Dual-task gait speed assessments with an electronic walkway and a stopwatch in older adults. A reliability study.

BACKGROUND/OBJECTIVES: Slow gait speed prospectively predicts elevated risk of adverse events such as falls, morbidity, and mortality. Additionally, gait speed under a cognitively demanding challenge (dual-task gait) predicts further cognitive decline and dementia incidence. This evidence has been mostly collected using electronic walkways; however, not all clinical set ups have an electronic walkway and comparability with simple manual dual-gait speed testing, like a stopwatch, has not yet been examined. Our main objective was to assess concurrent-validity and reliability of gait speed assessments during dual-tasking using a stopwatch and electronic walkway in older adults with mild and subjective cognitive impairment (MCI and SCI). DESIGN: Cross-sectional, reliability study. SETTING: Clinic based laboratory at an academic hospital in London, ON, Canada. PARTICIPANTS: 237 walk tests from 34 community-dwelling participants (mean age 71.84 SD 5.38; 21 female - 62%, 13 male - 38%) with SCI and MCI. were included from the Comprehensive Assessment of Neurodegeneration and Dementia (COMPASS-ND) study. INTERVENTION: Each participant performed seven walk tests: three single gait walks at their normal pace, three dual-task walks (walking and counting backwards by one, by sevens, and naming animals), and one fast walk. MEASUREMENTS: Gait speed (cm/s) for each walk was measured simultaneously with an electronic walkway (Zeno Mat®) and a handheld stopwatch (Ultrak chronometer®). Dual-task cost (DTC) was calculated for the three individual dual-task walks as [((single gait speed - dual-task gait speed) / single gait speed) ∗ 100]. Level of agreement between the two measurement methods was analyzed using Pearson correlations, paired t-tests, and Bland-Altman plots. RESULTS: Gait speed was consistently lower when measured with the stopwatch than with the electronic walkway (mean speed difference: 10.6 cm/s ± 5.1, p < 0.001). Calculating DTC, however, yielded very similar results with both methods (mean DTC difference: 0.19 ± 1.18, p = 0.872). The higher the DTC, the closer the measurement between methods. CONCLUSION: Assessing and calculating DTC with a stopwatch is simple, accessible and reliable. Its validity and reliability were high in this clinical sample of community older adults with SCI and MCI.

Vitamin D and white matter abnormalities in older adults: a cross-sectional neuroimaging study.

BACKGROUND AND PURPOSE: Morphological brain changes related to hypovitaminosis D have been poorly studied. In particular, the age-related decrease in vitamin D concentrations may explain the onset of white matter abnormalities (WMA) in older adults. Our objectives were (i) to investigate whether there was an association between serum 25-hydroxyvitamin D (25OHD) concentration and the grade of WMA in older adults and (ii) to determine whether the location of WMA was associated with 25OHD concentration. METHODS: One hundred and thirty-three Caucasian older community-dwellers with no clinical hydrocephalus (mean 71.6 ± 5.6 years; 43.6% female) received a blood test and a magnetic resonance imaging scan of the brain. The grades of total, periventricular and deep WMA were scored using semiquantitative visual rating scales from T2-weighted fluid-attenuated inversion recovery images. The association of WMA with as-measured and deseasonalized 25OHD concentrations was evaluated with the following covariates: age, gender, body mass index, use of anti-vascular drugs, number of comorbidities, impaired mobility, education level, Mini-Mental State Examination score, medial temporal lobe atrophy, serum concentrations of calcium, thyroid-stimulating hormone and vitamin B12, and estimated glomerular filtration rate. RESULTS: Both as-measured and deseasonalized serum 25OHD concentrations were found to be inversely associated with the grade of total WMA (adjusted ß = -0.32, P = 0.027), specifically with periventricular WMA (adjusted ß = -0.15, P = 0.009) but not with deep WMA (adjusted ß = -0.12, P = 0.090). Similarly, participants with 25OHD concentration <75 nM had on average a 33% higher grade of periventricular WMA than those with 25OHD ≥75 nM (P = 0.024). No difference in average grade was found for deep WMA (P = 0.949). CONCLUSIONS: Lower serum 25OHD concentration was associated with higher grade of WMA, particularly periventricular WMA. These findings provide a scientific basis for vitamin D replacement trials.

Diffusion tensor imaging of white matter tract evolution over the lifespan.

Diffusion tensor imaging (DTI) has been used widely to show structural brain changes during both development and aging. Lifespan studies are valuable because they connect these two processes, yet few DTI studies have been conducted that include both children and elderly subjects. This study used DTI tractography to investigate 12 major white matter connections in 403 healthy subjects aged 5-83 years. Poisson fits were used to model changes of fractional anisotropy (FA) and mean diffusivity (MD) across the age span, and were highly significant for all tracts. FA increased during childhood and adolescence, reached a peak between 20 and 42 years of age, and then decreased. MD showed an opposite trend, decreasing first, reaching a minimum at 18-41 years, and then increasing later in life. These trajectories demonstrate rates and timing of development and degradation that vary regionally in the brain. The corpus callosum and fornix showed early reversals of development trends, while frontal-temporal connections (cingulum, uncinate, superior longitudinal) showed more prolonged maturation and delayed declines. FA changes were driven by perpendicular diffusivity, suggesting changes of myelination and/or axonal density. Tract volume changed significantly with age for most tracts, but did not greatly influence the FA and MD trajectories. This study demonstrates clear age-related microstructural changes throughout the brain white matter, and provides normative data that will be useful for studying white matter development in a variety of diseases and abnormal conditions.

Mesial prefrontal cortex degeneration in amyotrophic lateral sclerosis: a high-field proton MR spectroscopy study.

BACKGROUND AND PURPOSE: Frontotemporal lobar degeneration is responsible for the cognitive abnormalities seen in patients with ALS. We sought to evaluate the in vivo neurochemical changes associated with this pathology indicative of neuronal loss and gliosis. MATERIALS AND METHODS: Twenty-four patients with ALS (2 with ALS-FTD) and 15 healthy controls were studied. High-field proton MR spectroscopy of the mesial prefrontal cortex was used to determine concentrations of NAA and mIns, markers of neuronal integrity and gliosis, respectively. Metabolite concentrations were correlated with cognitive tests (verbal fluency, ACE). RESULTS: NAA/mIns was decreased 17% (P =.002). Abnormalities were present to a lesser degree in the individual metabolites NAA (decreased 9%; P =.08) and mIns (increased 11%; P =.06) than the ratio of the 2 metabolites. These measures did not correlate significantly with verbal fluency or the ACE. CONCLUSIONS: Prefrontal lobe degeneration exists in patients with ALS as indicated by an abnormal mesial prefrontal cortex neurochemical profile. Further study is necessary to determine the potential utility of the NAA/mIns ratio as a biomarker for frontal lobe degeneration in ALS.

Gait and posture impairment, parkinsonism and cognitive decline in older people.

Our objective was to examine the frequency of gait and posture impairment and parkinsonism in 3 waves of the Canadians Study of Health and Aging (CSHA) and to determine their relationship to the development of cognitive impairment-not dementia (CIND) and dementia. A secondary analysis of a Canadian population-based cohort study was performed. People 65 years of age and older without cognitive impairment or dementia underwent examination for the presence of gait or posture impairment (GPI) or parkinsonism (based on the presence of 2/3 signs among resting tremor, rigidity or bradykinesia), both defined by a clinical examination. Risk for development of cognitive impairment or dementia was examined at 5 and 10 year follow up in pre-specified logistic regression models adjusted for age, sex, education and in separate models, frailty. The frequency of GPI ranged from 25 to 30% in cognitively unimpaired to 46-53% in CIND and demented subjects. Parkinsonism was more common with increasing cognitive impairment at each wave of the CSHA. Both GPI and parkinsonism predicted cognitive decline. Frailty reduced, but did not eliminate the impact of these motor measures and was itself a significant predictor of cognitive decline. In conclusion, motor impairment and frailty are common in older people and are associated with an increased risk of cognitive decline and dementia. GPI is common in CIND, while GPI and parkinsonism are both common in dementia.

The impact of depressive symptoms in early Parkinson disease.

BACKGROUND: Depressive disorders may affect up to 50% of patients with Parkinson disease (PD) and are associated with increased disability and reduced quality of life. No previous study has systematically examined the impact of depressive symptoms in early, untreated PD. METHODS: We administered the 15-item Geriatric Depression Scale (GDS-15) as part of two NIH-sponsored phase II clinical trials in PD, enrolling 413 early, untreated PD subjects. We used linear mixed models to examine the relationship of depressive symptoms, measured by the GDS-15, with motor function and activities of daily living (ADLs), as measured by the Unified PD Rating Scale (UPDRS). A time-dependent Cox model was used to examine the effect of demographic and clinical outcome measures as predictors of investigator-determined time to need for symptomatic therapy for PD. RESULTS: A total of 114 (27.6%) subjects screened positive for depression during the average 14.6 months of follow-up. Forty percent of these subjects were neither treated with antidepressants nor referred for further psychiatric evaluation. Depression, as assessed by the GDS-15, was a significant predictor of more impairment in ADLs (p < 0.0001) and increased need for symptomatic therapy of PD (hazard ratio = 1.86; 95% CI 1.29, 2.68). CONCLUSIONS: Clinically important depressive symptoms are common in early Parkinson disease (PD), but are often not treated. Depressive symptoms are an important contributor to disability and the decision to start symptomatic therapy for motor-related impairment in early PD, highlighting the broad importance of identifying and treating depression in this population.

Vitamins and entacapone in levodopa-induced hyperhomocysteinemia: a randomized controlled study.

Elevated homocysteine is associated with increased risk of heart disease, stroke, and dementia. Therapy of Parkinson disease (PD) with levodopa elevates homocysteine. The authors conducted a 6-week, multicenter, randomized, double-blind, placebo-controlled trial to test whether folate 1 mg/vitamin B(12) 500 microg or entacapone reduced serum homocysteine in 35 levodopa-treated PD patients. Levodopa initiation caused a small elevation in homocysteine. Vitamin therapy, but not entacapone, resulted in a decrease in homocysteine compared to placebo.

Asynchronous regional brain volume losses in presymptomatic to moderate AD.

To determine if rates and locations of brain volume loss associated with AD are phase-specific, occurring prior to clinical onset and at later stages, we performed longitudinal volumetric MRI analysis on 155 subjects enrolled in a prospective study of aging and dementia. Subjects were divided by Clinical Dementia Rating (CDR) scale into stages of Normal (CDR 0 --> 0), Very Mild (CDR 0 --> 0.5 and 0.5 --> 0.5), Mild (CDR 0.5 --> 1.0 and 1.0 --> 1.0) and Moderate (CDR 1.0 --> 2.0 and 2.0 --> 2.0) dementia. Rates of volume change in CSF spaces, lobar and medial temporal lobe regions were analyzed for group differences across stages. Annual rates of ventricular volume change differed between non-demented and very mild group (p<0.01). In later severity stages, ventricular, temporal, basal ganglia-thalamic region and total volumes show change. Rates of volume loss increase as dementia progresses, but not uniformly in all regions. These regional and phase-specific volume changes form targets for monitoring disease-modifying therapies at clinically relevant, defined stages of dementia.

Posterior cingulate metabolic changes occur in Parkinson's disease patients without dementia.

The basis for cognitive deficits in Parkinson's disease (PD) is unknown. Hippocampal atrophy has been shown in Alzheimer's disease (AD) and PD. N-Acetyl aspartate (NAA)/creatine (Cr) ratio in the posterior cingulate gyrus (PCG) is decreased in AD, but unknown in PD. Volumetric magnetic resonance (MR) imaging (at 1.5 T) determined corrected HC volume and MR spectroscopy (MRS) PCG metabolites in 12 non-demented mild to moderately affected PD patients (six male, six female) and ten controls (five male, five female). Age (PD=60.6 years, control=62.2; P=0.62), education (PD=14.1 years, controls=13.8; P=0.89) and global cognition (Mini-Mental State Exam score: PD=28.7, controls=29.6; P=0.14) did not differ. Only recall (CVLT-II, P=0.046) and NAA/Cr (PD=1.53, controls=1.78; P=0.03) were decreased in PD. Memory correlated with NAA/Cr (r=0.65, P=0.02) in PD. In conclusion, cingulate metabolic changes occur in PD.

Natural history of cognitive decline in the old old.

OBJECTIVE: To prospectively examine the occurrence and outcome of cognitive decline in healthy, community-dwelling elders. METHODS: Ninety-five elders (mean age 84 years) who at entry had no cognitive impairment were followed for up to 13 years. Cognitive decline was defined as obtaining either a Clinical Dementia Rating (CDR) = 0.5 or Mini-Mental State Examination (MMSE) score < 24 on two examinations. RESULTS: Three outcomes of aging were determined: intact cognition, persistent cognitive decline without progression to dementia, and dementia. Whereas 49% remained cognitively intact, 51% developed cognitive decline. Mean follow-up to first CDR 0.5 was 3.8 years and age at conversion was 90.0 years. Those who remained cognitively intact had better memory at entry and were less likely to have APOE4 than those who developed cognitive decline. Of the 48 participants with cognitive decline, 27 (56%) developed dementia (CDR > or =1) a mean of 2.8 years later. Participants with cognitive decline who progressed to dementia had poorer confrontation naming at the time of their first CDR 0.5 than those with persistent cognitive decline who did not progress during follow-up. CONCLUSION: The old old are at high risk for developing cognitive decline but many will not progress to dementia in the next 2 to 3 years or even beyond. These findings are important for understanding the prognosis of cognitive decline and for the design of treatment trials for AD. APOE genotype is a risk factor for cognitive decline.

Parkinsonism and occupational exposure to pesticides.

OBJECTIVE: To examine the risk of parkinsonism related to lifetime occupational exposure to pesticides among a cohort of men, mostly orchardists, in Washington State. METHODS: All 310 subjects in this study had previously participated in a cohort study of men occupationally exposed to pesticides. Subjects were given a structured neurological examination and completed a self administered questionnaire which elicited detailed information on pesticide (insecticide, herbicide, and fungicide) use throughout their working careers. Demographic characteristics were also sought. Subjects had a mean age of 69.6 years (range 49-96, SD 8.1). There were 238 (76.8%) subjects who reported some occupational exposure to pesticides, whereas 72 (23.2%) reported none. Parkinsonism was defined by the presence of two or more of rest tremor, rigidity, bradykinesia, and impairment of postural reflexes in subjects not on antiparkinsonian medication, or the presence of at least one sign if they were on such medication. Parkinson's disease was not studied explicitly because of the difficulty in distinguishing it from other parkinsonian syndromes. A generalised linear model was used to estimate prevalence ratios (PRs) for parkinsonism relative to history of farming, pesticide use, and use of well water. RESULTS: A PR of 2.0 (95% confidence interval (95% CI) 1.0 to 4.2) was found for subjects in the highest tertile of years of exposure to pesticides; a similarly increased, non-significant, PR was found for the middle tertile (1.9 (95% CI 0.9 to 4.0)), although a trend test did not show a significant exposure-response relation. No increased risks were found associated with specific pesticides or pesticide classes, nor with a history of farming or use of well water. CONCLUSION: Parkinsonism may be associated with long term occupational exposure to pesticides, although no associations with specific pesticides could be detected. This finding is consistent with most of the publications on this topic.

Methylphenidate increases the motor effects of L-Dopa in Parkinson's disease: a pilot study.

We determined whether methylphenidate, a dopamine transporter blocker, modifies motor, cognitive, or affective responses to L-Dopa in Parkinson's disease (PD). Five patients who reported benefit from L-Dopa/carbidopa and motor fluctuations were admitted and withdrawn from their usual antiparkinsonian medications. On 3 consecutive days in a randomized double-blinded fashion, they took 0.2 mg/kg oral methylphenidate or placebo followed 30 minutes later by a 1-hour intravenous L-Dopa (2 mg/kg per h) or placebo infusion. Vital signs, tapping, walking, dyskinesias, mood, anxiety, concentration, and arousal were monitored every 30 minutes. Cognitive testing was performed before and following the infusion. Methylphenidate combined with L-Dopa led to greater peak right-hand tapping speed than either alone. Dyskinesia severity increased most when methylphenidate and L-Dopa were co-administered. There were no differences between conditions on the Stroop test, digit ordering, simple reaction time, or covert orienting of attention validity effect. Methylphenidate alone led to improvement in choice reaction time. Change in self-assessed analogue ratings of mood, anxiety, arousal, or concentration did not differ between conditions. Methylphenidate increased the motor effects of L-Dopa with minimal effects on cognitive or affective functions, suggesting a physiologic role for the dopamine transporter in patients with PD with motor fluctuations.

Predictors of healthy brain aging.

To determine if superior health at old age protects against cognitive impairment (CI) and Alzheimer's disease (AD), we prospectively studied 100 optimally healthy oldest-old (> or =85 years) individuals. Initially, subjects represented the top 3% of the oldest old for health. During 5.6 +/- 0.3 years of follow-up, 34 subjects developed CI, and 23 progressed to AD. By age 100, probability of CI and AD were.65 +/-.09 and.49 +/-.10. Median onset age was 97 years for CI and 100 for AD. Clearly, superior health at old age does not guarantee protection against cognitive decline. Lifetime risks were similar to the general population but onset ages were later, suggesting factors that delay onset are key to improving cognitive health in the elderly. In this population, absence of apolipoprotein E-epsilon4 and male gender were associated with delayed onset, whereas estrogen use and education had no detectable effect on cognitive outcome.

Parkinson's disease, CYP2D6 polymorphism, and age.

OBJECTIVE: PD may be caused by genetic susceptibility to neurotoxins. CYP2D6 is a candidate gene for PD because it regulates drug and toxin metabolism, but association studies have been inconsistent. The aim of this study was to test if the CYP2D6*4 allele (poor metabolizer phenotype) is associated with earlier age at onset. METHODS: Five hundred seventy-six patients with PD and 247 subjects without PD were studied using standard diagnostic, genotyping, and statistical techniques. RESULTS: Surprisingly, mean onset age was significantly later in *4-positive patients. Frequency of *4 was significantly higher in late-onset PD than early-onset PD. When early- and late-onset PD were analyzed separately, *4 had no effect on onset age; hence, the association with delayed onset was likely an artifact of an elevated *4 frequency in late-onset PD. Contrary to a common assumption that CYP2D6 frequencies do not change with age, *4 frequency rose significantly with advancing age, both in patients with PD (from 0.16 at mean age of 56.5 years to 0.21 at mean age of 72) and subjects without PD (from 0.09 at mean age of 45.5 years to 0.21 at mean age of 72). *4 Frequencies in patients with early- and late-onset PD, although different from each other, were in agreement with similarly aged subjects without PD, suggesting the elevated *4 frequency in late-onset PD was likely an age effect, unrelated to PD. CONCLUSION: The CYP2D6*4 allele is not associated with earlier PD onset. *4 May be associated with survival. Inconsistent results from allelic association studies may have been due to an unrecognized age effect.

Memory testing in dementia: how much is enough?

Analyses of eight widely used memory measures (Word List Acquisition and Recall used in the Alzheimer's Disease Assessment Scale and the Consortium to Establish a Registry for Alzheimer's Disease neuropsychology battery, Wechsler Memory Scale-Revised [WMS-R] Logical Memory I and II, WMS-R Visual Reproduction I and II, the memory scores from the Neurobehavioral Cognitive Status Examination [NCSE], memory scores from the Mini-Mental State Examination [MMSE]), and the MMSE total score showed each to have moderate predictive power in differentiating between patients with mild dementia and healthy normal controls. When these instruments were combined in a logistic regression analysis, three of them had substantial predictive power. Together, the Word List Acquisition, WMS-R Logical Memory II, and WMS-R Visual Reproduction II were 97.26% accurate (100% sensitive and 94.59% specific) in distinguishing these two groups. The Word List Acquisition is a brief test that alone had high accuracy (92%). These memory tests are highly useful in the diagnosis of mild dementia.

Discriminating mild parkinsonism: methods for epidemiological research.

Methods for the efficient and accurate detection of parkinsonism are essential for epidemiological studies. We sought to determine whether parkinsonism could be detected by a neurologist from a videotaped assessment and whether neurobehavioral methods (motor, cognitive, and sensory) discriminated between patients with Parkinson's disease (PD) and controls. Fifteen patients with mild PD (Hoehn and Yahr I-III) were compared to 15 age-, sex-, and education- matched controls. Each participant underwent a videotaped neurological examination (based on the Unified Parkinson's Disease Rating Scale, UPDRS), administered by a trained technician, and reviewed by a neurologist, as well as a series of neurobehavioral tests. The neurologist identified PD patients with 86% sensitivity and 100% specificity. Among the neurobehavioral tests, finger tapping, combined with one or more among olfaction, visual contrast sensitivity, or Paired Associates Learning, correctly classified 90%, or more, of subjects. Individual psychological tests did not discriminate reliably between groups. We conclude that videotaped assessments of parkinsonism or objective tests of motor and sensory function can accurately detect patients with PD. Both approaches have potential for identifying PD cases, but the latter may be more efficient for screening.

Dementia in rural primary care practices in Lake County, Oregon.

Procedures used in assessing patients with dementia in rural settings are little studied. Among all patients aged 65 years and older in the four primary care practices in Lake County, Oregon, dementia cases were identified from computerized office databases using preselected International Classification of Diseases, Ninth Edition, codes. A semi-structured chart review determined (1) a dementia diagnosis, (2) cognitive and functional domains assessed, and (3) diagnostic studies performed. Of 1540 available records, 30 had dementia. Nineteen of them met National Institute of Neurological and Communicative Diseases and Stroke-Alzheimer's Disease and Related Disorders Association criteria for Alzheimer's disease (AD). Cognitive impairment was documented in 73% of the 51 identified charts and all with AD. Laboratory studies were recorded in 33% overall and in 42% with AD. Neuroimaging was documented in 18% overall and in 16% with AD. The prevalence of documented dementia in these rural practices may be low, possibly because cases of mild dementia may not be labeled as such. Laboratory studies were performed in a minority of cases of dementia.