Abnormal thiamine-dependent processes in Alzheimer's Disease. Lessons from diabetes.

Reduced glucose metabolism is an invariant feature of Alzheimer's Disease (AD) and an outstanding biomarker of disease progression. Glucose metabolism may be an attractive therapeutic target, whether the decline initiates AD pathophysiology or is a critical component of a cascade. The cause of cerebral regional glucose hypometabolism remains unclear. Thiamine-dependent processes are critical in glucose metabolism and are diminished in brains of AD patients at autopsy. Further, the reductions in thiamine-dependent processes are highly correlated to the decline in clinical dementia rating scales. In animal models, thiamine deficiency exacerbates plaque formation, promotes phosphorylation of tau and impairs memory. In contrast, treatment of mouse models of AD with the thiamine derivative benfotiamine diminishes plaques, decreases phosphorylation of tau and reverses memory deficits. Diabetes predisposes to AD, which suggests they may share some common mechanisms. Benfotiamine diminishes peripheral neuropathy in diabetic humans and animals. In diabetes, benfotiamine induces key thiamine-dependent enzymes of the pentose shunt to reduce accumulation of toxic metabolites including advanced glycation end products (AGE). Related mechanisms may lead to reversal of plaque formation by benfotiamine in animals. If so, the use of benfotiamine could provide a safe intervention to reverse biological and clinical processes of AD progression. This article is part of a Special Issue entitled 'Mitochondrial function and dysfunction in neurodegeneration'.

Development of the biases toward children with psychological and behavioral disorders scale.

Although there have been studies of individual professional disciplines and their attitudes toward children with emotional, behavioral, or educational problems, there has been no systematic determination using a single, psychometrically sound measure that compared different professional groups. The goal was to assess the biases toward children with emotional and behavioral difficulties in samples of professionals who are most likely to have contact with them (86 teachers, 83 psychologists, 47 social workers), as well as other adults (75 undergraduate students). After development from an item pool, the provisional Biases toward Children with Psychological and Behavioral Disorders scale consisted of 21 items in one factor which experts also had assigned to a Biases category. The scale had good internal consistency reliability (alpha = .84). Validity was supported by a team of experts, factor structure, and known-groups comparisons. Psychologists and social workers scored lower than did teachers and students.

New considerations on the neuromodulatory role of thiamine.

BACKGROUND: A nonmetabolic role for thiamine in cholinergic neurotransmission has long been suggested. The mechanism remains unclear. We sought to extend our previous research to elucidate the effect of the thiamine metabolic antagonist, oxythiamine, on the release of acetylcholine from the brain. METHODS: The potassium-stimulated release of acetylcholine from superfused rat brain slices was determined. Hand-cut slices of cerebral cortex were preincubated with tritiated choline to label acetylcholine stores. Two periods of stimulation (S1, S2) with 50 mmol/l solution for 3.5 min were performed as superfusate was collected. During S1, only 50 mmol/l potassium-containing Krebs-bicarbonate buffer with 2 mmol/l calcium was used. Using a two-by-two design, S2 consisted of exposure to 50 mmol/l potassium with or without 10(-4) mol/l oxythiamine, with or without calcium. The S2/S1 ratio was calculated. RESULTS: Oxythiamine enhanced the potassium-evoked release of acetylcholine by 60% but only when calcium was present in the superfusing medium. CONCLUSION: These data confirm earlier findings with oxythiamine on the calcium-mediated synaptic transmission of acetylcholine and support a possible neuromodulatory role for thiamine distinct from its actions as a cofactor during metabolic processes.

Virtual reality exposure therapy and hypnosis for flying phobia in a treatment-resistant patient: a case report.

Flying phobia is a problem that affects a significant portion of the population. There are a number of therapeutic approaches but no one is universally accepted as the gold standard. One therapy is hypnosis. A recent addition to the armamentarium is virtual reality exposure (VRE) therapy. Both therapies are short-term and compare favorably to in vivo desensitization. Heretofore a combination of both approaches has not been reported. This article presents a case of a 50-year phobia to flying that was refractory to traditional methods including pharmacotherapy, systematic desensitization, and cognitive behavioral therapy but was successfully treated using VRE therapy and hypnosis as the primary modalities. This treatment was supplemented by other approaches. The rationale for this multimodal therapy and possible mechanisms involved are discussed.

Expanded Exploration of the Auditory Naming Test in Patients with Dementia.

BACKGROUND: Auditory naming tests are superior to visual confrontation naming tests in revealing word-finding difficulties in many neuropathological conditions. OBJECTIVE: To delineate characteristics of auditory naming most likely to reveal anomia in patients with dementia, and possibly improve diagnostic utility, we evaluated a large sample of patients referred with memory impairment complaints. METHODS: Patients with dementia (N = 733) or other cognitive impairments and normal individuals (N = 69) were evaluated for frequency of impairment on variables of the Auditory Naming Test (ANT) of Hamberger & Seidel versus the Boston Naming Test (BNT). RESULTS: Naming impairment occurred more frequently using the ANT total score (φ= 0.41) or ANT tip-of-the tongue score (TOT; φ= 0.19) but not ANT mean response time compared to the BNT in patients with dementia (p < 0.001). Significantly more patients were impaired on ANT variables than on the BNT in Alzheimer's disease (AD), vascular dementia (VaD), mixed AD/VaD, and multiple domain mild cognitive impairment (mMCI) but not in other dementias or amnestic MCI (aMCI). This differential performance of patients on auditory versus visual naming tasks was most pronounced in older, well-educated, male patients with the least cognitive impairment. Impaired verbal comprehension was not contributory. Inclusion of an ANT index score increased sensitivity in the dementia sample (92%). Poor specificity (41%) may be secondary to the inherent limitation of using the BNT as a control variable. CONCLUSION: The ANT index score adds diagnostic utility to the assessment of naming difficulties in patients with suspected dementia.

Benfotiamine and Cognitive Decline in Alzheimer's Disease: Results of a Randomized Placebo-Controlled Phase IIa Clinical Trial.

BACKGROUND: In preclinical models, benfotiamine efficiently ameliorates the clinical and biological pathologies that define Alzheimer's disease (AD) including impaired cognition, amyloid-ß plaques, neurofibrillary tangles, diminished glucose metabolism, oxidative stress, increased advanced glycation end products (AGE), and inflammation. OBJECTIVE: To collect preliminary data on feasibility, safety, and efficacy in individuals with amnestic mild cognitive impairment (aMCI) or mild dementia due to AD in a placebo-controlled trial of benfotiamine. METHODS: A twelve-month treatment with benfotiamine tested whether clinical decline would be delayed in the benfotiamine group compared to the placebo group. The primary clinical outcome was the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog). Secondary outcomes were the clinical dementia rating (CDR) score and fluorodeoxyglucose (FDG) uptake, measured with brain positron emission tomography (PET). Blood AGE were examined as an exploratory outcome. RESULTS: Participants were treated with benfotiamine (34) or placebo (36). Benfotiamine treatment was safe. The increase in ADAS-Cog was 43% lower in the benfotiamine group than in the placebo group, indicating less cognitive decline, and this effect was nearly statistically significant (p = 0.125). Worsening in CDR was 77% lower (p = 0.034) in the benfotiamine group compared to the placebo group, and this effect was stronger in the APOEɛ4 non-carriers. Benfotiamine significantly reduced increases in AGE (p = 0.044), and this effect was stronger in the APOEɛ4 non-carriers. Exploratory analysis derivation of an FDG PET pattern score showed a treatment effect at one year (p = 0.002). CONCLUSION: Oral benfotiamine is safe and potentially efficacious in improving cognitive outcomes among persons with MCI and mild AD.

Integrating Hypnosis with Other Therapies for Treating Specific Phobias: A Case Series.

There is a high prevalence of anxiety disorders including specific phobias and panic disorder in the United States and Europe. A variety of therapeutic modalities including pharmacotherapy, cognitive behavioral therapy, systematic desensitization, hypnosis, in vivo exposure, and virtual reality exposure therapy have been applied. No one modality has been entirely successful. There has been only a limited attempt to combine psychological therapies in the treatment of specific phobias and panic disorder and what has been done has been primarily with systematic desensitization or cognitive behavioral therapy along with hypnotherapy. I present two cases of multiple specific phobias that were successfully treated with hypnotherapy combined with virtual reality exposure therapy or in vivo exposure therapy. The rationale for this integrative therapy and the neurobiological constructs are considered.

Vitamin B1 (thiamine) and dementia.

The earliest and perhaps best example of an interaction between nutrition and dementia is related to thiamine (vitamin B1). Throughout the last century, research showed that thiamine deficiency is associated with neurological problems, including cognitive deficits and encephalopathy. Multiple similarities exist between classical thiamine deficiency and Alzheimer's disease (AD) in that both are associated with cognitive deficits and reductions in brain glucose metabolism. Thiamine-dependent enzymes are critical components of glucose metabolism that are reduced in the brains of AD patients and by thiamine decline, and a decrease in their levels could account for the reduction in glucose metabolism. In preclinical models, reduced thiamine can drive AD-like abnormalities, including memory deficits, neuritic plaques, and hyperphosphorylation of tau. Furthermore, excess thiamine diminishes AD-like pathologies. In addition to dietary deficits, drugs or other manipulations that interfere with thiamine absorption can cause thiamine deficiency. Elucidating the reasons why the brains of AD patients are functionally thiamine deficient and determining the effects of thiamine restoration may provide critical information to help treat patients with AD.