3-12-09 Neurocognitive scales standardisation for dementia study: Adas Cog. and Mattis dementia scale (MDS) (original) (raw)
Frontiers, 2023
Despite extensive research, no disease-modifying therapeutic option, able to prevent, cure or halt the progression of Alzheimer’s disease [AD], is currently available. AD, a devastating neurodegenerative pathology leading to dementia and death, is characterized by two pathological hallmarks, the extracellular deposits of amyloid beta (Aβ) and the intraneuronal deposits of neurofibrillary tangles (NFTs) consisting of altered hyperphosphorylated tau protein. Both have been widely studied and pharmacologically targeted for many years, without significant therapeutic results. In 2022, positive data on two monoclonal antibodies targeting Aβ, donanemab and lecanemab, followed by the 2023 FDA accelerated approval of lecanemab and the publication of the final results of the phase III Clarity AD study, have strengthened the hypothesis of a causal role of Aβ in the pathogenesis of AD. However, the magnitude of the clinical effect elicited by the two drugs is limited, suggesting that additional pathological mechanisms may contribute to the disease. Cumulative studies have shown inflammation as one of the main contributors to the pathogenesis of AD, leading to the recognition of a specific role of neuroinflammation synergic with the Aβ and NFTs cascades. The present review provides an overview of the investigational drugs targeting neuroinflammation that are currently in clinical trials. Moreover, their mechanisms of action, their positioning in the pathological cascade of events that occur in the brain throughout AD disease and their potential benefit/limitation in the therapeutic strategy in AD are discussed and highlighted as well. In addition, the latest patent requests for inflammation-targeting therapeutics to be developed in AD will also be discussed
The Role of Anti-Inflammatory Drugs in the Prevention and Treatment of Alzheimer's Disease
Annual Review of Medicine, 1996
▪ Risk factor intervention is a useful strategy for prevention of poorly understood diseases. Fifteen studies have examined the relation of glucocorticoid and nonsteroid antiinflammatory treatments and onset or progression of Alzheimer's disease (AD). Fourteen of these studies suggest that such treatments (especially nonsteroidal agents) prevent or ameliorate symptoms of AD. Abundant circumstantial evidence implicates inflammation in the pathogenesis of AD. Inhibition of cyclooxygenases, the central action of nonsteroidal antiinflammatory drugs (but not a prominent effect of steroids), limits inflammation, but it may also alter neural metabolic pathways, resulting in cell death from excitotoxicity or oxidative stress. Randomized controlled trials are needed to determine whether steroids, nonsteroidal antiinflammatory drugs, or both can prevent or treat the symptoms of AD.
Staging anti-inflammatory therapy in Alzheimer's disease
2010
The use of non-steroidal anti-inflammatory drugs (NSAIDs) in Alzheimer's disease (AD) is controversial because conclusions from numerous epidemiological studies reporting delayed onset of AD in NSAID users have not been corroborated in clinical trials. The purpose of this personal view is to revise the case for NSAIDs in AD therapeutics in light of: (i) the last report from the only primary prevention trial in AD, ADAPT, which, although incomplete, points to significant protection in long-term naproxen users, and (ii) the recently proposed dynamic model of AD evolution. The model contends that there is a clinical silent phase in AD that can last up to 20 years, the duration depending on life style habits, genetic factors, or cognitive reserve. The failure of many purported disease-modifying drugs in AD clinical trials is forcing the view that treatments will only be efficacious if administered pre-clinically. Here we will argue that NSAIDs failed in clinical trials because they are disease-modifying drugs, and they should be administered in early stages of the disease. A complete prevention trial in cognitively normal individuals is thus called for. Further, the shift of anti-inflammatory treatment to early stages uncovers a knowledge void about the targets of NSAIDs in asymptomatic individuals. AD researchers have mostly relied on post-mortem analysis of Aβ plaque-laden brains from demented patients or animal models, thus drawing conclusions about AD pathogenesis based on late symptoms. We will discuss evidence in support that defective, not excessive, inflammation underlies AD pathogenesis, that NSAIDs are multifunctional drugs acting on inflammatory and non-inflammatory targets, and that astrocytes and microglia may play differing roles in disease progression, with an emphasis of ApoEε4 as a key, undervalued target of NSAIDs. According to a meta-analysis of epidemiological data, NSAIDs afford an average protection of 58%. If this figure is true, and translated into patient numbers, NSAID treatment may revive as a worth pursuing strategy to significantly reduce the socio-economical burden imposed by AD.
Preclinical" AD revisited: Neuropathology of cognitively normal older adults
Neurology, 2000
To classify neuropathologic alterations in the brains of nondemented older adults using current sets of criteria for AD. Background: AD neuropathologic alterations are found in the brains of some nondemented elderly subjects and suggest the possibility of presymptomatic AD. Three sets of guidelines have been developed to classify AD using senile plaques, neuritic plaques, and neurofibrillary tangles (NFT). Methods: Neuropathologic changes in 59 older adults followed longitudinally with a standard battery of mental status measures were investigated using Khachaturian, Consortium to Establish a Registry for Alzheimer's Disease (CERAD), and National Institute on Aging-Reagan Institute (NIA-RI) guidelines. AD neuropathologic markers were evaluated in neocortical and allocortical regions. Cases were categorized as neuropathologically "normal" or "AD-like" and compared for possible mental status differences. Results: Between 11 and 49% of cases met one or more of the three classifications of AD. With adjustments for multiple comparisons, only NFT in hippocampal CA1 region were associated with autopsy age, suggesting that this may represent a pathologic process associated with normal brain aging. Using the NIA-RI guidelines, subjects in the AD-like group performed less well on the immediate paragraph recall and word-list delayed recall than their counterparts who did not meet these guidelines. Conclusions: These data indicate that the prevalence of "preclinical" AD in our population is relatively low based on the NIA-RI classification. Although many subjects had AD-like changes based on CERAD and Khachaturian guidelines, they exhibited no differences in mental performance, suggesting that the aging brain may be able to withstand such structural changes without meaningful impact on mental functioning.
[Alzheimer's disease--the most common cause of severe dementia]
Lakartidningen
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Brun A. and L.Gustafson (1974): Extent and severity of cerebral lesions related to clinical and regional cerebral blood flow in presenile dementia. In: PPProc of the V11th Intnl Congr of Neuropathology, Akademiai Kiado, Budapest 1974, p44. Gustafson L, D.H.Ingvar and A. Brun (1975): Clinical and neurocirculatory findings in presenile dementia related to neuropathological changes. In proc. of 2nd Intnl congr of CIANS Prague 1975. p. 371 Brun A, L Gustafson, DHI Ingvar (1974/5): Neuropathological findings related to Neuropsychiatric symptoms and regional cerebral blood flow in presenile dementia. Excerpta medica, Amsterdam, Akademiai Kiado, Budapest. Pp 101-5. Brun, A. and Gustafson, L. (1976). Distribution of cerebral degeneration in Alzheimer's disease. A clinico-pathological study. Arch Psychiatr Nervenkr, 223, 15-33. Gustafson L, Brun A and Ingvar D H (1975): Clinical and neurocirculatory findings in presenile dementia related to neuropathological changes. Activ nerv Sub (Praha) 19, 2, 351 -354. Gustafson L, A Brun, DHI Ingvar (1977): Presenile dementia: Clinical symptoms, pathoanatomical findings and cerebral blood flow. Cerebral vascular disease. A Brun, E Englund (1980): degeneration av hjärnans vita substans vid demens. Riksstämman, Hygiea. P 213 Risberg J, Brun A, Johansson M and Gustafson L (1983): Differential diagnosis of dementia by rCBF and psychometric methods. J Cer Blood Flow and Metabolism, 3, 1, Raven Press, New York, 496 -497. + abstr Brun A and Dictor M (1981): Senile plaques and tangles in dialysis dementia. Acta Path. Microbiol Scand Sect A, 89, 193-198. Brun, A. and Englund, E. (1981). Regional pattern of degeneration in Alzheimer's disease: neuronal loss and histopathological grading. Histopathology, 5, 549-564. Englund E and Brun A (1981): Senile dementia -a structural basis for etiological and therapeutic considerations. Biological Psychiatry. Eds: C Perris and B Jonsson. Elsevier/North Holland Biomed Press 951 -956. Westermark P, Shirahama T, Skinner M, Brun A, Cameron R and Cohen A (1982): Immunohistochemical evidence for the lack of amyloid component in some intracrebral amyloids. Laboratory Investigation 5, 457 -460. Shirhama T, Skinner M, Westermark P, Rubinow A, Cohen A S, Brun A and Kemper T H (1982): Senile cerebral amyloid. Prealbumin as a common constituent in the neuritic plaques, in the neurofibrillary tangle and in the microangiopathic lesion. Am J Pathol 107, 41-50. Brun A (1982): Strukturellt underlag vid organisk senil demens. Symposium Sandoz: Demenstillstånd -synpunkter på etiologi och behandling, 23 -34. Brun A (1982): Alzheimer's disease and its clinical implications. In: Geriatrics. Ed: D Platt. Springer Verlag Heidelberg, NY, 343 -390. Brun A and Englund E (1982): White matter incomplete infarction in dementia. Abstract 9th Internat. Congr. Neuropath. 201. Brun A, L Gusrafson (1983). Down's syndrom -utvecklingsstörning och demens. Läkartidningen 80, 10, pp 936. Risberg J, Brun A, Johansson M and Gustafson L (1983): Differential diagnosis of dementia by rCBF and psychometric methods. J Cer Blood Flow and Metabolism, 3, 1, Raven Press, New York, 496 -497. Gustafson L, Brun A, Hagstadius S, Johansson M and Risberg J (1983): Evaluation of organic dementia and confusional states by rCBF, clinical and psychometric metods. Abstract: 2nd satellite symposium on: Effect of ageing on regulation of cerebral blood flow and metabolism. Eds: Sieshi and C V Loeb. European Neurology, 22, 2. S Karger Medical and Scientific Publishers, Basel. pp. Brun A (1983): Hjärnskada bakom vanliga former av demens. Forskning och Praktik, 15, 7, 103-106. Brun A (1983): An overview of light and electron microscopical changes. In: Alzheimer's disease. Ed: B Reisberg. The Free Press. New York, a division of Mac Millan Inc, 3 -47. Gustafson L, Brun A, Risberg J and Johansson M (1984): Evaluation of organic dementia by regional cerebral blood flow measurements and clinical psychometric methods. Monogr Neural Sci, 11, 111 -117. Karger, Basel. . Gustafson L, Brun A, Hagstadius S, Johansson M and Risberg J (1983): Evaluation of organic dementia and confusional states by rCBF, clinical and psychometric metods. Abstract: 2nd satellite symposium on: Effect of ageing on regulation of cerebral blood flow and metabolism. Eds: Sieshi and C V Loeb. European Neurology, 22, 2. S Karger Medical and Scientific Publishers, Basel. p 23. Brun A (1984): The neuropathological background of clinical signs and symptoms in organic dementia. 2 nd Nordic meeting in Neuropsychology. Lund Sweden. Pp 18-19. Brun A (1985): The structural development of Alzheimer's disease. Danish Medical Bulletin, 32, 1, 25 -27. Friedland R P, A Brun, T F Budinger (1985): Pathological and positron emission tomographic correlations in Alzheimer's disease. The Lancet 8422, vol. I/85, p 228. Brun A and Englund E (1985): Regional variations of cortical degeneration in Alzheimer's disease. Journal of Clinical and Experimental Neuropsychology, 7, 2, 167 Brun A and Englund E (1985): White matter changes in Alzheimer's presenile and senile dementia. In: Normal aging, Alzheimer's disease and senile dementia. Aspects on etiology, pathogenesis, diagnosis and treatment, Ed: C G Gottfries. Editions de lUniversité de Bruxelle's, 47 -50. Gustafson L, Brun A, Holmkvist-Franck A, Risberg J 1985: Regional Cerebral blood flow in degenerative frontal lobe dementia of non-Alzheimer type. Cerebr. Blood Flow Metabol. 5: 141-142. Gustafson L, A Brun, J Risberg (1985): Organic dementia: Clinical picture related to regional cerebral blood flow and neuropathologic al findings. Psychiatry vol. 2. Pp 605-611. Brun A, E Englund (1985): Alzheimer type dementia and white matter changes. Ata neurol. Scand. Vil 71. Pp 87-88. Gustafson L, A Brun, J Risberg (1985): Rating scales for diagnosis of Alzheimer´s disease and frontal lobe dementia of non-Alzheimer type. 26 Englund E, A Brun (1985): A White matter disorder common in Dementia of Alzheimer´s type. Pp 168-169. Englund E, A Brun (1985): demyelination contributes to Alzheimer´s disease. 18. Brun A, L Gustafson, E Englund (1985): Morphology of white matter, subcortical dementia in Alzheimer´s disease. Pp 79 -83. Brun A, Englund E (1986): A white matter disorder in dementia of the Alzheimer type: a pathoanatomical study. Ann Neurol 1986;19:253-262. -Brun A and Gustafson L (1990): Clinico-pathological correlates of dementia: The pathoanatomical substrate of Alzheimer's disease. Excerpta Medica. -Gustafson L, Brun A, Cronqvist S, Dalfelt G, Risberg J, Riesenfeldt W and Rosén I (1990): Regional cerebral blod flow, MRI and BEAM in Alzheimer's disease. J Cer Blood Flow Metab, 9, 1, 543. 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(IP), Rome, Italy, August 18 -23. Brun A (1992): Alzheimer -en demenssjukdom. Vandringar med Böcker. Bibliotekstjänst, Lund. Basun H, O Almquist, K Axelman , A Brun, T A Campbell, J Collinge, C Forsell . S Froelich , L-O Wahlund, L Wetterberg, L Lannfeldt (1997). Clinical characteristics of a family with chromosome 17 -linked rapidly progressive frontotemporal dementia . Arch Neurol, 54 : 539 -544 . Liu X and A Brun (1996): Regional and laminar synaptic pathology in frontal lobe degeneration of non-Alzheimer type. Int. J. Ger. Psych.11, 47-55. Liu X, C Erikson, A Brun (1996). Cortical synaptic changes and gliosis in normal aging, Alzheimer´s disease and frontal lobe degeneration. Dementia 7, 128-134. A 136 Brun A and Passant U (1996): Frontal lobe degeneration of non-Alzheimer type. Structural changes, diagnostic criteria and relation to other fronto-temporal dementias. Acta Neurol.Scand. Suppl 168 28 -30 . A Swedish state of the art document on dementia diseases .Eds L -O Wahlund , B Winblad . Ohlsson Y. A Brun, E Englund (1996): Fundamental pathological lesions in vascular dementia . Acta Neurol Scand Suppl 168, 31-38.A Swedish state of the art document on dementia diseases. ( 1997 ): Misclassification of dementia subtype using the Hachinski ischemic score : results of a meta-analysis of patients with pathologically verified dementias . Annals New York Academy of Sciences. 490 -492....
Is There a Causal Link between Inflammation and Dementia?
BioMed Research International, 2013
Neuroinflammation is a constant event in Alzheimer's disease (AD), but the current knowledge is insufficient to state whether inflammation is a cause, a promoter, or simply a secondary phenomenon in this inexorably progressive ailment. In the current paper, we review research data showing that inflammation is not a prerequisite for onset of dementia, and, although it may worsen the course of the disease, recent evidence shows that chronic inhibition of inflammatory pathways is not necessarily beneficial for patients. Prospective clinical trials with anti-inflammatory drugs failed to stop disease progression, measurements of inflammatory markers in serum and cerebrospinal fluid of patients yielded contradictory results, and recent bench research proved undoubtedly that neuroinflammation has a protective side as well. Knockout animal models for TNFRs or ILRs do not seem to prevent the pathology or the cognitive decline, but quite the contrary. In AD, the therapeutic intervention on inflammatory pathways still has a research future, but its targets probably need reevaluation.