Failure to Recognize Memory Loss Predicts Alzheimer's Conversion

Pauline Anderson

February 21, 2018

Impaired awareness of or lack of insight into memory loss in patients with amnestic mild cognitive impairment (MCI) is associated with increased Alzheimer's disease (AD) pathophysiology and risk for rapid conversion to dementia, new research shows.

The results indicate that lack of self-awareness, also known as anosognosia, in this patient population is "a very important clinical sign or flag" that a patient with MCI may progress to dementia "very fast," lead study author, Joseph Therriault, a Master's student in Neuroscience, McGill University, Montreal, Quebec, Canada, told Medscape Medical News.

Another author, Pedro Rosa-Neto, MD, PhD, associate professor of neurology, neurosurgery, and psychiatry at McGill University, told Medscape Medical News that the findings underline the importance of asking not just patients themselves but also their caregivers about lack of awareness of cognitive decline.

The study was published online February 14 in Neurology.

Alzheimer's Pathology

Clinicians have long suspected that patients with MCI who are unaware of their illness are at a higher risk for rapid progression to dementia, but this hasn't been empirically demonstrated in the literature, said Therriault.

For the study, investigators accessed the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. The goal of ADNI is to test whether serial MRI, positron emission tomography (PET), other biological markers, and clinical and neuropsychological assessments can be combined to measure the progression of MCI and early AD.

To determine impaired awareness of cognitive deficits, researchers used patient and caregiver scores on the everyday cognition (ECog) questionnaire. The ECog asks participants to compare current cognitive abilities, such as episodic memory and planning, to those 10 years earlier.

Discrepancies in scores between patient and caregiver that were lower than 0.5 indicated impaired self-awareness. Although the Ecog is not strictly a measure of self-awareness, this cutoff provides a reliable degree of confidence in separating impaired from intact self-awareness, said Therriault. 

The study included 468 patients with amnestic MCI (mean age about 71.5 years). Of these, 293 patients had intact self-awareness and 175 had impaired self-awareness.

The two groups did not differ on Mini-Mental State Examination scores, but the impaired awareness group had lower global cognitive ability as measured by the Alzheimer's Disease Assessment Scale-cognitive subscale and performed worse on verbal memory and delayed recall tests.

Researchers evaluated associations between self-awareness status and baseline levels of brain β-amyloid (Aβ) as measured by [18F] florbetapir PET, and cerebrospinal fluid (CSF) levels of Aβ, total tau, and phosphorylated tau (p-tau).

In addition, they investigated glucose metabolism using [18F] fluorodeoxyglucose PET at baseline and at 24-month follow-up.

They looked at various regions of the brain, including the precuneus, prefrontal, orbitofrontal, parietal, temporal, anterior, and posterior cingulate cortices (PCC).

Compared with patients with intact self-awareness, those with impaired self-awareness had increased AD pathophysiology "across the board" at baseline, said Therriault.

They had higher levels of brain amyloid and of CSF p-tau and total tau and lower Aβ. Lower Aβ concentrations in CSF indicate higher concentrations in the brain. The authors adjusted for age, sex, years of education, and APOE ε4 status.

Key Brain Region

Patients with impaired self-awareness had increased amyloid deposition in the PCC compared with individuals with intact self-awareness. They also had signs of hypometabolism in the PCC.

"This is a structure in the brain that's known to be involved in self-referential mental processing and in retrieval of autobiographical memories," Therriault noted.

"When you project yourself mentally into a future situation or you imagine yourself in a past situation, you're often using the PCC of the brain, so it's vey interesting to see that the individuals who had impaired awareness also had hypometabolism in the structure that is involved in self-awareness."

The PCC is a "very important brain region" that is "essentially the output of the memory system" and is "highly connected with the hippocampal memory system," added Rosa-Neto.

Although decreased metabolism in the PCC is regarded as a key feature of the early clinical stages of AD, the precise mechanisms of decreased metabolism in the PCC leading to anosognosia in MCI is not known, the authors note.

The analysis also showed that impaired self-awareness in MCI predicts lower [18F]FDG uptake at 24 months not only in the PCC but also in the bilateral medial temporal lobes, right lateral temporal lobe, and basal forebrain.

Study participants with impaired awareness had almost a threefold increased likelihood of conversion to dementia within a 2-year time frame (odds ratio [OR], 2.86; 95% confidence interval [CI], 1.6 - 5.25.)

The only other factor more closely associated with diagnostic conversion at 24 months was APOE ε4 status (OR, 3.42; 95% CI. 1.88 - 6.39).

Lack of self-awareness appeared to be more common among men than women. In the intact self-awareness group, 69.5% were female, compared with 30.5% in the impaired self-awareness group.

It's not clear why this is, but it's consistent with other studies, said Therriault.

"It's really hard to know whether this is driven by the gender or sex, or if it's more a sociological phenomenon where men may be less likely to admit certain problems even if they're aware of them."

This, he added, is "an excellent question for future research."

Patients' awareness of cognitive decline is not incorporated into standard screening procedures said Rosa-Neto, but can be detected by asking a simple question: Is the patient aware of memory problems?

Clinicians can also use several questionnaires, including the ECog, to assess self-awareness, Rosa-Neto added.

Validated Scale Needed

The ECog is not validated for anosognosia, and when used in amnestic MCI, cognitive impairment may be underestimated, Pinky Agarwal, MD, Evergreen Health, Kirkland, Washington, professor of neurology, University of Washington, and a fellow of the American Academy of Neurology, told Medscape Medical News.

"One limitation of this study is that if a caregiver is currently spending 10 hours per week, but has not known the patient for several months or years, for example, a paid caregiver, their report of ECog may not be reliable," said Agarwal.

"We need a validated scale for anosognosia to make screening easier in clinical practice to predict conversion" of MCI patients to AD.

Whatever tool is used, Therriault stressed the importance of asking both the patient and the caregiver or partner about memory deficit.

"In this study, the clinically meaningful information is not just from the patient, and not just from the caregiver, but kind of in the discrepancy between the two. If there's a discordance between the two opinions, that's very, very meaningful information."

Although no current treatments can delay progression to dementia, there are advantages to knowing that a patient has impaired self-awareness and is at high risk for developing dementia within a very short time frame, said Rosa-Neto.

For example, patients and families might want to make immediate lifestyle decisions and opt to be included in a clinical trial, he said.

Agarwal noted that the study is "well designed" and highlights the importance of screening for anosognosia in patients with MCI.

Although a "substantial proportion" of individuals with MCI convert to AD over 2 to 5 years, not all will do so because of heterogeneity in the underlying pathology, said Agarwal.

"It would have been useful to have control groups in the study — for example, normal individuals and multiple-domain MCI — to deal with the confounding effect."

She emphasized the importance of prospective population-based studies to assess conversion of amnestic MCI to AD in patients with anosognosia.

Therriault, Rosa-Neto, and Agarwal have disclosed no relevant financial relationships.

Neurology. Published online February 14, 2018. Full text

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