Effortful and automatic cognitive processes in depression.

Ten patients with major depression and ten age- and sex-matched normal controls were presented with two contrasting cognitive tasks: one required sustained effort and information processing, and the other required only superficial information processing that could be accomplished automatically, with little effort. Depressed patients performed more poorly only on the effort-demanding cognitive task.

Plasma 3-methoxy-4-hydroxyphenylglycol (MHPG) and clinical symptoms in Alzheimer's disease.

Postmortem findings point to significant abnormalities in central noradrenergic function in Alzheimer's disease (AD) which may be associated with changes in peripheral markers. In this study, the relationship between the peripheral noradrenergic marker, plasma 3-methoxy-4-hydroxyphenylglycol (MHPG), and clinical symptoms was examined in 23 patients with probable AD. Basal MHPG levels correlated significantly with increased cognitive impairment (r = .58, p = .005), controlling for age, age at onset, gender, and time interval between plasma MHPG determination and cognitive testing. These results suggest that plasma MHPG increases as cognitive function in AD deteriorates, further supporting preliminary evidence for increases in noradrenergic indices in association with disease severity in AD.

Neuropeptide deficits in schizophrenia vs. Alzheimer's disease cerebral cortex.

Neuropeptide concentrations were determined in the postmortem cerebral cortex from 19 cognitive-impaired schizophrenics, 4 normal elderly subjects, 4 multi-infarct dementia (MID) cases, and 13 Alzheimer's disease (AD) patients. Only AD patients met criteria for AD. The normal elderly and MID cases were combined into one control group. Somatostatin concentrations were reduced in both schizophrenia and AD. Neuropeptide Y concentrations were reduced only in schizophrenia, and corticotropin-releasing hormone concentrations were primarily reduced in AD. Concentrations of vasoactive intestinal polypeptide and cholecystokinin also were reduced in schizophrenia, although not as profoundly as somatostatin or neuropeptide Y. In AD, cholecystokinin and vasoactive intestinal peptide were unchanged. Neuropeptide deficits in schizophrenics were more pronounced in the temporal and frontal lobes than in the occipital lobe. The mechanisms underlying these deficits in schizophrenia and AD are likely distinct. In schizophrenia, a common neural element, perhaps the cerebral cortical gaba-aminobutyric acid (GABA)-containing neuron, may underlie these deficits.

Severe cognitive impairment in elderly schizophrenic patients: a clinicopathological study.

The severe cognitive impairment that affects many of the elderly schizophrenic patients could represent the outcome of schizophrenia in old age for the very severe and chronically ill patients or may be the result of lengthy institutionalization and somatic treatment. Alternatively, it could be due to the presence of concurrent dementing disorders, such as Alzheimer's disease (AD) or multi-infarct dementia. Using an identical neuropathological protocol, brain specimens from schizophrenic patients who showed evidence of severe cognitive impairment were compared with 12 age-matched control cases and the same number of age-matched cases of neuropathologically confirmed patients with AD. Despite their relatively advanced age (mean age 77.1 years +/- 2.8), none of the schizophrenia cases showed sufficient degree of senile plaques and neurofibrillary tangle formations to confirm a diagnosis of AD. Other neurodegenerative disorders associated with dementia were also not identified. These studies suggest that alternative explanations need to be sought for the severe cognitive impairment commonly encountered in elderly schizophrenic patients.

Platelet phospholipid synthesis in Alzheimer's disease.

The rates of incorporation of [3H]choline and [3H]ethanolamine into membrane phospholipids of platelets from 22 drug-free Alzheimer's disease patients and 18 normal elderly controls were compared. No significant differences between groups were found. If alterations in lipid metabolism are involved in the pathophysiological processes underlying Alzheimer's disease, such alterations are not manifest in measures of radiolabeled base incorporation into platelet phospholipids.

Low cortisol and risk for PTSD in adult offspring of holocaust survivors.

OBJECTIVE: The study examined the association between cortisol and putative risk factors for posttraumatic stress disorder (PTSD) in a sample of subjects at increased risk for the development of PTSD. METHOD: Twenty-four-hour urinary cortisol excretion was measured in 35 adult offspring of Holocaust survivors and 15 healthy comparison subjects who were not offspring of Holocaust survivors. Subjects were also characterized with regard to clinical symptoms, presence or absence of psychiatric diagnoses including PTSD, and presence or absence of PTSD in their parents. RESULTS: Low cortisol levels were significantly associated with both PTSD in parents and lifetime PTSD in subjects, whereas having a current psychiatric diagnosis other than PTSD was relatively, but nonsignificantly, associated with higher cortisol levels. Offspring with both parental PTSD and lifetime PTSD had the lowest cortisol levels of all study groups. CONCLUSIONS: Parental PTSD, a putative risk factor for PTSD, appears to be associated with low cortisol levels in offspring, even in the absence of lifetime PTSD in the offspring. The findings suggest that low cortisol levels in PTSD may constitute a vulnerability marker related to parental PTSD as well as a state-related characteristic associated with acute or chronic PTSD symptoms.

Evidence for early vulnerability of the medial and inferior aspects of the temporal lobe in an 82-year-old patient with preclinical signs of dementia. Regional and laminar distribution of neurofibrillary tangles and senile plaques.

Detailed neuropathologic studies of neurofibrillary tangle and senile plaque distribution have shown that key elements of certain neocortical and hippocampal circuits are either compromised or lost in Alzheimer's disease. It has been suggested that a global corticocortical disconnection underlies dementia and leads to the dramatic disruption of integrated functions exhibited by patients with Alzheimer's disease. To investigate the distribution of lesions associated with the earliest indications of incipient dementia, we performed a quantitative neuropathologic evaluation of a non-demented 82-year-old patient demonstrating globally intact intellectual function but initial signs of impairment of specific cognitive functions before death. We observed densities of senile plaques comparable to those found in Alzheimer's disease throughout the cerebral cortex, whereas extensive neurofibrillary tangle formation was restricted to selective areas of the temporal lobe. The results of this systematic quantitative and comparative analysis of medial and inferior temporal lobe structures suggest a functional relationship between the degree of cognitive decline evidenced in the earliest stages of Alzheimer's disease and the anatomic progression of Alzheimer's disease-related pathologic changes along specific elements of the cortical circuitry.

Neocortical neurofibrillary tangles correlate with dementia severity in Alzheimer's disease.

OBJECTIVE: To determine the relationships between dementia severity and the extent of histopathologic lesions in a variety of brain regions. Neocortical and hippocampal ratings for neurofibrillary tangles (NFTs) and senile plaques (SPs) were compared in 70 cases of clinically and neuropathologically confirmed Alzheimer's disease. DESIGN: Neuropathologic case series. Dementia severity was assessed by postmortem chart review with use of the extended Clinical Dementia Rating Scale (CDR). Linear association between CDR scores and NFT and SP scores were assessed by partial correlation, controlling for age at death. SETTING: Studies were conducted at the Alzheimer's Disease Research Center of the Mount Sinai Medical Center, New York, NY. MAIN OUTCOME MEASURE: Association between CDR scores and neuropathologic changes assessed with the Consortium to Establish a Registry for Alzheimer's Disease semiquantitative scale. RESULTS: Among these lesion scores, only NFTs showed a significant association with CDR score, and only for neocortical regions. In particular, NFT densities in the superior temporal cortex were most strongly correlated with dementia severity, followed by those in the inferior parietal and midfrontal cortex. No such correlations were apparent for the amygdala, hippocampus, or entorhinal cortex. Medial temporal lobe structures displayed high NFT scores, even in cases of mild dementia. Senile plaques did not correlate significantly with CDR score in any region. CONCLUSIONS: These data support the notion that neocortical neuronal degeneration, as indicated by NFT formation, is a critical determinant of the clinical progression of Alzheimer's disease and suggest that medial temporal lobe structures may represent the initial site of NFT formation. While SP density correlates with age at death, there is no correlation between SP counts and dementia severity. These results further suggest that the clinical presentation of dementia may be closely related to neurodegeneration in neocortical regions within the temporal lobe.

Cortical cholinergic markers in schizophrenia.

Cortical cholinergic deficits have been implicated in the cognitive deficits produced by a variety of neurodegenerative diseases including Alzheimer's disease (AD). Recent studies have suggested that many of the chronically institutionalized geriatric schizophrenic patients are also cognitively impaired. In this postmortem study we compared cholinergic marker activity in six different cortical regions derived from elderly controls, chronically institutionalized geriatric schizophrenic patients, and AD patients. All of the Alzheimer's disease cases met neuropathological criteria for AD, while none of the schizophrenic cases met criteria for AD. Cholinergic marker activity (choline acetyltransferase and acetylcholinesterase) was significantly diminished in the AD cohort but not in the schizophrenic cohort. Additionally, cortical choline acetyltransferase activity was significantly and negatively correlated with Clinical Dementia Rating scores (CDR), whereas no such correlations were evident in the schizophrenic cohort. These results suggest that cognitive deficits in geriatric schizophrenics are not due to diminished cortical cholinergic activity.

Relationship of parental trauma exposure and PTSD to PTSD, depressive and anxiety disorders in offspring.

This study examined the relationship of parental trauma exposure and PTSD to the development of posttraumatic stress disorder (PTSD), depressive and anxiety disorders in the adult offspring of Holocaust survivors. One hundred and thirty-five subjects (55 men and 80 women) were divided into three groups according to parental trauma exposure and PTSD: 60 subjects were offspring of Holocaust survivors who endorsed having at least one parent with PTSD, 33 were offspring of Holocaust survivors who reported having no parent with PTSD, and 42 were demographically similar subjects with no parental Holocaust exposure. All subjects underwent a comprehensive psychiatric interview in which information about lifetime psychiatric diagnoses and exposure to traumatic events was obtained. Subjects also completed a checklist based on the 17 DSM-IV symptoms of PTSD, to estimate the symptom severity of PTSD in their parents. A presumptive diagnosis of parental PTSD was assigned according to DSM-IV criteria. Forward and forced entry stepwise logistic regression analyses were used to determine the effects of parental exposure, parental PTSD, and the subject's own history of trauma in the development of PTSD, depressive, and anxiety disorders in the offspring. The findings demonstrate a specific association between parental PTSD and the occurrence of PTSD in offspring. Additionally, parental trauma exposure, more than parental PTSD, was found to be significantly associated with lifetime depressive disorder. The identification of parental PTSD as a risk factor for PTSD in offspring of Holocaust survivors defines a sample in which the biological and psychological correlates of risk for PTSD can be further examined.

Widespread deficits in somatostatin but not neuropeptide Y concentrations in Alzheimer's disease cerebral cortex.

Somatostatin-like immunoreactivity (SLI) and neuropeptide Y-like immunoreactivity (NPYLI) were measured in the cerebral cortex of 49 patients with Alzheimer's disease (AD), and 9 elderly controls. Concentrations of SLI were lower in AD patients relative to controls in 9 of 10 cortical regions. In contrast, no significant differences in NPYLI concentrations between the two groups were observed in any of 10 regions. These studies suggest a dissociation between SLI deficits and NPYLI concentrations in the postmortem cerebral cortex of AD patients. The apparent sparing of NPYLI-containing neurons suggests that neuropeptide Y may be located within a separate group of neurons compared to somatostatin.

Deterioration on the Blessed test in Alzheimer's disease: longitudinal data and their implications for clinical trials and identification of subtypes.

One hundred eleven patients with probable Alzheimer's disease (AD) were given the Blessed test (BT) of information, memory, and concentration (scored 0-33) at 6-month intervals over periods of 6-96 months. For each patient, the change in the total BT score between pairs of visits at 6- and 12-month intervals was measured. Mean deterioration scores over 6 and 12 months were 2.2 (SD = 3.2) and 4.1 (SD = 4.1) points, respectively. There was no significant correlation between degree of dementia on the BT and the rate of deterioration. Gender, age of onset, and family history had no significant effect on the rate of deterioration. The implications of the results for treatment trials and investigations of clinical heterogeneity are discussed.

L-deprenyl and physostigmine for the treatment of Alzheimer's disease.

The present study evaluated the safety of and obtained preliminary data on the cognitive effects of L-deprenyl and physostigmine in patients with Alzheimer's Disease. Seventeen outpatients with Alzheimer's Disease participated in a double-blind crossover study in which they received 4 weeks of L-deprenyl at a dose of 10 mg p.o., q.d., and 4 weeks of placebo in random order. During both the L-deprenyl and placebo periods, patients received cognitive assessments during physostigmine (0.5 mg) and placebo infusions separated by 2 days. The cognitive effects of these agents alone and in combination were measured with digit span, verbal fluency, list learning, praxis, delayed recall, and delayed recognition tasks. Fifteen patients completed the study. The two drugs, used alone or in combination, were safe and well tolerated. Analyses of variance demonstrated that neither physostigmine nor L-deprenyl, whether given alone or in combination, significantly improved cognition, when compared with the double placebo condition.

Post-mortem examination of dopaminergic parameters in Alzheimer's disease: relationship to noncognitive symptoms.

Dopaminergic mechanisms have been implicated in depression, agitation, and psychosis--symptoms that are frequently observed in patients with Alzheimer's disease (AD). In a longitudinal study, 23 prospectively assessed AD patients underwent autopsies in which concentrations of dopamine, homovanillic acid, and dihydroxyphenylacetic acid were assayed in the temporal lobe (Brodmann areas 20 and 21). Data-reduction techniques were used to minimize the number of relationships tested. For this series of AD patients, no significant correlation was found between indices of dopaminergic neurotransmission and maximal severity of psychosis, depression, or agitation.

Combined administration of physostigmine and clonidine to patients with dementia of the Alzheimer type: a pilot safety study.

Reports of cholinergic and noradrenergic deficits in brain specimens from Alzheimer patients have suggested that concomitant augmentation of cholinergic and noradrenergic neurotransmission can benefit some dementia of the Alzheimer type (DAT) patients. However, pharmacological agents that enhance central cholinergic and noradrenergic neurotransmission, like physostigmine and clonidine, might have serious adverse effects. Therefore, prior to the commitment of major resources in efficacy studies, feasibility pilot studies are necessary to ensure that physostigmine and clonidine, combined, can be safely administered to DAT patients. Physostigmine, 2 mg every 2 h, and clonidine, up to 0.3 mg/day, were tolerated by the nine DAT patients without clinically meaningful adverse effects.

Selective accumulation of aluminum and iron in the neurofibrillary tangles of Alzheimer's disease: a laser microprobe (LAMMA) study.

We report the results of an examination of the elemental content of neurofibrillary tangle-bearing and neurofibrillary tangle-free neurons identified within the hippocampus of 10 subjects with Alzheimer's disease and 4 neuropathologically intact age-matched control subjects. The study employed laser microprobe mass analysis (LAMMA), a technique that provides extremely sensitive multielement detection in plastic-embedded, semithin-sectioned tissues. Evidence for the selective accumulation of aluminum within the neurofibrillary tangle-bearing neurons was obtained in all 10 subjects with Alzheimer's disease. The site of aluminum deposition within these cells was the neurofibrillary tangle itself, and not the "nuclear region," as we previously reported. Iron accumulation was also detected within neurofibrillary tangles. Evaluation for the accumulation of other elements within the tangle-bearing neurons failed to reveal any other metallic element as being consistently present. In addition, probe sites directed to neurons identified in snap-frozen cryostat sections from 2 subjects with Alzheimer's disease revealed similar spectra with prominent aluminum-related peaks, confirming that our findings are not related to exogenous contamination through fixation, embedding, or other procedures prior to analysis. This study further confirms the association of aluminum and neurofibrillary tangle formation in Alzheimer's disease.

A pilot study of clonidine plus physostigmine in Alzheimer's disease.

To assess the feasibility of one approach to combined cholinergic/noradrenergic treatment in Alzheimer's disease, ten patients were enrolled in a 2-week placebo-controlled study of oral physostigmine plus clonidine. The Alzheimer's Disease Assessment Scale (ADAS) was used as the primary outcome measure. Neither physostigmine alone, nor the combination of physostigmine plus clonidine, was associated with a statistically significant improvement for the group. Three patients did show an improvement of at least 4 points on the total ADAS score with the drug combination. The implications of these results for treatment strategies are discussed.