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阿茲海默症之最新研究報告 – L. Neergaard
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Silent brain changes precede Alzheimer's. Researchers have new clues about which come first

, 02/22/24

WASHINGTON (AP) — Alzheimer’s quietly ravages the brain long before symptoms appear and now scientists have new clues about the dominolike sequence of those changes — a potential window to one day intervene.

A large study in China tracked middle-aged and older adults for 20 years, using regular brain scans, spinal taps and other tests.

Compared to those who remained cognitively healthy, people who eventually developed the mind-robbing disease had higher levels of an Alzheimer's-linked protein in their spinal fluid 18 years prior to diagnosis, researchers reported Wednesday. Then every few years afterward, the study detected another so-called biomarker of brewing trouble.

Scientists don’t know exactly how Alzheimer’s forms. One early hallmark is that sticky protein called beta-amyloid, which over time builds up into brain-clogging plaques. Amyloid alone isn’t enough to damage memory — plenty of healthy people’s brains harbor a lot of plaque. An abnormal tau protein that forms neuron-killing tangles is one of several co-conspirators.

The new research, published in the New England Journal of Medicine, offers a timeline for how those abnormalities pile up.

The study’s importance “cannot be overstated,” said Dr. Richard Mayeux, an Alzheimer’s specialist at Columbia University who wasn’t involved in the research.

“Knowledge of the timing of these physiological events is critical” for testing new ways of treating and maybe eventually even preventing Alzheimer’s, he wrote in an accompanying editorial.

The findings have no practical implications yet.

More than 6 million Americans, and millions more worldwide, have Alzheimer’s, the most common form of dementia. There’s no cure. But last year a drug named Leqembi became the first approved with clear evidence that it could slow the worsening of early Alzheimer’s — albeit for a few months.

It works by clearing away some of that gunky amyloid protein. The approach also is being tested to see if it's possible to delay Alzheimer's onset if high-risk people are treated before symptoms appear. Still other drugs are being developed to target tau.

Tracking silent brain changes is key for such research. Scientists already knew that in rare, inherited forms of Alzheimer’s that strike younger people, a toxic form of amyloid starts accumulating about two decades ahead of symptoms and at some point later tau kicks in.

The new findings show the order in which such biomarker changes occurred with more common old-age Alzheimer’s.

Researchers with Beijing’s Innovation Center for Neurological Disorders compared 648 people eventually diagnosed with Alzheimer’s and an equal number who remained healthy. The amyloid finding in future Alzheimer's patients was the first, 18 years or 14 years prior to diagnosis depending on the test used.

Differences in tau were detected next, followed by a marker of trouble in how neurons communicate. A few years after that, differences in brain shrinkage and cognitive test scores between the two groups became apparent, the study found.

“The more we know about viable Alzheimer’s treatment targets and when to address them, the better and faster we will be able to develop new therapies and preventions,” said Claire Sexton, the Alzheimer's Association's senior director of scientific programs. She noted that blood tests are coming soon that promise to also help by making it easier to track amyloid and tau.


The Associated Press Health and Science Department receives support from the Howard Hughes Medical Institute’s Science and Educational Media Group. The AP is solely responsible for all content.


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《老年癡呆開始前語言能力下滑》小評
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0.  前言

這篇文章以大腦神經科學和語言學兩個領域為重點(請見本欄上一篇),但其結果對研究「意識」的學者應該有幫助;在此略表淺見。下文「作者」一詞指德澤克斯先生。

1. 
原文簡介

1.1
前言 (原文無此子標題)

學者經實驗發現: 忘性型輕度認知能力障礙指標之一的「語意/句型」處理能力降低,是在記憶力衰退之外,另一個可以預測「阿茲海默症」的狀況。

1.2 Anaphora and ambiguity

作者在本節中說明什麼是「『語意/句型』處理能力」,並詳細描述了上述實驗這一節倒數第2段中的mind一詞應該了解為:「大腦處理身體與意識兩個層面活動的能力」。請自行參考。

1.3 Looking for a path to treatment

作者指出:此實驗可能導致今後對輕度認知能力障礙或其它老年癡呆症狀的研究(後者如漸進式失語症)將注意力轉到大腦處理語言的部位同時,此研究也可以幫助語言學家進一步了解:不同語境下,前置名詞決定在其後面代名詞意義的機制

作者引述研究者之一的弗林教授:「如果我們能夠了解導致此症狀的大腦神經網絡軌跡,它可以幫助我們對症下藥。」

2. 
小評

1) 
我認為個人的「意識「她/他經驗的總和」;而這個「經驗總和」儲存在每個人的「記憶」中。這是「失憶」導致「癡呆」的原因。

2) 
處理語言的能力來自學習學習是構成經驗的過程;因此,處理語言能力降低,並不一定蘊含處理語言的大腦部位發生病變它很可能是「失憶」導致的副作用或併發症。

我是大腦神經學的門外漢,以上觀察純屬「看過豬走路」效應。

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老年癡呆開始前語言能力下滑 - Peter Dizikes
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索引(請參看本攔下一篇《小評》)

ambiguity
不精確,模糊不清,模稜兩可
amnestic mild cognitive impairment忘性型輕度認知能力障礙
anaphora
字、詞的意義視其前置名詞決定的作文方式和/或修辭風格
aphasia失語症
deterioration
惡化,退化
semantics
語意語意學
subtlety
微妙,精細,敏銳;微妙之處,細微的差別
syntax
句法,句子結構


How cognition changes before dementia hits

Study finds language-processing difficulties are an indicator — in addition to memory loss — of amnestic mild cognitive impairment.

MIT News02/29/24

Language-processing difficulties are an indicator of amnestic mild cognitive impairment (aMCI), a risk factor for dementia due to Alzheimer’s disease, according to a new study. Credits: Image: Christine Daniloff, MIT; iStock (
請至原網頁差看插圖)

Individuals with mild cognitive impairment, especially of the “amnestic subtype” (aMCI), are at increased risk for dementia due to Alzheimer’s disease relative to cognitively healthy older adults. Now, a study co-authored by researchers from MIT, Cornell University, and Massachusetts General Hospital has identified a key deficit in people with aMCI, which relates to producing complex language.

This deficit is independent of the memory deficit that characterizes this group and may provide an additional “cognitive biomarker” to aid in early detection — the time when treatments, as they continue to be developed, are likely to be most effective.

The researchers found that while individuals with aMCI could appreciate the basic structure of sentences (syntax) and their meaning (semantics), they struggled with processing certain ambiguous sentences in which pronouns alluded to people not referenced in the sentences themselves.

“These results are among the first to deal with complex syntax and really get at the abstract computation that’s involved in processing these linguistic structures,” says MIT linguistics scholar Suzanne Flynn, co-author of a paper detailing the results.

The focus on subtleties in language processing, in relation to aMCI and its potential transition to dementia such as Alzheimer’s disease is novel, the researchers say.

“Previous research has looked most often at single words and vocabulary,” says co-author Barbara Lust, a professor emerita at Cornell University. “We looked at a more complex level of language knowledge. When we process a sentence, we have to both grasp its syntax and construct a meaning. We found a breakdown at that higher level where you’re integrating form and meaning.”

The paper, “
Disintegration at the syntax-semantics interface in prodromal Alzheimer’s disease: New evidence from complex sentence anaphora in amnestic Mild Cognitive Impairment (aMCI),” appears in the Journal of Neurolinguistics.

The paper’s authors are Flynn, a professor in MIT’s Department of Linguistics and Philosophy; Lust, a professor emerita in the Department of Psychology at Cornell and a visiting scholar and research affiliate in the MIT Department of Linguistics and Philosophy; Janet Cohen Sherman, an associate professor of psychology in the Department of Psychiatry at Massachusetts General Hospital and director of the MGH Psychology Assessment Center; and, posthumously, the scholars James Gair and Charles Henderson of Cornell University.

Anaphora and ambiguity

To conduct the study, the scholars ran experiments comparing the cognitive performance of aMCI patients to cognitively healthy individuals in separate younger and older control groups. The research involved 61 aMCI patients of Massachusetts General Hospital, with control group research conducted at Cornell and MIT.

The study pinpointed how well people process and reproduce sentences involving “anaphora.” In linguistics terms, this generally refers to the relation between a word and another form in the sentence, such the use of “his” in the sentence, “The electrician repaired his equipment.” (The term “anaphora” has another related use in the field of rhetoric, involving the repetition of terms.)

In the study, the researchers ran a variety of sentence constructions past aMCI patients and the control groups. For instance, in the sentence, “The electrician fixed the light switch when he visited the tenant,” it is not actually clear if “he” refers to the electrician, or somebody else entirely. The “he” could be a family member, friend, or landlord, among other possibilities.

On the other hand, in the sentence, “He visited the tenant when the electrician repaired the light switch,” “he” and the electrician cannot be the same person. Alternately, in the sentence, “The babysitter emptied the bottle and prepared the formula,” there is no reference at all to a person beyond the sentence.

Ultimately, aMCI patients performed significantly worse than the control groups when producing sentences with “anaphoric coreference,” the ones with ambiguity about the identity of the person referred to via a pronoun.

“It’s not that aMCI patients have lost the ability to process syntax or put complex sentences together, or lost words; it’s that they’re showing a deficit when the mind has to figure out whether to stay in the sentence or go outside it, to figure out who we’re talking about,” Lust explains. “When they didn’t have to go outside the sentence for context, sentence production was preserved in the individuals with aMCI whom we studied.”

Flynn notes: “This adds to our understanding of the deterioration that occurs in early stages of the dementia process. Deficits extend beyond memory loss. While the participants we studied have memory deficits, their memory difficulties do not explain our language findings, as evidenced by a lack of correlation in their performance on the language task and their performances on measures of memory. This suggests that in addition to the memory difficulties that individuals with aMCI experience, they are also struggling with this central aspect of language.”

Looking for a path to treatment

The current paper is part of an ongoing series of studies that Flynn, Lust, Sherman, and their colleagues have performed. The findings have implications for potentially steering neuroscience studies toward regions of the brain that process language, when investigating MCI and other forms of dementia, such as primary progressive aphasia. The study may also help inform linguistics theory concerning various forms of anaphora.

Looking ahead, the scholars say they would like to increase the size of the studies as part of an effort to continue to define how it is that diseases progress and how language may be a predictor of that.

“Our data is a small population but very richly theoretically guided,” Lust says. “You need hypotheses that are linguistically informed to make advances in neurolinguistics. There’s so much interest in the years before Alzheimer’s disease is diagnosed, to see if it can be caught and its progression stopped.”

As Flynn adds, “The more precise we can become about the neuronal locus of deterioration, that’s going to make a big difference in terms of developing treatment.”

Support for the research was provided by the Cornell University Podell Award, Shamitha Somashekar and Apple Corporation, Federal Formula Funds, Brad Hyman at Massachusetts General Hospital, the Cornell Bronfenbrenner Center for Life Course Development, the Cornell Institute for Translational Research on Aging, the Cornell Institute for Social Science Research, and the Cornell Cognitive Science Program.


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