Effects of hormone replacement therapy on cognitive aging and dementia risk in postmenopausal women: a review of ongoing large-scale, long-term clinical trials.

The aim of this review is to discuss the purpose, design, and expected findings of several ongoing large-scale, long-term clinical trials studying the effects of hormone replacement therapy (HRT) on cognitive aging and risk of developing dementia. The Women's Health Initiative Study of Cognitive Aging (WHISCA) and the cognitive component of the Women's International Study of long Duration Oestrogen after Menopause--Cognition (WISDOM-COG) (to be completed in 2005 and 2006, respectively) will provide information about the effects of HRT on cognitive aging. The Preventing Postmenopausal Memory Loss and Alzheimer's with Replacement Estrogens study (PREPARE), the Women's Health Initiative Memory Study (WHIMS) and the dementia component of WISDOM-COG (to be completed in 2003, 2005 and 2009, respectively) will address the question of whether estrogens can delay or prevent dementia. These ongoing clinical trials will also be the first to study the effects of estrogen with and without progesterone, and the effects of HRT in women with natural versus surgical menopause, on cognitive aging and risk of dementia. Based on the existing literature, we discuss which specific cognitive areas are most likely to be affected by HRT. We also raise the issue that the type of estrogen agent may affect the outcome of these studies.

Long-term consequences of severe closed head injury on episodic memory.

This is the first systematic investigation of the very long-term effects of severe closed head injury (CHI) on objective measures of memory, and the first to employ both a normal control group and an 'other injury' control group consisting of spinal cord injury (SCI) patients. The CHI group displayed significantly poorer performance on every memory measure, and the effect sizes were large. This impairment in episodic memory is neither due to pre-injury nor post-injury differences between CHI and normal control subjects because the same differences were found when the CHI group was compared to a group of SCI patients. The findings demonstrate severe impairment in learning and retention many years after sustaining a severe CHI, which is likely in part due to the bilateral hippocampal damage shown in neuropathological studies. This life-long memory impairment needs to be addressed by community service programs.

A comparison of phonemic, semantic, and alternating word fluency in Parkinson's disease.

Word fluency in 45 medicated non-demented Parkinson's disease (PD) patients and 45 normal control subjects was studied with a Phonemic Word Fluency (PWF) task using the letters F, A, and S, a Semantic Word Fluency (SWF) task using the categories animals, boys' names, and states, and an Alternating Word Fluency (AWF) task requiring the person to alternate between colors and occupations, animals and states, and words beginning with C and P. The number of words generated did not differ for trials with F, A, S, or states, but PD patients generated significantly fewer animal names and boys' names. PD patients also generated significantly fewer words on each of the three AWF trials. The PD patients scored 21% lower than the normal control group on the total AWF score, but only 10% lower for the PWF and SWF scores. The greater impairment on the AWF task which requires the use of internal attentional control to rapidly shift mental set can be considered a type of executive functioning deficit. This is consistent with the growing literature suggesting frontal systems dysfunction in PD and with the view that dopaminergic treatment only incompletely restores functioning in the frontostriatal system.

The neuropsychology of aging.

There are three general categories of causes of the cognitive decline associated with aging: disuse, disease, and aging per se. People tend to use certain skills or abilities less with age and, thus, those skills decline due to the disuse. Physical illnesses tend to increase with age, which will tend to compromise cognitive functioning. Further, there are actual neurobiological changes with age that will contribute to deterioration of cognitive abilities. Variability of performance between different individuals within an age group increases with age due to each of these three major contributing factors to age decline. The best defense against age-related cognitive deterioration is practice. Practice tends to mitigate the effects of aging by not allowing disuse to occur. In addition, practice can overcompensate for age effects by building a larger reserve capacity to offset any real neurobiological effects of age. Practice can also lead to compensatory strategies in which alternative way of maintaining performance levels are found.

Neuropsychology of schizophrenia according to Kraepelin: disorders of volition and executive functioning.

Emil Kraepelin was the first to identify schizophrenia as a distinct disease in 1896. The purpose of this paper is to rediscover and reexamine the neuropsychology of schizophrenia according to Kraepelin. Kraepelin thought that the "dementia" of dementia praecox was primarily a disorder of volition, rather than one of intellect. "Volition" or "will" referred to the ability to make conscious decisions and to carry them out. By quoting relevant passages in his classic textbook, Dementia Praecox and Paraphrenia, the case is made that Kraepelin's detailed description of volitional deficits in patients with dementia praecox clearly documents impairments in executive functioning in schizophrenia patients during the preneuroleptic era. To a large extent, these deficits may be responsible for the "dementia" of dementia praecox and the "chronicity" of chronic schizophrenia. If this hypothesis is correct, the long-range prognosis of patients with schizophrenia may be considerably improved by treatment programs designed to facilitate executive functioning.

Alzheimer disease assessment scale: useful for both early detection and staging of dementia of the Alzheimer type.

The Alzheimer Disease Assessment Scale (ADAS) was administered to 61 patients with dementia of the Alzheimer type (DAT) and 52 elderly controls. The DAT group was subdivided into different severity levels of dementia based on scores from the Mini-Mental State Exam: very mild (greater than or equal to 24), mild (20 to 23), moderate (10 to 19), and severe (0 to 9). The mean scores on the ADAS Cognitive subscale for the four levels of dementia (very mild = 23.1 +/- 7.7, mild = 22.9 +/- 8.9, moderate = 38.6 +/- 9.8, severe = 54.8 +/- 7.6) were statistically different from one another (p less than 0.0001, except very mild vs. mild) and were significantly worse than the scores of the elderly control group (5.5 +/- 2.7, p less than 0.0001, ANOVA). Furthermore, the ADAS Cognitive subscale was highly effective in discriminating individual Alzheimer patients from elderly controls. The ADAS Cognitive score correctly classified 100% of the very mild group, 91% of the entire mild group, and 100% of the moderate and severe groups when a cutoff score of 2 SDs above the control group mean was used. Age and education had only minimal effects on the ADAS Cognitive score. The ADAS is a valuable screening test that only takes 30 min to administer and has utility in both early detection and staging of DAT.

Alzheimer Disease Assessment Scale: a subtest analysis.

The Alzheimer Disease Assessment Scale (ADAS) was administered to 61 Alzheimer patients, 52 elderly controls, and 80 controls between age 7 and 54 years. The Alzheimer group was categorized into different severity levels of dementia based on MMSE scores: very mild (> or = 24), mild (> or = 20), moderate (10-19), and severe (0-9). All 11 ADAS Cognitive subtest scores for the mild, moderate, and severe dementia groups were statistically worse than the elderly control group. This was also the case for the very mild group, except for Naming, Commands, Constructional Praxis, and Ideational Praxis. In terms of magnitude of effect, memory and spontaneous language items were the earliest indicators on the ADAS, while praxis, commands, and naming items were only sensitive later in the course of the disorder. The best single indicators of progression throughout the severity continuum of dementia (i.e., from normal to severe) were the Orientation subtest, the ADAS Cognitive score, and the ADAS Total score. The ADAS Noncognitive subtests generally did not show the progression with increasing dementia that was evident on the ADAS Cognitive subtest. Differences in educational level had no statistically significant effects on any of the ADAS subtest scores, and age differences were few and small in magnitude. The differential rate of decline of the various ADAS subtests appears to reflect both the changing pattern of cognitive impairments as a function of severity of DAT and also to some extent the psychometric limitations of some of the subtests.

Parallel distributed processing and neural networks: origins, methodology and cognitive functions.

Parallel Distributed Processing (PDP), a computational methodology with origins in Associationism, is used to provide empirical information regarding neurobiological systems. Recently, supercomputers have enabled neuroscientists to model brain behavior-relationships. An overview of supercomputer architecture demonstrates the advantages of parallel over serial processing. Histological data provide physical evidence of the parallel distributed nature of certain aspects of the human brain, as do corresponding computer simulations. Whereas sensory networks follow more sequential neural network pathways, in vivo brain imaging studies of attention and rudimentary language tasks appear to involve multiple cortical and subcortical areas. Controversy remains as to whether associative models or Artificial Intelligence symbolic models better reflect neural networks of cognitive functions; however, considerable interest has shifted towards associative models.

Electrocortical mapping, MRI, and neuropsychological measures: evidence of Alzheimer's disease in the presence of vascular lesions.

We report here a case study of a 76-year-old woman with a high school education, whose presenting psychiatric symptomatology indicated dementia of unknown etiology. Neuropsychological test results were consistent with AD, but diagnosis was complicated by an MRI showing a large right hemisphere cortical infarct and scattered subcortical changes leading to a diagnosis of possible AD. Electrocortical mapping showed the right hemisphere infarct, and gave independent evidence suggestive of AD in the relatively intact left hemisphere. This case demonstrates the utility of multidimensional assessment as an aid to differential diagnosis.

Neuropsychological "systems efficiency" and positron emission tomography.

Positron emission tomography (PET) has dramatically improved our ability to examine the functioning of the living brain. PET studies of neural pathways of the major sensory modalities--auditory, visual, somatosensory--have confirmed many traditional neuropsychological concepts, such as cross-lateral representation and regional functioning to particular primary sensory cortical areas. Other PET studies have used radioisotopes to examine relationships between radiopharmaceutical agents and neurobehavioral functioning in both normal and neuropathological states. In some areas, PET methodology requires further refinement. For example, effort should be made to develop the technology to do multiple scans within a short time frame; statistical procedures to examine relationships between neuropsychological tasks and the activity or presence of radiopharmaceutical agents in multiple sites; adequate controls for experimental error; and activation paradigms controlling the nonspecific effects of simple arousal. PET activation models of cognition suggest that a "systems efficiency" approach to assessing neuropsychological test performance involving both serial and parallel processing would be useful. These developments will improve empirical methodology and our understanding of brain-behavior relationships.

Prefrontal cortical blood flow and cognitive function in Huntington's disease.

To examine the relationship between cortical physiology and dementia in Huntington's disease, rCBF during three different behavioural conditions, one of which emphasised prefrontal cognition, was determined by xenon-133 inhalation in 14 patients with Huntington's disease and in matched controls. Cortical rCBF was not reduced in Huntington's disease patients even while they manifested overt prefrontal-type cognitive deficits. Caudate atrophy on CT and rCBF were significantly correlated, but only during the prefrontal behaviour where the correlation was positive. These results suggest a qualification of the subcortical dementia concept as applied to Huntington's disease and implicate an interaction between pathology that is subcortical and cognitive function that is cortical.

A relationship between anatomical and physiological brain pathology in schizophrenia: lateral cerebral ventricular size predicts cortical blood flow.

The authors studied the relationship between lateral cerebral ventricular size and regional cerebral blood flow during mental activation in 30 patients with schizophrenia. Patients with large ventricles had diffusely lower cortical gray matter blood flow than patients with small ventricles. In addition, an inverse correlation between ventricular size and prefrontal blood flow was observed while patients were attempting to solve a neuropsychological test specifically related to the prefrontal cortex. These data suggest that structural brain pathology impairs prefrontal physiology in schizophrenia, implicating a neural mechanism for the intellectual deficits characteristic of this disorder.

Relationship between CT scan findings and neuropsychological performance in chronic schizophrenia.

Studies relating CT abnormalities to impairments on neuropsychological tests in schizophrenic patients are critically reviewed. The overall conclusion is that there appears to be an association between CT abnormalities and neuropsychological deficits in at least some schizophrenic patient samples. It is proposed that there may be two classes of CT abnormalities in schizophrenia: "incidental" versus "essential" CT abnormalities and that neuropsychological impairment above the baseline levels found in most schizophrenic patients may be associated only with the former type. Only attempts to replicate these findings in different schizophrenic samples drawn from different settings can reveal whether this association between CT abnormalities and neuropsychological deficits is widely generalizable.

Physiologic dysfunction of dorsolateral prefrontal cortex in schizophrenia. II. Role of neuroleptic treatment, attention, and mental effort.

We conducted two xenon Xe 133 inhalation regional cerebral blood flow (rCBF) studies to clarify earlier findings of dorsolateral prefrontal cortex (DLPFC) dysfunction in medication-free patients with chronic schizophrenia. In the first study, 24 neuroleptic-treated patients and 25 normal controls underwent three rCBF procedures, first while at rest, then during the Wisconsin Card Sort (WCS), which tests DLPFC cognitive function, and during a number-matching task that controlled for aspects of the WCS-rCBF experience not specifically related to DLPFC. The results were qualitatively identical to those previously reported for medication-free patients. In the second study, rCBF was determined while 18 medication-free patients and 17 normal control subjects each performed two versions of a visual continuous performance task (CPT). No differences in DLPFC blood flow between the two groups were found during either CPT condition. These data suggest that DLPFC dysfunction in schizophrenia is independent of medication status and not determined simply by state factors such as attention, mental effort, or severity of psychotic symptoms. Dysfunction of DLPFC appears to be a cognitively linked physiologic deficit in this illness.

Physiologic dysfunction of dorsolateral prefrontal cortex in schizophrenia. I. Regional cerebral blood flow evidence.

To evaluate dorsolateral prefrontal cortex (DLPFC) physiology and function simultaneously, 20 medication-free patients with chronic schizophrenia and 25 normal controls underwent three separate xenon Xe 133 inhalation procedures for determination of regional cerebral blood flow (rCBF): first at rest, then while performing an automated version of the Wisconsin Card Sort (WCS), a DLPFC-specific cognitive test, and while performing a simple number-matching (NM) test. During rest, patients had significantly reduced relative, but not absolute, rCBF to DLPFC. During NM, no specific region differentiated patients from controls. During WCS, however, both absolute and relative rCBF to DLPFC significantly distinguished patients from controls. While controls showed a clear increase in DLPFC rCBF, patients did not. The changes were regionally specific, involving only DLPFC. Furthermore, in patients, DLPFC rCBF correlated positively with WCS cognitive performance, suggesting that the better DLPFC was able to function, the better patients could perform. Autonomic arousal measures, the pattern of WCS errors, and results of complementary studies suggest that the DLPFC finding is linked to regionally specific cognitive function and is not a nonspecific epiphenomenon.