commissural, association, and projection fibres. The best discrimination between aMCI and controls was achieved by combining FA measures of the splenium of corpus callosum and crus of fornix, with accuracy of 74.8% (sensitivity 71.0%, specificity 76.2%). For naMCI subjects, WM abnormality was more anatomically widespread, but the temporal lobe WM was relatively spared. These results suggest that aMCI is best characterized by pathology consistent with early Alzheimers disease, whereas underlying pathology in naMCI is more heterogeneous, and DTI analysis of white matter structural integrity can serve as a potential biomarker of MCI and its subtypes.

Mild cognitive impairment in a community sample: The Sydney Memory and Ageing Study

Mild cognitive impairment (MCI) is associated with an increased dementia risk. This study reports incidence of MCI subtypes, rates of progression to dementia, and stability of MCI classification.

Plasma Apolipoprotein Levels Are Associated with Cognitive Status and Decline in a Community Cohort of Older Individuals

Objectives Apolipoproteins have recently been implicated in the etiology of Alzheimer’s disease (AD). In particular, Apolipoprotein J (ApoJ or clusterin) has been proposed as a biomarker of the disease at the pre-dementia stage. We examined a group of apolipoproteins, including ApoA1, ApoA2, ApoB, ApoC3, ApoE, ApoH and ApoJ, in the plasma of a longitudinal community based cohort. Methods 664 subjects (257 with Mild Cognitive Impairment [MCI] and 407 with normal cognition), mean age 78 years, from the Sydney Memory and Aging Study (MAS) were followed up over two years. Plasma apolipoprotein levels at baseline (Wave 1) were measured using a multiplex bead fluorescence immunoassay technique. Results At Wave 1, MCI subjects had lower levels of ApoA1, ApoA2 and ApoH, and higher levels of ApoE and ApoJ, and a higher ApoB/ApoA1 ratio. Carriers of the apolipoprotein E ε4 allele had significantly lower levels of plasma ApoE, ApoC3 and ApoH and a significantly higher level of ApoB. Global cognitive scores were correlated positively with ApoH and negatively with ApoJ levels. ApoJ and ApoE levels were correlated negatively with grey matter volume and positively with cerebrospinal fluid (CSF) volume on MRI. Lower ApoA1, ApoA2 and ApoH levels, and higher ApoB/ApoA1 ratio, increased the risk of cognitive decline over two years in cognitively normal individuals. ApoA1 was the most significant predictor of decline. These associations remained after statistically controlling for lipid profile. Higher ApoJ levels predicted white matter atrophy over two years. Conclusions Elderly individuals with MCI have abnormal apolipoprotein levels, which are related to cognitive function and volumetric MRI measures cross-sectionally and are predictive of cognitive impairment in cognitively normal subjects. ApoA1, ApoH and ApoJ are potential plasma biomarkers of cognitive decline in non-demented elderly individuals.

Mild Cognitive Impairment as a Predictor of Falls in Community-Dwelling Older People

OBJECTIVE : Incidence of falls in people with cognitive impairment with or without a formal diagnosis of dementia is estimated to be twice that of cognitively intact older adults. This study aimed to investigate whether mild cognitive impairment (MCI) is associated with falls in older people. DESIGN : Prospective cohort study. SETTING : Community sample, Sydney Memory and Ageing Study. PARTICIPANTS : A total of 419 nondemented community-dwelling adults, age 70-90 years. MEASUREMENTS : A comprehensive neuropsychological test battery measuring four cognitive domains provided classification being with or without MCI on the basis of objective published criteria. Assessments of medical, physiologic, and psychological measures were also performed. Fallers were defined as people who had at least one injurious fall or at least two noninjurious falls during a 12-month follow-up period. RESULTS : Of the participants, 342 (81.6%) had normal cognitive functioning, 58 (13.8%) had nonamnestic MCI, and 19 (4.5%) had amnestic MCI. People with MCI performed worse than people without MCI in measures of general health and balance. Logistic regression analyses showed that fall risk was significantly greater in people with MCI (odds ratio [OR]: 1.72, 95% confidence interval [95% CI]: 1.03-2.89). This association was mainly apparent when the analysis was restricted to those with nonamnestic MCI (OR: 1.98, 95% CI: 1.11-3.53), where the relationship was primarily explained by impaired executive functioning (OR: 1.27, 95% CI: 1.02-1.59). CONCLUSION : The findings indicate that objectively defined MCI is an independent risk factor for injurious or multiple falls in a representative sample of community-dwelling older people. The presence of nonamnestic MCI, based primarily on executive function, was found to be an important factor in increasing fall risk.

Microstructural white matter changes in cognitively normal individuals at risk of amnestic MCI

Objective: Since Alzheimer disease (AD) is a slowly progressive disorder and its pathologic features are likely to be present for many years before symptoms become manifest, we investigated whether microstructural white matter changes similar to those identified in patients with AD can be detected in cognitively normal individuals without dementia destined to develop amnestic mild cognitive impairment (aMCI). Methods: We studied 193 cognitively normal individuals, of whom 173 remained cognitively stable (CN-stable) and 20 were diagnosed with aMCI (CN-aMCI converter) 2 years later. Structural MRI and diffusion tensor imaging were acquired at baseline to assess gray matter atrophy and microstructural white matter changes, respectively. Results: At baseline, compared with CN-stable, CN-aMCI converters had substantial reductions in white matter integrity in the precuneus, parahippocampal cingulum, parahippocampal gyrus white matter, and fornix. Other diffuse white matter changes were observed in the frontal, parietal, and subcortical regions, whereas gray matter structures were relatively intact. The fractional anisotropy (FA) values of the precuneus were found to be a predictor of conversion from cognitively normal to aMCI. In addition, the FA values of the left parahippocampal gyrus white matter were predictive of subsequent episodic memory decline. Conclusions: Microstructural white matter changes are present in cognitively normal individuals in the pre-aMCI stage, and may serve as a potential imaging marker of early AD-related brain changes.

The relationship of neuropsychological function to instrumental activities of daily living in mild cognitive impairment

While activities of daily living are by definition preserved in mild cognitive impairment (MCI), there is evidence of poorer instrumental activities of daily living (IADL) functioning in MCI compared to normal ageing. The aims of the present study were to examine differences in IADL between individuals with MCI and cognitively normal elderly, and to examine the relationships of IADL with cognitive functions.

Microstructural White Matter Changes, Not Hippocampal Atrophy, Detect Early Amnestic Mild Cognitive Impairment

Background Alzheimer’s disease (AD) is generally considered to be characterized by pathology in gray matter of the brain, but convergent evidence suggests that white matter degradation also plays a vital role in its pathogenesis. The evolution of white matter deterioration and its relationship with gray matter atrophy remains elusive in amnestic mild cognitive impairment (aMCI), a prodromal stage of AD. Methods We studied 155 cognitively normal (CN) and 27 ‘late’ aMCI individuals with stable diagnosis over 2 years, and 39 ‘early’ aMCI individuals who had converted from CN to aMCI at 2-year follow up. Diffusion tensor imaging (DTI) tractography was used to reconstruct six white matter tracts three limbic tracts critical for episodic memory function - the fornix, the parahippocampal cingulum, and the uncinate fasciculus; two cortico-cortical association fiber tracts - superior longitudinal fasciculus and inferior longitudinal fasciculus; and one projection fiber tract - corticospinal tract. Microstructural integrity as measured by fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD) and axial diffusivity (AxD) was assessed for these tracts. Results Compared with CN, late aMCI had lower white matter integrity in the fornix, the parahippocampal cingulum, and the uncinate fasciculus, while early aMCI showed white matter damage in the fornix. In addition, fornical measures were correlated with hippocampal atrophy in late aMCI, whereas abnormality of the fornix in early aMCI occurred in the absence of hippocampal atrophy and did not correlate with hippocampal volumes. Conclusions Limbic white matter tracts are preferentially affected in the early stages of cognitive dysfunction. Microstructural degradation of the fornix preceding hippocampal atrophy may serve as a novel imaging marker for aMCI at an early stage.