M. Bobinski

Prediction of cognitive decline in normal elderly subjects with 2-[18F]fluoro-2-deoxy-d-glucose/positron-emission tomography (FDG/PET)

Neuropathology studies show that patients with mild cognitive impairment (MCI) and Alzheimers disease typically have lesions of the entorhinal cortex (EC), hippocampus (Hip), and temporal neocortex. Related observations with in vivo imaging have enabled the prediction of dementia from MCI. Although individuals with normal cognition may have focal EC lesions, this anatomy has not been studied as a predictor of cognitive decline and brain change. The objective of this MRI-guided 2-[18F]fluoro-2-deoxy-d-glucose/positron-emission tomography (FDG/PET) study was to examine the hypothesis that among normal elderly subjects, EC METglu reductions predict decline and the involvement of the Hip and neocortex. In a 3-year longitudinal study of 48 healthy normal elderly, 12 individuals (mean age 72) demonstrated cognitive decline (11 to MCI and 1 to Alzheimers disease). Nondeclining controls were matched on apolipoprotein E genotype, age, education, and gender. At baseline, metabolic reductions in the EC accurately predicted the conversion from normal to MCI. Among those who declined, the baseline EC predicted longitudinal memory and temporal neocortex metabolic reductions. At follow-up, those who declined showed memory impairment and hypometabolism in temporal lobe neocortex and Hip. Among those subjects who declined, apolipoprotein E E4 carriers showed marked longitudinal temporal neocortex reductions. In summary, these data suggest that an EC stage of brain involvement can be detected in normal elderly that predicts future cognitive and brain metabolism reductions. Progressive E4-related hypometabolism may underlie the known increased susceptibility for dementia. Further study is required to estimate individual risks and to determine the physiologic basis for METglu changes detected while cognition is normal.

Frequency of hippocampal formation atrophy in normal aging and Alzheimer's disease

We used CT and MR to examine the frequency of occurrence of hippocampal formation atrophy (HA) in a research clinic population of 130 normal elderly, 72 nondemented patients with very mild memory and cognitive impairments (MCI), 73 mild Alzheimers disease (AD) patients, and 130 patients with moderate to severe AD. HA was found in 29% of the normal elderly group and its frequency of occurrence was strongly related to increasing age. For normal elderly 60-75 years of age, 15% had HA: the proportion rose to 48% in subjects 76-90 years of age. Among the three groups of impaired patients, the frequencies of HA ranged from 78% in the MCI patients to 96% in the advanced AD group. Unlike the normal elderly group, the percentages were not related to age. In both the normal elderly group and MCI group disproportionately more males than females had HA. After controlling for learning and the effects of generalized brain changes as reflected in ventricular size, only in the normal group was HA associated with reduced delayed verbal recall performance. Follow-up examinations for 15 individuals with baseline HA. 4 who at entry were MCI and 11 probable AD, yielded clinical and neuropathologic diagnoses of AD in all cases. The results of the present study indicate that hippocampal formation atrophy is associated with memory and cognitive impairments. Further longitudinal and neuropathologic work is required to validate the relationship between hippocampal formation atrophy and AD.

The histological validation of post mortem magnetic resonance imaging-determined hippocampal volume in Alzheimer's disease

For 11 AD cases and four normal elderly controls, post mortem volumes of the hippocampal subdivisions were calculated by using magnetic resonance imaging and histological sections. After at least six weeks of fixation in formalin, brains were examined on a 1.5-T Philips Gyroscan imager producing T1-weighted coronal images with a 3-mm slice thickness. Brains were then processed and embedded in paraffin. Serial coronal sections, 3 mm apart and stained with Cresyl Violet, were used for the planimetry and unbiased estimation of the total numbers of neurons in the hippocampal subdivisions. For all 15 cases, magnetic resonance imaging- and histology-based measurements were performed along the whole rostrocaudal extent of the hippocampal formation and included three subvolumes: (i) the hippocampus (CA1-CA4 and the dentate gyrus); (ii) hippocampus/subiculum; and (iii) hippocampus/parahippocampal gyrus. After controlling for shrinkage, strong correlations were found between magnetic resonance imaging and histological measurements for the hippocampus (r = 0.97, P < 0.001), hippocampus/subiculum (r = 0.95, P < 0.001) and hippocampus/parahippocampal gyrus (r = 0.89, P < 0.001). We also calculated the total number of neurons in the hippocampus and hippocampus/subiculum subvolumes. Strong correlations between the magnetic resonance imaging subvolumes and neuronal counts were found for the hippocampus (r = 0.90, P < 0.001) and the hippocampus/subiculum subvolume (r = 0.84, P < 0.001). We conclude that very accurate volumetric measurements of the whole hippocampal formation can be obtained by using a magnetic resonance imaging protocol. Moreover, the strong correlations between magnetic resonance imaging-based hippocampal volumes and neuronal numbers suggest the anatomical validity of magnetic resonance imaging volume measurements.

Relationships between regional neuronal loss and neurofibrillary changes in the hippocampal formation and duration and severity of Alzheimer disease

The total numbers of neurons with and without neurofibrillary changes in the hippocampal subdivisions were estimated in 16 subjects with Alzheimer disease (AD) and in 5 normal elderly controls. On the basis of clinical symptoms, AD patients were subdivided into relatively less (AD-1, Functional Assessment Staging [FAST] stages 7a to 7c) and more severely affected (AD-2, FAST stages 7e to 7f) patient groups. In the AD-1 group relative to controls, the total number of neurons was reduced only in CA1 and in the subiculum. In the AD-2 group, neuronal losses were found in all sectors of the cornu Ammonis and in the subiculum and ranged from 53% in CA3 to 86% in CA1. The dentate gyrus was the only hippocampal subdivision without significant neuronal loss. Within the combined AD patient groups, significant correlations were noted between both clinical stage and duration of AD and both the total number of neurons and the percentage of neurons with neurofibrillary changes in CA1, CA4, and the subiculum. Regression analyses predicted neuronal losses over the maximal observed duration of 22 years of 87% in CA1, 63% in CA4, and 77% in the subiculum. Our data suggest that over the course of AD, continuous neurofibrillary tangle formation and continuous neuronal loss occur in the hippocampal subdivisions. The rate of neuronal loss appears to be similar for CA1, CA4, and the subiculum.

Neurofibrillary pathology — correlation with hippocampal formation atrophy in Alzheimer disease

The three-dimensionally reconstructed hippocampal formations in three patients with very severe, immobile Alzheimer disease (AD) and three age-matched nondemented individuals were examined for a correlation between atrophy of hippocampal formation subdivisions and neurofibrillary changes, neuronal loss, and extent of amyloid deposition in plaques and vessels. In AD, a similar severe volume loss was observed in both cellular layers and layers composed of fibers. A strong correlation between the decrease in the volume of hippocampal formation subdivisions and the decrease in the total number of neurons suggests a causative role for neuronal loss in hippocampal formation volumetric loss. Strong regional correlations between the relative decreases in the total number of neurons and the relative increases in the total number of neurofibrillary tangles implicates neurofibrillary pathology as a possible etiologic proximate factor in neuronal and volumetric loss in the hippocampal formation of AD patients.

HIPPOCAMPAL ATROPHY IN EARLY ALZHEIMER'S DISEASE: ANATOMIC SPECIFICITY AND VALIDATION

We evaluated three groups of elderly individuals who were carefully screened to rule out clinically significant diseases that could affect cognition. They were matched for age and education. The groups included normals (N=18), Alzheimers Disease (AD) patients (N=15), and minimally impaired individuals with memory complaints and impairments but who did not fulfill criteria for AD (N=17). Volumetric measurements of different regions of the temporal lobe on the coronal scan as well as ratings of the perihippocampal cerebrospinal fluid (CSF) accumulation (HCSF) on the negative angle axial MR were carried out. Volume reductions were found in AD relative to the normals for both medial and lateral temporal lobe volumes. Only hippocampal volume reductions were found in the minimal group. The minimally impaired individuals had equivalent hippocampal volume reductions and significantly larger parahippocampal and lateral temporal lobe gyri than the AD group. The axial HCSF was validated using the coronal volumes. The combination of coronal hippocampal and perihippocampal CSF was the best predictor of the axial HCSF rating. The parahippocampal volume did not add to the predictive ability of the hippocampal-perihippocampal CSF combination. Future work should validate these findings with longitudinal designs as well as assess the issue of normal aging of these structures and their relationship to cognitive function.

Neuronal and volume loss in CA1 of the hippocampal formation uniquely predicts duration and severity of Alzheimer disease

In a series of multiple regression models predicting either duration or severity of Alzheimer disease (AD) patients, significant linear correlations were found consistently for the volume of CA1, the subiculum, and the entorhinal cortex. Similarly, the total number of neurons in CA1, CA4, and the subiculum was correlated significantly with both the duration and the severity of AD. A hierarchical multiple regression model was used to examine whether any of these intercorrelated measures had any unique relationship to disease duration or severity. The results showed that only CA1 demonstrated a unique contribution to the explained variance in predicting duration or severity of AD for volume and for neuronal numbers. These results indicate that in the hippocampal formation, volume and neuronal numbers of CA1 appear to show a unique relationship with clinical measures of AD.

Atrophy of Hippocampal Formation Subdivisions Correlates with Stage and Duration of Alzheimer Disease

The hippocampal formations of 13 subjects with severe Alzheimer disease [AD; Global Deterioration Scale (GDS) stage 7] and of 5 age-matched subjects without symptoms of dementia were reconstructed from serial sections. Functional assessment staging (FAST) was used at the time of demise to assess 9 patients at stages 7a-c (incipient averbal and nonambulatory) and 4 patients at stages 7e-f (immobile). The duration of the disease from FAST stage 5 until demise ranged from 2 to 8 years in the first of these subgroups, and from 10 to 13 years in the second. The volumes of the entire hippocampal formation and of the cornu ammonis, its sectors and layers, the dentate gyrus, the subicular complex, and the entorhinal cortex were calculated. Hippocampal formation volume decreased by 36% in the incipient averbal and nonambulatory patients and by 60% in the severely functionally impaired immobile patients, in comparison with controls. In the final substages of AD, immobile patients exhibited significant atrophy, in comparison with controls, in the cornu ammonis and all of its sectors and layers except CA4, the subicular complex and all of its parts, and the entorhinal cortex (p < 0.05). Within the AD patient group, significant correlations were noted between both the magnitude of functional severity and the duration of AD and the volumes of most hippocampal formation subdivisions studied. For the cornu ammonis, subicular complex, and entorhinal cortex, volumetric loss correlations with FAST stage 7 ordinally enumerated substages were r = -0.71, -0.79, and -0.62, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Duration of neurofibrillary changes in the hippocampal pyramidal neurons

The total number of neurons with and without neurofibrillary changes in sectors CA1 to CA4, subiculum, and dentate gyrus of 16 subjects with Alzheimer disease (AD) was estimated. The duration of neurofibrillary changes was calculated on the basis of regressions between the duration of AD and neuronal numbers. In the CA1 and subiculum, it takes 3.4 and 5.4 years, respectively, for an intact neuron affected by neurofibrillary pathology to become a ghost tangle.

FREQUENCY OF STAGES OF ALZHEIMER-RELATED LESIONS IN DIFFERENT AGE CATEGORIES

A consensus regarding the precise nature and causes of neuropathology accompanying Alzheimer’s disease (AD) has yet to emerge (5). Nevertheless, there is broad agreement that accumulation of b-amyloid containing plaques and neurofibrillary changes both are involved in pathogenesis of AD and dementia. Braak and Braak (2) have described the characteristics of amyloid deposits and neurofibrillary changes in a series of 2661 unselected brains. This large sample, with its broad range in age at death (25–95 years of age), provides a truly unique opportunity to evaluate the possible relationships among age, amyloid-deposition, and neurofibrillary changes. Individual cases were classified based on their age at death and the development of b-amyloid and neurofibrillary pathology by employing the staging developed previously by Braak and Braak (1). Briefly, b-amyloid pathology, when present, can be subcategorized into three ordinal levels (stages A–C), and neurofibrillary changes can be subcategorized into six ordinal levels (stages I–VI), with progression defined largely on the basis of topographic expansion in lesion distributions. [In their data presentation, the six stages of neurofibrillary changes were collapsed into three (I and II, III and IV, and V and VI)]. It should also be noted that Braak and Braak (1,2) are using a somewhat idiosyncratic nomenclature for describing b-amyloid plaques, and, therefore, it is difficult to interpret their findings with respect to the more generally accepted descriptions of: 1) diffuse, with minimal or no fibrillization, that are thioflavin-S negative or benign, 2) neuritic, with clearly fibrillized substructures that are thioflavin-S positive or malignant, 3) primitive, referring to neuritic plaques lacking a central core or star of amyloid, and 4) classical, referring to neuritic plaques with a central core or star of amyloid (7). In fact, in working with sections of 70 to 100 m, as described by Braak and Braak (2), we have found this type of subclassification of b-amyloid plaques to be extremely difficult and sometimes impossible. As the disector technique is fast becoming the procedural standard, this possible limitation should be recognized. In addition, the importance of categorizing classical and primitive plaques with respect to their PHF immunoreactivity (PHF1 or PHF2) has been demonstrated (7), and this cannot be done using the staining procedures described (2). To stage their cases, Braak and Braak (2) examined only two blocks of tissue, including anteromedial portions of the temporal lobe at the mid-uncal level and portions of the occipital lobe. However, their figures obviously refer to their earlier procedures that included sampling of many additional areas (1). Therefore, although there is some empirical support for making generalizations beyond the two regions sampled, this can introduce some inaccuracy in individual classifications. Staging according to Braak and Braak (1,2) is not based on quantitative criteria, and the schematics of lesion distributions are therefore somewhat oversimplified. In our experience, neurofibrillary and b-amyloid pathology can often be broadly distributed within brains, although at low densities, even during neurofibrillary stages I and II and b-amyloid stage A. Further, we have observed evidence for quantitative progression of neurofibrillary pathology in advanced cases of AD clearly meeting criteria for stages V and VI. Therefore, it seems likely that the staging system, as described, omits details of case descriptions that may be meaningfully related to clinical progression. Results indicated that neurofibrillary changes localized within transentorhinal and entorhinal cortex (stages I and II) could be found at surprisingly young ages when amyloid deposits were absent (2), suggesting that in the progression of AD, neurofibrillary changes anticipate b-amyloid pathology. However, when these data were examined employing a slightly different strategy, a more complicated picture seemed to emerge. The age distributions of cases in the various Braak and Braak stages were recalculated from their Tables 2 and 3, assuming that every case at a later stage would have also been classified as positive at all earlier stages. The proportion of cases meeting or exceeding stage criteria were then plotted against age to generate the curves illustrated in Figure 1. Several features of these curves are of interest. First, as indicated in Figure 1a, neurofibrillary changes characteristic of stages I–II are indeed observed quite early in lifespan development and well before b-amyloid pathology is a factor. Progression to stages III–IV seems to require a great deal of time, several decades in fact, and further progression to stages V–VI occurs in roughly half that time, or over the course of approximately 15 years. The increase in prevalence of stages III–IV with age have an acceptable correspondence to the age-associated increase in risk for dementia of the Alzheimer type (3), suggesting that there are clear functional