Ultrastructural studies of biopsied cortical tissue from the right frontal lobe of 8 patients with mild to moderate Alzheimer's disease (AD) revealed that the number of synapses in lamina III of Brodmann's area 9 was significantly decreased when compared with the number in age-matched control brains (n = 9; postmortem time, less than 13 hours). Further decline in synaptic number was seen in age-matched autopsied AD specimens. In the AD brains there was significant enlargement of the mean apposition length, which correlated with degree of synapse loss; as synapse density declined, synapse size increased. The enlargement of synapses, coupled with the decrease in synaptic number, allowed the total synaptic contact area per unit volume to remain stable in the patients who underwent biopsy. In autopsied subjects who had AD, there was no further enlargement of mean synaptic contact area. There was a significant correlation between synapse counts and scores on the Mini-Mental State examination in the patients who underwent biopsy. Lower mental status scores were associated with greater loss of synapses. Choline acetyltransferase activity was significantly decreased in the biopsied group and declined further in the autopsied specimens of AD. There was no relationship between choline acetyltransferase activity and scores on the Mini-Mental State examination or synapse number. There is evidence of neural plasticity in the AD neuropil; synaptic contact size increased in patients who had biopsy and possibly compensated for the numerical loss of synapses. But by end stage of the disease, the ability of the cortex to compensate was exceeded and both synapse number and synaptic contact area declined.(ABSTRACT TRUNCATED AT 250 WORDS)

Synapse loss in frontal cortex biopsies in Alzheimer's disease: Correlation with cognitive severity

Objective. —To evaluate the efficacy and safety of high-dose tacrine hydrochloride over 30 weeks in patients with probable Alzheimer's disease. Design. —A 30-week randomized, double-blind, placebo-controlled, parallel-group trial. Setting. —Outpatients at 33 US centers. Patients. —Men and women at least 50 years of age with mild to moderate Alzheimer's disease and otherwise in good health. Interventions. —Group 1 received placebo; group 2 received 40 mg/d of tacrine for 6 weeks, then 80 mg/d for 24 weeks; groups 3 and 4 received 40 mg/d of tacrine for 6 weeks, 80 mg/d for 6 weeks, and 120 mg/d for 6 weeks. Group 3 remained on a dosage of 120 mg/d for a total of 18 weeks; after 6 weeks at 120 mg/d, group 4 titrated to 160 mg/d for the last 12 weeks. Primary Outcome Measures. —Clinician Interview-Based Impression (CIBI), Alzheimer's Disease Assessment Scale—Cognitive subscale (ADAS-Cog), and Final Comprehensive Consensus Assessment (FCCA). Results. —A total of 663 patients entered the study; 653 patients were included in an intent-to-treat (ITT) analysis; 263 had evaluable data at 30 weeks. The results of the ITT analysis revealed significant (P≤.05) dose-response trends and between-group comparisons on CIBI and ADAS-Cog. In evaluable patients, significant dose-response trends were observed for all three primary measures (P≤.001). Significant differences in favor of 160 mg/d of tacrine vs placebo were observed on the CIBI (P≤.002) and ADAS-Cog and FCCA (P≤.001), as well as caregiver-global and quality-of-life assessments (P≤.05). On the CIBI, 23% and 42% of tacrine-treated patients in the ITT and evaluable-patient populations, respectively, were rated improved compared with 17% and 18% of placebo patients, respectively. The primary reasons for withdrawal of tacrine-treated patients were asymptomatic liver transaminase elevations (28%) and gastrointestinal complaints (16%). These adverse events were reversible on discontinuation of treatment, and many patients were able to restart tacrine. Conclusions. —Tacrine produced statistically significant, dose-related improvements on objective performance-based tests, clinician- and caregiver-rated global evaluations, and measures of quality of life. There was no evidence that the large number of patient withdrawals biased the overall conclusions of the study. (JAMA. 1994;271:985-991)

https://jamanetwork.com/journals/JAMA/articlepdf/368751/jama_271_13_029.pdf

A 30-Week Randomized Controlled Trial of High-Dose Tacrine in Patients With Alzheimer's Disease

Cholinergic synapses are ubiquitous in the human central nervous system. Their high density in the thalamus, striatum, limbic system, and neocortex suggest that cholinergic transmission is likely to be critically important for memory, learning, attention and other higher brain functions. Several lines of research suggest additional roles for cholinergic systems in overall brain homeostasis and plasticity. As such, the brain's cholinergic system occupies a central role in ongoing research related to normal cognition and age-related cognitive decline, including dementias such as Alzheimer's disease. The cholinergic hypothesis of Alzheimer's disease centres on the progressive loss of limbic and neocortical cholinergic innervation. Neurofibrillary degeneration in the basal forebrain is believed to be the primary cause for the dysfunction and death of forebrain cholinergic neurons, giving rise to a widespread presynaptic cholinergic denervation. Cholinesterase inhibitors increase the availability of acetylcholine at synapses in the brain and are one of the few drug therapies that have been proven clinically useful in the treatment of Alzheimer's disease dementia, thus validating the cholinergic system as an important therapeutic target in the disease. This review includes an overview of the role of the cholinergic system in cognition and an updated understanding of how cholinergic deficits in Alzheimer's disease interact with other aspects of disease pathophysiology, including plaques composed of amyloid-β proteins. This review also documents the benefits of cholinergic therapies at various stages of Alzheimer's disease and during long-term follow-up as visualized in novel imaging studies. The weight of the evidence supports the continued value of cholinergic drugs as a standard, cornerstone pharmacological approach in Alzheimer's disease, particularly as we look ahead to future combination therapies that address symptoms as well as disease progression.

/pdf/the-cholinergic-system-in-the-pathophysiology-and-treatment-4yb18w7479.pdf

The cholinergic system in the pathophysiology and treatment of Alzheimer's disease.

On neurodegenerative diseases, models, and treatment strategies: lessons learned and lessons forgotten a generation following the cholinergic hypothesis.

OP/nerve agents are still considered as important chemicals acting on living organisms and are widely used. They are characterized according to their action as compounds influencing cholinergic nerve transmission via inhibition of AChE. Modeling of this action and extrapolation of experimental data from animals to humans is more possible for highly toxic agents than for the OP. The symptoms of intoxication comprise nicotinic, muscarinic, and central symptoms; for some OP/nerve agents, a delayed neurotoxicity is observed. Cholinesterases (AChE and BuChE) are characterized as the main enzymes involved in the toxic effect of these compounds, including molecular forms. The activity of both enzymes (and molecular forms) is influenced by inhibitors (reversible, irreversible, and allosteric) and other factors, such as pathological states. There are different methods for cholinesterase determination; however, the most frequent is the method based on the hydrolysis of thiocholine esters and subsequent detection of free SH-group of the released thiocholine. The diagnosis of OP/nerve agent poisoning is based on anamnesis, the clinical status of the intoxicated organism, and on cholinesterase determination in the blood. For nerve agent intoxication, AChE in the red blood cell is more diagnostically important than BuChE activity in the plasma. This enzyme is a good diagnostic marker for intoxication with OP pesticides. Some other biochemical examinations are recommended, especially arterial blood gas, blood pH, minerals, and some other specialized parameters usually not available in all clinical laboratories. These special examinations are important for prognosis of the intoxication, for effective treatment, and for retrospective analysis of the agent used for exposure. Some principles of prophylaxis against OP/nerve agent poisoning comprising the administration of reversible cholinesterase inhibitors such as pyridostigmine (alone or in combination with other drugs), scavengers such as preparations of cholinesterases, some therapeutic drugs, and possible combinations are given. Basic principles of the treatment of nerve agent OP poisoning are described. They are based on the administration of anticholinergics (mostly atropine but some other anticholinergics can be recommended) as a symptomatic treatment, cholinesterase reactivators as a causal treatment (different types but without a universal reactivator against all OP/nerve agents) as the first aid and medical treatment, and anticonvulsants, preferably diazepam though some other effective benzodiazepines are available. New drugs for the treatment are under experimental study based on new approaches to the mechanism of action. Future trends in the complex research of these compounds, which is important not only for the treatment of intoxication but also for the quantitative and qualitative increase of our knowledge of toxicology, neurochemistry, neuropharmacology, clinical biochemistry, and analytical chemistry in general, are characterized.

Organophosphates⧸Nerve Agent Poisoning: Mechanism of Action, Diagnosis, Prophylaxis, And Treatment

We treated 17 patients who had moderate to severe Alzheimer's disease with oral tetrahydroaminoacridine (THA), a centrally active anticholinesterase, in a three-phase study. In the nonblinded first phase of the study, significant improvement occurred in subjects who received the drug, as compared with their pretreatment status, on the global assessment (P = 0.001), the Orientation Test (P = 0.001), and the more sophisticated Names Learning Test (P = 0.001). During the second phase, the subjects served as their own controls in a double-blind, placebo-controlled, cross-over study in which the order of administration of the drug and placebo was randomly assigned. Among the 14 subjects completing Phase II, THA treatment produced significantly better results than placebo on the global assessment (P = 0.003), the Orientation Test (P = 0.004), the Alzheimer's Deficit Scale (P = 0.003), and the Names Learning Test (P = 0.001). Twelve subjects have entered Phase III, which involves long-term administration of oral THA. The average duration of treatment in these subjects at present is 12.6 months; symptomatic improvements have occurred, and no serious side effects attributable to THA have been observed. These encouraging initial results suggest that THA may be at least temporarily useful in the long-term palliative treatment of patients with Alzheimer's disease. We stress that further observations will be required before a clear assessment of the role of this agent can be made.

Oral tetrahydroaminoacridine in long-term treatment of senile dementia, Alzheimer type.

Oral Tetrahydroaminoacridine in the Treatment of Senile Dementia, Alzheimer's Type

Standards of assessment of treatment effect in Alzheimer's disease have been wanting. We report here a comparison of seven methods of assessment of the severity of Alzheimer's disease used in demented subjects (n = 18) and in nondemented controls (n = 18). The instruments tested were the Names Learning test, the Orientation test, the Mini-Mental State Examination, the Alzheimer's Staging Scale (the AZSS), the Global Deterioration Scale, the Clinical Dementia Rating Scale, and the Alzheimer's Deficit Scale (ADS). Two examiners did the testing per telephone methodology, and test/retest design. Results showed all tests to be reliable. A ceiling and/or basement effect was noted in all but the AZSS and the ADS.

Comparison of seven psychometric instruments used for evaluation of treatment effect in Alzheimer's dementia.

53 children diagnosed as having minimal brain dysfunction by the criteria of Clements had X-rays of their left wrist and hand for the determination of bone age. All X-rays were read independently by three physicians skilled in radiology. The films were read blind, that is, sex and case numbers but not age were available. The degree of inter-rater reliability was very high (r = 0.87). Bone age for the minimal brain dysfunction group was significantly retarded (p < 0.01) compared with the standard group's norms. Bone ages of more than 2 SD below the mean occurred in 10 children, while only one child showed a bone age of more than 2 SD above the mean. Two-thirds of the children in the minimal brain dysfunction group fell below the mean of the standard norms. No correlation was found between bone age and thyroid level. These findings suggest that children diagnosed as having minimal brain dysfunction may be physiologically retarded in their bone age, although marked individual variations remain. The concept o...

Bone age in children with minimal brain dysfunction

:Methylphenidate is a useful, proven method for the effective treatment of minimal brain dysfunction (MBD). Dosage should be titrated individually for each patient, and it is best to start with small doses given at least 15 to 30 minutes before meals. Toxicity, side effects, and drug abuse a

Lawrence V. Majovski

Papers

Oral tetrahydroaminoacridine in long-term treatment of senile dementia, Alzheimer type.

Oral Tetrahydroaminoacridine in the Treatment of Senile Dementia, Alzheimer's Type

Comparison of seven psychometric instruments used for evaluation of treatment effect in Alzheimer's dementia.

Bone age in children with minimal brain dysfunction

Methylphenidate: a review.