Aetiology
Neurodegenerative, inflammatory/infectious, metabolic, vascular, traumatic, episodic, neoplastic, and endocrine processes can all cause memory impairment. These conditions ultimately affect the hippocampal and limbic pathways, albeit through a variety of mechanisms. It is important to take into consideration all causes of memory loss because about 9% of the causes of dementia are potentially reversible.[3]
Neurodegenerative
Neurodegenerative processes that lead to memory loss include:
Alzheimer's dementia (AD). AD is the most common cause of dementia in the ageing population. It is characterised by short-term episodic memory loss (e.g., repetitive questioning, misplacing belongings) in early disease with preservation of long-term memory, personality, social conduct, and motor function until later stages. In the early stages, language problems (e.g., difficulty naming things, difficulty speaking), loss of insight, and mild personality changes (e.g., apathy, depression) might occur. Patients have difficulty in reasoning, abstraction, and judgement. Performing tasks such as planning activities, organising events, and managing money becomes more challenging. As the disease progresses, deficits in visuo-spatial function, problems with driving, prosopagnosia (not recognising familiar faces), and autoprosopagnosia (not recognising oneself in the mirror) may develop. Language difficulties in later disease include non-fluent speech, paraphrasing, and conveying information inappropriately.
Vascular dementia. As well as memory loss, cognitive symptoms include slowed processing, difficulty initiating activity, perseveration in behaviour, disinhibition, difficulty in problem solving or using familiar equipment, and difficulty in managing finances. Slowing of gait, shuffling, feet stuck to the floor when commencing walking, increasing loss of balance, and falls may all be supportive of vascular brain disease. Patients may report depression, hallucinations, and delusions. Temporal relation of cognitive symptoms to a clear clinical stroke event or multiple stroke events may strongly suggest a vascular cause for cognitive impairment. Patients may have risk factors for ischaemic heart disease or cardioembolic disease. Vascular dementia is classically assumed to be a stepwise progression in cognitive symptoms, although a gradual progression is also possible. May co-exist with AD.
Dementia with Lewy bodies (DLB). Core clinical features are: cognitive fluctuations, recurrent visual hallucinations, spontaneous motor signs, and REM sleep behaviour disorder.[4] Symptoms may have some overlap with Parkinson's disease dementia, which is characterised by the development of parkinsonian motor symptoms at least 1 year before dementia. Hallucinations are present in about 80% of patients with DLB.[4] These are typically complex and may include children or animals. Emotional responses to hallucinations vary. Spontaneous motor signs are present in over 85% of patients with DLB and may include bradykinesia in combination with rest tremor, rigidity, or both.[4] Fluctuations in awareness encompass several symptoms, including excessive daytime sleep (>2 hours per day), rambling and illogical thoughts, and frank loss of consciousness. A notable distinguishing feature of DLB compared with AD is attention and visuospatial abnormalities, in contrast to the prominent amnestic syndrome of most cases of AD. Motor signs are diagnostically helpful when they occur early in the disease course. REM sleep behaviour disorder is a common feature of DLB.[5] It often occurs years before other features appear, and manifests as excessive jerking and complex movements during REM sleep.[6]
Frontotemporal dementia (FTD) including sub-types: behavioural variant, semantic dementia, and progressive non-fluent aphasia. FTD is characterised by profound personality changes, social conduct changes, and cognitive decline early in the course of the disease. These changes generally precede the development of memory impairment, disorientation, or apraxia. FTD may also be associated with falls and parkinsonian symptoms. Such features are suggestive of FTD with parkinsonism, corticobasal degeneration, and progressive supranuclear palsy. FTD can also be associated with muscle wasting and weakness, which are suggestive of amyotrophic lateral sclerosis. Patients with semantic dementia lose knowledge of what things are (semantics); they may also experience an inability to recognise emotions on the faces of others and to empathise.
Corticobasal syndrome (typically due to corticobasal degeneration, progressive supranuclear palsy, or AD). Depression, apathy, and/or anxiety early in disease are common behavioural symptoms in corticobasal degeneration. Corticobasal degeneration does not always start with motor symptoms; it can begin with cognitive symptoms, including aphasia.[7] AD might present as corticobasal syndrome with a unilateral cortical syndrome (aphasia, apraxia, neglect).
Progressive supranuclear palsy (also known as Steele-Richardson-Olszewski's syndrome). Progressive supranuclear palsy often presents with early falls, followed by onset of impaired downwards gaze, neck and trunk stiffness, personality changes, dysphagia, and poor response to levodopa therapy.
Creutzfeldt-Jakob disease (CJD). CJD occurs typically between 50 and 70 years of age (peak age 68) and presents with cognitive impairment, visual disturbances, ataxia, and behavioural or personality changes. It has been reported that only about 20% of patients are diagnosed correctly as having CJD at the first assessment. Correct diagnosis is not usually made until a patient is approximately two-thirds through the disease course. CJD is often misdiagnosed as viral encephalitis, paraneoplastic disorder, AD, stroke, or central nervous system vasculitis.[8]
Normal pressure hydrocephalus is a rare and reversible cause of dementia. It classically presents with a triad of memory loss, gait disorder, and urinary incontinence.[9] Magnetic resonance imaging (MRI) shows ventricles out of proportion to any atrophy.
These disorders typically present with a chronic course, although sometimes they are subacute.
When a patient presents to the neurologist with memory loss, the patient or the family is frequently concerned about a neurodegenerative process or dementia. Dementia is often defined as impairment of memory and at least one other cognitive domain that leads to a decline in ability to perform activities of daily living.[10] A more simple definition of dementia requires a decline in more than one cognitive domain (e.g., memory, language, visuospatial, or frontal executive function) that interferes with one's ability to function independently.
In general, memory loss affecting daily functioning is not considered part of normal ageing and an aetiology should be thoroughly investigated.
Patients with memory problems who do not fit a diagnosis of dementia because they are not functionally impaired are often referred to as having mild cognitive impairment (MCI). Deficits in patients with MCI, by definition, are not severe enough to interfere with their normal activities of daily living. The most common form of MCI is amnestic MCI, in which memory is the primary problem. Prevalence increases with age, from about 6% of adults aged 60-64 years to over 25% of adults aged 80-84 years.[11] About 50% of patients diagnosed with amnestic MCI will progress to dementia within 5 years. The rate of progression to dementia is about 12% per year.[12]
MCI can occur in cognitive domains other than memory, including language, visuospatial, and frontal executive (e.g., problems organising, planning, multi-tasking). Less is known about these other forms of MCI. Many feel that MCI is a precursor or a continuum of dementia and that it should be treated proactively, through prevention of cardiovascular risk factors, an active cardiovascular exercise programme, and an active and social lifestyle.[13]
Inflammatory/infectious
Disease processes with infectious (e.g., syphilis, HIV [particularly in setting of seroconversion]) and inflammatory aetiologies (e.g., Hashimoto's encephalopathy, limbic encephalopathy) often have a subacute time course. These conditions frequently result in the production of auto-antibodies that impair the function of circuitry within the limbic system.
Hashimoto's encephalopathy is associated with markedly elevated anti-thyroperoxidase or anti-thyroglobulin antibodies, found in autoimmune thyroiditis, and characterised by rapid dementia with fluctuating symptoms, hallucinations, altered consciousness, cognitive dysfunction, stroke-like symptoms, and seizures. This disorder is also known as steroid-responsive encephalitis associated with autoimmune thyroiditis, because it is usually very responsive to treatment with high-dose steroids, which can help confirm the diagnosis.
Limbic encephalopathy is associated with memory loss, altered awareness, behavioural changes, and sometimes seizures. MRI often shows T2-weighted hyperintensity in the medial temporal lobes.
HIV-associated dementia (HAD) is a marked acquired impairment in cognitive functioning involving at least two ability domains, documented by the performance of at least two standard deviations below demographically corrected means, and associated with a marked impairment in performing daily activities. HIV-associated cognitive disorders represent a spectrum of progressive neurocognitive impairment, of which HAD is the most severe.[14]
In the secondary stage of infection, 25% to 60% of patients develop early neurosyphilis. In addition to memory deficits, patients may have cranial nerve palsy (nerves II and VII), uveitis, iritis, monocular blindness, meningitis, or secondary vasculitis with stroke. Associated symptoms include the classic diffuse, symmetric, copper, maculopapular, possibly pruritic rash of any morphology except vesicular. A rash on the palms or soles is common (11% to 70%). Condylomata lata, patchy alopecia, fever, headaches, and generalised painless adenopathy may also occur in secondary syphilis. The chancre at the original site of infection may still be present.[15]
Tertiary neurosyphilis causes a range of syndromes, including cognitive and motor impairment, which are sometimes grouped under the broad term 'general paresis'. Features of general paresis may include:
personality change
memory impairment
altered mood
confusion
seizures
tremor
Argyll-Robertson pupils.
Herpes simplex virus can cause isolated memory loss through an infectious limbic encephalitis.
Traumatic
Traumatic brain injury (TBI) frequently results in bi-temporal contusions, leading to memory dysfunction. Patients with TBI often have behavioural manifestations in addition to the memory loss. Symptoms may include headache, dizziness, fatigue, noise intolerance, neuropsychiatric symptoms, and signs and symptoms of basal skull fracture (haemotympanum, 'panda' eyes, cerebrospinal fluid leakage from the ear or nose, Battle's sign).
Chronic traumatic encephalopathy (CTE) is a progressive tauopathy occurring after repetitive mild TBI.[16] CTE is primarily associated with boxing, but also occurs from other contact sport such as rugby and wrestling, as well as exposure to blast or concussive injury from military service. CTE often begins with headache and loss of attention and concentration, followed by depression, explosivity, and short-term memory loss. In more severe cases there is often more severe cognitive impairment, including executive dysfunction, difficulty in finding words, and even frank dementia, as well as aggression.
Risk factors for persistent neurocognitive difficulties include early post-traumatic headache, fatigue/fogginess, early amnesia, altered mental status, disorientation (probable risk factor), and prior history of headache (possible risk factor). Furthermore, the APOE e4 genotype is highly associated with chronic cognitive impairments. Pre-existing learning disability may also contribute to post-traumatic cognitive impairment. In athletes who have a history of prior concussion or pre-existing learning disabilities/attention deficit/hyperactivity disorder, obtaining baseline scores on concussion assessment is useful.[17] There are several overlapping pathological features with Alzheimer's disease, but CTE also has distinct pathological features as well, including neurofibrillary tangles at the perivascular regions and the base of sulci, transactive response DNA binding protein TDP-43 positivity, neuronal and axonal loss, and atrophy of frontal and temporal lobes.[16][18]
One cohort study found an association between TBI and dementia.[19] The investigators found that although the risk of dementia diagnosis decreases over time after TBI, it was still evident more than 30 years after the trauma. The association was stronger for more severe forms of TBI and multiple TBIs, and the risk persisted even after adjustment for familial factors.
Endocrine
Hypothyroidism commonly causes memory dysfunction, and is often associated with other symptoms such as fatigue, weight gain, and brittle hair. Disease course is usually subacute or chronic. Response to treatment is often good.
Vascular
Vascular causes include ischaemic or haemorrhagic stroke, and vascular dementia. Vascular dementia is typically chronic, but strokes are acute.
In patients with an ischaemic stroke, there is usually the presence of multiple stroke risk factors (i.e., advanced age, hypertension, coronary artery disease, high cholesterol, diabetes, prior stroke), as well as mental status changes, visual field cut, slurred speech, and numbness. Anterior thalamic infarcts might result in chronic symptoms of apathy or perseveration and memory loss. In patients with a haemorrhagic stroke, there is usually the presence of risk factors (e.g., hypertension, amyloid angiopathy, venous sinus thrombosis, haemorrhagic tumour, arteriovenous malformation), as well as sudden onset of severe headache, or lethargy.
Patients with hypoxic injury secondary to cardiac arrest have been shown to demonstrate episodic memory loss on neuropsychological testing.[20]
Episodic/neurological
Episodic processes, such as seizures, migraine, and transient global amnesia, can cause temporary, reversible periods of memory loss lasting minutes to hours. The memory loss associated with these conditions occurs acutely and is usually temporary.
Seizures are defined as repeated, stereotyped episodes of altered consciousness (in complex seizures) that might be accompanied by generalised tonic-clonic motor activity (generalised tonic-clonic seizures). Risk factors (e.g., prior history of head injury, developmental delay, infantile febrile seizures, prior meningoencephalitis, and intra-parenchymal mass lesions such as tumour) might be present. Confusion and amnesia often occur following a generalised tonic-clonic seizure. A history of tongue biting and urinary incontinence support the diagnosis of a seizure. Patients with temporal lobe epilepsy suffer from chronic deficits of encoding, storage, and retrieval of new information, in addition to memory loss during the seizure.[21] Patients with complex partial non-convulsive status epilepticus may present with altered awareness or affect.
In migraine, episodes of repeated unilateral, throbbing head pain, which may or may not be accompanied by a visual aura, occur. Typically associated with nausea, vomiting, phonophobia, or photophobia. Specific triggers (e.g., wine, cheese) might be elucidated from history. Cognitive symptoms, including memory loss, sometimes occur. Symptoms may last for 4 to 72 hours.
Transient global amnesia is frequently preceded by stress, excessive physical activity, or an emotional event, and resolves spontaneously over hours. Nausea, vomiting, and headache rarely occur with this disorder.
Neoplastic
Mass lesions within or compressing the areas of the brain involved in memory processing and retrieval may cause memory deficit. Patients may present with focal neurological deficits, with signs of elevated intracranial pressure (e.g., headache, diminished consciousness, or nausea and vomiting), or with seizures. Tumours may be benign (e.g., meningioma), primary malignant brain tumours (e.g., astrocytoma), or metastases from cancer in another part of the body. Lung, breast, colorectal and kidney cancer, and melanoma are the most likely to metastasise to the brain.
Metabolic
Toxic-metabolic processes such as Wernicke-Korsakoff's syndrome and vitamin B12 deficiency result from decreased intake or poor absorption of B vitamins.
Wernicke-Korsakoff's syndrome results from thiamine deficiency, which can be caused by alcohol use disorder, bariatric surgery, or malnutrition. The thiamine deficiency in Wernicke-Korsakoff's syndrome leads to preferential involvement of metabolically active structures, such as the mediodorsal thalamic nucleus, fornix, and mammillary bodies.[22] The diagnosis should be considered in any patient with at least two of the following:[23]
nutritional deficiency
altered mental state or memory impairment
oculomotor abnormalities (e.g., nystagmus, ophthalmoplegia)
cerebellar dysfunction (e.g., gait disturbance, ataxia).
Patients with vitamin B12 deficiency often have risk factors for deficiency (e.g., strict vegan diet without vitamin supplements, malnutrition, pernicious anaemia, extensive bowel surgery, institutionalisation, anaemia, gastric atrophy). Vision loss in one eye and cognitive impairment (e.g., irritability, apathy, somnolence, suspiciousness, emotional instability, confusion) might also be present. Vitamin B12 deficiency can also cause white matter lesions.[24]
Disease course is usually subacute or chronic.
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