Brain structure and verbal function across adulthood while controlling for cerebrovascular risks.

The development and decline of brain structure and function throughout adulthood is a complex issue, with cognitive aging trajectories influenced by a host of factors including cerebrovascular risk. Neuroimaging studies of age-related cognitive decline typically reveal a linear decrease in gray matter (GM) volume/density in frontal regions across adulthood. However, white matter (WM) tracts mature later than GM, particularly in regions necessary for executive functions and memory. Therefore, it was predicted that a middle-aged group (MC: 35-45 years) would perform best on a verbal working memory task and reveal greater regional WM integrity, compared with both young (YC: 18-25 years) and elder groups (EC: 60+ years). Diffusion tensor imaging (DTI) and magnetoencephalography (MEG) were obtained from 80 healthy participants. Objective measures of cerebrovascular risk and cognition were also obtained. As predicted, MC revealed best verbal working memory accuracy overall indicating some maturation of brain function between YC and MC. However, contrary to the prediction fractional anisotropy values (FA), a measure of WM integrity, were not greater in MC (i.e., there were no significant differences in FA between YC and MC but both groups showed greater FA than EC). An overall multivariate model for MEG ROIs showed greater peak amplitudes for MC and YC, compared with EC. Subclinical cerebrovascular risk factors (systolic blood pressure and blood glucose) were negatively associated with FA in frontal callosal, limbic, and thalamic radiation regions which correlated with executive dysfunction and slower processing speed, suggesting their contribution to age-related cognitive decline. Hum Brain Mapp 38:3472-3490, 2017. © 2017 Wiley Periodicals, Inc.

Characterization of a normal control group: are they healthy?

We examined the health of a control group (18-81years) in our aging study, which is similar to control groups used in other neuroimaging studies. The current study was motivated by our previous results showing that one third of the elder control group had moderate to severe white matter hyperintensities and/or cortical volume loss which correlated with poor performance on memory tasks. Therefore, we predicted that cardiovascular risk factors (e.g., hypertension, high cholesterol) within the control group would account for significant variance on working memory task performance. Fifty-five participants completed 4 verbal and spatial working memory tasks, neuropsychological exams, diffusion tensor imaging (DTI), and blood tests to assess vascular risk. In addition to using a repeated measures ANOVA design, a cluster analysis was applied to the vascular risk measures as a data reduction step to characterize relationships between conjoint risk factors. The cluster groupings were used to predict working memory performance. The results show that higher levels of systolic blood pressure were associated with: 1) poor spatial working memory accuracy; and 2) lower fractional anisotropy (FA) values in multiple brain regions. In contrast, higher levels of total cholesterol corresponded with increased accuracy in verbal working memory. An association between lower FA values and higher cholesterol levels were identified in different brain regions from those associated with systolic blood pressure. The conjoint risk analysis revealed that Risk Cluster Group 3 (the group with the greatest number of risk factors) displayed: 1) the poorest performance on the spatial working memory tasks; 2) the longest reaction times across both spatial and verbal memory tasks; and 3) the lowest FA values across widespread brain regions. Our results confirm that a considerable range of vascular risk factors are present in a typical control group, even in younger individuals, which have robust effects on brain anatomy and function. These results present a new challenge to neuroimaging studies both for defining a cohort from which to characterize 'normative' brain circuitry and for establishing a control group to compare with other clinical populations.

Development and decline of memory functions in normal, pathological and healthy successful aging.

Many neuroimaging studies of age-related memory decline interpret resultant differences in brain activation patterns in the elderly as reflecting a type of compensatory response or regression to a simpler state of brain organization. Here we review a series of our own studies which lead us to an alternative interpretation, and highlights a couple of potential confounds in the aging literature that may act to increase the variability of results within age groups and across laboratories. From our perspective, level of cognitive functioning achieved by a group of elderly is largely determined by the health of individuals within this group. Individuals with a history of hypertension, for example, are likely to have multiple white matter insults which compromise cognitive functioning, independent of aging processes. The health of the elderly group has not been well-documented in most previous studies and elderly participants are rarely excluded, or placed into a separate group, due to health-related problems. In addition, recent results show that white matter tracts within the frontal and temporal lobes, regions critical for higher cognitive functions, continue to mature well into the 4th decade of life. This suggests that a young age group may not be the best control group for understanding aging effects on the brain since development is ongoing within this age range. Therefore, we have added a middle-age group to our studies in order to better understand normal development across the lifespan as well as effects of pathology on cognitive functioning in the aging brain.

Different strategies for auditory word recognition in healthy versus normal aging.

To explore the effects of commonly encountered pathology on auditory recognition strategies in elderly participants, magnetoencephalographic (MEG) brain activation patterns and performance were examined in 30 elderly [18 controls and 12 elderly with mild cognitive impairment (MCI) or probable Alzheimer's disease (AD)]. It was predicted that participants with known pathology would reveal different networks of brain activation, compared to healthy elderly, which should correlate with poorer performance. Participants heard a list of words representing common objects, twice. After 20 minutes a list of new and old words was presented and participants judged whether each word was heard earlier. MEG responses were analyzed using a semiautomated source modeling procedure. A cluster analysis using all subjects' MEG sources revealed three dominant patterns of activity which correlated with IQ and task performance. The highest performing group revealed activity in premotor, anterior temporal, and superior parietal lobes with little contribution from prefrontal cortex. Performance and brain activation patterns were also compared for individuals with or without abnormalities such as white matter hyperintensities and/or volume reduction evidenced on their MRIs. Memory performance and activation patterns for individuals with white matter hyperintensities resembled the group of MCI/AD patients. These results emphasize the following: (1) general pathology correlates with cognitive decline and (2) full characterization of the health of elderly participants is important in studies of normal aging since random samples from the elderly population are apt to include individuals with subclinical pathology that can affect cognitive performance.

Trends in antiepileptic drug prescribing for older patients with new-onset epilepsy: 2000-2004.

BACKGROUND: Newer antiepileptic drugs (AEDs) have been shown to be equally efficacious as older seizure medications but with fewer neurotoxic and systemic side effects in the elderly. A growing body of clinical recommendations based on systematic literature review and expert opinion advocate the use of the newer agents and avoidance of phenobarbital and phenytoin. This study sought to determine if changes in practice occurred between 2000 and 2004--a time during which evidence and recommendations became increasingly available. METHODS: National data from the Veterans Health Administration (VA; inpatient, outpatient, pharmacy) from 1998 to 2004 and Medicare data (1999-2004) were used to identify patients 66 years and older with new-onset epilepsy. Initial AED was the first AED received from the VA. AEDs were categorized into four groups: phenobarbital, phenytoin, standard (carbamazepine, valproate), and new (gabapentin, lamotrigine, levetiracetam, oxcarbazepine, topiramate). RESULTS: We found a small reduction in use of phenytoin (70.6% to 66.1%) and phenobarbital (3.2% to 1.9%). Use of new AEDs increased significantly from 12.9% to 19.8%, due primarily to use of lamotrigine, levetiracetam, and topiramate. CONCLUSIONS: Despite a growing list of clinical recommendations and guidelines, phenytoin was the most commonly used antiepileptic drug, and there was little change in its use for elderly patients over 5 years. Research further exploring physician and health care system factors associated with change (or lack thereof) will provide better insight into the impact of clinical recommendations on practice.

Controlled trial of N-acetylcysteine for patients with probable Alzheimer's disease.

The antioxidant N-acetylcysteine (NAC) or placebo was administered in a double-blind fashion to patients who met National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association criteria for probable AD. Testing for efficacy occurred after 3 and 6 months of treatment. Comparison of interval change favored NAC treatment on nearly every outcome measure, although significant differences were obtained only for a subset of cognitive tasks.

Sneddon's syndrome: a cause of cognitive decline in young adults.

OBJECTIVE: To review the clinical, psychometric, laboratory, and radiologic findings of 6 patients with Sneddon's syndrome (SS) who presented with cognitive dysfunction rather than stroke. DESIGN AND METHODS: Case series. All patients fulfilled were diagnosed as SS based on the co-occurrence of livedo racemosa and neurologic disease. Patients presenting with clinical stroke were excluded. RESULTS: Patients presented with cognitive complaints at an early age and all noted skin lesions from 6 months to 10 years before onset of cognitive symptoms. Associated systemic disorders included hypertension and seizures. Laboratory evidence of a hypercoagulable condition was identified in 4 of 6 cases. Brain MRI scans demonstrated atrophy, especially in parieto-occipital regions and cerebral blood flow on brain SPECT scan was reduced in a similar distribution. CONCLUSION: Patients with SS can develop dementia without antecedent clinical stroke. While the specific pathogenic mechanism of dementia in SS remains speculative, the disease predominantly injures brain tissue in vascular "watershed" territories.

Cognitive impairment in elderly who are not yet demented.

Patients with neuropathological changes of Alzheimer disease may not be demented during initial evaluation of memory disturbance. Understanding current issues regarding the patient with incipient degenerative dementia should help identify those at greatest risk for progression and may help delay onset of symptoms.

Apolipoprotein E epsilon4 association with dementia in a population-based study: The Framingham study.

Apolipoprotein E type 4 allele (apoE epsilon4) is associated with Alzheimer's disease (AD) in the late-onset familial form and in sporadic cases, but the age-associated risk in a randomly sampled elderly population is not established. We examined the association of apoE epsilon4 with AD and other dementias (mainly multi-infarct or dementia following stroke) in 1,030 persons aged 71 to 100 years in the population-based Framingham Study cohort. Kaplan-Meier survival analysis revealed that 55% of the apoE epsilon4/epsilon4 homozygotes developed AD by age 80, whereas 27% of apoE epsilon3/epsilon4 heterozygotes developed AD by age 85, and 9% of those without a 4 allele developed AD by age 85 years. In comparison with persons without a 4 allele, the risk ration for AD was 3.7 (95% CI = 1.9 to 7.5) for apoE epsilon3/epsilon4 heterozygotes and 30.1 (95% CI = 10.7 to 84.4) for apoE epsilon4 homozygotes. ApoE epsilon2 (2/2, 2/3, or 2/4 genotypes) was associated with an absence of AD. One-half (n=21) of the 43 AD patients were either homozygous or heterozygous for apoE epsilon4. We found evidence for an association of apoE epsilon4 with other dementia, primarily multi-infarct dementia and stroke. The risk ratio was 2.3 (95% CI = 0.9 to 6.1) for non-AD dementias among persons with apoE epsilon3/epsilon4. Although the apoE epsilon4 allele is a potent risk factor for AD and may be associated with other forms of dementia, most apoE epsilon4 carriers do not develop dementia, and about one-half of AD is not apoE epsilon4 associated. The low positive predictive value of this marker (0.10) suggest that use of apoE genotyping as a screening test for AD is not supported.

The 'preclinical phase' of probable Alzheimer's disease. A 13-year prospective study of the Framingham cohort.

OBJECTIVE: To evaluate the interval between the onset of detectable cognitive impairment and clinical diagnosis in individuals with probable Alzheimer's disease (AD), and to identify the pattern of the earliest changes in cognition in probable AD. DESIGN: Longitudinal follow-up of a community-based cohort sample. In 1976 through 1978, a screening neuropsychological examination was administered to Framingham Study participants. These subjects were then followed up prospectively for development of probable AD for up to 13 years. SETTING: This study was conducted at a community-based center for epidemiologic research. PARTICIPANTS: The surveillance sample consisted of 1045 participants in the Framingham Study aged 65 to 88 years who were free of dementia at the time of the neuropsychological screening examination. MAIN OUTCOME MEASURES: Scores on a group of neuropsychological tests were entered into a series of age- and education-adjusted multiple regression procedures, with the presence or absence of probable AD as the outcome variable. RESULTS: Considered individually, most of the screening neuropsychological measures were significantly related to later AD diagnosis. When stepwise regression procedures were employed, only measures of verbal memory and immediate auditory attention span remained significantly related to AD diagnosis. Of note, subjects later diagnosed with probable AD performed at higher levels than normal subjects on the Digit Span test at initial screening. Regression results were essentially unchanged even when the AD sample was restricted to those individuals for whom the screening examination preceded the clinical onset of dementia by 7 years or more. CONCLUSIONS: These findings support previous contentions that a "preclinical phase" of detectable cognitive deficits can precede the clinical diagnosis of probable AD by many years, and they also support the hypothesis that problems with secondary verbal memory are among the first signs of AD.

Are multiple cerebral infarcts synergistic?

OBJECTIVE: The goal of this study was to characterize the cumulative effects of multiple strokes on cognition. DESIGN: We conducted a prospective, longitudinal case study with neuropsychological, neurological, and radiological evaluations. SETTING: Research was conducted at the Boston (Mass) Veterans Administration Medical Center, Neurology Service, on successive inpatient hospital admissions. PATIENT: We followed up a 66-year-old right-handed man with multiple subcortical lacunae during a 3.5-year period during which he suffered two additional cortical infarctions. MAIN OUTCOME MEASURES: Each evaluation included approximately 3 hours of neuropsychological testing spanning a range of cognitive domains (attention, language, memory, visuospatial functions, response inhibition, and mental flexibility), full neurological examination, and computed tomographic scan. RESULTS: The patient's stepwise cognitive decline was characterized by unexpected exacerbation of "frontal" neurobehavioral features following the occurrence of two posterior cortical lesions. At initial evaluation, the computed tomographic scan showed bilateral subcortical lacunae in basal ganglia and periventricular white matter, and symptoms included dysarthria and perseveration. The second evaluation, following a left posterior parietal lesion, revealed a range of new frontal features, including impulsivity, pull-to-stimulus, and difficulty shifting set. Following a subsequent right occipital infarct, further frontal lobe impairments emerged: forced grasp reflex and incontinence. CONCLUSIONS: We hypothesize that the cumulative effects of infarcts were synergistic. That is, the posterior cortical infarcts elicited frontal features that would not be expected from a simple sum of these lesions' effects.

Incidence of dementia and probable Alzheimer's disease in a general population: the Framingham Study.

OBJECTIVE: To determine the incidence of dementia and Alzheimer's disease (AD) in a general population sample. BACKGROUND: Utilizing subjects in the Framingham Study cohort determined to be free of dementia in 1976 to 1978, or on biennial examination 17 in 1982, all new cases of dementia arising in this cohort over a maximum of 10 years of follow-up were ascertained. METHODS: On biennial examination 14/15, a screening neuropsychologic examination was administered to 2,117 subjects, and cases of probable prevalent dementia were identified. Beginning on examination 17 and on all successive biennial examinations, a Mini-Mental State Examination was administered. Subjects previously free of dementia and falling below age-education levels were evaluated by a neurologist and neuropsychologist to determine if dementia was present and to ascertain the dementia type using standard criteria. RESULTS: Five-year incidence of dementia increased with age, doubling in successive 5-year age groups. Dementia incidence rose from 7.0 per 1,000 at ages 65 to 69 to 118.0 per 1,000 at ages 85 to 89 for men and women combined. Incidence of probable AD also doubled with successive quinquennia from 3.5 at ages 65 to 69 to 72.8 per 1,000 at ages 85 to 89 years. Incidence of dementia and of probable AD did not level off with age and was not different in men and women. CONCLUSIONS: In a general population sample, we determined incidence of dementia and of probable AD and will use these incident cases for study of precursors and natural history in this elderly cohort, which has been under close surveillance for over 40 years.

Prevalence of dementia and probable senile dementia of the Alzheimer type in the Framingham Study.

We determined the prevalence of dementia and probable senile dementia of the Alzheimer type (SDAT) for biennial Exam 17 of the Framingham cohort (1982/1983). The prevalence of dementia was 30.5/1,000 for men and 48.2/1,000 for women and increased with advancing age. Cases of probable SDAT constituted 55.6% of all dementia cases. THe prevalence of SDAT was 11.7/1,000 for men and 30.1/1,000 for women and also increased with advancing age. Prevalence of dementia and probable SDAT were greater for women than men. The female:male ratio of prevalence for cohort members 75 years of age and older was 1.8 for all cases of dementia and 2.8 for cases of probable SDAT.

Cognitive changes in patients with multiple cerebral infarcts.

Consensus has not been achieved regarding the impact of multiple cerebral infarcts on neurobehavioral status. To evaluate cognitive function in patients with multiple cerebral infarcts, we administered a comprehensive neuropsychological test battery to 23 consecutive male patients with clinical and brain computed tomographic findings consistent with at least two separate areas of cerebral infarction. Based on brain computed tomographic findings, patients were classified as having either mixed (n = 12) or lacunar (n = 11) infarcts. Results of these two groups were compared with those of 11 age-, sex-, and education-matched controls with no clinical or brain computed tomographic evidence of cerebrovascular disease. The mixed group had significantly lower mean scores than the controls for every cognitive domain tested. The lacune group showed cognitive impairment on most neuropsychological measures but did not differ from the controls in the attention domain. Although some degree of cognitive impairment was detected by the neuropsychological test battery in virtually every patient, only seven of 23 (30%) had Mini-Mental State Examination scores indicating dementia (less than 24). We conclude that virtually every patient with multiple cerebral infarcts has some degree of cognitive impairment but that only a minority can be classified as demented if the Mini-Mental State Examination is used as the primary defining examination.

Frontal systems impairment following multiple lacunar infarcts.

To characterize cognitive impairments following multiple subcortical lacunar infarcts (lacunes), we prospectively compared the neuropsychological performance of 11 subjects with multiple lacunes with 11 medical control subjects matched for age and education who had no clinical or computed tomographic evidence of central nervous system disease. Subjects with multiple subcortical lacunes displayed neuropsychological signs of frontal system dysfunction, even though only 27% met the criteria for clinical diagnosis of dementia. They exhibited significant deficits in shifting mental set, response inhibition, and executive function. In addition, they were more often rated apathetic on a behavior-rating scale. We propose a continuum of cognitive impairments in lacunar states, ranging from frontal systems impairment to dementia.

Coffin-Siris syndrome. Neuropathologic findings.

We studied the neuropathologic features of a patient with Coffin-Siris syndrome. Two previously reported cases showed Dandy-Walker (D-W) malformations. In the present case there was no evidence of D-W malformation; instead there were hindbrain abnormalities of inferior and medial accessory olives, large arcuate nuclei, heterotopic olivary nuclei, and heterotopic nuclei in the white matter of the cerebellum. Although the hindbrain abnormalities in this case are different from those previously reported, they all have in common an intimate developmental relationship with the same embryological areas. This study suggests that the Coffin-Siris syndrome is a neurocutaneous disorder with hindbrain abnormalities in cerebellum and brain stem.