Comparison of sertraline and nortriptyline in the treatment of major depressive disorder in late life.

OBJECTIVE: This study was designed to evaluate the comparative efficacy and safety of sertraline and nortriptyline for the treatment of major depressive disorder in older adults. METHOD: A double-blind, parallel group design was used to compare 210 outpatients, 60 years of age and older, who met DSM-III-R criteria for major depressive episode and had a minimum Hamilton Depression Rating Scale score of 18. The patients were randomly assigned to 12 weeks of treatment with either sertraline (50-150 mg/day) or nortriptyline (25-100 mg/day). RESULTS: The safety profiles of the two treatments were similar except that nortriptyline treatment was associated with a significant increase in pulse rate, whereas sertraline was associated with a nonsignificant decrease. Efficacy of both drugs was similar for both treatments at all time points, with 71.6% (N=53 of 74) of the sertraline-treated patients and 61.4% (N=43 of 70) of the nortriptyline-treated patients achieving responder status by week 12. Time to response was also similar, with more than 75% of the improvement in scores on the Hamilton depression scale having occurred by week 6. Secondary efficacy measures (posttreatment measures of cognitive function, memory, and quality of life) revealed a significant advantage for sertraline treatment. CONCLUSIONS: Primary efficacy measures showed sertraline and nortriptyline to be similarly effective. With secondary outcome measures there was consistent evidence of an advantage for the sertraline-treated group. The clinical impact of these measures on the long-term well-being of elderly depressed patients should be examined in a study of maintenance treatment.

Production of paired helical filament, tau-like proteins by PC12 cells: a model of neurofibrillary degeneration.

Neuron-like cells derived from a rat pheochromocytoma cell line (PC12) and differentiated with nerve growth factor produce a paired helical filament (PHF)-like antigen when they are subjected to heat shock (Wallace et al.: Mol Brain Res 19:149-155, 1993). It accumulates in a localized region of the perinuclear cytoplasm and reacts with monoclonal antitau antibodies, which identify epitopes in the N- and C-terminal halves and the microtubule-binding domain of tau protein. The observed profile of immunoreactivity suggests the presence of full-length and C-terminally truncated tau in a region of perinuclear cytoplasm in which no structurally intact PHFs could be demonstrated by conventional transmission electron microscopy. The accumulated tau protein colocalized with antibodies raised against mitochondrial outer membrane proteins and was associated with the presence of numerous mitochondrial profiles that were demonstrated with electron microscopy. Because differentiated PC12 cells pretreated with colcemid or Taxol prior to heat shock fail to exhibit perinuclear PHF-like immunoreactivity, the reported response to heat shock appears to require an intact system of intracellular microtubules. This PC12 system provides a model in which the metabolic and molecular biological underpinnings of neuronal degeneration in Alzheimer's disease can be manipulated. The system may eventually be applicable to the development of pharmaceutical agents that interfere with formation and/or degeneration of PHF-tau in Alzheimer's disease.

Lipopigment Changes in Purkinje Cells in Alzheimer's Disease.

Cerebellar tissue was examined from 22 patients with Alzheimer's disease (AD) and from an age-matched group of 20 non-diseased subjects. Intraneuronal lipopigment in the bodies of 1344 Purkinje cells (PCs) (32 per brain) was identified by fluorescence microscopy. The mean total area (per PC) of the outlines of discrete regions of lipopigment in a PC perikaryon for the AD-related group of PCs was significantly greater than the mean for the comparison group (p<0.001). Also, the two groups of PCs showed significant (

Spouses of demented patients with low cobalamin levels: a new risk group for cobalamin deficiency.

Low serum cobalamin levels are common in conditions such as dementia and often represent mild deficiency. We surveyed serum cobalamin levels prospectively in spouses and blood relatives of demented patients to determine if any familial predisposition exists for the low levels. Cobalamin status in most of the relatives found to have low levels was assessed further by means of blood counts, metabolic tests, neurologic evaluation, absorption studies and response to cobalamin therapy. Serum cobalamin levels in 36 spouses correlated with those of the 36 demented patients related to them (r = 0.46, p = 0.004). A significant association was not seen in 34 blood relatives of 34 demented patients (r = 0.27). Most importantly, 67% of the spouses of demented patients with low serum cobalamin had low values themselves, compared with only 3% of the spouses of patients with normal levels (p = 0.001). Detailed study of 4 of the 5 spouses (and 3 blood relatives) with low cobalamin levels showed no anemia in any case. Nevertheless, 4 of the subjects had metabolic evidence of deficiency and one had electrophysiological abnormalities; all these defects improved with cobalamin therapy. These observations identify a hitherto unsuspected group of people at high risk for cobalamin deficiency and suggest that spouses of demented patients with low cobalamin levels should also have their cobalamin levels measured. The increased frequency of low serum cobalamin levels in spouses of demented patients with low levels represents in most cases a true, mild cobalamin deficiency that responds to treatment.

Absence of abnormal hyperphosphorylation of tau in intracellular tangles in Alzheimer's disease.

Adult human nerve cells contain tau protein, a phosphorylated microtubule-associated protein, that is hyperphosphorylated in the fetus and in patients with Alzheimer's disease. Hyperphosphorylation, which diminishes the microtubule-binding capacity of tau, destabilizes microtubules and may enhance the formation of paired helical filaments that constitute neurofibrillary tangles in Alzheimer's disease. Here, we use phosphorylation-dependent anti-tau antibodies to detect specific epitopes that characterize hyperphosphorylated tau. Our demonstration of intracellular tangles containing full-length tau that are not immunolabeled by these antibodies suggests that hyperphosphorylation of tau is not obligatory in the formation of neurofibrillary tangles in Alzheimer's disease.

The frequently low cobalamin levels in dementia usually signify treatable metabolic, neurologic and electrophysiologic abnormalities.

Cobalamin levels are frequently low in patients with dementia, but it is unclear if they represent definable deficiency and what the mechanisms are. Therefore, patients being evaluated for dementia who had low cobalamin levels but no obvious evidence of deficiency were studied hematologically, neurologically and with metabolic tests and were re-evaluated after cobalamin treatment. Abnormalities suggestive of or diagnostic for deficiency were documented in most of the 16 demented and nondemented patients. Metabolic results: 50% of patients tested had abnormal deoxyuridine suppression and 44% had increased serum methylmalonic acid and/or homocysteine levels; these test results correlated with each other. Neurologic results: 73% of patients had clinical abnormalities, primarily mild neuropathies, not attributable to other causes, 75% had electroencephalographic abnormalities, 77% had abnormal visual evoked potentials and 33% had abnormal somatosensory potentials. Metabolic and neurologic dysfunction were present together or absent together in all but 2 cases. Cobalamin therapy improved 50-100% of the various types of abnormalities, although it did not improve cognitive function in the 13 demented patients. Food-cobalamin malabsorption was found in 60% of the patients. Despite the absence of megaloblastic anemia and rarity of traditional malabsorption of free cobalamin, low cobalamin levels in demented patients frequently represent mild cobalamin deficiency and are often associated with food-cobalamin malabsorption. Perhaps most importantly, this is accompanied not only by metabolic changes but by evidence of mild neurologic dysfunction. Their frequent reversibility by cobalamin confirms that these defects indeed arise from cobalamin deficiency. Although the long-standing dementia does not improve, treating such patients with cobalamin has other concrete benefits.

Tau-like immunoreactivity in Alzheimer and control skin fibroblasts.

The presence of the microtubule-associated protein tau in skin fibroblasts derived from Alzheimer patients and normal controls was investigated using a panel of well-characterized anti-tau antibodies against epitopes spanning the tau protein from the amino to the carboxyl end. The antibodies immunolabeled a fine, fibrillar cytoplasmic network in all skin fibroblasts. Disruption of the microtubule network with colchicine did not affect the immunolabeling of the fibrillar network nor did treatment with cytochalasin B known to disrupt the microfilament network. Immunoelectron microscopy with the anti-tau antibodies revealed colocalization of the label with the 10 nm intermediate filaments. Furthermore, immunoblots found no reactivity against purified vimentin, suggesting that the antibodies recognize an intermediate filament-associated protein. The findings indicate the presence of tau or a protein with considerable homology to tau in fibroblasts associated with intermediate filaments and not microtubules.

Presence of axonal paired helical filament-tau in Alzheimer's disease: submicroscopic localization.

While normal adult tau protein is found typically in axons, paired helical filament (PHF) tau has been shown immunohistochemically to be in the somatodendritic compartment in Alzheimer's disease (AD). The small amount of PHF-tau (8-11%) found in white matter with immunochemical methods is shown here by immunoelectron microscopy to be located in axons. It is localized to straight filament variants of PHFs. The small amount of PHF-tau in white matter, therefore, appears not to result from the contamination of immunochemical preparations but to be an integral constituent of affected axons in AD.

Immunohistochemical staging of neurofibrillary degeneration in Alzheimer's disease.

Antibodies to different phosphorylated and non-phosphorylated tau epitopes have been used to identify three histologically distinct types of neurofibrillary tangles in Alzheimer's disease. Intracellular tangles (Type 1) were identified by antibodies recognizing epitopes throughout the tau molecule, including the NH2-terminus. Compact extracellular tangles (Type 2) were characterized by the loss of NH2-terminal immunoreactivity and retention of other tau epitopes. Dispersed extracellular tangles (Type 3) were characterized by the presence of epitopes associated with the microtubule binding region and the COOH-terminus. These three types of tangles, found in situ in hippocampus, could be created experimentally by proteolytic treatment of brain sections. These findings suggest that three stages of neurofibrillary degeneration can be understood as a sequential stripping of paired helical filaments in which the loss of amino-terminus epitopes, followed by loss of phosphorylated epitopes, results in the appearance of dispersed extracellular tangles containing PHF-core epitopes.

Evidence of subtypes of Alzheimer's disease and implications for etiology.

OBJECTIVE: Because age of onset does not reliably define two subtypes of Alzheimer's disease, classification based on the severity of neuronal degeneration was tested. DESIGN: Numbers of extracellular tangles and pyramidal neurons in the hippocampus were used to group patients. PATIENTS: The study population consisted of 46 elderly patients satisfying DSM-III criteria for dementia and NINCDS-ADRDA criteria for definite Alzheimer's disease after death. RESULTS: Univariate logistic regression analysis showed the numbers of neurofibrillary tangles and pyramidal neurons and the duration of dementia were significantly associated with grouping based on the presence of abundant extracellular tangles. Ninety-one percent of patients were correctly classified as compared with 85% correctly classified by age of onset data. Odds ratios showed that increasing numbers of neurofibrillary tangles predicted greater severity of neuronal loss. CONCLUSION: The results of the study indicate the importance of neurofibrillary degeneration, not the deposition of amyloid, in the pathogenesis of Alzheimer's disease. They support a classification of Alzheimer's disease related more closely to the severity of neurofibrillary degeneration than to age at onset.

Clinical, neuroimaging, and environmental risk differences in monozygotic female twins appearing discordant for dementia of the Alzheimer type.

OBJECTIVE: The study of monozygotic twins can elucidate possible environmental causes for a disease in genetically identical subjects. To this end, we studied a pair of monozygotic female twins appearing discordant for dementia of the Alzheimer type (DAT). DESIGN: Clinical and neuroimaging findings were compared in terms of potential environmental risk factors. SETTING: University referral center. PARTICIPANTS: An 81-year-old female monozygotic twin pair. OUTCOME MEASURES: Clinical assessments, standardized rating scales, and brain imaging studies, including magnetic resonance imaging, positron emission tomography, and electroencephalography, were performed. Neuropsychological tests were performed initially and after 1 year. RESULTS: Although DAT was confirmed clinically in only one twin, neuropsychological and brain imaging studies suggested that the unaffected twin may be developing the prodrome of DAT. The twins' varied life histories suggest that environmental risk factors may contribute to apparent discordance for DAT and possible delay in disease onset for the currently nondemented twin. CONCLUSIONS: These results suggest that both genetic and nongenetic factors influence disease onset and expression. Moreover, review of previous reports of monozygotic twin pairs concordant or discordant for Alzheimer's disease, with adequate family history data, suggest a pattern indicating interactions among age at dementia onset, sex, and familiarity. Such patterns point to hypotheses regarding neurobiologically meaningful Alzheimer's disease subgroups.

Sequestration of tau by granulovacuolar degeneration in Alzheimer's disease.

Antibodies directed against three regions of tau have been used in a histologic study of granulovacuolar degeneration (GVD) in Alzheimer's disease (AD). Granulovascular degeneration complexes, consisting of a dense granule in a less-dense vacuole, were found in hippocampal pyramidal neurons in all patients studied. Anti-tau antibodies directed against the N-and C-termini, and the repeat region of tau, were found to immunolabel the granule of the GVD complex. Intracellular neurofibrillary tangles also were labeled by these antibodies. In particular, MAb6.423, which recognizes tau protein sequestered in paired helical filaments (PHF) in AD, but not the normal tau proteins so far described in human brain, labeled GVD granules. Contrarily, a generic tau marker (MAb7.51), which immunolabels all known isoforms of isolated and expressed tau protein, including PHF-tau, did not label the GVD granule. These findings demonstrate that the entire tau molecule is sequestered within the GVD granule, and that the tau protein found in GVD complexes is antigenically related to that found in PHFs. There is, however, a difference in the way in which the repeat region of tau is incorporated into the two structures, making the MAb7.51 epitope unavailable in the GVD complex. These findings suggest that the formation of GVD complexes in hippocampal pyramidal neurons vulnerable to neurofibrillary degeneration may represent an alternative pathway for dealing with an aberrant molecular complex, which contributes to the formation of GVD granules and neurofibrillary tangles in AD.

Molecular analysis of neurofibrillary degeneration in Alzheimer's disease. An immunohistochemical study.

Antibodies directed against three regions of tau, ubiquitin, and B-amyloid were used in a histologic study of neurofibrillary degeneration in Alzheimer's disease to distinguish two populations of neurofibrillary tangles. Intracellular tangles were immunolabeled exclusively by two antibodies raised against antigens in the fuzzy coat of the paired helical filament (PHF). Extracellular tangles were distinguished by selective immunolabeling with a monoclonal antibody raised against antigens in the PHF core. This was associated with removal of the fuzzy coat and exposure of PHF-core epitopes. In the transition from intracellular to extracellular compartments in vivo, tangles appeared to undergo changes similar to protease digestion in vitro. The transition was associated with the appearance of amyloid immunoreactivity. These findings suggest that tangle degradation occurs in a series of distinct stages, including ubiquitination of some unknown molecule, a change in tau immunoreactivity, and partial proteolysis of tangle-bound tau in extracellular tangles.

Magnetic resonance imaging and the severity of dementia in older adults.

Periventricular white-matter lesions were visualized in the brains of elderly patients being assessed for possible Alzheimer's disease. The magnitude of these lesions, expressed as lesion-brain ratios, correlated closely with the severity of dementia indicated by scores on the Blessed Dementia Scale and the Folstein Mini-Mental State Examination. Impairment in several domains of cognitive functioning tested by the Mini-Mental State Examination was also correlated with the relative quantity of periventricular lesions. Correlations were significant with systolic blood pressure, approached significance with age, and were not significant with duration of dementia or the magnitude of the lateral ventricles. These findings indicate the potential utility of structure-function correlations that are possible with magnetic resonance imaging in identifying mechanisms underlying dementia. They suggest that magnetic resonance imaging may be more useful than computed tomography in following the course of dementia.

Neurofibrillary degeneration and neuronal loss in Alzheimer's disease.

Neuronal loss in Alzheimer's disease, especially in cerebral cortex and hippocampus, appears closely associated with the process of neurofibrillary degeneration. In certain noncortical nuclei neuronal loss appears not to depend upon the formation of neurofibrillary tangles. Neurofibrillary tangles and neurons were counted in the same populations of neurons in five brain regions. In the locus ceruleus and nucleus basalis, where tangles have a loose or globose structure, correlations with neuronal counts were not significant. In cerebral cortex and hippocampus, tangles have a more dense and often a flame-like appearance and their correlations with neuronal counts were significant. The relationships between tangles and noncortical neurons reported here suggest that the appearance of tangles does not necessarily herald the demise of a neuron in Alzheimer's disease. It can be reasonably anticipated that these relationships depend upon the clinical heterogeneity of Alzheimer's disease, regional differences in the brain and/or the macromolecular composition of neurofibrillary tangles.

Quantitative magnetic resonance imaging and the severity of dementia in Alzheimer's disease.

The T2 component of the magnetic resonance imaging (MRI) signal was measured in 11 brain loci in six elderly patients diagnosed as having probable Alzheimer's disease. T2 values and relative amount of periventricular high-intensity foci were significantly correlated with dementia severity, indicated by the Blessed-Roth Dementia Scale score. Although the mean T2 value for left hemispheric structures was more closely correlated with the dementia score, T2 values did not differ significantly in the right and left hemispheres or in gray and white matter. These findings suggest that more severe dementia in Alzheimer's disease is associated with more water in the brain.

Changes in the brain in aging and Alzheimer's disease assessed by neuronal counts.

Changes in the magnitude of neuronal loss, which represent the end point of neuronal degeneration, are controversial and of limited utility as a measure of functional decline in aging and Alzheimer's disease (AD). Changes in the size of neurons and organelles, in the distributions of dendritic and synaptic fields, and in the relationships between neurons and the transmitter substances they produce, may be more useful in that they estimate changes in neuronal function prior to neuronal loss. The quantitative assessment of metabolic change in individual neurons by measuring histochemical reactivity, or more directly measuring enzyme activity or the amounts of its products might more reliably reflect degenerative changes associated with aging or AD, prior to the loss of neurons.

Age and histopathologic heterogeneity in Alzheimer's disease. Evidence for subtypes.

In support of heterogeneity in Alzheimer's disease (AD), the existence of clinical and biologic subtypes has been claimed. We have investigated this claim by a statistical analysis of the relationships between the number of neurons in nucleus locus ceruleus (nLC), cortical levels of neurotransmitters, number of cortical plaques and tangles, and age. We separated AD patients into two groups: AD-1, with a less severe loss of nLC neurons; and AD-2, with a greater loss. The AD-2 cases were associated with less choline acetyltransferase activity, smaller concentrations of somatostatin and norepinephrine, and more plaques and tangles in the cerebral cortex. Although the mean age at death was less and the duration of dementia was greater in AD-2 patients than in AD-1 patients, the differences in these age-related variables were not significant. Further evidence of heterogeneity came from discriminant function analyses based on nLC neuronal counts and age at death. These findings, suggesting two subtypes of AD, suggest heterogeneity.

Neuronal degeneration in locus ceruleus and cortical correlates of Alzheimer disease.

Relationships were examined between neuronal degeneration in the nucleus locus ceruleus (nLC), a parameter of central noradrenergic impairment, and neocortical markers of Alzheimer disease (AD). The loss of nLC neurons was found to correlate significantly with norepinephrine concentration, choline acetyltransferase (ChAT) activity, and numbers of plaques and tangles on Brodmann area 24 (cingulate); ChAT and plaque counts in area 21 (temporal); and with ChAT activity in area 10 (frontal). In addition, nLC neuronal counts were correlated significantly with the severity and estimated duration of dementia. The number of neurofibrillary tangles in nLC, which did not correlate significantly with neocortical markers of AD, correlated with the estimated duration and severity of dementia. These data suggest that changes in central noradrenergic pathways are related to the pathophysiology of AD.