Faculty Bibliography

With advancing age, the periventricular and subcortical white matter becomes susceptible to a heterogeneous assortment of tissue alterations that cannot be easily categorized in terms of traditionally defined neuropathologic disease. These alterations, which appear radiolucent on CT and hyperintense on T2-weighted MR imaging, are more common in patients with chronic hypertension and perhaps other microvascular arteriosclerotic risk factors. Examination of the affected tissue reveals a spectrum of histologic change that is graded with respect to pathologic severity. The majority of the alterations are of low histopathologic grade and exert minimal clinical effects. Frequently observed microscopic changes include dilated perivascular (Virchow-Robin) spaces, mild demyelination, gliosis, and diffuse regions neuropil vacuolation. Associated clinical abnormalities, when present, are usually confined to deficits of attention, mental processing speed, and psychomotor control. These deficits may often be demonstrable only through neuropsychologic testing. There is some evidence that the cognitive symptoms of AD may be exacerbated by the concomitant presence of these white matter alterations, but an etiologic link between AD and radiographically detectible white matter changes remains speculative. Occasionally, histologically severe white matter lesions may occur that result in dementia and focal neurologic impairment. These lesions are characterized by extensive arteriosclerosis, diffuse white matter necrosis, and lacunar infarction; affected patients may receive a diagnosis of Binswanger's disease or subcortical arteriosclerotic encephalopathy. Nevertheless, severe ischemic white matter pathology of this type is uncommon as an explanation for serious neurologic dysfunction, and clinicians must carefully weigh other categories of neuropathology before making a diagnosis of Binswanger's disease. Alternative diagnostic considerations include neurodegenerative illnesses such as AD, cerebral infarction, neoplasm, and other forms of white matter pathology such as those due to infection, inflammation, a primary demyelinative condition, or metabolic leukodystrophy

Measurements of hippocampal formation atrophy using MRI have been useful in distinguishing demented patients with a diagnosis of probable Alzheimer's disease from cognitively normal controls. To determine whether there is a similar relationship between hippocampal size and dementia in elderly patients suspected of normal pressure hydrocephalus (NPH), the authors obtained mini-mental status examination (MMSE) scores and MRI measurements of hippocampal size and CSF volume on 16 elderly patients whose severe ventriculomegaly and unexplained gait impairment made NPH a probable diagnosis. Hippocampal size correlated strongly with MMSE score (r = 0.75, p < 0.001); no significant MMSE correlation was found for ventricular CSF volume or extra-ventricular/ventricular CSF ratio. It was concluded that hippocampal atrophy is associated with severe cognitive dysfunction in many elderly patients with a diagnosis of NPH. As a hypothesis for further investigation, the detection of such atrophy may help identify cases where the presence of a pathology of Alzheimer's disease complicates the diagnosis of NPH

Although mild progressive memory impairment is commonly associated with normal human aging, it is unclear whether this phenomenon can be explained by specific structural brain changes. In a research sample of 54 medically healthy and cognitively normal elderly persons (ages 55-87, x = 69.0 +/- 7.9), magnetic resonance imaging (MRI) was used to derive head-size-adjusted measurements of the hippocampal formation (HF) (dentate gyrus, hippocampus proper, alveus, fimbria, subiculum), the superior temporal gyrus (STG), and the subarachnoid cerebrospinal fluid (CSF) (to estimate generalized cerebral atrophy). Subjects were administered tests of primary memory (digit span) and tests of secondary memory with immediate and delayed recall components (paragraph, paired associate, list recall; facial recognition). Separate composite scores for the immediate and delayed components were created by combining, with equal weighting, the subtests of each category. The WAIS vocabulary subtest was used as a control measure for language and intelligence. A highly significant correlation (P < 0.001), independent of age, gender, and generalized cerebral atrophy was found between HF size and delayed memory performance. No significant correlations were found between HF size and primary or immediate memory performance. STG size was not significantly correlated with any of the composite memory variables. These results suggest that HF atrophy may play an important independent role in contributing to the memory loss experienced by many aging adults

OBJECTIVE--To estimate the prevalence of radiographically detectable hippocampal atrophy (HA) in a normal aging sample and to test whether such atrophy is associated with memory dysfunction. DESIGN--One hundred fifty-four medically healthy and cognitively normal elderly persons (aged 55 to 88 years) received magnetic resonance imaging and/or computed tomographic scans designed to identify HA. One hundred forty-five of these subjects also underwent psychometric tests of memory function. Multivariate analyses of variance were used to evaluate differences in memory performance between subjects with and without HA. SETTING--This study was conducted at a research clinic for the investigation of age-associated neuropsychological and neuroradiologic changes. PARTICIPANTS--Based on the following criteria, 154 subjects were consecutively selected from a larger group of elderly research volunteers participating in a study of normal aging: age of 55 years or greater; Global Deterioration Scale score of 2 or less; and Mini-Mental State examination score of 28 or greater. Subjects with evidence for significant medical, psychiatric, or neurologic disease were excluded. MAIN OUTCOME MEASURES--Outcome measurements included individual psychometric test scores and computed tomographic-magnetic resonance imaging hippocampal atrophy ratings. RESULTS--Nearly 33% of the subjects had radiographic evidence for HA. The prevalence of HA increased significantly with age and was more common in male than female subjects. After controlling for age, level of education, and vocabulary, subjects with HA were found to perform more poorly on tests of recent (secondary) verbal memory when compared with subjects without HA (P < .01). No significant differences were found for tests of immediate (primary) memory. CONCLUSION--We conclude that HA is a common accompaniment of normal aging and is associated with mild memory impairment. Additional research is needed to determine whether HA constitutes a significant risk for future dementia

Phenomenologic, cross-sectional and longitudinal studies have resulted in the identification of characteristic stages of normal aging and progressive Alzheimer's disease (AD). A staging system resulting from these studies is known as the ''GDS Staging System.'' Three optimally concordant and potentially independent clinical rating instruments are incorporated in this staging system, the Global Deterioration Scale (GDS), the Brief Cognitive Rating Scale (BCRS) and the Functional Assessment Staging measure (FAST). Definitions of each of the elements of this staging system as well as reliability and concurrent validity data have been published. Clear advantages of the GDS Staging System over other available staging measures include: (1) readily interpretable and clinically meaningful stages and substages; (2) improved definition of the boundaries of normal aging and incipient AD, and (3) the ability to chart the course of the severely impaired, conventionally ''untestable,'' portion of AD. Widespread usage of this staging system can potentially advance current research and clinical understanding of normal brain aging and the nature, course and treatment of AD and related conditions