Richard Camicioli

Volume loss of the hippocampus and temporal lobe in healthy elderly persons destined to develop dementia

Objective To determine initial locus and rate of degeneration of temporal lobe structures (total lobe, hippocampus and parahippocampus) in preclinical dementia. Background Postmortem studies suggest that the earliest changes in Alzheimers disease are neurofibrillary tangle formation in hippocampus and adjacent cortex. MRI volume analysis of temporal lobe structures over time in subjects prior to developing dementia may allow the identification of when these processes begin, the rate they develop, and which areas are key to symptom development. Methods 30 nondemented (NOD), healthy, elderly individuals enrolled in a prospective study of healthy aging evaluated annually over a mean of 42 months. Twelve subjects with subsequent cognitive decline were assigned to the preclinical dementia group (PreD). All 120 annual MRI studies analyzed by volumetric techniques assessed group differences in temporal lobe volumes and rates of brain loss. Results NOD as well as PreD subjects had significant, time-dependent decreases in hippocampal and parahippocampal volume. Rates of volume loss between the groups did not significantly differ. PreD cases had significantly smaller hippocampi when asymptomatic. Parahippocampal volume did not differ between PreD and NOD cases. Significant time-dependent temporal lobe atrophy was present only in PreD. Conclusions Hippocampal and parahippocampal atrophy occurs at a similar rate regardless of diagnostic group. Those who develop dementia may have smaller hippocampi to begin with, but become symptomatic because of accelerated loss of temporal lobe volume. Temporal lobe volume loss may mark the beginning of the disease process within six years prior to dementia onset.

Talking while walking The effect of a dual task in aging and Alzheimer's disease

We determined the effects of distraction on gait in healthy elderly subjects and Alzheimers disease (AD) patients. The effects of simultaneous performance of a verbal fluency task (effect of reciting male or female names) on the time and number of steps taken to walk 30 feet were compared using a repeated-measures design with between-group comparison between community-dwelling healthy old old (oOld; n = 20; mean age ± SD, 86 ± 4.4), healthy young old (yOld; n = 23; mean age ± SD, 72 ± 3.6), and probable AD subjects without parkinsonism (n = 15; mean age ± SD, 74 ± 13). AD patients slowed more than the yOld (p = 0.005) and the oOld (p = 0.002). The yOld and oOld did not differ from each other (p = 0.68). Mean (±SD) differences in time were as follows: yOld, −2.2 ± 1.9; oOld, −1.6 ± 2.0; AD, −7.1 ± 9.2 seconds. The change in steps did not differ between groups. Walking speed of AD patients slowed more than that of elderly subjects during the dual task. This may contribute to the risk of falls in AD.

Heterozygosity for a mutation in the parkin gene leads to later onset Parkinson disease

Background: The vast majority of the parkin mutations previously identified have been found in individuals with juvenile or early onset PD. Previous screening of later onset PD cohorts has not identified substantial numbers of parkin mutations. Methods: Families with at least two siblings with PD were ascertained to identify genes contributing to PD susceptibility. Screening of the parkin gene, by both quantitative PCR and exon sequencing, was performed in those families with either early onset PD (age onset ≤50 years) or positive lod score with a marker in intron 7 of the parkin gene. Results: A total of 25 different mutations in the parkin gene were identified in 103 individuals from 47 families. Mutations were found in both parkin alleles in 41 of the individuals, whereas a single mutation in only one of the two parkin alleles was observed in 62 individuals. Thirty-five of the subjects (34%) with a parkin mutation had an age at onset of 60 years or above with 30 of these 35 (86%) having a detectable mutation on only one parkin allele. Few significant clinical differences were observed among the individuals with two, one, or no mutated copies of the parkin gene. Conclusion: Mutations in the parkin gene occur among individuals with PD with an older age at onset (≥60 years) who have a positive family history of the disease. In addition, the clinical findings of parkin-positive individuals are remarkably similar to those without mutations.

Motor slowing precedes cognitive impairment in the oldest old

Eighty-five healthy elderly subjects were prospectively evaluated for 3 years to determine motor differences between those who remain cognitively intact and those who developed cognitive impairment during prospective follow-up. The 18 subjects who developed cognitive impairment had slower finger tapping and took longer to walk 30 feet before or at the time of cognitive impairment. Coordination was more impaired and steps, but not balance, deteriorated more rapidly, independent of other variables.

Significant Linkage of Parkinson Disease to Chromosome 2q36-37

Parkinson disease (PD) is the second most common neurodegenerative disorder, surpassed in frequency only by Alzheimer disease. Elsewhere we have reported linkage to chromosome 2q in a sample of sibling pairs with PD. We have now expanded our sample to include 150 families meeting our strictest diagnostic definition of verified PD. To further delineate the chromosome 2q linkage, we have performed analyses using only those pedigrees with the strongest family history of PD. Linkage analyses in this subset of 65 pedigrees generated a LOD score of 5.1, which was obtained using an autosomal dominant model of disease transmission. This result strongly suggests that variation in a gene on chromosome 2q36-37 contributes to PD susceptibility.

Brain volume preserved in healthy elderly through the eleventh decade

Objective: To determine which brain regions lose volume with aging over time in healthy, nondemented elderly. Background: Cross-sectional studies suggest widespread loss of brain volume with aging. These studies may be biased by significant numbers of preclinically demented elderly in the oldest comparison groups. Longitudinal studies may allow closer determination of the effect of aging unaffected by dementia. Methods: Quantitative volumetric MRI was performed annually on 46 healthy subjects older than age 65 who had maintained cognitive health a mean of 5 years. Comparisons (analysis of variance) were made of rates of volume loss (slopes) divided into 11 young-old (mean age, 70 years), 15 middle-old (mean age, 81 years), and 20 oldest-old (mean age, 87 years) subjects. Regions of interest included CSF spaces, lobar regions, and limbic-subcortical regions. Results: There were significant differences between groups in intracranial, total brain, left hemisphere, right hemisphere, temporal lobe, basilar-subcortical region, and hippocampus volumes, with oldest-old subjects showing the smallest volumes, followed by middle-old and young-old subjects. Oldest-old subjects had significantly greater subarachnoid volumes than the younger groups. There were no significant differences in rates of change of regions of interest across age groups. Conclusions: After age 65 there is minimal brain volume loss observed over time in healthy elderly. Brain volume differences seen cross-sectionally, at any age, likely reflect small, constant rates of volume loss with healthy aging. Healthy oldest-old subjects do not show greater rates of brain loss compared with younger elderly, suggesting that large changes seen in cross-sectional studies reflect the presence of preclinical dementia in older groups.

Verbal fluency task affects gait in Parkinson's disease with motor freezing.

We examined the effects of a simultaneous verbal fluency task on walking in Parkinsons disease (PD) patients with freezing of gait (PD-F) compared to nonfreezing patients (PD-NF) or control subjects (C). Effects of antiparkinsonian medications on gait in PD-F were examined. PD-F patients exhibited a greater increase in the number of steps to complete the walk with verbal fluency, even when the effect of medication was taken into account (mean increase ± SD): PD-F = 4.2 ± 4.6, n = 10; PD-NF = 0.1 ± 1.6, n = 9; C = 1.5 ± 1.5, n = 19; P = .007. Medications improved walking in PD-F patients by decreasing the number of steps, the time to walk, and freezing. PD-F patients may be more dependent on attention for walking.

Age-related brain changes associated with motor function in healthy older people.

OBJECTIVE: To identify the MRI imaging findings associated with motor changes in healthy older people.

Delays in the diagnosis of dementia: Perspectives of family caregivers

Obtaining a diagnosis of dementia for a relative can be a protracted and anxious time for family members. This paper reports results from a focus group study and a subsequently mailed survey of family caregivers on factors which delayed obtaining a diagnosis for a dementing illness. The average time between initial symptom recognition and diagnosis was 30 months. Four kinds of factors were identified as delaying diagnosis, including the caregivers lack of knowledge or reluctance to seek help, and patient, family, and physician-related factors. Of the 57 percent of survey respondents who reported a delay of at least 12 months between initial symptom recognition and diagnosis, 68 percent reported at least one factor related to their interaction with physicians. Qualitative data provide insight into family caregiver perspectives on factors delaying diagnosis.

Neuropsychiatric adverse effects of antiparkinsonian drugs. Characteristics, evaluation and treatment

SummaryParkinson’s disease (PD) is a progressive neurological condition that causes considerable disability in the elderly. Drugs used to treat PD, such as levodopa, offer symptomatic relief but often have neuropsychiatric adverse effects, most prominently psychosis and delirium. Aged patients and those with dementia are particularly vulnerable to these adverse effects. Evaluating PD patients with drug-induced neuropsychiatric adverse effects is made difficult by their complex clinical presentations.The treatment of drug-induced psychosis and delirium begins with manipulating the antiparkinsonian drug regimen, but this frequently worsens motor function. Atypical antipsychotics such as clozapine have been successfully employed to treat the psychosis without worsening the motor disability. Patient intolerance of clozapine therapy has prompted open-label studies with newer agents such as risperidone, remoxipride, zotepine, mianserin and ondansetron.