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1.  Proteinopathy-induced neuronal senescence: a hypothesis for brain failure in Alzheimer's and other neurodegenerative diseases 
Alzheimer's disease (AD) and a host of other neurodegenerative central nervous system (CNS) proteinopathies are characterized by the accumulation of misfolded protein aggregates. Simplistically, these aggregates can be divided into smaller, soluble, oligomeric and larger, less-soluble or insoluble, fibrillar forms. Perhaps the major ongoing debate in the neurodegenerative disease field is whether the smaller oligomeric or larger fibrillar aggregates are the primary neurotoxin. Herein, we propose an integrative hypothesis that provides new insights into how a variety of misfolded protein aggregates can result in neurodegeneration.
We introduce the concept that a wide range of highly stable misfolded protein aggregates in AD and other neurodegenerative proteinopathies are recognized as non-self and chronically activate the innate immune system. This pro-inflammatory state leads to physiological senescence of CNS cells. Once CNS cells undergo physiological senescence, they secrete a variety of pro-inflammatory molecules. Thus, the senescence of cells, which was initially triggered by inflammatory stimuli, becomes a self-reinforcing stimulus for further inflammation and senescence. Ultimately, senescent CNS cells become functionally impaired and eventually die, and this neurodegeneration leads to brain organ failure.
This integrative hypothesis, which we will refer to as the proteinopathy-induced senescent cell hypothesis of AD and other neurodegenerative diseases, links CNS proteinopathies to inflammation, physiological senescence, cellular dysfunction, and ultimately neurodegeneration. Future studies characterizing the senescent phenotype of CNS cells in AD and other neurodegenerative diseases will test the validity of this hypothesis. The implications of CNS senescence as a contributing factor to the neurodegenerative cascade and its implications for therapy are discussed.
PMCID: PMC2874257  PMID: 19822029
2.  Cerebral amyloid angiopathy in the aetiology and immunotherapy of Alzheimer disease 
Amyloid is deposited in the walls of arteries and capillaries as cerebral amyloid angiopathy (CAA) in the brains of older individuals and of those with Alzheimer disease (AD). CAA in AD reflects an age-related failure of elimination of amyloid-beta (Aβ) from the brain along perivascular lymphatic drainage pathways. In the absence of conventional lymphatic vessel in the brain, interstitial fluid and solutes drain from the brain to cervical lymph nodes along narrow basement membranes in the walls of capillaries and arteries, a pathway that is largely separate from the cerebrospinal fluid. In this review we focus on the pathology and pathogenesis of CAA, its role in the aetiology of AD and its impact on immunotherapy for AD. The motive force for lymphatic drainage of the brain appears to be generated by arterial pulsations. Failure of elimination of Aβ along perivascular pathways coincides with a reduction in enzymic degradation of Aβ, reduced absorption of Aβ into the blood and age-related stiffening of artery walls that appears to reduce the motive force for lymphatic drainage. Reduced clearances of Aβ and CAA are associated with the accumulation of insoluble and soluble Aβs in the brain in AD and the probable loss of homeostasis of the neuronal environment due to retention of soluble metabolites within the brain. Tau metabolism may also be affected. Immunotherapy has been successful in removing insoluble plaques of Aβ from the brain in AD but with little effect on cognitive decline. One major problem is the increase in CAA in immunised patients that probably prevents the complete removal of Aβ from the brain. Increased knowledge of the physiology and structural and genetic aspects of the lymphatic drainage of Aβ from the brain will stimulate the development of therapeutic strategies for the prevention and treatment of AD.
PMCID: PMC2874258  PMID: 19822028
3.  Persistent treatment with cholinesterase inhibitors and/or memantine slows clinical progression of Alzheimer disease 
There are no empiric data to support guidelines for duration of therapy with antidementia drugs. This study examined whether persistent use of antidementia drugs slows clinical progression of Alzheimer disease (AD) assessed by repeated measures on serial tests of cognition and function.
Six hundred forty-one probable AD patients were followed prospectively at an academic center over 20 years. Cumulative drug exposure was expressed as a persistency index (PI) reflecting total years of drug use divided by total years of disease symptoms. Baseline and annual testing consisted of Mini-Mental State Examination (MMSE), Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), Baylor Profound Mental Status Examination (BPMSE), Clinical Dementia Rating-Sum of Boxes (CDR-SB), Physical Self-Maintenance Scale (PSMS), and Instrumental Activities of Daily Living (IADL). Annual change in slope of neuropsychological and functional tests as predicted by follow-up time, PI, and the interaction of these two variables was evaluated.
PI was associated with significantly slower rates of decline (with, without adjustment for covariates) on MMSE (P < 0.0001), PSMS (P < 0.05), IADL (P < 0.0001), and CDR-SB (P < 0.001). There was an insignificant trend (P = 0.053) for the PI to be associated with slower rate of decline on BPMSE. The association of PI with ADAS-Cog followed a quadratic trend (P < 0.01). Analysis including both linear and quadratic terms suggests that PI slowed ADAS-Cog decline temporarily. The magnitude of the favorable effect of a rate change in PI was: MMSE 1 point per year, PSMS 0.4 points per year, IADL 1.4 points per year, and CDR-SB 0.6 points per year. The change in mean test scores is additive over the follow-up period (3 ± 1.94 years).
Persistent drug treatment had a positive impact on AD progression assessed by multiple cognitive, functional, and global outcome measures. The magnitude of the treatment effect was clinically significant. Positive treatment effects were even found in those with advanced disease.
PMCID: PMC2874259  PMID: 19845950
4.  Angiotensins and Alzheimer's disease: a bench to bedside overview 
The pathology of Alzheimer's disease (AD) features amyloid β peptide deposition, intracellular neurofibrillary tangles and deficits in the cholinergic pathway. Abnormal blood pressure is recognised as a risk factor for the development of AD, although the underlying mechanisms remain unproven. This review proposes angiotensins and associated enzymatic pathways as important mediators of recognised but undefined links between blood pressure and AD. Evidence in support of this involvement translates consistently from the most basic in vitro, in vivo and ex vivo experimental paradigms to more complex human-based observational and experimental studies, which also fortunately offer potential for therapeutic interventions against AD.
PMCID: PMC2719108  PMID: 19674436
5.  Alzheimer's disease therapeutic research: the path forward 
The field of Alzheimer's disease therapeutic research seems poised to bring to clinic the next generation of treatments, moving beyond symptomatic benefits to modification of the underlying neurobiology of the disease. But a series of recent trials has had disappointingly negative results that raise questions about our drug development strategies. Consideration of ongoing programs demonstrates difficult pitfalls. But a clear path forward is emerging. Successful strategies will utilize newly available tools to reconsider issues of diagnosis, assessment and analysis, facilitating the study of new treatments at early stages in the disease process at which they are most likely to yield major clinical benefits.
PMCID: PMC2719107  PMID: 19674435
7.  Beyond mild cognitive impairment: vascular cognitive impairment, no dementia (VCIND) 
Identifying the causes of dementia is important in the search for effective preventative and treatment strategies. The concept of mild cognitive impairment (MCI), as prodromal dementia, has been useful but remains controversial since in population-based studies it appears to be a limited predictor of progression to dementia. Recognising the relative contribution of neurodegenerative and vascular causes, as well as their interrelationship, may enhance predictive accuracy. The concept of vascular cognitive impairment (VCI) has been introduced to describe the spectrum of cognitive change related to vascular causes from early cognitive decline to dementia. A recent review of this concept highlighted the need for diagnostic criteria that encompass the full range of the VCI construct. However, very little is known regarding the mildest stage of VCI, generally termed 'vascular cognitive impairment, no dementia' (VCIND). Whether mild cognitive change in the context of neurodegenerative pathologies is distinct from that in the context of cerebrovascular diseases is not known. This is key to the definition of VCIND and whether it is possible to identify this state. Distinguishing between vascular (that is, VCIND) and non-vascular (that is, MCI) cognitive disorders and determining how well each might predict dementia may not be possible due to the overlap in pathologies observed in the older population. Here, we review the concept of VCIND in an effort to identify recent developments and areas of controversy in nosology and the application of VCIND for screening individuals at increased risk of dementia secondary to vascular disease and its risk factors.
PMCID: PMC2719105  PMID: 19674437

Results 1-7 (7)