80 Diagram to show the components of memory.
LTM: long-term memory;
STM: short-term memory.
80
Memory
Explicit (declarative)
Implicit (procedural)
STM
(working) LTM Conditioning Priming Motor skills
Verbal Spatial Episodic (event)
Semantic (fact)
and nondominant hemisphere for visual material.
Asking a patient to recall a name and address given 10 minutes previously, or anything longer tests long-term memory. Long-long-term memory is further subdivided into episodic and semantic memory:
episodic memory refers to personally experienced events (e.g. recalling a conversation earlier in the day or a previous holiday), while semantic memory refers to facts, concepts, and words and their meaning (e.g.
boiling point of water, capital of France). Episodic memory and semantic memory require different brain regions. While semantic memory utilizes mainly dominant temporal neocortex, the structures crucial for establishing and retrieving episodic memories appear to be components of the limbic system (81).
The limbic system comprises the hippocampus, the thalamus and mamillary bodies, and the basal
forebrain. Although all limbic structures are involved in episodic memory, different components have differing roles (Table 12). The hippocampus is primarily involved with laying down new memories, and consolidating recently acquired ones.
Hippocampal pathology can cause difficulty encoding new ongoing memories (i.e. an anterograde amnesia) and impaired consolidation of those very recently acquired, before injury (i.e. a temporally-limited retrograde amnesia). The thalamus, by contrast, is involved not only in laying down new memories, but also in retrieving previously acquired memories.
Thalamic pathology (e.g. Korsakoff’s syndrome, thalamic infarction) will manifest clinically as an anterograde amnesia with a temporally extensive retrograde amnesia, i.e. patients have difficulty in recalling events which occurred years or decades before the onset of the pathology.
Memory disorders
The practical relevance of knowing the above anatomy is that identifying a specific type of memory disorder will allow the clinician to localize the site of the pathology. Accepting the above subdivisions, it should be noted that there are many different types of memory disorder, the commonest of which will be described here. Memory disorders may be pure (i.e. amnesias) or mixed (with additional cognitive deficits, i.e. confusion if acute, dementia if chronic). Table 13 presents the causes of memory impairment.
81 Diagram illustrating the anatomy of the limbic system.
81 Fornix
Mamillothalamic tract
Hippocampus Mamillary body
Anterior nucleus of
thalamus
Table 12 Divisions within long-term memory
Type Role Neural substrate
Episodic New learning, retrieval Limbic system of autobiographical
events
Semantic Knowledge of Temporal neocortex the world
Implicit Motor skills, Basal ganglia, e.g. playing a cerebellum musical instrument
Table 13 Causes of memory impairment
Type Pure amnesia Mixed
Transient Transient global amnesia Delirium Transient epileptic amnesia
Drugs
Psychogenic amnesia
Persistent Dementia
Hippocampal
❏ Early Alzheimer's disease
❏ HSV encephalitis Diencephalic
❏ Korsakoff's syndrome HSV: herpes simplex virus.
Cingulate gyrus Corpus callosum
Acute transient disorders of episodic memory
Many pathological conditions are responsible for transient impairment of episodic memory. Any disorder that transiently impairs medial temporal function will result in a reversible episodic memory deficit.
Transient global amnesia is a disorder in which the patient becomes acutely amnesic for several hours, usually with a cycle of repetitive questions. It is benign, tends not to recur, and is thought to have a migrainous basis. Psychogenic amnesia results in loss of previous autobiographical memory and may result in loss of personal identity, which almost never occurs in organic disease. There is usually a major precipitating life event, and usually a psychiatric background. The condition may last for up to months. Epilepsy can occasionally present as transient episodes of pure amnesia, but this usually occurs in the context of more obvious seizures.
Chronic disorders of episodic memory – the amnesic syndrome
Here, there is inability to learn new information, but there can also be a retrograde amnesia of variable duration. It is broadly divided into hippocampal and diencephalic amnesia. Hippocampal damage results in dense anterograde amnesia with temporally limited retrograde amnesia, while parahippocampal pathology can cause a more extensive retrograde amnesia.
Hippocampal pathology may arise as a result of conditions as varied as herpes simplex virus (HSV) encephalitis, hypoxia, or early Alzheimer’s disease.
In diencephalic amnesia, in addition to anterograde amnesia, there is an extensive retrograde amnesia with a temporal gradient (i.e. relative preservation of distant memories). A classic example of this is Korsakoff’s syndrome, in which acute thiamine deficiency results in damage to the mamillary bodies. Bilateral thalamic infarcts or third ventricle tumours may also damage the diencephalon.
Disorders of semantic memory
Damage to temporal neocortex classically occurs in semantic dementia (temporal variant fronto-temporal dementia) (82). The pathology affects the temporal neocortex and tends to spare the hippocampus, resulting in profound semantic memory impairment with relative sparing of episodic memory. On occasion, HSV encephalitis or stroke may selectively impair semantic memory.
Mixed disorders of episodic and semantic memory
The above discrete syndromes are useful for delineating the functional neuroanatomy of memory.
In practice, mixed episodic and semantic memory disorders are more common, such as occur in neuro-degenerative disease such as Alzheimer’s disease.
CLINICAL ASSESSMENT
History taking from the patient and relative is crucial to the diagnostic process for memory disorders. In assessing a patient complaining of memory impairment, the following questions need to be addressed:
❏ Is there a memory problem?
❏ If yes, what aspect(s) of memory is/are affected?
❏ What is the neuroanatomical substrate?
❏ Is the memory problem transient or chronic?
❏ Is it a pure amnesia or a mixed picture (i.e. is it purely a memory problem, or are others aspects of cognition such as language or
visuo-perceptual function also impaired)?
❏ Are the memory complaints organic?
❏ Does the tempo of the illness suggest the likely pathological process?
❏ If the clinical picture suggests dementia, is the pathology likely to be cortical or subcortical?
❏ Which disease is causing the dementia?
The patient interview
Patients with memory complaints are often aware that the possibility of dementia is being considered.
Initial questions regarding background (occupation, family circumstances) will establish rapport, and establish whether history taking from the patients themselves will be informative. It is helpful to establish whether the patient knows why they have been referred to the clinic. Further open-ended questions regarding how symptoms began, what current difficulties there are, and the effect this has had on activities are worth recording, as they illustrate the extent of the problem.
It is imperative to know what is meant by ‘poor memory’. This can be used to mean forgetting the names of things or people (semantic memory), forgetting new information or past events (episodic memory), or forgetting what one has gone into a room to get (attention). A further useful distinction is between memories acquired before and after onset of pathology (i.e. anterograde and retrograde). It is, however, not always easy to determine the date of onset of pathology, especially in early dementia,
whereas this is straightforward in the case of head injury or acute stroke. Specific probing questions can elucidate which aspects of cognition are impaired.
With regard to the subdivisions within memory, the most important issue is whether the patient can learn new information, as impaired anterograde episodic memory is the first manifestation of Alzheimer’s disease. This can be assessed by whether the patient can recall conversations, describe current affairs, or current TV programmes. Has the patient started to make lists, become repetitive, or started frequently to lose things at home? Retrograde memory can be assessed by asking autobiographical questions (e.g.
holidays, previous houses) or asking about old news events, which occurred before the onset of symptoms.
Semantic memory can be assessed by testing general factual knowledge (e.g. capitals of countries, names of people, places, and things). Is there a recent history of word-finding and naming problems, or loss
of meaning of less common words? The patient’s employment, education, and premorbid intelligence quotient (IQ) must be taken into account in assessing a patient’s cognitive status, especially when testing semantic memory. Specific difficulties indicating a language disorder include word-finding problems, word errors, grammatical mistakes, difficulty understanding words and grammar, or problems with reading and writing. Ability to dress and route finding are a measure of visuo-spatial function. It is always worth enquiring about mood, energy, sleeping and eating patterns, as depressive pseudodementia can superficially resemble early dementia.
The informant interview
Relatives can often identify when symptoms were first noted, and what the initial symptom was. This is of diagnostic use as different dementias present specifically, while latterly they merge. The suddenness of onset and rate of progression are again diagnostically useful. How symptoms sequentially have affected activities of daily living is also informative.
Other history
Past medical history should pay particular attention to previous head trauma, epilepsy, meningitis, or psychiatric illness. Drug history is important, as is family history. Alcohol and other drug consumption is also relevant.
Clinical examination
In addition to the general and neurological examinations, the bedside cognitive examination is crucial in the patient with memory disorder. While it is important to assess all aspects of cognition (e.g.
language, visuo-spatial function) to see if the memory complaint is part of a more widespread dementing illness, the following will focus on memory in particular.
The Mini-Mental State Examination (MMSE) is a widely used test, initially developed as a screening tool for dementia. Due to its brevity it has several limitations. In terms of this chapter, it has deficiencies in assessing memory. The ability to learn and retain new information is very important in bedside cognitive testing of memory, as impaired delayed recall is often the first indication of early Alzheimer’s disease. In the MMSE, the patient is asked to remember three items. The ability to subtract 7 from 100 repeatedly is then tested, and then the patient is 82 Magnetic resonance image showing anterior temporal lobe
atrophy in semantic dementia, i.e. temporal variant fronto-temporal dementia.
82
asked to recall the three items. This is not properly delayed recall, as insufficient time is allowed to pass before testing recall. An intelligent patient may do serial 7s very quickly, and may in fact have been holding the three items in working memory during this task, so that recall of three items is not in fact testing true delayed episodic memory.
In an effort to improve on this, the Addenbrooke’s Cognitive Examination (ACE) significantly expands on bedside testing of memory.
In addition to the MMSE, the patient is also given a name and address to remember. To ensure that they have had a chance to register the new information, the address is given three times. Secondly, delayed recall is not tested until towards the end of the ACE, with many intervening items having been given in the interim. It is thus a proper test of delayed recall.
The ACE also assesses semantic memory through category fluency (as many animal names in 1 minute), and in more rigorous testing of object naming. It is brief enough to use in a busy outpatient setting. It is clearly shorter than a full neuropsychological assessment but serves to screen those patients who might require more detailed neuropsychology.
Bedside cognitive function comprises tests of orientation, attention, frontal executive function, memory, language, calculation, and praxis and right hemisphere function. Given that this chapter refers to forgetfulness, comment is restricted to those components that assess memory.
Working (or short-term memory) may be assessed using digit span, with items presented at one per second. The patient should be able to repeat at least five digits. For practical purposes, the most important part of memory testing is whether the patient can learn and retain new information. This is best done by giving a name and address three times, testing immediate registration after each presentation, and then testing recall after an interval of not less than 5 minutes. True hippocampal pathology, such as early Alzheimer’s disease, should result in a patient scoring 7/7 on each of the trials of immediate recall, yet scoring 0/7 on delayed recall. By contrast, subcortical pathology, such as depressive pseudodementia, results in impaired immediate registration, e.g. 1, 3, 5/7, yet the proportion retained after an interval is above baseline, e.g. 3/7. This distinction is by no means absolute, but is a useful clinical pointer. Quizzing the patient about previous conversations and so on may also test anterograde memory.
Should a patient fail to recall a name and address, this may be due to either impaired encoding of this information, or failure to retrieve it. By then giving a choice of three items, should the patient tend to choose correctly, then a retrieval defect seems likely.
If, however, they score at no more than chance, then it is likely that information was not encoded in the first place. More detailed assessments of anterograde verbal memory include story recall and word-list learning.
Anterograde nonverbal memory impairment usually parallels that of verbal memory disturbance.
Damage to nondominant hippocampus can cause anterograde nonverbal memory impairment, but there is no easy bedside test of this. Walking a route outside the clinic and asking the patient to repeat it can suffice. Delayed recall of the Rey figure (an abstract design, see 40), also tests nonverbal memory.
Remote memory may also be assessed, e.g. previous major news events, but also autobiographical memory. This is necessarily more subjective and there is significant variation in individuals’ knowledge of famous events. Autobiographical memory also requires cross-verification with relatives to ensure that plausible responses are not merely confabulation.
Semantic memory may be assessed by category fluency, asking for the names of as many exemplars as possible in 1 minute, e.g. animals. Object naming also taps semantic memory.
SUMMARY
❏ The clinician cannot accept a complaint of ‘poor memory’ at face value, but must further clarify what this means.
❏ Different areas of the brain subserve different aspects of memory.
❏ It is often best to interview the patient and informant separately for part of the
examination, as the presence of the patient can inhibit the informant from relaying a clear account of the symptoms.
❏ It is necessary to ascertain whether the cognitive deficit is restricted to memory, or whether other areas of cognition are involved.
❏ Inability to recall a name and address given 10 minutes previously is a useful screening test, which can be of some use in detecting patients with early Alzheimer’s disease.
CLINICAL SCENARIOS
CASE1
A 66-year-old male presents to the Memory and Cognitive Disorders Clinic complaining that his memory is failing. He has been troubled with this for a few months. He has been failing to keep appointments and finds it difficult to follow weekly TV series from one week to the next. He has started using lists for the first time. He denies low mood. His wife has noted forgetfulness for over a
year. It was of insidious onset, and is progressing. He has become repetitive, and does not learn new information. He appears otherwise unchanged, with no alteration of personality
.
Insidious progressive forgetfulness is very suggestive of early dementia. Examples of his memory problems are of failing to keep appointments or to remember TV programmes from one week to the
next, i.e. true episodic memory deficit. The patient denies low mood, making depressive pseudodementia less likely. No early change in personality makes a frontal dementia unlikely
.
On bedside cognitive examination, he was oriented except for the date. Cognitive deficits were restricted to memory. While immediate registration of name and address was normal, delayed recall was poor at 0.
Normal bedside cognitive testing with very poor delayed recall demonstrates a specific deficit of episodic memory. As definitions of dementia require impairment in at least two areas of cognition, he
is not by definition demented. However
, the very early changes of Alzheimer’
s disease affect the
perihippocampal areas, resulting in a pure amnesia initially
. He thus is not demented, but his
progressive amnesia is likely to be due to Alzheimer’
s disease.
Magnetic resonance imaging (MRI) showed bilateral hippocampal atrophy (
83), while single
photon emission computed tomography revealed bilateral temporo-parietal hypoperfusion ( 84). He
was commenced on anticholinesterases.
84 Single photon emission computed tomography scan showing temporo-parietal hypoperfusion in Alzheimer's disease.
84
83 Magnetic resonance image showing medial temporal atrophy in Alzheimer's disease.
83
CASE3
A 60-year-old male was admitted with acute confusion under the influence of alcohol. He was found to be dehydrated, and was given intravenous dextrose infusion. On recovery
, it was noted that he tended to ask nursing staff the same questions repeatedly. He also insisted that he was 25 years old, and needed to go back to his army base.
Repeated questioning suggests that he is amnesic.
His insistence that he is 25 indicates that the amnesia also has a significant retrograde component. The sudden onset of his symptoms precipitated by alcohol raises the possibility of Wernicke’s encephalopathy followed by Korsakoff psychosis. ’s
His sister commented that he was sure it was the 1960s, and he appeared to have no knowledge of his personal life events since then. He was unable to learn new information about the family which she had told him. He had been living alone, on an inadequate diet, and had been drinking heavily before admission.
Inability to learn new information shows that he has anterograde amnesia. His lack of
knowledge of personal events since the 1960s demonstrates retrograde amnesia. The inadequate diet suggests that he may have thiamine deficiency
. Administration of
intravenous dextrose in hospital can precipitate Wernicke–Korsakoff syndrome.
On general examination, he had evidence of a mild peripheral neuropathy
, but also had a broad based gait, and was unable to tandem gait. On bedside cognitive examination, he was disoriented for time, thinking it was 1968. Letter fluency was reduced with perseverations. On testing memory
, he registered name and address, but delayed recall was 0. He had an extensive retrograde memory deficit, and could not describe public or autobiographical events more recent than the 1960s. Language and visuo-spatial function were normal.
(Continued on page 93) CASE2
A 55-year-old female presented complaining of poor memory and concentration. This had come on fairly suddenly 6 months previously. She admitted to early morning wakening and poor appetite. She felt low, but was adamant that this was a consequence of her poor memory. She was worried she had the beginnings of dementia. Her family described her as having become very apathetic and no longer attending to much around her. She had also become more irritable.
Subacute onset of symptoms is not in keeping with early dementia. She has some somatic markers of depression, as well as low mood.
Apathy and irritability are in keeping with depression.
On cognitive assessment, she was poorly oriented for time. She had difficulty with serial 7s, could not spell WORLD backwards and digit span was reduced to four. Category and letter fluency were both reduced. Anterograde memory was impaired: she had great difficulty with immediate registration of name and address. She had a tendency to answer, 'I don’t know' to many questions.
She has problems with tests of attention and concentration. The tendency to say, 'I don’t know' or to give up easily is suggestive of depressive
She has problems with tests of attention and concentration. The tendency to say, 'I don’t know' or to give up easily is suggestive of depressive