Table of Contents

Pathology of Dementias

Dementia is a devastating and prevalent condition that has profound implications, both for the provision of health and social services care for the elderly and for the lives of those touched by these illnesses. As a term, dementia encompasses a number of diseases that share the common attributes of an acquired and usually relentlessly progressive condition affecting higher cortical functions. Consciousness is maintained and the deficits are global rather than restricted simply to amnesic problems.

Alzheimer’ s Disease

Alzheimer’s disease is the commonest cause of dementia affecting approximately 5% of the population over the age of 65 and 20% of those over 85. Age is the outstanding risk factor - Alzheimer’s disease in middle age being exceedingly rare.

Clinical features

Amnesia :

There is a failure both in the ability to acquire new memories and in the ability to recall old memories - initially a failure to commit information to the long-term memory storage and then a failure of retrieval of information. The loss of memory is usually the first and most apparent of the clinical symptoms.

Aphasia

An early symptom, but often not the most noticeable. Commonly nominal dysphasia - an inability to ‘find’ words. Later the disorder may progress to manifest expressive and receptive dysphasias and even complete loss of comprehensible language.

Apraxia

One of the symptom clusters that can be the cause of most handicap, dyspraxias are an inability to perform complex tasks because of cortical (as opposed to peripheral) defects. The patient might be unable to dress or to perform relatively straightforward tasks around the home thus necessitating these tasks to be performed by others.

Agnosia

Just as apraxias can be the cause of intense distress to the patient, agnosias can be the cause of the most distress to the relatives. Agnosia is a ‘not knowing’ - a failure to recognise stimuli. The inability to recognise faces (prosopagnosia) - not to know the face of a spouse is particularly upsetting. Other visual agnosias are relatively common.

Associated symptoms

  • personality changes (ubiquitous)
  • delusions (20%)
  • hallucinations (10%)
  • misidentification syndromes (20-30%)
  • depression(?60%)
  • loss of insight

Physical changes

A general physical decline is almost invariable with accompanying wasting. The commonest cause of death is bronchopneumonia. Urinary and faecal incontinence can have a multiplicity of causes. Neurological signs are common and include primitive reflexes (snout and grasp), alterations of tone, tremor, myoclonus and epileptic fits.

Natural History

Presentation may be delayed, either by an insightful patient or a worried relative. The earliest manifestations of the disease are subtle - the individual may forget a familiar name and hurriedly cover up the omission; lists may be written to compensate for a more general amnesia. Topographical dyspraxia (and getting lost) and nominal dysphasia may become apparent. Affective symptoms are relatively common in this early stage.

After some time the progression is such that all areas of intellect and personality are affected and the symptoms discussed above will be apparent. In the later stages the physical symptoms dominate and the patient may become increasingly bed bound and all needs must be met by carers - whether relatives or nurses.

The usual duration is from 3 to 8 years. Onset can be from the age of 40. Arbitrarily onset before 65 is known as pre-senile and onset after 65 as senile. It remains an unanswered question as to whether early onset cases form a different type of the disease. It does however appear that early onset is associated with a more aggressive variant.

Management

Management of dementia requires a multi-disciplinary approach addressing the problems not only as they pertain to the patient but also to their family. Relatives ‘lose’ their loved ones who remain alive and in need of increasingly intimate care. This has been termed a ‘living bereavement’. Attention will be paid to minimising ‘problem’ behaviour (by the use of modification in the environment and medication) and to maximising available function. The vast majority of patients with dementia will be cared for outside of institutional care. In latter years the private sector (for good or bad) has taken over much of the care of those who are unable to remain at home.

DIFFUSE LEWY BODY DEMENTIA (DLBD)

The relationship between DLBD and AD is currently hotly disputed. The neuropathological features of both are frequently found together. The clinical features show an admixture of symptoms of classical AD and parkinsonism. It is increasingly realised that many patients - previously thought of as suffering from ‘atypical AD’ have DLBD at post mortem. A fluctuating mental state (suggestive of delirium) and hallucinations combined with an underlying dementia andr parkinsonism is highly suggestive of DLBD. These patients are said to be highly sensitive to the adverse effects of neuroleptic medication.

NEURODEGENERATIVE NEUROPATHOLOGY

Predominant clinical features:

Neurodegenerative diseases range from those presenting with mainly dementia to those mainly manifested as a motor disturbance. Patients may be:

a) Invariably demented:

  • Alzheimer’s Disease (AD)
  • Diffuse Lewy body Disease (DLBD)
  • Down Syndrome
  • Huntingdon’s Disease (HD)
  • Pick’s Disease
  • Creutzfeldt-Jacob Disease (CJD)
  • Wilson’s Disease (WD).

b) May be demented:

  • Parkinson’s Disease;
  • Motor Neurone Disease
  • Cerebrovascular Disease.

b) Not demented:

  • Spinal muscular atrophies
  • Friedreich’s ataxia
  • Multiple-system atrophies.

Some patients (DLBD, HD, CJD, WD) frequently have both movement and cognitive disorder.

Pathology of Alzheimer’ s Disease

a) Macroscopic appearance:

  1. There is often, but not always, a low brain weight. The loss of weight is more prominent in the cerebrum rather than the brainstem and cerebral and cerebellum.

  2. There is widened cortical sulci and narrowed gyri. The is brain affected symmetrically, with the medial temporal lobe worst affetced.

  3. Enlarged lateral ventricles

  4. Often a pale locus coeruleus.

b) Microscopic appearance:

extra- and intra-cellular pathology

  1. Neuritic plaques: These are extracellular deposits of amyloid in the gray matter of the brain. They are diffuse; neuritic; of amyloid core; up to 50–150 μm in diameter; argyrophilic processes; surrounded by microglial and astrocytic halo.

  2. Neurofibrillary tangles: These are mostly intracellular; argyrophilic cytoskeletal structures appearing under the electron microscope as paired helical filaments; more frequently found in medial temporal lobe; neocortex and Mynert nucleus.

  3. Hirano Bodies: These are also mostly intracellular; but eosinophilic needle shaped cytoskeletal in origin which appear in hippocampal neurones only.

  4. Granulovacuoles: intracellular vesicles which appear as a dot within a perikaryal vacuole; in the hippocampal neurones only.

  5. Neuronal loss: This is seen mostly in the frontal neocortex pyramidal cells; Mynert nucleus; locus coeruleus; and raphe nucleus; as well as other places.

  6. Vascular changes: amyloid deposit in the leptomeningeal and parenchymal vessels.

c) The differentiation from normal aging is by the of extent and degree only.

Diffuse Lewy Body Disease:-

a) ## Macroscopic appearance: ## There is often a low brain-weight with more marked temporal and frontal lobe atrophy and pale Substantia Nigra

b) ## Microscopic appearance: ##

  1. There is neocortical plaques and tangles, although the latter are often relatively few.

  2. Characteristic cortical Lewy bodies in particular in the cingulate and parahippocampal gyrus

  3. Hippocampal plaques and tangles

  4. Lewy bodies in the substantia nigra

  5. Vascular amyloid: it is unclear if this is significantly increased.

Pick’s Disease

a) Macroscopic appearance: There is usually low brain weight, with severe frontal and/or temporal ‘knife-edge’ atrophy , while the posterior third of the superior temporal gyrus is preserved. In addition the hippocampus is very shrunken and often the caudate nucleus shows atrophy. the big dilated lateral ventricles are prominent feature.

b) Microscopic appearance:

  1. Pick cells: these are swollen cortical neurones, mainly in layers V and VI of the cortex.

  2. Pick Bodies: These are cytoplasmic inclusions bodies, formed of neurofilaments, organelles, made of straight and paired-helical filaments

  3. Gliosis in the grey and white matter

  4. Neuronal loss

Huntingdon’s Disease

Macroscopic appearance:

Low brain weight and severe atrophy of the caudate nucleus; milder atrophy in lentiform nucleus; and cortex (especially the fronto-parietal lobes); with variable atrophy in the cerebellum.

Microscopic appearance:

  1. Neuronal loss in the caudate nucleus especially the small and medium-sized spiny cells; and cells in the neocortex

  2. gliosis in the caudate nucleus and neocortex.

  3. There no inclusion bodies.

Creutzfeld-Jacob Disease

a) Macroscopic: Early in the disease there is evidence of dementia coexisting with normal-sized brain. Later, cerebral atrophy of more than 850g is evident in the cortex , striatum, thalamus, brainstem and cerebellum.

b) Microscopic:

  1. Spongiform change: spongiform change, which is characterised by a fine vacuole-like appearance in the neuropil. Cortical involvement is detectable in most cases of CJD, and is usually accompanied by spongiform change in the basal ganglia, thalamus and cerebellar cortex. Cerebellar involvement is present in most cases, although the severity and distribution of the spongiform change is markedly variable

  2. neurone loss is widespread or patchy.

  3. Astrocytosis: sometimes include areas without cell-loss, and WM

  4. Amyloid plaques: unicentric appearing often in the granule-cell layer of cerebellum

Parkinson ‘ s Disease

a) Macroscopic: There is change in the colour of Substantia Nigra which appears pale, unilaterally or bilaterally and inconstant cerebral atrophy (sometimes only seen in demented cases)

b) Microscopic:

1.Lewy bodies appear in the Substantia Nigra; Mynert nucleus; dorsal Raphe nuclei; locus coeruleus; and dorsal vagal nucleus.

  1. neuronal loss with nuclei that contain inclusions.

Motor neurone Disease

a) Macroscopic:

  1. The anterior (motor) roots appear thin compared to sensory roots.

  2. Muscle wasting

  3. Sometimes, atrophy of the precentral gyrus.

b) Microscopic:

  1. loss of neurones in the anterior horns of the spinal cord; hypoglossal, facial, and trigeminal cranial nerves. Betz cells in the cortex are lost or shrunk.

  2. Neuronophagia (Destruction of nerve cells by phagocytes) is evident where neurones were lost.

  3. Loss of axons in the corticospinal tract.

  4. inclusion “Bunina bodies” in motorneurones of the cord.


Reference: Greenfield’s Neuropathology (5th ed.)