Leukoaraiosis and disability: The LADIS (leukoaraiosis and disability) study experience

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Abstracts / Journal of the Neurological Sciences 283 (2009) 240–320

Methods: Using cDNA microarray (containing mouse embryonically expressed 11,283 cDNAs), we measured mRNA changes in cerebral cortex tissues of Tg2576 mice and age-matched wild-type mice at three stages of disease progression: long before (2 months of age), immediately before (5 months) and after (18 months) the appearance of Abeta plaques. Further, verified gene expression data using Northern blot and in situ hybridation analyses. In addition, using real-time PCR analysis, we also investigated mitochondrial genes (that were abnormally expressed in AD transgenic mice) in postmortem brains of AD patients and control subjects. Results: Our global gene expression analysis revealed that the genes related to mitochondrial energy metabolism and apoptosis were upregulated in 2-month-old Tg2576 mice and that the same genes were upregulated at 5 and 18 months of age. These microarray results were confirmed using Northern blot analysis. Results from in situ hybridization of mitochondrial genes—ATPase-6, heat-shock protein 86 and programmed cell death gene 8—suggest that the granule cells of the hippocampal dentate gyrus and the pyramidal neurons in the hippocampus and the cerebral cortex are up-regulated in Tg2576 mice compared with WT mice. Results from double-labeling in situ hybridization suggest that in Tg2576 mice only selective, over-expressed neurons with the mitochondrial gene ATPase-6 undergo oxidative damage. Our real-time PCR data from AD patients revealed an abnormal mitochondrial gene expression, suggesting that mitochondrial dysfunction is an early event in both familial and sporadic AD. Conclusions: Our cDNA gene expression, Northern blot and in situ hybridization results, suggest that mitochondrial energy metabolism is impaired by the expression of mutant APP and/or Abeta, and that the upregulation of mitochondrial genes is a compensatory response in AD mice. These findings have important implications for understanding the mechanism of Abeta toxicity and mitochondrial dysfunction in AD and for developing early mitochondrial therapeutics for AD. Supported by NIH, and American Federation For Aging Research. doi:10.1016/j.jns.2009.02.125

Preventative effect of mitochondrial antioxidants in apoe deficiency mouse model of brain hypoperfusion

endothelium and neurons were seen. ALCAR+LA treatment significantly improved cognitive performance and eliminated brain pathology in ApoE4 mice. Conclusions: Our data showed for the first time that ApoE deficiency appears to be a major factor in the age-dependent CBF reduction and brain cellular damage that is characteristic of AD pathology, which can be diminished by treating with selective mitochondrial antioxidants and/or their derivatives. Supported by NIH and Alzheimer's Association. doi:10.1016/j.jns.2009.02.126

Systemic metabolic abnormalities in Alzheimer's disease

R.H. Swerdlow, I. Onyango, H.S. Anderson, W.M. Brooks, J.M. Burns University of Kansas School of Medicine, Kansas City, KS, USA Although Alzheimer's disease (AD) is considered a prototypical brain disease, extra-cerebral metabolic manifestations occur. On a clinical level, it is possible to demonstrate peripheral tissue insulin resistance. On a basic biochemical level, activity of the mitochondrial enzyme cytochrome oxidase is reduced in AD subject platelets and fibroblasts. Using mitochondria from AD subject platelets, we have generated neuronal-based cytoplasmic hybrid (cybrid) cell lines that facilitate studies of AD subject-derived mitochondria. Relative to cybrid cell lines populated with mitochondria from control subjects platelets, AD cybrid cell lines show reduced cytochrome oxidase Vmax activity, increased peroxide levels in the setting of increased antioxidant enzyme activities, altered calcium homeostasis, Akt pathway activation, reduced mitochondrial membrane potentials, and increased levels of beta amyloid protein. In addition to our cybrid work, we have now probed potential consequences of altered mitochondrial function in fibroblasts derived from AD subjects. Complementing work by other laboratories showing metabolic impairments in AD fibroblasts, we find metabolism-relevant intracellular signaling pathways are altered in AD fibroblasts. Extra-cerebral metabolic abnormalities in AD may prove relevant to the enhancement of angiopathy and leukoariosis that is associated with this disease. doi:10.1016/j.jns.2009.02.127

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G. Aliev , J.C. Shenk , J. Liu , M. Puchowicz , K. Xu , M.A. Smith , S.L. Siedlak , M.E. Obrenovichd, B.N. Amesb, J.C. de la Torred, J. Koistinahoe, J.C. LaMannac, G. Perrya a Department of Biology, College of Sciences and Microscopy Research Center, University of Texas At San Antonio, San Antonio, TX, USA b Children's Hospital Oakland Research Institute, Oakland, CA, USA c Department of Anatomy, Case Western Reserve University, Cleveland, OH, USA d Department of Pathology, Case Western Reserve University, Cleveland, OH, USA e A.I. Virtanen Institute For Molecular Sciences, University of Kuopio, Kuopio, Finland Background and aims: The apolipoprotein E gene knockout (ApoE4) mouse is an excellent animal model for studying Alzheimer's disease pathology. ApoE-deficient (ApoED) and wild-type (WT) mice were tested for aging effects, including cerebral blood flow (CBF) as an indicator of vascular hypoperfusion, mitochondrial function and ultrastructural integrity, and cognitive tests, and for comparative amelioration from being fed acetyl-lcarnitine and R-alpha-lipoid acid (ALCAR+LA). Methods: CBF was measured using [14C] iodoantipyrene autoradiography in conjunction with a mathematical algorithm and an assumed arterial concentration profile derived from arterial concentration measurements; electron microscopy was employed to assess changes in neuronal, glial and microvascular ultrastructure and immunochemistry; and cognitive performance was determined using Morris Water Maze and Peak Procedure Test, with and without drug treatment (ALCAR, 0.2% (wt./vol.) in drinking water and LA, 0.1% (wt./wt.) in diet). Results: Compared to the WT mice, cortical blood flow (mean ± SD, ml/g/min) was lowered significantly (p < 0.05) in the ApoE-deficient mice in both the 6-month-(0.68± 0.21 vs. 0.98±0.23) and 12-month-(1.06± 0.09 vs. 1.54 ±0.12) old aged groups. In addition, 6-week-old ApoE-deficient mice had a lower cortical blood flow (0.63 ± 0.15) in comparison to WT mice (0.82 ± 0.15); however, differences did not reach statistical significance. Microvessels from ApoED mice showed vascular endothelial damage; significant overproliferation and deletion of the mitochondrial DNA and oxidative stress markers in

Leukoaraiosis and disability: The LADIS (leukoaraiosis and disability) study experience L. Pantonia, A. Poggesia, G. Pracuccia, A.M. Basilea, H. Chabriatb, T. Erkinjunttic, F. Fazekasd, J.M. Ferroe, M. Hennericif, P. Langhorneg, J.T. O'Brienh, F. Barkhofi, M.C. Visseri, L.O. Wahlundj, G. Waldemark, A. Wallinl, M. Simonia, D. Inzitaria a Department of Neurological and Psychiatric Sciences, University of Florence, Italy b Department of Neurology, Hopital Lariboisiere, Paris, France c Memory Research Unit, Department of Clinical Neurosciences, Helsinki University, Helsinki, Finland d Department of Neurology and MRI Institute, Medical University Graz, Austria e Serviço de Neurologia, Centro de Estudos Egas Moniz, Hospital de Santa Maria Lisboa, Portugal f Department of Neurology, University of Heidelberg, Klinikum Mannheim, Mannheim, Germany g Academic Department for Geriatric Medicine, Glasgow Royal Infirmary, Glasgow, Scotland h Institute for Ageing and Health, University of Newcastle, Newcastle-upon-Tyne, United Kingdom i Department of Radiology and Neurology, VU Medical Center, Amsterdam, The Netherlands j Karolinska Institute, Department of Clinical Neuroscience and Family Medicine, Huddinge University Hospital, Huddinge, Sweden k Copenhagen University Hospital, Copenhagen, Denmark l Institue of Neuroscience and Physiology, Götenborg University, Götenborg, Sweden Background: Age-related white matter changes (ARWMC) are frequently detected on neuroimaging and have been associated with motor, cognitive, urinary, and mood disorders. The LADIS Study primarily aims to assess ARWMC as a determinant of global functional decline in the elderly.

Abstracts / Journal of the Neurological Sciences 283 (2009) 240–320

Methods: We enrolled 639 patients (mean age 74.1 ± 5.0 years, 45.1% males), referred for non-disabling complaints, who had ARWMC on brain MRI of mild, moderate, or severe grade according to the Fazekas et al.'s scale. 619 patients were re-assessed for Instrumental Activities of Daily Living (IADL) at one year. Of these, 506 were totally independent at baseline, and 113 were impaired in only one item of the IADL scale. We studied the oneyear transition to 2 or more activities limited, and selective functional impairments as co-factors of functional decline. Findings: The rate of transition was 9%, 15%, and 26%, in the mild, moderate, and severe ARWMC group. Comparing the severe with the mild ARWMC groups and adjusting for age and for other predictors of decline, the risk was more than twice as high (OR 2.38; CI 1.29–4.38) in patients with 0 or 1 activity limited, and three time higher (OR 3.02, 95% CI 1.34–6.78) among patients fully independent at baseline. Both motor and cognitive deterioration predominantly explained the effect of ARWMC on global functional decline. Conclusion: Elderly patients who are functionally independent and who have severe ARWMC are at considerable risk of becoming more dependent in a short period of time, mostly due to motor and cognitive deterioration. doi:10.1016/j.jns.2009.02.128

Silent brain infarction—Is it really silent? A. Slowik, A. Szczudlik Department of Neurology, Jagiellonian University, Krakow, Poland Silent brain infarction (SBI) denotes small lacunar infarction not related to acute neurological deficit. SBIs are relatively common in the elderly population; their estimated frequency is 20 to 35%. Most of them (65%) are single, and they are more frequent in females. The risk factor profile of SBIs is similar to that of ischemic stroke. The following risk factors were found to increase the risk of SBIs: hypertension, diabetes mellitus, smoking, carotid stenosis > 50%, leukoaraiosis on neuroimaging, increased homocysteine levels, increased CRP levels, etc. Most of patients with SBIs are neurologically intact, but they may present with chronic neurological deficits, like cognitive decline, dementia, some motor dysfunction, Parkinsonism, gait disorder, urinary incontinence, etc. SBIs may increase the risk of stroke and dementia. At least one SBI on neuroimaging increases the risk of acute stroke 2 to 10 times in a long-term follow-up. Hypertension, intima-media thickness and atrial fibrillation increase the risk of acute stroke in this group of patients. At least two SBIs on neuroimaging double the risk of acute stroke in a 4-year follow up. SBIs also double the risk of dementia in a 3-year follow up. Until now, the only therapeutic strategy is prevention, focused on management of vascular risk factors. doi:10.1016/j.jns.2009.02.129

Retinal photography: A diagnostic tool for small vessel disease of the brain? P.T. de Jonga,b,c, M.K. Ikrama,d, F.J. de Jonga,d, A. Hofmana, A.M. vd Maagdenberge,f, G.M. Terwindtf, R.R. Frantse, M.D. Ferrarif, M.M. Bretelera a Department of Epidemiology and Biostatistics, ErasmusMC, Rotterdam, The Netherlands b The Netherlands Institute For Neuroscience, RAAS, Amsterdam, The Netherlands c Department of Ophthalmology, Academic Medical Center, Amsterdam, The Netherlands e Department of Neurology, ErasmusMC, Rotterdam, The Netherlands d Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands f Department of Neurology, Leiden University Medical Center, Leiden, The Netherlands Background and aim: Lately, retinal vessel diameters can be reliably measured in a semi-automated way. Autosomal dominant retinal vasculopathy with cerebral leucodystrophy (adRVCL) is characterized by capillary non-perfusion in persons without e.g. diabetes or hypertension, while there are prominent cerebral white matter infarcts. Our aims were to describe 1.

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The associations between retinal vessel diameters and neurological diseases, and 2. The mutations causing adRCLV. Methods: 1. Population based, prospective study in white people (n = 6780) aged 55 years and over. 2. Genetic study in two large families with adRCLV. Results: Cross-sectional, lower arterial oxygen saturation (< 96%) was associated in a sub-sample (n = 696) with 5.6 μm wider venules (95%CI 1.2; 10) in participants having the lowest tertile of cerebral blood flow. Larger retinal venular diameters at baseline were associated with increased risk of progression of cerebral small vessel disease. Per SD increase in diameter the ORs were 1.71 (95%CI 1.11; 2.61) for periventricular and 1.72 (95%CI 1.09; 2.71) for subcortical white matter lesion progression, while the OR for incident lacunar infarcts was 1.59(95%CI 0.72–2.12). Per SD increase in retinal venular diameter the HR of stroke was 1.12 (95% CI 1.02; 1.24) and of cerebral infarction 1.15 (95%CI 1.02; 1.29). Each standard deviation (SD) increase in venular diameter heightened the risk of dementia, hazard ratio (HR) 1.21 (95%CI 1.07–1.37), without any difference between Alzheimer's disease and vascular dementia; arteriolar diameters did not show any association. Frameshift mutations in TREX1 are associated with adRCLV. The limited knowledge about its pathophysiology will be discussed. Conclusions: Carefully standardized measurements of retinal venular diameters are a valuable tool for predicting cerebral small vessel disease, stroke, and dementia. The rare adRVCL disorder should be included in the differential diagnosis of retinal capillary occlusion. doi:10.1016/j.jns.2009.02.130

Beta-amyloid induced neuroinflammation: Regulation by natural and pharmacological compounds M.T. Heneka Dept. of Neurology, University of Muenster, Muenster, Germany In Alzheimer's disease (AD) inflammatory changes including activated microglia and astrocytes, chemo and cytokines and induced inflammatory enzyme systems are found next to beta-amyloid deposits and neurofibrillary tangles, the classical histopathological hallmarks of the disorder. While this neuroinflammatory component most likely occurs secondary to neurodegenerative events and in particular to the secretion and deposition of beta-amyloid peptides, it may well contribute to neuronal dysfunction and cell death. Moreover, increasing evidence suggests that inflammatory molecules interact directly with disease relevant mechanisms such as APP processing and phosphorylation of tau. Endogenous molecules including neurotransmitters such as norepinephrine (NE) and acetylcholine may serve as anti-inflammatory brain protectants and therefore influence the occurrence and extent of brain inflammation. The early loss of locus ceruleus neurons and the subsequent decrease of NE levels in its projection areas, the hippocampus and neocortex, may facilitate and promote micro and astroglial activation in response to beta-amyloid peptides in these brain regions. In addition to modulation by endogenous antiinflammatories, epidemiological evidence suggests that non-steroidal anti-inflammatory drugs (NSAIDs) decrease the risk and delay the onset of AD. The mechanism by which this neuroprotection is achieved remains unknown so far. Accumulating experimental data suggest that NSAIDs may not act by a single but rather by several different mechanisms. Thus, neuroprotection may be mediated by the inhibition of gamma-secretase, by activation of the nuclear receptor peroxisome proliferator-activated receptor gamma (PPARs) or by inhibition of cyclooxygenase 1 and 2. The mode of action, however, may also depend on disease state and brain region. In summary, endogenous and exogenous anti-inflammatory molecules may modulate the course of AD and future therapeutic avenues may be opened by further analysis and investigation of AD neuroinflammation. doi:10.1016/j.jns.2009.02.131

The neuroinflammatory response in plaques and amyloid angiopathy in Alzheimer's disease P. Eikelenbooma, R. Veerhuisb, A. Familianb, W.A. van Goola, J.M. Rozemullerc a Dept. Neurology, Academic Medical Center, Amsterdam, the Netherlands