Dementia is a condition characterized by a generalized deterioration in brain function. Dementia most commonly affects the elderly; about 1 in 20 people over the age of 65, and up to 1 in 5 people over the age of 80, have the disorder

Causes and types

Dementia is caused by damage to brain tissue. It is most commonly due to Alzheimer's disease, which causes changes in the structure and chemistry of the brain. The second most common form is multi-infarct dementia. In this condition, narrowed or blocked arteries in the brain deprive the tissue of blood and oxygen; repeated small strokes (episodes of tissue damage due to a lack of blood) occur, causing deterioration that develops gradually and in stages. Other, less common forms of dementia include Lewy body dementia (in which small, spherical structures called Lewy bodies appear in the brain tissue); AIDS-related dementia; and deterioration that occurs as a result of progressive brain disorders such as Parkinson's disease.

Symptoms

The main symptoms of dementia are progressive memory loss, disorientation, and confusion. The affected person may not remember recent events, he or she may become easily lost in a familiar neighbourhood, and may be confused over days and dates. These symptoms may come on gradually and they may be hardly noticeable at first; in addition, the person may cover up any problems by confabulation (making up explanations in order to fill the gaps in his or her memory). Sudden outbursts or embarrassing behaviour may be the first obvious signs of dementia. Unpleasant personality traits may be magnified; families of those affected may have to endure accusations, unreasonable demands, or even assault. Paranoia, depression, and delusions may occur as the disease progresses. Irritability or anxiety gives way to indifference towards all feelings and events. Personal care and hygiene are neglected, and speech becomes incoherent. Affected people may eventually need total nursing care.

Treatment 

The management of the most common Alzheimer-type illness is based on the treatment of symptoms. The affected person should be kept clean and well-nourished, in comfortable surroundings and with good nursing care. Sedative drugs may be given to reduce restlessness or paranoid beliefs. These measures can help to ease distress for both the patient and their family. For some people with mild to moderate Alzheimer's disease, drug treatment with acetylcholinesterase inhibitors such as donepezil may halt the deterioration in mental function, or may even restore function to the level the person experienced six months previously. Regardless of treatment, however, Alzheimer's disease is progressive, and usually leads to death within 10 years of onset.

Dementia in more detail

The relative frequencies of causes of dementia differ depending on age, but it is notable that Alzheimer’s disease is the most common cause in both groups. The genetic forms of Alzheimer’s disease and other rarer causes are more common in the younger age group. Before considering the common and treatable causes of dementia, we discuss the main differential diagnoses to be considered as alternatives to dementia.

Differential diagnosis

Definition

Alzheimer’s disease is the most common cause of dementia. Of the 5 to 10% of the population aged over 65 years who have some kind of cognitive decline, over 50% of cases will be due to Alzheimer’s disease and, although accounting for a smaller percentage of presenile cases, Alzheimer’s disease is still the single largest cause. The initial disease description by Alzheimer in 1907 was of a woman in her 50s with a progressive dementia and behavioural disturbance, who was found to have neurofibrillary tangles and amyloid plaques throughout her cerebral cortex. The term ‘Alzheimer’s disease’ was then applied to similar cases with a presenile dementia, before it was realized that identical pathological changes were seen in most elderly demented patients. As plaques and tangles are found in a very high proportion of nondemented older individuals, debate continues about whether Alzheimer’s disease represents a continuum or a distinct disease process that increases in frequency with age. With recognition of a number of causative gene mutations (see below), Alzheimer’s disease is now generally believed to be a multifactorial disease with familial and sporadic forms.

Histological diagnosis remains the ‘gold standard’, but current research criteria, such as the widely used NINCDS-ADRDA (Table 3), are accurate in up to 90% of cases. Rather than merely being a diagnosis of exclusion, Alzheimer’s disease is now recognized as a clinicopathological entity amenable to positive diagnosis. Much recent research has focused on methods of early and accurate diagnosis, which is particularly important in view of the advent of potential disease-modifying treatments.

Epidemiology and risk factors

Age is the most important overall risk factor for Alzheimer’s disease. A positive family history is also a risk factor, although autosomal dominant presentations account for less than 5% of cases. To date, three major causative gene mutations have been established: mutations in the presenilin genes I and II on chromosome 14 and 1, respectively, and involving the amyloid precursor protein (APP) gene on chromosome 21. In these families the onset is invariably at an early age (35 to 55 years), with remarkable consistency within families and, as with Huntington’s disease, penetrance is complete. Dementia is rapidly progressive and seizures and myoclonus are common. Individuals with Down’s syndrome (trisomy 21) develop Alzheimer’s disease during their third and fourth decades. This is thought to be due to the extra copy of the amyloid precursor gene on chromosome 21.

Apolipoprotein E (ApoE) is a risk factor rather than a causative gene for Alzheimer’s disease in both early and late-onset cases, which at present is thought to be the single most common genetic determinant of a susceptibility to late-onset Alzheimer’s disease. ApoE is a component of several classes of plasma and cerebrospinal fluid (CSF) lipoproteins. The brain is the most important site of ApoE production outside the liver, and ApoE is thought to be important in lipid homoeostasis in the brain. There are three common alleles for the ApoE gene: ε2, ε3, and ε4. One or two ε4 alleles confer an increased risk of Alzheimer’s disease and lower the age of onset in a ‘dose-dependent’ fashion.

Many meticulous epidemiological studies have established that women are at an increased risk for Alzheimer’s disease, even after adjusting for confounding factors such as the increased longevity of women and their over-representation in the elderly population, and the increased vascular disease in men. Possible explanations include hormonal effects and the postmenopausal loss of the potentially protective effects of oestrogen. Significant head trauma in earlier life is also a risk factor that may summate with ApoE status, and there appears to be an unexplained protective effect of nonsteroidal anti-inflammatory drugs.

Pathology

Pathologically, the macroscopic features of Alzheimer’s disease are cortical atrophy, particularly involving the medial temporal lobe and parietotemporal association areas, with relative sparing of the primary sensory motor and visual cortices. The pathological process is thought to start in the entorhinal cortex, hippocampus, and other medial temporal lobe structures before spreading to the temporoparietal neocortex and basal frontal cortex, and then to the other association areas. The histological hallmarks are the senile plaques and neurofibrillary tangles. Neither lesion is specific for Alzheimer’s disease, as both are found to a lesser extent in the ageing brain; neurofibrillary tangles are also seen in a range of diseases, including progressive supranuclear palsy, encephalitis lethargica, postencephalitic parkinsonism, cerebral trauma, and dementia pugilistica.

Neurofibrillary tangles are formed from bundles of paired helical filaments that replace the normal neuronal cytoskeleton. The central core of the paired helical filaments is the microtubule-associated protein tau. The abnormal phosphorylation of the tau protein causes the microtubular abnormalities and the subsequent collapse of the cytoskeleton. The neurofibrillary tangles are seen as intensely staining intraneuronal inclusions with silver stains or specific anti-tau immunochemistry.

The senile or neuritic plaque is the other major lesion found in Alzheimer’s disease. Plaques range in size from 50 nm to 200 nm and consist of an amyloid core with a corona of argyrophilic axonal and dendritic processes, amyloid fibrils, and microglia. The amyloid core is composed of 5- to 10-nm filaments made up of a 40 to 43 amino acid peptide referred to as Aβ peptide because of its secondary structure of β-pleated sheets. The use of antibodies against Aβ reveals more widespread deposition of amyloid throughout the neocortex, especially in layers II, III, and V. The role of microvascular pathology in Alzheimer’s disease remains controversial. Cerebral congophilic angiopathy can be seen in a high proportion of cases and almost certainly contributes to the hyperintense lesions commonly seen on T ₂-weighted MRI.

Besides a reduction in synaptic loss from neurons, which may explain some cognitive sequelae of the pathology, there is a major loss of neurotransmitters— especially of acetylcholine. The ‘cholinergic hypothesis’ of neurotransmitter loss causing attentional and mnemonic dysfunction has been much investigated. There is certainly evidence of severe neuronal loss in the nucleus basalis of Meynert in the basal forebrain, the major site of cholinergic neurons, and the current therapies are aimed at improving cognitive function through inhibition of anticholinesterases. There is also disruption to other neurotransmitters including the serotonin system.

Pathophysiology

Over the past decade a great deal has been learnt about the molecular basis of Alzheimer’s disease. The dominant hypothesis to explain the mechanisms leading to Alzheimer’s disease is the amyloid cascade model, which states that the Aβ fragment of the APP plays an essential role in the pathogenesis. Aβ is produced proteolytically from APP by so-called β- and γ-secretases. It is believed that the accumulation of Aβ (in particular the Aβ 42 peptide) in the brain initiates a cascade of events that ultimately leads to neuronal dysfunction, the accumulation of hyperphosphorylated tau, and cell death. The strongest argument supporting a causal role for β amyloid comes from the identification of mutations of the APP gene and the genes for presenilin 1 and 2 responsible for the early onset forms of familiar Alzheimer’s disease. These mutations modify the generation of Aβ peptides in such a way that the relative proportion of the highly amyloidogenic Aβ 42 form is increased. Recent evidence suggests that, rather than the highly aggregated Aβ species, soluble oligomeric forms of Aβ may represent the neurotoxic entity that causes synaptic dysfunction. Transgenic mice expressing APP mutations have been developed. These animal models, which develop typical plaques, help to understand the role of amyloid and are ideal test beds for the development and trial usage of novel drug compounds.

Clinical features

The earliest cognitive deficit is impairment of so-called episodic memory (memories for events or episodes, including day-to-day memory and new learning), which is thought to reflect the earliest site of pathology in the medial temporal lobe structures. ‘Mild cognitive impairment’ (MCI) is a term increasingly used for people who are impaired on episodic memory tasks but who do not otherwise fit the criteria for a diagnosis of dementia. It is becoming clear that many, if not all, such people are in the predementia or early stage of Alzheimer’s disease, but progression to a full-blown dementia syndrome can take several years. Recent studies indicate a conversion rate to dementia of around 10 to 20% per annum. The main clinical features at this stage are severe forgetfulness, often with repetitive questioning and impairments in social function or job performance, particularly concerning the retention of new information. As the disease progresses to mild Alzheimer’s disease, memory function worsens, particularly affecting recall (e.g. forgetting recent visits or family events), increasing disability in managing complex day-to-day activities such as finances and shopping, mental inflexibility, and poor concentration, which reflects involvement of attentional and executive function.

Insight is variably affected; often patients retain a partial awareness into their difficulties but underestimate the extent of the problem. Remote memory is relatively well preserved with a temporally graded pattern (i.e. sparing of most distant memories). As the disease continues to progress patients often develop impairments in language, most typically word-finding difficulties, a shrinking vocabulary, and poor understanding of complex words and concepts. Visuospatial impairments and apraxia, which may develop at this stage, are particularly disabling, causing difficulty in dressing, cooking, and performing other daily activities. In a small subgroup of patients, language or visuospatial difficulties can be the first or most prominent presenting feature. As the cognitive deficits progress there is worsening of language function and semantic memory, and behavioural problems can be prominent.

Neuropsychiatric symptoms are also common in the earliest stages of Alzheimer’s disease, particularly apathy, anxiety, and mood disturbance. Delusions and hallucinations occur in up to 50 and 30% of patients, respectively, in the later stages. Agitation, restlessness, wandering, and disinhibition also cause a considerable burden for carers. The final stages of the disease are characterized by reduced speech output (or mutism), ambulatory difficulties, dependence, and incontinence. Seizures and myoclonus are common late features. There is considerable variation in the time to this stage, but the average time from diagnosis to death is around 10 years.

Neurological examination is unremarkable in the early stages, although increased tone (often frontal resistant, or gegenhalten, in type) and mild extrapyramidal features can occur as the disease progresses. Reflex changes such as extensor plantar responses (Babinski’s reflex) and—in contrast to frontotemporal dementia—pout, snout, and grasp reflexes occur late. In the final stages, there can be greatly increased rigidity and joint contractures.

Investigations

The aims of neuropsychological, imaging, and laboratory investigations in Alzheimer’s disease are twofold: first to exclude other potentially reversible causes of dementia, and second to confirm the diagnosis of probable Alzheimer’s disease. The extent and nature of investigation obviously need to be tailored to the individual, but all patients should undergo brain imaging and have a neuropsychological assessment to confirm the diagnosis of dementia. The neuropsychological profile can also be informative in the differential diagnosis of dementia (see Table 2). Particularly characteristic is early impairment in delayed verbal recall of new material, followed by reduced category fluency (in which individuals are asked to generate exemplars from a given category, e.g. ‘animals’), impaired naming of low-frequency words, and difficulty with complex visuospatial tasks such as copying complex figures or block design from the revised Wechsler Adult Intelligence Scale (WAIS-R).

The basic laboratory investigations required in all patients, particularly to exclude treatable causes of dementia, and some of the other investigations that may be indicated in certain cases depending on the patient’s age, family history, or specific medical history are shown in Table 4. Research into biological markers of Alzheimer’s disease has yet to yield a consistent biological or surrogate marker. Screening for specific gene mutations in young-onset familial cases is available only in specialist centres.

MRI of patients with Alzheimer’s disease in the earliest stages (including MCI) show evidence of atrophy of the hippocampus and entorhinal cortex (parahippocampal gyrus) reflecting the pathology. Unfortunately, the variability in size of these structures in normal older people means that, at present, these imaging abnormalities are not specific enough to be of predictive value. The coregistration of serial MR scans appears capable of detecting abnormal rates of brain atrophy, even before the onset of clear-cut cognitive symptoms in at-risk familial cases, but it remains a research instrument. T ₂-weighted MRI often reveals periventricular high-signal changes, even in ‘pure’ early onset cases. Single-photon emission computed tomography (SPECT) scans similarly demonstrate typical abnormalities in the parietotemporal regions but the specificity is relatively low in individual cases. Newer technological developments, such as diffusion tensor MRI, MR spectroscopy (MRS), and position emission tomography (PET) may enhance diagnostic accuracy but are expensive and not yet suitable for routine clinical use. Very recently it has become possible to image amyloid deposition in vivo using a PET ligand that binds to amyloid.

Management and prognosis

The management of a patient with dementia involves many sensitive issues. It is crucial to provide medical and psychological support to patients as well as to their families and carers. During the progression of the disease there will be different treatment goals at different stages, ranging from aiding failing memory in the setting of independent living to managing behavioural problems and aggression, and eventually full supportive nursing care. There is great variation in the rate of progression, young-onset cases and those with prominent aphasia appearing to deteriorate most rapidly. On average, patients spend several years in the mild or minimal stages (although it can be as long as 5–10 years), between 4 and 5 years in the moderate disease stages, and, depending on the quality of care in the dependent stages, a year or more requiring full nursing care.

Nonpharmacological treatment

The mainstay of treatment is social support and increasing assistance with day-to-day activities. Issues such as driving and planning for future financial affairs are important and should be discussed early in the course of the disease. Throughout the course of the illness there will be different requirements for the support services listed below:

• ◆ information and education
• ◆ carer support groups
• ◆ community dementia team, including home nursing and personal care
• ◆ community services such as meals-on-wheels, community transport services, home maintenance assistance
• ◆ sitter service
• ◆ day centre
• ◆ respite care
• ◆ residential/nursing home
• ◆ diet, exercise, mental activity.

Pharmacological treatment

Pharmacological treatments can be divided into symptom- and disease-oriented approaches. Symptom modification relates to the treatment of depression, agitation, and psychotic phenomena, and requires the input from a specialist psychiatrist. The cholinesterase inhibitors donepezil, galantamine, and rivastigmine are licensed for use in the United Kingdom as is the N-methyl–D-aspartate (NMDA) receptor antagonist memantine. The importance of acetylcholine depletion in Alzheimer’s disease is established; these cholinesterase inhibitors generally achieve modest improvements in cognition in around 25 to 50% of the patients studied. The disease-modifying effects of these drugs remain controversial. Antioxidants (such as vitamin E), ginkgo biloba, and monoamine oxidase B (MAO-B) inhibitors have shown minor benefits in some clinical trials, although again their long-term benefit has yet to be established. Pilot trials and experimental studies are being conducted at present in this area. Ideally, the goal is to prevent patients developing further cognitive deficits and to prevent those with MCI from progressing to dementia. The epidemiological findings of protection from cognitive decline in women using hormone replacement therapy (HRT) are of interest in developing preventive strategies. Trials to look at the effect of HRT in preventing or delaying the onset of dementia have been disappointing. A number of disease-modifying drug and other therapeutic approaches have been developed based on the amyloid cascade hypothesis, ranging from inhibitors of β- and γ-secretase, anti-Aβ immunization, and tau kinase, to aggregation inhibitors.

Frontotemporal dementia

Definition

Frontotemporal dementia (FTD) is now preferred to the older term ‘Pick’s disease’, to describe patients with focal frontal and/or temporal focal atrophy, because the underlying pathology of these syndromes is heterogeneous. Arnold Pick (1851 to 1924) first described patients with both progressive aphasia and associated severe left temporal cortical atrophy post mortem, and patients with behavioural disturbances associated with frontal lobe atrophy. In 1910, Alzheimer described the histological changes in patients with focal lobar degeneration as distinct from the syndrome that bears his name. Alzheimer described both argyrophilic intracytoplasmic inclusions (Pick bodies) and diffusely staining ballooned neurons (Pick cells). More recently it has become clear that the spectrum of pathology that accompanies the clinical syndromes of frontal and temporal dementias is much broader, with a range of distinct inclusions as described below. There is also considerable overlap between FTD and two categories of motor disorders: motor neuron disease (MND, also referred to as amyotrophic lateral sclerosis) and corticobasal degeneration, in terms of both clinical features and pathology.

Epidemiology

FTD is increasingly recognized as a common cause of dementia, particularly in the younger age groups (see Fig. 24.4.2.1a)— the peak incidence of onset being 45 to 65 years of age. In hospital series, the ratio FTD:Alzheimer’s disease has been found to vary from 1:5 to 1:20, with men and women being equally affected. Many cases are familial, with up to 40% having an affected family member.

The gross pathological appearance of FTD is that of profoundly atrophied frontotemporal regions which may be so severe as to produce the so-called knife-edged gyri and deep widened sulci. The histopathological hallmarks are widespread cortical and subcortical gliosis, loss of large cortical nerve cells, and microvacuolation. Immunohistochemical staining reveals two major patterns based on the presence of interneuronal inclusions. The first pattern is a build-up of either tau in the form of classic Pick bodies, diffuse neuronal and glial, and pathology typically seen in patients with mutations of the tau gene, or corticobasal degeneration. The second major pattern consists of ubiquitin-positive but tau-negative pathology, first identified in patients with MND without dementia, but then later found in those with MND-associated FTD, and more recently in patients with progranulin gene mutations. A small proportion of patients have neither tau- nor ubiquitin-positive inclusions.

About 20 to 30% of patients with FTD have a positive family history, although in some cases this may be coincidental. Two major causative gene mutations occur on chromosome 17. The first mutation, found in the late 1990s, involves the microtubule-associated protein tau gene (MAPT). In 2006, the second major locus close to MAPT was discovered, the progranulin gene. Familial MND with FTD has been linked to chromosome 9 although no gene has yet been identified.

Clinical features

The presentation of FTD mirrors the distribution of neuropathological changes; in the early stages two major presentations can be distinguished.

Frontal or behavioural presentations

Patients present with insidiously progressive changes in personality and behaviour that reflect the early locus of pathology in orbital and medial parts of the frontal lobes. There is often impaired judgement, an indifference to domestic and professional responsibilities, and a lack of initiation and apathy. Social skills deteriorate and there can be socially inappropriate behaviour, fatuousness, jocularity, abnormal sexual behaviour with disinhibition, or theft. Many patients are restless with an obsessive–compulsive and ritualized pattern of behaviour, such as pacing or hoarding. Emotional labiality and mood swings are seen, but other psychiatric phenomena such as delusions and hallucinations are rare. Patients become rigid and stereotyped in their daily routines and food choices. A change in food preference towards sweet foods is very characteristic. Of importance is the fact that simple bedside cognitive screening tests such as the Mini-Mental State Examination (MMSE) are insensitive at detecting frontal abnormalities. More detailed neuropsychological tests of frontal function (such as the Wisconsin Card Sorting Test or the Stroop Test) usually show abnormalities. Speech output can be reduced with a tendency to echolalia (repeating the examiner’s last phrase). Memory is relatively spared in the early stages, although it does deteriorate as the disease advances. Visuospatial function remains remarkably unaffected. Primary motor and sensory functions remain normal. Primitive reflexes such as snout, pout, and grasp develop during the disease process. Muscle fasciculations or wasting, particularly affecting the bulbar musculature, can develop in the FTD subtype associated with MND.

Language presentations

Less common than the behavioural variant is a presentation with progressive aphasia which can be of a fluent or nonfluent type. In progressive fluent aphasia, also known as semantic dementia, there is a profound loss in conceptual knowledge (or semantic memory), causing anomia and impaired comprehension of words, objects, or faces. The patient typically complains of ‘loss of memory for words’ and has fluent, empty speech with substitutions such as ‘thing’ and ‘one of those’, but the grammatical aspects are preserved. Naming is impaired with semantically based errors (such as ‘animal’ or ‘horse’ for zebra). Patients are unable to understand less frequent words and fail on a range of semantically based tasks such as matching words to pictures and matching pictures according to their meaning. Repetition of words and phrases is normal even though patients are unaware of their meaning. Unlike patients with Alzheimer’s disease, day-to-day memory (episodic memory) with good visuospatial skills and nonverbal problem-solving ability is relatively preserved, at least in the early stages. As the disease progresses behavioural changes often emerge.

In progressive nonfluent aphasia, by contrast, there is a gradual loss of expressive language abilities with impairments in the phonological (sound based) and grammatical aspects of language production. This leads to nonfluent, agrammatical, and poorly articulated speech with phonological errors (e.g. sitter for sister or fencil for pencil). Repetition of multisyllabic words and phrases is impaired but, in contrast to semantic dementia, word comprehension and object recognition are well preserved. Orobuccal apraxia is common and some patients develop parkinsonism and limb apraxia.

Diagnosis

The diagnosis of FTD is based on the clinical, neuropsychological, and imaging assessments. The consensus broad clinical criteria are shown in Table 5. The differences between the various syndromes described above are obvious early in the disease, but there is increasing overlap between the temporal and frontal syndromes as the disease progresses. MRI demonstrates a characteristic pattern of frontal and/or temporal lobe atrophy: in contrast to Alzheimer’s disease, the changes involve the polar and lateral temporal structures and are asymmetrical, commonly involving the left side to a greater extent. The functional imaging (SPECT or PET) findings mirror the structural imaging results, with reduced frontotemporal perfusion and hypometabolism.

Management and prognosis

There is no curative treatment at present, so the general management of the person with dementia and their family, as discussed above, is of prime importance. Patients with a family history of dementia should be screened for tau or progranulin mutations after appropriate genetic counselling. The prognosis can be variable with different rates of progression between individuals. The disease is progressive and the average duration from diagnosis is around 5 to 10 years.

Dementia with Lewy bodies 

Definition

Since the discovery in the 1960s that patients with Lewy bodies (ubiquitin-positive inclusions) in the cortex have a distinctive pattern of dementia with features of both Parkinson’s and Alzheimer’s diseases, it has been increasingly recognized as an important cause of dementia. The terminology has been confusing, with multiple designations including: Lewy body dementia, dementia of Lewy body type, diffuse Lewy body disease, and cortical Lewy body disease. The consensus clinical criteria for ‘dementia with Lewy bodies’ (DLB), the term now preferred, are shown in Table 24.4.2.6.

Epidemiology

Dementia with Lewy bodies is a common cause of dementia in the elderly population, although the true prevalence remains unclear. As many as 12 to 36% of patients with a clinical diagnosis of Alzheimer’s disease reach the pathological criteria for a diagnosis of dementia with Lewy bodies.

Pathology

Pathological criteria require the presence of cortical and subcortical Lewy bodies. Confusingly, there is considerable overlap with the histological features of both Parkinson’s and Alzheimer’s diseases, although the distribution of pathology is the key to distinguishing these conditions. Lewy bodies are intracytoplasmic eosinophilic neural inclusions formed from altered cytoskeleton components that can be seen on haematoxylin and eosin staining, but are more prominently shown using anti-ubiquitin immunohistochemistry. The major component of the Lewy body is α-synuclein and anti-synuclein immunohistochemistry in the method of choice for detecting these lesions. Cortical Lewy bodies are found in the temporal lobe, insular cortex, and cingulate gyrus, and are always accompanied by typical ‘core-and-halo’ Lewy bodies in the substantia nigra (the pathological hallmark of Parkinson’s disease). Dystrophic ubiquitin-positive neurites are also seen in the hippocampus, amygdala, nucleus basalis of Meynert, and other brainstem nuclei.

Changes of Alzheimer disease—neurofibrillary tangles and amyloid plaques—are seen in up to 50% of cases, raising nosological issues with Alzheimer’s disease. The distribution of changes is of importance in distinguishing the conditions, e.g. neurofibrillary tangles in DLB commonly spare the hippocampus, which is severely affected in Alzheimer’s disease.

The neurotransmitter changes in DLB reflect the areas of pathology, with severe dopamine depletion in the basal ganglia and marked reduction in acetylcholine throughout the cortex.

Clinical features

Patients typically present with a progressive cognitive decline paralleling that seen in those with Alzheimer’s disease. There are, however, a number of characteristic and distinguishing features. First, there is a tendency to marked spontaneous fluctuations in cognitive abilities, particularly alertness and attention, producing a delirious state lasting days or even weeks. Second, visual hallucinations, illusions, and fleeting misidentification phenomena occur in 50 to 80% of those with the condition even at an early stage and without drug provocation. The hallucinations are commonly well-formed images of people or animals. The marked cholinergic deficit is postulated to be the cause of their tendency to visual hallucinations. Third is the occurrence of spontaneous parkinsonism, which is usually mild in the early stages. Rigidity, gait disturbance, and bradykinesia are all common, although in contrast to patients with Parkinson’s disease the tremor is usually mild, atypical (with postural and action components), and symmetrical. Repeated falls also occur. In the later stages the akinetic rigid syndrome can cause severe disabilities in mobility and swallowing, and an increase in the number of falls. Fourth, there is often an exquisite sensitivity to neuroleptic medication, producing the malignant neuroleptic syndrome (delirium, hyperpyrexia, muscle rigidity, massive elevation of creatine phosphokinase, and renal failure).

Diagnosis

Neuropsychologically there is a mixture of subcortical and cortical features, with prominent cognitive slowing plus impairment of executive (planning and organizational) abilities and visuoperceptual abilities. Compared with patients with Alzheimer’s disease, those with DLB tend to have greater deficits in attention and visuospatial processing. Memory loss may be less prominent than in Alzheimer’s disease. There is no diagnostic test for this condition and the diagnosis in vivo relies on the clinical features described above and in Table 6. MRI shows similar changes to Alzheimer’s disease, although there is a suggestion that medial temporal lobe atrophy is less pronounced. SPECT shows occipitoparietal hypoperfusion.

Management

The symptomatic management of this disorder is complicated by the presence of both hallucinations and an akinetic rigid syndrome. Patients are notoriously sensitive to the side effects of dopamine-enhancing medications used for the treatment of the akinetic rigid syndrome. However, although dramatic motor improvements are not to be expected, a cautious medication trial is worth attempting. Even though neuroleptic drugs should be avoided whenever possible, neuropsychiatric features, if severe, can be ameliorated with the newer atypical neuroleptics such as clozapine and olanzapine, without exacerbation of the parkinsonism. Thus, the main aim is to maintain a balance between the patient being mobile and the patient being lucid.

Marked improvement in attentional cognitive deficits in response to treatment with cholinesterase inhibitors, such as donepezil and rivastigmine, has been reported Although there have been few controlled trial reports patients with DLB may respond better than those with Alzheimer’s disease to this drug therapy.

Vascular dementia 

Definition and epidemiology

Vascular dementia can be defined as a dementia resulting from a cerebrovascular disorder. This is obviously a broad categorization and many different aetiologies may be included in this rubric, e.g. multiple infarcts from cardiac emboli, vasculitides including systemic lupus erythromatosus, primary cerebral amyloid angiopathy, and cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL). The term ‘multi-infarct dementia’ was introduced in the 1970s to emphasize the contribution of multiple cerebral infarcts to clinical dementia syndromes, and to replace the older label of ‘atherosclerotic dementia’, although it is now apparent that diffuse small-vessel disease contributes significantly in the absence of clinically overt strokes. Traditionally regarded as the second most common cause of dementia, it is increasingly difficult to estimate the true contribution of vascular disease. Postmortem studies of patients with multi-infarct dementia show that Alzheimer’s disease changes commonly coexist. Conversely, the advent of sensitive instruments for detecting cerebral vascular lesions in vivo (MRI) has revealed that presumed vascular changes are common in patients with the clinical diagnosis of Alzheimer’s disease, even in young patients with known gene mutations, and that the presence of vascular lesions may be contributing to the severity of Alzheimer’s disease. Finally, it is increasingly apparent that traditional risk factors for vascular dementia—including hypertension, diabetes, and hypercholesterolaemia—are also factors that increase the likelihood of developing both vascular dementia and Alzheimer’s disease.

Clinicopathological vascular syndromes

The varieties of vascular diseases that affect the brain are legion, and the resultant clinical features and underlying pathology widely different (see Table 1). The most important vascular syndromes are considered below.

Large infarcts

Recurrent cerebral infarcts involving multiple main arterial territories (e.g. posterior or middle cerebral artery territories), resulting from thrombosis or embolism, can cause dementia with a stepwise cognitive decline. There is commonly a history of atherosclerotic risk factors (e.g. hypertension, smoking, and hypercholesterolaemia), other evidence of atherosclerotic cardiac or peripheral vascular disease, and neurological signs on examination (e.g. spasticity, hyperreflexia, extensor plantar responses, and a pseudobulbar palsy). There are often asymmetries on the neurological examination, and gait apraxia and/or bladder dysfunction can be early features. The cognitive picture is characterized by cortical features and is dependent on the sites of the lesions. There is often severe language impairment, visuospatial disturbance, amnesia, and dyspraxia, related to lesions in the middle and posterior cerebral artery distributions. Specific syndromes can result from discrete lesions, e.g. lesions of the left angular gyrus result in a fluent aphasia, agraphia, acalculia, right–left disorientation, and finger agnosia known as Gerstmann’s syndrome.

Lacunar infarcts

The small multiple lacunar lesions are caused by occlusion in the deep penetrating arterial branches. The underlying pathogenic mechanism is a distinct small-vessel arteriopathy with replacement of the muscle and elastin in the arterial wall by collagen, leading to tortuous vessel and microaneurysm formation as a result of long-standing hypertension. The basal ganglia, thalamus, and deep white matter are common sites for lesions, due to the nature of the arterial supply. These lacunes may coexist with the larger infarcts (described above), thereby contributing to a mixed picture. However, the typical presentation of the lacunar state is with a more subcortical syndrome causing impaired attention and frontal executive malfunction, forgetfulness, apathy, and emotional lability. Thalamic lacunes can result in a speech disorder and, if bilateral, in amnesia. Examination features are similar to those seen with larger infarcts, with rigidity, gait disturbance, and extrapyramidal and pyramidal signs.

Small-vessel disease (Binswanger’s disease)

‘Binswanger’s disease’ (or ‘diffuse leucoaryosis’) is the term applied to the radiologically defined syndrome of confluent subcortical and corpus callosal demyelination and loss of the cerebral white matter, which again typically complicates severe or accelerated hypertension. The clinical features are similar to those of the lacunar state described above. On CT there is symmetrical, diffuse, low-density periventricular hypodensity, which can be accompanied by ventricular dilatation. This is visualized with great sensitivity on T ₂-weighted MRI as a diffuse white matter of high intensity. Pathologically, there is demyelination, axonal loss, and gliosis, thought to be due to diffuse ischaemia in the territory of the long perforating arteries.

Cerebral amyloid angiopathy

Amyloid is deposited in the cerebral vessels both with increasing age and in a proportion of cases with ordinary Alzheimer’s disease. However, there is also a rare and sometimes familial form of cerebral amyloidosis that produces recurrent cerebral haemorrhages and an Alzheimer’s disease-type dementia. Amyloid deposition in the vessel walls causes structural weakness leading to intracerebral haemorrhages and narrowing of the vessel to produce ischaemia. The haemorrhages tend to be lobar and can be recurrent.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL)

This recently established disorder may be a more common cause of vascular dementia than previously realized. Patients present in their early 20s with migraine-like headaches and subsequently develop stroke-like episodes, which are sometimes ascribed to migraine or may mimic the attacks of acute demyelination. A subcortical dementia syndrome develops during their fifth and sixth decades. MRI shows multiple subcortical infarcts and diffuse white-matter disease. Other clues to the diagnosis are the absence of risk factors for atherosclerotic disease and the strong family history. Pathologically there is a distinctive, nonamyloid, nonatherosclerotic angiopathy of the leptomeningeal and perforating arteries of the brain, with eosinophilic granular substance replacing smooth muscle. The diagnosis can also be confirmed with the finding of the same pathological changes in the cutaneous blood vessels in a skin biopsy. Mutations in the notch3 gene on chromosome 19 have been reported in patients with CADASIL.

Treatment of vascular dementia

The treatment should be directed to the amelioration of any underlying cause of the vascular disorder, such as reducing cardiac embolism and treating vasculitides and hypertension. The potential for altering the progression of the disease is alluring. Nevertheless, efforts directed at altering atherosclerotic risk factors tend to produce disappointing results. The course of vascular dementia can be as severe as or even more rapid than that of Alzheimer’s disease.

Subcortical dementias

Despite shortcomings, the differentiation between cortical and subcortical dementias continues to be useful in clinical practice. This classification highlights the fact that, although disease of diverse cerebral structures can result in dementia, the resultant patterns of cognitive deficits are very different. Alzheimer’s disease is the prototypical cortical dementia; vascular syndromes can present with a spectrum of features from cortical to subcortical, as can dementia with Lewy bodies. Purer forms of subcortical dementia result from pathology of the basal ganglia and white matter, the prototypical examples being Huntington’s disease and progressive supranuclear palsy (Steele–Richardson–Olszewski syndrome). The typical cognitive pattern is that of attentional and executive dysfunction with marked cognitive slowing (bradyphrenia), causing problems with mentation and information retrieval. Memory is moderately impaired due to reduced attention and poor registration, but is not as severely impaired as in Alzheimer’s disease. There is often an associated personality change and mood disturbance with prominent apathy. Spontaneous speech is impoverished and slow.

Huntington’s disease

Huntington’s disease is an autosomal dominant inherited disorder with an incidence of about 4 per 100 000. The mutation is an expansion of the trinucleotide repeat (CAG) in the IT-15 gene on chromosome 4, which encodes the polyglutamine protein, huntingtin, essential for nervous system development. There is a clear dose–response relationship between the length of the CAG repeat and the age of onset of the disorder. Psychiatric symptoms, such as depression, irritability, and personality changes, often precede the motor disorder, which is typically choreiform. The other cognitive changes that develop over the next 10 to 20 years are of a subcortical pattern, with deficits in attention and concentration, executive function, and retrieval from memory.

Progressive supranuclear palsy

Progressive supranuclear palsy (PSP) is a rare, but increasingly recognized, disorder with an incidence of 1 to 2 per 100 000. The subcortical dementia is accompanied by an atypical parkinsonian syndrome. The motor deficits are symmetrical in onset, with severe rigidity in the axial muscle groups and bulbar symptoms. A supranuclear gaze palsy invariably develops, but in the early stages the only feature may be slowing of fast downward movement (saccadic slowing). Another early feature is a marked tendency to falls. The pathological features are neurofibrillary tangles, neuropil threads, and neuronal loss and gliosis in the subthalamic nucleus, red nucleus, substantia nigra, and dentate nucleus. The main neurotransmitter deficit is in dopamine. Unlike Parkinson’s disease, PSP does not respond well to levodopa. The disease progresses rapidly with an average time course of around 5 years.

Parkinson’s disease

Subcortical dementia occurs in about one-third to one-half of patients with Parkinson’s disease, which develops at a late stage in the motor disorder in contrast to dementia with Lewy bodies.

Corticobasal degeneration

Corticobasal degeneration is a rare cause of a dementia and motor signs. Patients present with an asymmetrical akinetic rigid syndrome, together with limb apraxia, and the almost pathognomonic feature of alien limb phenomenon in which the hand(s) acts as if ‘with a will of its own’. Myoclonus and dystonia also occur. Dementia is common in the later stages and there is considerable overlap with frontotemporal dementia. The pathology is focused in the frontal and parietal cortices as well as the substantia nigra, basal ganglia, and thalamus.

Treatable causes of dementia

Normal-pressure hydrocephalus

Normal-pressure hydrocephalus has a classic triad of presenting features: cognitive impairment, gait disturbance, and incontinence. The cognitive features are typically those of a subcortical dementia with frontal features and psychomotor slowing. The gait disorder is a dyspraxia and may show the pathognomonic feature of ‘being stuck to the floor’, although there is an absence of signs when the patient is examined in the supine position. The condition may be secondary to a prior disturbance of CSF flow (resulting from, for example, a head injury, meningitis, or a subarachnoid haemorrhage), but often no cause is found in older people. Neuroimaging shows ventricular enlargement disproportionate to the degree of cortical atrophy. The presence of periventricular lesions can make the distinction from vascular dementia difficult. The investigation and management of these patients should be undertaken by neurosurgeons, the definitive treatment being ventricular shunting. If treated early the prognosis is good.

Chronic subdural haematomas

This treatable cause of dementia is caused by head trauma. It is common in individuals at risk of recurrent head injuries, such as older people, those with alcohol problems, and people with epilepsy. Risk is also increased by coagulation disorders, either pathological or iatrogenic. The clinical features are of a subacute dementia with symptoms of raised intracranial pressure, fluctuating cognitive performance, and focal neurological signs. Diagnosis is confirmed by neuroimaging, the peripheral mass lesions may be of varying signal density on CT, depending on the age of the lesion. If the lesions are isodense with the brain tissue, the diagnosis can be easily overlooked. Treatment is by neurosurgical evacuation, except in clinically insignificant collections. Although the outcome is good, about 10 to 40% of patients have a recurrence that may require further drainage.

Benign tumours

Subfrontal meningiomas are the classic tumours that present with features of a frontal dementia. The onset is usually insidious with personality changes and other frontal features. Besides the neuropsychological abnormalities there may be anosmia or unilateral visual failure and optic atrophy. Other relatively benign midline tumours occasionally present with hydrocephalus and cognitive impairment secondary to this (e.g. colloid cysts of the third ventricle and nonsecretory pituitary tumours).

Metabolic and endocrine disorders

Metabolic derangements can give rise to acute-onset cognitive impairments, but the features are invariably those of a delirium rather than a dementia. Chronic hypocalcaemia and recurrent hypoglycaemia can result in a dementia often accompanied by ataxia and involuntary movements. Endocrine disorders can more frequently present with a dementia syndrome, with or without psychiatric features (e.g. hypothyroidism, Addison’s disease, and hypopituitarism). The prominent complaints common to most disorders are mental slowing, apathy, and poor memory. Cushing’s disease can present with psychiatric features, although a dementia syndrome is rarer. Although not strictly an endocrine disorder, Hashimoto’s encephalopathy is a recently recognized cause of chronic delirium or dementia, often accompanied by seizures and fluctuating focal neurological signs. The diagnosis is made by finding extremely high levels of antithyroid antibodies despite a euthyroid state. Patients respond well to high-dose steroid therapy.

Deficiency states

Vitamin B₁₂ deficiency can cause the classic picture of subacute combined degeneration of the spinal cord and a dementia. The dementia can be variable in severity and it is unusual to present without some features of peripheral neurological disease, at least diminished vibration sense in the lower limbs and/or sensory ataxia. Reflexes can be increased, decreased, or mixed. Although most patients have a macrocytic anaemia, neurological manifestations can occasionally occur in the absence of haematological features. Severe thiamine (vitamin B₁) deficiency results in the Wernicke–Korsakoff syndrome, with delirium, ataxia, and ophthalmoplegia. The most common causes are alcoholism and recurrent prolonged vomiting, such as hyperemesis gravidarum. If not promptly treated a chronic amnesic syndrome can occur.

Infections

Neurosyphilis, once a common cause of dementia, is now rare. The associated neurological features include pupillary abnormalities, optic atrophy, ataxia, and pyramidal signs. The diagnosis is confirmed with serology and examination of CSF. Treatment with penicillin can result in some improvement. Those at increased risk are people inadequately treated for syphilis and those infected with the human immunodeficiency virus (HIV). HIV infection is an increasingly common cause of dementia in some parts of the world. The encephalopathy (AIDS–dementia complex) is characterized by psychomotor slowing, personality change, and other features of a subcortical dementia. Examination of the CSF can show a pleocytosis and increased protein and oligoclonal bands. White-matter changes are visible on neuroimaging. Cognitive changes in patients with HIV may also be due to opportunistic infections such as cerebral toxoplasmosis and cryptococcal meningitis, and progressive multifocal leucoencephalopathy, which all require specific treatment.

Further reading