Alzheimer's disease

Symptomatic White Matter Changes in Mild Traumatic Brain Injury Resemble Pathologic Features of Early Alzheimer Dementia

Authors: Fakhran S, Yaeger K, Alhilali L.

Purpose:To evaluate white matter integrity in patients with mild traumatic brain injury (TBI) who did not have morphologic abnormalities at conventional magnetic resonance (MR) imaging with diffusion-tensor imaging to determine any relationship between patterns of white matter injury and severity of postconcussion symptoms.Materials and Methods:The institutional review board approved this study, with waiver of informed consent. Diffusion-tensor images from 64 consecutive patients with mild TBI obtained with conventional MR imaging were evaluated retrospectively. Fractional anisotropy (FA) maps were generated as a measure of white matter integrity. All patients underwent a neurocognitive evaluation. Correlations between skeletonized FA values in white matter, total concussion symptom score, and findings of sleep and wake disturbances were analyzed with regression analysis that used tract-based spatial statistics.Results:Total concussion symptom scores varied from 2 to 97 (mean ± standard deviation, 32.7 ± 24.4), with 34 patients demonstrating sleep and wake disturbances. Tract-based spatial statistics showed a significant correlation between high total concussion symptom score and reduced FA at the gray matter-white matter junction (P < .05), most prominently in the auditory cortex (P < .05). FA in the parahippocampal gyri was significantly decreased in patients with sleep and wake disturbances relative to patients without such disturbances (0.26 and 0.37, respectively; P < .05).Conclusion:The distribution of white matter abnormalities in patients with symptomatic mild TBI is strikingly similar to the distribution of pathologic abnormalities in patients with early Alzheimer dementia, a finding that may help direct research strategies.

Genetics of Alzheimer Disease

Authors: Rao AT, Degnan AJ, Levy LM.

SUMMARY:Alzheimer disease prevails as a major cause of disability in the elderly population and ranks as the most common form of dementia that affects 1 of 8 individuals older than 65 years of age. Most AD cases are late in onset and are probably influenced by both genetic and environmental factors. Apart from age, the risk factors include family history; brain injury, both traumatic and vascular; and metabolic diseases, such as diabetes, hypercholesterolemia, and obesity. Based on twin studies, inheritance plays a role in approximately 80% of cases (familial and sporadic).

Increased Cerebrospinal Fluid Production as a Possible Mechanism Underlying Caffeine's Protective Effect against Alzheimer's Disease

Authors: Wostyn P, Van Dam D, Audenaert K, De Deyn PP.

Alzheimer's disease (AD), the most common type of dementia among older people, is characterized by the accumulation of β-amyloid (Aβ) senile plaques and neurofibrillary tangles composed of hyperphosphorylated tau in the brain. Despite major advances in understanding the molecular etiology of the disease, progress in the clinical treatment of AD patients has been extremely limited. Therefore, new and more effective therapeutic approaches are needed. Accumulating evidence from human and animal studies suggests that the long-term consumption of caffeine, the most commonly used psychoactive drug in the world, may be protective against AD. The mechanisms underlying the suggested beneficial effect of caffeine against AD remain to be elucidated. In recent studies, several potential neuroprotective effects of caffeine have been proposed. Interestingly, a recent study in rats showed that the long-term consumption of caffeine increased cerebrospinal fluid (CSF) production, associated with the increased expression of Na(+)-K(+) ATPase and increased cerebral blood flow. Compromised function of the choroid plexus and defective CSF production and turnover, with diminished clearance of Aβ, may be one mechanism implicated in the pathogenesis of late-onset AD. If reduced CSF turnover is a risk factor for AD, then therapeutic strategies to improve CSF flow are reasonable. In this paper, we hypothesize that long-term caffeine consumption could exert protective effects against AD at least in part by facilitating CSF production, turnover, and clearance. Further, we propose a preclinical experimental design allowing evaluation of this hypothesis.

Genes involved in cerebrospinal fluid production as candidate genes for late-onset Alzheimer's disease: a hypothesis

Authors: Wostyn P, van Dam D, Audenaert K, de Deyn PP.

In rare patients with autosomal dominant, early-onset Alzheimer's disease (AD), pathogenic mutations in the genes encoding β-amyloid precursor protein, and the γ-secretase-complex components presenilin-1 and presenilin-2 appear to result in β-amyloid (Aβ) overproduction. The pathological accumulation of Aβ in the far more common late-onset AD is more likely to be the result of deficient clearance of Aβ. There is evidence that production and turnover of cerebrospinal fluid (CSF) help to clear toxic molecules such as Aβ from the interstitial fluid space of the brain to the bloodstream. CSF production and turnover have been shown to be decreased in aging and in pathological conditions, such as normal pressure hydrocephalus and AD. Reduced formation of CSF, with diminished clearance of Aβ, may play an important role in the onset and progression of AD. If reduced CSF turnover is a risk factor for AD, then its incidence ought to be increased under conditions of CSF circulatory failure. In this paper, the authors hypothesize that genes and variations of genes involved in the CSF production and absorption may contribute to the pathogenesis of late-onset AD.

Cerebral blood flow in Alzheimer's disease

Authors: Roher AE, Debbins JP, Malek-Ahmadi M, Chen K, Pipe JG, Maze S, Belden C, Maarouf CL, Thiyyagura P, Mo H, Hunter JM, Kokjohn TA, Walker DG, Kruchowsky JC, Belohlavek M, Sabbagh MN, Beach TG.

BACKGROUND: Alzheimer's disease (AD) dementia is a consequence of heterogeneous and complex interactions of age-related neurodegeneration and vascular-associated pathologies. Evidence has accumulated that there is increased atherosclerosis/arteriosclerosis of the intracranial arteries in AD and that this may be additive or synergistic with respect to the generation of hypoxia/ischemia and cognitive dysfunction. The effectiveness of pharmacologic therapies and lifestyle modification in reducing cardiovascular disease has prompted a reconsideration of the roles that cardiovascular disease and cerebrovascular function play in the pathogenesis of dementia.
METHODS: Using two-dimensional phase-contrast magnetic resonance imaging, we quantified cerebral blood flow within the internal carotid, basilar, and middle cerebral arteries in a group of individuals with mild to moderate AD (n = 8) and compared the results with those from a group of age-matched nondemented control (NDC) subjects (n = 9). Clinical and psychometric testing was performed on all individuals, as well as obtaining their magnetic resonance imaging-based hippocampal volumes.
RESULTS: Our experiments reveal that total cerebral blood flow was 20% lower in the AD group than in the NDC group, and that these values were directly correlated with pulse pressure and cognitive measures. The AD group had a significantly lower pulse pressure (mean AD 48, mean NDC 71; P = 0.0004). A significant group difference was also observed in their hippocampal volumes. Composite z-scores for clinical, psychometric, hippocampal volume, and hemodynamic data differed between the AD and NDC subjects, with values in the former being significantly lower (t = 12.00, df = 1, P = 0.001) than in the latter.
CONCLUSION: These results indicate an association between brain hypoperfusion and the dementia of AD. Cardiovascular disease combined with brain hypoperfusion may participate in the pathogenesis/pathophysiology of neurodegenerative diseases. Future longitudinal and larger-scale confirmatory investigations measuring multidomain parameters are warranted.

Association between Chronic Blood Pressure Changes and Development of Alzheimer's Disease

Authors: Feldstein CA.

Epidemiological studies suggest an association between chronic blood pressure (BP) changes and Alzheimer's disease (AD). In particular, there is growing evidence that hypertensive people that do not have their BP adequately treated and controlled in midlife are more likely to develop AD in late-life. It has been hypothesized that cerebrovascular disease is a common pathway which connects hypertension and AD in individuals with apolipoprotein E genotype through brain hypoperfusion and hypoxia. This could accelerate amyloid-β aggregation that disrupts cell-to-cell connectivity and leads to eventual brain neuron loss. Also, high BP contributes to worsen AD by raising oxidative stress and inflammatory response. Aging-related structural and functional disturbances appear to exacerbate the deleterious effect of chronic hypertension on cerebral blood flow autoregulation. There is evidence suggesting that some antihypertensive drug classes reduce the risk and progression of AD more than others. Further prospective randomized studies comparing different classes of antihypertensive drugs are needed to provide more evidence regarding their effects on AD risk. Hypotension could be a consequence of the incident dementia and conversely deteriorate the outcome of AD by worsening brain hypoperfusion. Frequent home BP monitoring should be carried out in AD patients to detect harmful orthostatic hypotension.

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