Disorders of cognition

Perhaps the commonest cognitive complaint presenting in the clinic is gradually worsening memory. Symptoms of forgetfulness may simply be due to mild depression, but equally can be the harbinger of neurodegenerative illness such as Alzheimer’s disease. In order to exploit fully the clinical examination in making the diagnosis, it is essential for the clinician to have a detailed understanding of the anatomy, physiology, and pathology of memory. There are many different types of memory, e.g. learning a name and address, recalling a previous holiday, knowing the capital of France. These different types of memory rely on different brain structures. Disease affecting different areas of the brain can therefore result in different types of memory impairment.

MEMORY AND ITS DIVISIONS

The taxonomy of memory is complex, but the broadest distinction is between explicit and implicit memory (80). Explicit memory refers to memories which can reach consciousness. By contrast, implicit

memory refers to unconscious learned responses, including conditioning and motor skills, which rely on cerebellum and basal ganglia.

Knowledge of the neural substrates underlying the above subcomponents of memory allows the clinician detecting a memory deficit to know which brain structures are affected.

Explicit memory is divided into short-term (or working) and long-term memory. Strictly speaking, short-term memory refers to a system that retains information for seconds at most, while long-term memory refers to memories held even for as short as a few minutes. These terms are widely misused by clinicians, who use short-term memory to mean events of a few weeks’ or months’ standing, and longterm memory to refer to memories of years’ standing. The terms will be used here as correctly defined by neuropsychologists.

Short-term memory can be tested by digit span or by asking a patient to immediately repeat a name and address. Working memory requires the frontal lobes, language areas for verbal material such as digit span,

and nondominant hemisphere for visual material. Asking a patient to recall a name and address given 10 minutes previously, or anything longer tests longterm memory. 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.

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Fornix

81 Diagram illustrating the anatomy of the limbic system.

Table 12 Divisions within long-term memory

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.

Table 13 Causes of memory impairment

HSV: herpes simplex virus.

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 neurodegenerative 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 visuoperceptual 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.

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82 Magnetic resonance image showing anterior temporal lobe atrophy in semantic dementia, i.e. temporal variant frontotemporal dementia.

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

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.

83 Magnetic resonance image showing medial temporal atrophy in Alzheimer's disease.

84 Single photon emission computed tomography scan showing temporo-parietal hypoperfusion in Alzheimer's disease.