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  • Updated 07.23.2020
  • Released 11.24.1997
  • Expires For CME 07.23.2023

Memory loss



In this article, the authors provide an overview of memory loss and its most common presentations in the clinical setting (mild cognitive impairment, Alzheimer disease, vascular dementia, dementia with Lewy bodies, Wernicke-Korsakoff syndrome, and chronic traumatic encephalopathy). Risk factors for mild cognitive impairment are reviewed, along with lifestyle changes that have been suggested to slow progression from mild cognitive impairment to dementia.

Key points

• Early-onset Alzheimer disease patients are more likely to be younger, male, and have atrophy in both parietal lobes, rather than in medial temporal lobes, as is seen in late-onset Alzheimer disease. They also have more problems with language, attention, visuospatial function, and executive tasks, compared to the memory loss seen in late-onset typical or limbic-predominant Alzheimer patients.

• Chronic traumatic encephalopathy causes early memory loss in boxers, football players, and war veterans. The neurofibrillary tangles and extracellular plaques in the brains of these patients at autopsy are similar to those seen in the brains of Alzheimer disease patients, but chronic traumatic encephalopathy is defined pathologically by an abnormal accumulation of tau protein that is different from the pattern seen in Alzheimer disease. The duration of football played bears a strong dose-response relationship to the severity of neuropathology in these patients.

• There has been a recent cluster of young people (mean age = 35 years) who developed anterograde amnesia after waking up after acute episodes of substance abuse (62% involving heroin or other opiates). MRI in several of these patients showed ischemic changes in both hippocampi.

• Longitudinal studies in older adults have demonstrated that a higher level of total daily physical activity is associated with reduced risk of cognitive decline and Alzheimer disease. Animal studies have shown that both exercise and sleep accelerate glymphatic clearance of beta amyloid from the brain and reduce the accumulation of amyloid plaques.

• Several longitudinal cohort studies have followed biomarker profiles of brain amyloid, brain tau, and neurodegeneration in cognitively normal older adults over a mean of seven years and have found that abnormal markers of both amyloid and tau are necessary for the occurrence of the accelerated neurodegeneration and memory loss that precedes Alzheimer disease. Subtle cognitive changes can be measured before or concurrently with early Alzheimer biomarker changes before signs of mild cognitive impairment appear.

Historical note and terminology

Wernicke-Korsakoff syndrome. In 1881, Carl Wernicke described two male alcoholics and one female with persistent vomiting who presented with acute confusion and ataxia (all three died by the end of two weeks). In 1887, Sergei Korsakoff reported 20 patients with either alcoholism or vomiting who developed chronic memory loss and polyneuropathy. We now use the term “Wernicke-Korsakoff syndrome” to describe this biphasic illness, where the acute phase is called Wernicke encephalopathy, and the chronic disorder is known as Korsakoff syndrome (145). MRI signs of Wernicke-Korsakoff syndrome include the chronic signs of shrunken mammillary bodies and acute signs of hyperintense T2 signal in thalami and periaqueductal grey (154).

Vascular dementia. In 1894, Otto Binswanger wrote about eight patients who were middle-aged when they developed acute confusion, then chronic memory loss, focal neurologic signs, gait disorder, and functional impairment. Their memory disorder fluctuated over time, but at autopsy all of them showed evidence of diffuse subcortical demyelination with sparing of cortical neurons. Hypertension and diabetes are the most important risk factors for vascular dementia, especially the subtype known as Binswanger disease (62; 110).

Alzheimer disease. In 1906, Alois Alzheimer described two women who experienced the insidious onset of memory problems in their 50s. Their memory disorders steadily progressed, and when they died several years later, Dr. Alzheimer found microscopic changes (tangles and plaques) in and around cortical neurons. Genetic analysis from one of these first patients identified a point mutation in the presenilin 1 gene, leading to a Phe176Leu amino acid substitution (111). This could explain the early memory loss in this first case.

In 2007, research criteria were developed to capture Alzheimer disease patients at their very earliest stage when there is a problem with episodic memory, but before full-blown dementia appears. These criteria stipulate that in addition to memory loss, there must be an abnormality in at least 1 or more biomarker, including thinning of the entorhinal cortex (MRI), amyloid or tau accumulation (PET), and/or an abnormality in CSF protein (beta-amyloid or tau) (37).

Frontotemporal dementia. In the late 19th century, Arnold Pick described the first cases of frontotemporal dementia (170). Now, frontotemporal dementia refers to a diverse group of disorders that involve atrophy of specific areas of the frontal or temporal lobes, or both (brain MRI and neuropsychological testing are both needed for an accurate diagnosis). The presenting features are behavioral changes (behavioral variant), language problems (progressive nonfluent aphasia, semantic dementia), or behavioral changes associated with motor neuron disease rather than memory loss.

Dementia with Lewy bodies. Lennox and others described diffuse Lewy body disease as being different from Alzheimer disease in that it has a more fluctuating clinical course, extrapyramidal signs, well-formed visual hallucinations, and increased sensitivity to neuroleptic drugs (92). An autopsy study from one large dementia clinic in North America showed that dementia with Lewy bodies accounted for at least 20% of the total number of brains, although many of these brains showed features of Lewy body disease and Alzheimer pathology (14). Besides dementia, dementia with Lewy body patients must have at least 2 of these 4 clinical features for a probable diagnosis: (a) visual hallucinations, (b) fluctuating levels of alertness, (c) signs of parkinsonism, or (d) REM sleep disorder (104).

Mild cognitive impairment. In 1999, Petersen and others described mild cognitive impairment as being a transitional state between normal aging and dementia (127). Symptoms of mild cognitive impairment can vary depending on whether they are preclinical manifestations of Alzheimer disease (memory complaints), vascular dementia (executive dysfunction), dementia with Lewy bodies (fluctuations in cognition), or other dementias (65; 108). Duff and others showed that nearly 40% of those genetically at risk for Huntington disease meet criteria for mild cognitive impairment (38), just as about 40% of Parkinson patients have mild cognitive impairment (82). In 2019, the AAN Quality Improvement Committee defined someone with mild cognitive impairment as having acquired objective cognitive deficits that were insufficiently severe to affect most usual daily activities (43).

Chronic traumatic encephalopathy. In 2009, McKee and others described a condition in football players and war veterans that is now known as chronic traumatic encephalopathy (103). In these brains, there are deposits of neurofibrillary tangles of tau protein and extracellular amyloid plaques that are similar to those seen in Alzheimer disease. These brains also look similar to those of boxers (dementia pugilistica). Jordon and others earlier showed that the risk of dementia was higher in victims of sports injuries if they had one or two of the apolipoprotein E epsilon 4 alleles (72).

Subjective cognitive decline. When patients complain of memory loss, but have unimpaired performance on cognitive tests, we say that they have subjective cognitive decline (142). The newest criteria for subjective cognitive decline have been reported by the Subjective Cognitive Decline Working Group (68). Stage 3 of preclinical Alzheimer disease, for example, is defined by biomarker evidence for Alzheimer disease plus subjective cognitive decline without the objective cognitive impairment that is seen with mild cognitive impairment. One study provided evidence that subtle cognitive decline can sometimes precede the accumulation of beta-amyloid or the thinning of the entorhinal cortex in cases of preclinical Alzheimer disease (159).

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