queen square summary of chapter dementias

1. Chapter 8
Dementia and Cognitive
Impairment
Dr rzgar hamed abdwl

3. * Delirium: referred to as an acute confusional state, is characterised by fluctuation, prominent
impairment of attention and/or arousal, and accompanied often by agitation and autonomic
features.
* Dementia: refers to widespread cognitive impairment in the setting of normal arousal and
formally defined as the disruption of cortical function should involve more than one cognitive
domain which should include memory, more specifically episodic memory.

5. Epidemiology:
* Delirium occur in 5–15% of patients in general hospital wards, and a higher
proportion in intensive care units.
* Prevalence rates:
- Above 65 years: 6% for all causes of dementia and approximately 4% for AD.
- under the age of 65 years 67–81/100 000
* The young onset forms:
- familial,
- degenerative dementias such as variant Creutzfeldt–Jakob disease
- frontotemporal dementia (FTD)
- alcohol‐ related dementia
* DLB, a common cause in patients over 65 years of age

12. Cognitive functions and their clinical syndromes
1- Attention
* is the ability to gate and focus sensory
information and to direct awareness.
* The syndrome of hemi‐neglect manifests as
unawareness of contralateral stimuli, or
contralateral stimuli may be perceived when
presented alone

14. 2- Memory
* Explicit memory: the contents of which can be consciously accessed
* Implicit memory: the contents of which are accessed automatically
and do not depend on conscious mediation (e.g. the sequence of
procedural skills required when driving a car).
* Explicit memory has ‘short‐term’ (typically, less than a minute) and
‘long‐term’ components.
* Long‐term memory can be further subclassified into:
- Episodic memory : the individual’s past experience
- Semantic memory : conceptual knowledge about the world, i.e.
remembering what something is
* semantic memory loss occurs in FTD

15. * Episodic memory : further divides into
- anterograde memory: encoding and subsequent retrieval of new events
- retrograde memory: retrieval of events prior to the onset of the illness
- memory for different types of material (e.g. verbal material, faces and
topography).
* Severe deficits of anterograde and retrograde memory in the setting of a
clear sensorium and with preserved immediate (short‐term) recall occurs in :
- thiamine deficiency in chronic alcoholism (Wernicke–Korsakoff syndrome)
- bilateral temporal lobe resection for intractable epilepsy
- herpes simplex encephalitis
- traumatic brain injury

18. * incomplete deficits of verbal, visual and topographical memory are common early in the course
of AD, DLB, vascular dementia and other diseases.
* Impaired verbal episodic memory is the most sensitive cognitive marker of early AD, although
it is not specific.
* Impaired topographical memory commonly presents as a difficulty with route finding, and a
tendency to become lost in unfamiliar locations.
* The ascending cholinergic projection pathways, which exert important modulatory and
attentional influences on the medial temporal lobe and neocortex are disrupted in cholinergic
deficient dis ease states such as AD and DLB.
* Posterior cortical areas including the posterior cingulate, retrosplenial and temporoparietal
association cortex are densely connected via the diencephalic system with the medial temporal
lobes and have also been implicated in AD.
* Working memory deficits : AD, DLB, VaD and FTD.
* It is likely that verbal short‐term memory is supported by a fronto‐parietal network in the left
cerebral hemisphere, and visuo‐spatial short‐term memory by a corresponding network in the
right cerebral hemisphere.

20. Paramnesias
* false or distorted recall
* confabulation: the patient may describe events that never occurred, often observed in the
setting of frontal lobe or fronto-limbic damage
* Reduplicative paramnesias : the belief that particular places or persons have been transposed
or duplicated
Transient global amnesia
* the sudden onset of severe anterograde amnesia generally lasting less than 24 hours.
* There is no disturbance of alertness and, in contrast to psychogenic fugue, personal identity is
retained.
* Procedural and semantic memory are spared
* other cognitive functions are intact and the neurological examination is normal.
* occurs in later life.
* causes: physical exertion, exposure to cold, strong emotion, sexual activity and migraine;
* mimics : temporal lobe lesions
* Recurrent attacks, especially on waking from sleep, suggest the syndrome of transient epileptic

21. Perception
* Selective impairments of visual functions such as motion detection (akinetopsia) and colour
perception (achromatopsia) have been described in :
- posterior circulation strokes
- AD, cortico‐basal degeneration (CBD) and DLB
- prion disease
* Anton’s syndrome: denial of blindness or visual anosognosia due bilateral cortical lesion.
* Metamorphopsia : objects in the environment or body parts (especially faces) may appear
distorted
* palinopsia : is the persistent recurrence of a visual image after the stimulus has been removed
* polyopia: describes seeing two or more images arranged in ordered rows, columns, or
diagonals after fixation on a stimulus
* Apperceptive visual agnosia: inability to form structural representations of visual objects
* prosopagnosia: impaired face perception ,inferior temporal lobe damage

22. * Visuospatial deficits are often prominent in dementias affecting the posterior
cerebral hemispheres such as AD and DLB.
* Visuospatial disorders can be broadly classified as:
- visual disorientation: the impaired perception of space relative to self
(egocentric space) like Threading a needle and such individuals become
functionally blind
- visuo‐spatial agnosia: the impaired perception of spatial configurations that are
not referenced to one’s own position (exocentric space).
* Balint’s syndrome: frag mented perception of the visual field (simultanagnosia),
inability to perform visually guided movements (optic ataxia) and/or inability to
direct the eyes to a point in space (ocular apraxia). resemble hemi‐ or
quadrantanopic field defects.

23. * Patients with visuo‐spatial agnosia may be unable to orient clothing
when dressing, a camera when taking a photograph or an envelope
when posting a letter. Loss of the ability to tell the time from a clock is
characteristic.
* Skills such as reading text or maps, writing and calculation, are often
degraded. On examination, copying and constructional tasks are poorly
performed and there may be specific deficits of spatial discrimination or
spatial search (such as counting dots in an array).
* Anatomically, visuo‐spatial deficits are associated with damage to the
superior and posterior parietal lobes,
* Cortical deafness due to bilateral damage of auditory cortex and
ascending auditory pathways, and auditory agnosia for complex sounds
such as music and environmental noises may occur with diseases
involving either temporal lobe.

24. * Loss or distortions of taste (dysgeusia) occurs with damage of the insula.
* Olfactory identification deficits may occur early in the course of AD, Parkinson’s
disease and other degenerative dementias, and are likely to be at least partly
central in origin.
* Disorders of cortical somatosensory function such as impaired perception of
shape (astereognosis) and spatial configurations on the body surface (such as
drawn numbers: agraphaesthesia) and impaired recognition of objects by touch
(tactile agnosia) may occur with both acute damage involving the parietal lobes
and in degenerative conditions such as CBD.

25. Hallucinations
* perceptual experiences in the absence of an external sensory stimulus.
* at the onset of sleep is called hypnagogic hallucinations
* In organic brain disease, hallucinations occur most commonly in the visual
modality, and are a frequent feature of delirium.
* in other disease states non‐visual modalities are well recognized (e.g. olfactory
hallucinations in temporal lobe epilepsy).
* auditory hallucinations are typical of psychiatric disorders such as schizophrenia
but distinctly unusual in organic disease.
* Visual hallucinations : the retino‐calcarine and cortical ventral visual pathways.
* Hallucinations may arise from two general mechanisms:
- abnormal release of sensory cortex
- abnormal excitation or disinhibition of sensory cortex by irritative processes such
as seizures or migraine.

26. * Deafferentation of early visual cortex in the setting of peripheral visual loss may
be associated with isolated well‐formed visual hallucinations in the absence of
cognitive decline (Charles Bonnet syndrome).
* Musical hallucinations may occur acquired deafness.
* ventral midbrain lesion produce vivid ‘dream‐like’ peduncular hallucinations of
cartoon‐like images or complex scenes
* early visual cortices may produce elementary visual hallucinations (exemplified
by ‘fortification spectra’ or teichopsia in migraine)
* complex or multimodal hallucinations, sometimes involving distortions of
self‐perception, may occur in the setting of temporal lobe disease.
*The ‘phantom boarder’ delusion : the sense that there is another person in the
house when there is not

27. Knowledge
* In semantic dementia (SD) produces a progressive impairment of word‐finding and word
comprehension
* visual agnosia: temporo‐occipital lesions or may develop in the course of SD.
* prosopagnosia : unable to recognise familiar faces
* Impaired word knowledge in SD is associated with atrophy involving the dominant (left)
anterolateral temporal lobe.
* The left anterior and inferolateral temporal lobe representing verbal information (such as personal
names) and corresponding regions of the right temporal lobe representing familiar face
information.
Voluntary action
* apraxia: a disturbance of voluntary movement that cannot be explained by elementary motor or
sensory deficits.
* disorders that affect unfamiliar, novel or meaningless actions is called ideomotor apraxia
* disorders that affect previously learned actions ideational apraxia.
* Apraxia : dominant parietal or frontal lobes

28. * Apraxia for novel and meaningless actions is a prominent feature of dementias such as AD that
involve the posterior hemispheres.
* Asymmetric limb apraxia is a cardinal presenting feature of CBD, where it is characteristically
accompanied by asymmetric rigidity and other extrapyramidal or cortical sensory signs.
* Actions involving the affected limb comprise coarse, uncoordinated or mutilated constituent
movements, sometimes termed limb‐kinetic apraxia.
* Orofacial apraxia is frequently observed in association with impaired speech production. The
patient may lose the ability to whistle and may complain of difficulty initiating chewing or
swallowing. When instructed to cough, yawn or sigh the patient may produce an inadequate
facsimile or simply repeat the instruction emphatically.
* constructional apraxia: impaired ability to copy drawings of objects or designs, is observed both
with focal lesions and degenerative diseases variously affecting visuo‐spatial perception, spatial
attention and executive processes.
* dressing apraxia
* apraxia of eyelid opening which in many cases has the features of a focal dystonia.
* gait apraxia, the selective impairment of walking is associated with focal lesions and
degenerative processes affecting the frontal lobes and subcortical projections (as in
hydrocephalus)

29. * the alien limb phenomenon: asymmetric limb apraxia may have difficulty in
making cooperative movements using both hands The patient may complain that
the affected arm is useless or seems not to belong to them occurs in CBD
* Orofacial : focal lesions or degenerative syndromes (such as progressive
non‐fluent aphasia) with asymmet ric atrophy predominantly involving left inferior
frontal and opercular regions.
Speech and language
* The complex operations of human speech can be broadly classified as sensory
decoding, comprehension, repetition, retrieval and production.
* Speech and language impairments (the dysphasias) : dominant (left) cerebral
hemisphere
*

30. • it is important to distinguish fluent dysphasia from confusion (e.g. in
the context of delirium); this can usually be accomplished by a
careful analysis of the patient’s spontaneous speech, in particular
the presence of speech errors (paraphasias).
* word deafness : acute bilateral or left‐sided damage and
degenerative disease affecting the posterior temporal lobe. Such
patients have difficulty both in understanding and repeating spoken
words despite normal comprehension of written material.
* a transcortical sensory aphasia: posterior watershed infarcts or SD
* Impaired sentence comprehension occurs in dementias such as
progressive non‐fluent aphasia (PNFA) in which there is disturbed
processing of grammatical structure.

32. * conduction aphasia: the left parieto‐temporal junction and the
arcuate fasciculus.
* anomia: during the recovery phase of stroke and Progressive anomia
is a hallmark of SD also observed in AD and many other dementias.
* Dynamic aphasia: characteristics similar to transcortical motor
aphasia: reduced spontaneous propositional speech despite the ability
to produce speech relatively normally in specific contexts such as
naming, repetition or reading occurs in dementias that damage frontal
or fronto‐subcortical circuitry.
* The breakdown of grammatical output (syntax) is a hallmark of Broca’s
aphasia, observed classically with focal lesions involving the inferior
frontal gyrus of the dominant hemisphere.
*

33. • Phonemic paraphasias (such as ‘stirel’ for ‘squirrel’) are often
accompanied by articulatory errors. Prosody, the pattern of stress and
timing that constitutes the melody of speech, is frequently abnormal.
• It is also important to distinguish dysfluency resulting from a primary
disorder of speech production from interrupted output resulting from
prolonged word‐finding pauses (‘logopenic’ aphasia), which may occur
in other conditions including AD.
* The spontaneous production of novel non‐words (neologisms) and
jargon may accompany fluent aphasia in acute disorders but rarely in
degenerative disease.

34. Literacy and numeracy
* alexia without agraphia: produced by the conjunction of a right homonymous hemianopia and
damage involving the posterior corpus callosum, precluding the transfer of information from the
left hemi‐field (right occipital lobe) to the verbal left hemisphere.
* alexia with agraphia results from more extensive lesions involving the posterior left
hemisphere.
* a peripheral dyslexia : disturbed visual analysis of written words (often with preserved writing
ability) which is a prominent feature of PCA, in which associated visuo‐perceptual and
visuo‐spatial impairments, These individuals typically read letter by letter … (left‐sided
occipito‐temporo‐parietal damage )
* a central dyslexia : disturbed analysis of written words for sound or meaning (often with
associated deficits of written output)…. (left anterior and inferior temporal lobe)
* phonological dyslexia: reading by sound is damaged,
* surface dyslexia : reading by sight vocabulary is damaged which is a characteristic feature of SD.

35. Dysgraphias: Impairments of writing and spelling, can be broadly classified
according to whether the core defect lies with spelling processes (central
dysgraphias) or the motor programming and execution of writing (peripheral
dysgraphias) and mixed forms are common.
phonological dysgraphia : Impaired spelling by sound
surface dysgraphia: The breakdown of vocabulary‐ based spelling
* Dysgraphia : the left parietal lobe;
* Disorders of calculation can be classified according to whether the core defect
lies with computation proper or with the procedures required to process written
and spoken numbers, is often a prominent feature of diseases affecting the
dominant parietal lobe.
* The association of dysgraphia and dyscalculia with finger agnosia and right–left
disorientation is known as Gerstmann’s syndrome

36. Executive function
* the capacity to plan ,manipulate information ,initiate and terminate activity ,recognize error
,problem solve and think abstractly
* Function of frontal lobe cortex and its subcortical connections
* Apathy (abulia), inertia, passivity, perseveration, and motor and verbal stereotypies
* utilisation behaviour (e.g. the patient may don spectacles or peel a piece of fruit automatically
when the item is placed before them)
* hyperorality
* Echolalia and echopraxia
* Slowness of thought (bradyphrenia)
* Palilalia (repetition of the patient’s own words or terminal phrases) .
* impaired performance on dual tasks (such as tracking a visual target while reciting a list of
numbers)
* difficulty grasping simple rules (sorting multi‐dimensional items by size, shape or colour) or in
devising a problem‐solving strategy (such as the ‘Tower of London’ puzzle).

37. Emotion
* the Klüver–Bucy syndrome : following bilateral temporal lobe ablation And in the
context of acute destructive processes such as herpes simplex encephalitis, and is
characterised by loss of normal emotional reactivity, abulia, altered sexual
responses and hyperorality.
* Disturbances of mood (in particular, depression and dysphoria) are commonly
associated with stroke, temporal lobe epilepsy and head injury, and with AD and
other degenerative disorders
* Specific deficits of emotion comprehension have been documented in both acute
and chronic disor ders with mesolimbic damage, and are a hallmark of certain
degenerative diseases, notably FTD and Huntington’s disease.

38. Investigation of the patient with cognitive impairment

39. Neuropsychometry
* Brief mental state schedules such as the 30‐point Mini Mental State Examination
* Other standardised tests include : the National Adult Reading Test (NART) and the Wechsler Adult Intelligence
Scale (WAIS; revised, WAIS‐R)

42. Brain imaging
* indicated in all patients with dementia where no systemic cause is identified.
• T1 MRI : detecting pathological atrophy
• T2‐weighted sequences are used to assess white matter signal change and tissue
oedema.
• FLAIR sequences to assess basal ganglia and thalamic signal in suspected prion disease,
• DWI to detect acute ischaemic damage and prion disease with cortical diffusion signal
change, reflecting spongiform histology.
Electroencephalography
* generalised slowing of cerebral rhythms indicating diffuse cortical dysfunction.
* Conditions such as AD : loss of the normal alpha rhythm
* focal dementias such as FTD alpha rhythm is generally preserved at presentation.
* The EEG may also detect covert epileptiform changes in amnestic syndromes resulting
from partial seizures, or periodic complexes in classic CJD, subacute sclerosing
panencephalitis (SSPE) and other condi tions with severe cortical derangement.

43. Cerebrospinal fluid examination
* To detect infections
* Polymerase chain reaction (PCR) to detect viral and other infectious agent DNA.
* cytology: malignant cells
* Elevated protein 14‐3‐3 is associated with rapid neuronal destruction in classic CJD, while
elevated S‐100 is associated with gliosis.
* AD is associated with a reduction in CSF Aβ1–42 and an increase in tau, and diagnostically
specific CSF protein biomarkers are increasingly entering routine clinical practice.
Additional investigations
* vasculitic, infectious, autoimmune, neoplastic and toxicological investigations
* in younger patients, copper studies, white cell enzymes and genetic testing.
* HIV serology
* Genetic testing: (e.g. in Huntington’s disease)
* Tissue biopsy

44. * Skin biopsy (including apocrine sweat glands) may detect abnormal accumula-
tions in Lafora, Kufs or other storage diseases and in CADASIL
* Nerve biopsy may be diagnostic in rare dementias with peripheral nerve
involvement.
* Muscle biopsy including histochemistry and respiratory enzyme analysis may
confirm a mitochondrial disorder.
* Marrow biopsy may identify the ‘sea‐blue histiocyte syndrome’ of Niemann–Pick
disease type C and other storage diseases, and may also be indicated in the
diagnosis of haematological and other malignancies in suspected paraneoplastic
syndromes.
* Small bowel biopsy may be indicated to exclude Whipple’s disease, and liver
biopsy is occasionally indicated to exclude Wilson’s disease.
* brain biopsy may be necessary where there is unresolved suspicion of a
treatable (inflam matory or infectious) process where the diagnosis cannot be
made by other means and potentially toxic treatment is contemplated.

45. Alzheimer’s disease

46. Alzheimer’s disease
* most common cause of cognitive decline
* 50% of all cases of dementia.
* 1% ……65–69 years
* 20% …….85 years or over.
* AD is also the most common cause of early onset dementia, arbitrarily defined as symptom
onset before the age of 65 years.
* sporadic AD starting before the age of 50 years is very rare
* A definitive diagnosis : histopathological examination of brain tissue with excess accumulation
of extracellular amyloid plaques and intracellular neurofibrillary tangles
* Primary motor and sensory cortices are relatively spared
* The vast majority of AD is ‘sporadic
* in minority there is a strong family history usually with an early age at onset. Mutations in
three genes (APP, PSEN1and PSEN2) cause autosomal dominant AD with a high level of
penetrance comprises 1% of all cases of AD.
* familial AD has a rare atypical presentations such as a spastic paraparesis in PSEN1.

48. Clinical features and assessment
* Memory problems : repetitive in questioning, forgetting that they asked the
same question recently, be it minutes, hours or days ago.
* impairment of episodic memory.
* Recall is usually worse than recognition memory and although patients
commonly lack insight into the severity of their problems they are often aware that
memory is a problem.
* Dementia should be established before diagnosis of AD is made.
* AD is very likely if memory deficits are accompanied by evidence of cerebral amy-
loid deposition, from CSF measurement showing low Aβ1–42or from PET amyloid
imaging; or a typical pattern of AD atrophy or hypo metabolism .
* if the carer is more aware of the problems than the patient, the probability of the
symptoms being caused by AD is more likely. Conversely, if it is the patient who is
complaining more of their problems than the informant, an alternative
non‐neurodegenerative cause is more likely.

49. * Depression and AD commonly coexist and depressive symptomatology may mimic AD.
* It is sensible to have a low threshold for suspecting and treating depression, ideally avoiding
antidepressants with anticholinergic activity.
* In addition to memory and orientation problems there are often early subtle impair ments of
planning, decision‐making and working out complex sequences, and learning new tasks (e.g.
failures to master new equipment either at home or at work).
* The presence of posterior dysfunction (i.e. parietal and/or occipital problems – such as cal
culation, spelling, praxis or visual processing problems) should be sought, as this makes an
alternative diagnosis of FTD less likely.
* Unlike FTD or the frontal subcortical deficits of VaD, AD is not usually associated with marked
behavioural and personality change in the early stages apart from a loss of confidence and some
apathy.
* As the disease progresses, all these initially subtle cognitive deficits become more marked and
generalised and behavioural problems become more common.
* Visuo‐spatial difficulties may manifest as a deterioration in an individual’s ability to drive
* get lost in unfamiliar circumstances, and errors of judgement.

50. * Delusions are common
* the examination may be normal. Myoclonus (often most noticeable in the
fingers) may occur later in the disease, although patients with autosomal
dominant AD tend to have early and prominent myoclonus, often a harbinger of
seizures later on.
* In the late stages, there may be a generalised increase in tone in a Gegenhalten
fashion
* marked sleep–wake cycle reversal.
* problems with continence
• Swallowing difficulties in the late stage
• Survival is age‐related (lower with older patients) but is typically 4–8 years from
diagnosis of AD although may be up to 15 years in a minority; survival from first
symptoms is 2–3 years longer because of delays in diagnosis.

53. Investigations
* Neuropsychometry
* all patients with dementia should have MRI
* Marked medial temporal lobe atrophy, bilateral hippocampal atrophy associated with ventricular
enlargement and generalised cortical atrophy symmetrically involving both parietal and frontal lobes.
* NICE guidelines recommend functional imaging (SPECT or PET) to be used to help differentiate AD,
vascular dementia and frontotemporal dementia if the diagnosis is in doubt.
* Amyloid imaging has high sensitivity for the presence of cerebral amyloid. 25% of healthy elderly
individuals aged about 75 years have positive amyloid scans.
* EEG may be important to exclude seizure activity
* In AD the EEG typically shows generalised slowing and loss of alpha rhythm, although in
mild cases may appear normal.
* CSF markers to differentiate AD from other neurodegenerative dementias. In AD the CSF is usually
acellular with normal protein. CSF tau (total levels and specific phosphorylated forms) are increased in AD
while CSF Aβ1‐42 is reduced.
* The combination of these markers appears to differentiate AD from controls with sensitivity and
specificity of approxi mately 90% but rather lower discriminatory ability to separate AD from other
dementias such as FTD or DLB

56. Management
* Treatment of depression must not be missed.
1- Cholinesterase inhibitors: Donepezil (Aricept) … Galantamine (Reminyl) …. Rivastigmine
(Exelon).
* symptomatic treatment for AD.
* By inhibiting the breakdown of ACh, AChEIs enhance the levels of ACh in cerebral cortex.
* They have similar symptomatic efficacy and there is no evidence of any disease slowing
benefit.
* Once daily modified release formulations, oral solutions and patches are available
* The clinical efficacy of AChEIs has been measured using the Alzheimer’s Disease Assessment
Scale (ADAS‐Cog)
* They should be used in mild to moderate AD and can be continued into the more severe
stages of the disease as long as it is felt they are still providing benefit.
* If in doubt, the drug should be with drawn for a few weeks and if there is rapid decline in
behaviour and/or cognition, the drug should be restarted.

58. 2- Memantine:
* preventing glutamate‐mediated neurotoxicity.
* non‐competitive N‐methyl‐d‐aspartate (NMDA) receptor antagonist and blocks
the effects of pathologically elevated tonic levels of glutamate by preventing
calcium influx into the neurone.
* It has beneficial effects in slowing cognitive decline in mild to moderate AD, but
also in vascular dementia and is generally well tolerated.
* It is currently used when AChEIs are thought to have lost efficacy, in AD patients
intolerant of AChEIs or in whom these are contraindicated.
* There is some evidence that a combination of donepezil and memantine gives
greater improvement
* Side effects are uncommon; they include hallucinations, confusion, dizziness,
headaches and tiredness.

59. Frontotemporal dementia

60. • Frontotemporal dementia (FTD) is a
heterogeneous group of non‐Alzheimer’s
neurodegenerative disorders, characterized by
relatively focal frontal and temporal cerebral
atrophy.
• prevalence : 4–15/100 000 under 65 years.
• onset : 50 and 70 years
• survival: 6–12 years. However,
• onset can be much earlier (twenties) or much
later (eighties)
• half of the patients are behavioural variant
FTD
• PPA subtypes:
-semantic dementia: impaired comprehension,
naming semantic impairment
- progressive non‐fluent aphasia : impaired
speech production

61. 1- Behavioural variant frontotemporal dementia
• personality change and breakdown in behaviour, including apathy, disinhibition, loss of
empathy and abnormal eating behaviour such as the development of a sweet tooth.
• Repetitive, obsessive or compulsive behaviours may also be seen.
• As the disease progresses, often develop inappropriate antisocial behaviours, and may even be
arrested for stealing or disorderly behaviour.
• Angry outbursts are common
• Neuropsychological testing early on can be remarkably normal.
• Specific deficits : a tendency to perseverate (verbal fluency), impaired planning (Wisconsin
card sorting test), loss of inhibition (go‐no‐go task), sequencing (Luria’s test), failure of recall
with improvement on cueing (Wechsler Memory Scale), limited problem‐solving (Raven’s
progressive matrices) and concreteness of thought (Cognitive Estimates test).
• In contrast to executive dysfunction, memory and posterior functions tend to be relatively
spared.
• Social cognition (including theory of mind) is commonly impaired early in the disease process
but is rarely tested in formal neuropsychometric batteries

62. • Imaging (MRI) : normal in the early stages, but usually reveals focal atrophy of the
frontal and/or temporal lobes, often asymmetrical.
• FDG‐PET can be useful in patients where structural imaging is normal to reveal frontal
hypometabolism.
• A subgroup of patients with bvFTD present with behavioural symptoms consistent with
the diagnostic criteria and yet do not seem to progress over many years.
• They have been called FTD ‘phenocopies’ and have normal structural and functional
imaging.
2- primary progressive aphasias:
A- Semantic dementia
• insidious onset
• progressive deterioration in semantic memory.
• loss of understanding of what a word means is pathognomonic of SD.
• Spontaneous speech is fluent and grammatically correct but empty of content, with
word‐finding difficulties, circumlocution, impaired confrontation naming and reduced
verbal fluency, especially for conceptual categories for example, ‘owl’ becomes ‘bird’
* with progression, semantic impairment of other modalities occurs, for example
recognition of faces (prosopagnosia) or of visual objects (visual agnosia).

63. • phonology, prosody and grammar remain relatively intact.
• surface dyslexia such that irregularly spelt words (such as ‘sew’ or
‘pint’) are read according to typical spelling‐sound mappings (in this
example, to rhyme with ‘few’ and ‘mint’).
• Behavioural changes similar to those seen in bvFTD will develop as the
disease progresses.
• Other cognitive domains such as episodic memory, perceptual and
visuo‐spatial abilities are relatively preserved until late in the course of
the disease.
• MRI is characteristic : severe asymmetrical antero‐inferior temporal
lobe atrophy, in particular affecting the fusiform gyrus
• The temporal poles often appear as ‘knife‐blade’.

65. B- Progressive non‐fluent aphasia
• have a non‐fluent language disorder, produce hesitant, effortful speech (often
called ‘apraxia of speech’) and/or agrammatism with the presence of phonemic
errors.
• Agrammatism: phrases become telegraphic, sentences short and disjointed, and
comprehension is often impaired at the sentence level.
• Writing is similarly affected in many cases.
• Insight is usually retained, often with extreme distress.
• orofacial apraxia, which can be tested by asking the patient to cough or yawn.
• there may be evidence of executive dysfunction
• MRI : dominant left peri‐sylvian atrophy involving the inferior frontal and
anterior insular cortex; however, findings vary widely.

66. C- Logopenic aphasia
• associated with underlying AD pathology.
• The presentation is one of word‐finding difficulties, anomia and poor working memory leading
to difficulty repeating phrases rather than single words
Overlap with other syndromes :
• Neurological examination in FTD is usually normal, although there is overlap with other clinical
syndromes including motor neurone disease and atypical parkinsonism, particularly PSP and
cortico‐basal syndrome.
• In FTD‐MND, behavioural symptoms (or more rarely language problems) are present in
conjunction with weakness and wasting in limb and/or bulbar muscles, although in the early
stages the only sign of MND may be fasciculations.
• Around 10–15% of patients with FTD develop MND and, vice versa, 10–15% of patients with
MND develop FTD (although up to 50% will develop cognitive impairment not meeting criteria
for FTD).

67. Investigations
• Previously mentioned
• Neuropsychological
• CSF Aβ1–42 and tau assays are used to diagnose underlying AD pathology in
those cases where differentiation from FTD is difficult.
Genetic pathological correlations
• 35–50% of patients with FTD have a family history of dementia with an
autosomal dominant inheritance pattern or an identified genetic mutation in
around 20%.
• Most cases have mutations in the MAPT (microtubule associated protein tau),
GRN(progranulin) or C9orf72genes.

68. * frontotemporal lobar degeneration (FTLD) is a collective term sometimes used to
denote the three major pathological forms that cause FTD, characterised by the
abnormally aggregated proteins found in the neuronal inclusions:
1 Tauopathies :
- around 40–50% of cases
- Subtypes of the tauopathies include Pick’s disease, PSP, CBD
2 TDP‐43 proteinopathies:
- around 40–50% of cases
- Four subtypes : named A to D. Patients
3 FUS proteinopathies:
- 5–10% of cases
- Very young onset sporadic FTD (age of onset <40) is commonly associated with FUS
pathology
Management: There are currently no disease‐modifying treatments for FTD.

69. Dementia with Lewy bodies and
Parkinson’s disease dementia

70. • They together constitute the second or third
most common cause of dementia in later life
in most series.
• 30% of patients with idiopathic Parkinson’s
disease have dementia
• Risk factors for development of PDD include :
- older age
- duration of disease
- motor disability (especially symmetric,
non‐tremor dominant disease with postural
instability and gait disturbance)
- diminished response to levodopa
- levodopa‐induced confusion
- early visual hallucinations
- olfactory dysfunction
- mood and sleep disturbance.
* Pathologically, both DLB and PDD
are characterised by the formation of
Lewy bodies which are found in the
neocortex, limbic cortices and
subcortical nuclei and there is
associated neuronal loss.
* Pathological subtypes of DLB have
been categorised as:
- brainstem predominant
- limbic (transitional) or diffuse
neocortical based on the
predominant distribution of
pathological changes.

71. * DLB is typically a sporadic disease of later life with an overall survival similar to
AD; however, young adult, familial and rapidly progressive forms, although rare,
are well described
* the fluctuations in DLB are more marked and often paroxysmal within a 24‐hour
period. They may manifest as drowsiness, decreased responsiveness or
disorganisation of speech or behavior.
* Visual hallucinations should be enquired about specifically: in DLB, they are
generally animate, vivid, stereotyped and silent, and often emerge from
background visual features or pat terns under low‐light conditions.
* Other characteristic features of DLB are marked neuroleptic sensitivity and REM
sleep behaviour disorder, the occurrence of complex and bizarre (often violent)
sleep‐related behaviour because of acting of dream content
* Additional supportive features include recurrent syncope and falls, significant
autonomic dysfunction, hallucina tions in non‐visual modalities and early
prominent delusions ,apathy and depression.

73. • PDD has a very similar neuropsychological profile to DLB
• Visual hallucinations are common in PDD even after medication effects are taken
into account.
• drug‐induced hallucinations in treated Parkinson’s disease are often perceived as
frightening or threatening and accompanied by paranoid delusions.
• REM sleep behaviour disorder is also a feature of PDD.
• Parkinsonism in both PDD and DLB may closely mimic that of uncomplicated
idiopathic Parkinson’s disease, although predominant axial involvement with
postural instability, absence of tremor and limited response to levodopa are more
common.
* On structural brain MRI, mesial temporal structures tend to be relatively better
preserved than in AD.
* Metabolic brain imaging typically shows reduced striatal dopamine transporter
uptake, and cortical perfusion and metabolism are globally reduced, often with a
posterior emphasis.
* Degradation of alpha rhythm in the EEG occurs as a non‐specific marker of
cortical degeneration.

78. Treatment :
1- Cholinesterase inhibitors (AchEIs) modestly improve cognitive function, attention, alertness
and behaviour in a substantial proportion of patients, and indeed may be more effective than in
AD at a comparable disease stage.
2- Neuroleptic drugs should in general be avoided in DLB and PDD (extrapyramidal SE) However,
these drugs may sometimes be necessary for the management of agitation or hallucinations
where behavioural strategies or cholinesterase inhibitors have failed.
• In this situation, a new generation agent such as quetiapine or aripiprazole should be
introduced cautiously and titrated slowly to the smallest effective dose.
• Clozapine is probably the most effective neuroleptic and least likely to cause extrapyramidal
side effects, but its use is limited by the requirement for close supervision and blood monitor-
ing because of the risk of agranulocytosis.
3- Management of parkinsonism in both DLB and PDD similar to in idiopathic Parkinson’s
disease, although dopamine agonists are generally avoided because of their higher incidence of
psychiatric side effects.

79. Dementia with other movement disorders

80. 1- Progressive supranuclear palsy (Steele–Richardson–Olszewski syndrome) is frequently accompanied by profound
bradyphrenia and executive deficits
• The ‘applause sign’, when a patient asked to clap three times as fast as possible after the examiner, makes
additional handclaps or may initiate applause, is suggestive of PSP.
2- Cortico‐basal degeneration: can present as a purely motor, purely cognitive, or more commonly mixed disorder.
• cortico‐basal syndrome : early prominent cortical deficits such as limb and orofacial apraxia, parietal signs and
impaired speech production, which may be relatively focal or asymmetric, and which overlap with disorders in the
FTD spectrum. The presence of alien limb phenomena of is characteristic,
3- Multiple system atrophy: Although severe cognitive decline is an exclusion criterion ,many patients do have mild
executive deficits and cognitive slowing.
4- Huntington’s disease: Cognitive impairment is a core feature , Attentional deficits and behavioural disturbances ,
Visuo‐spatial deficits often dominate early in the disease course
• Cognitive decline in Huntington’s disease has been shown to correlate with caudate atrophy and frontal
hypometabolism
4- Inherited spinocerebellar ataxias: Cognitive dysfunction is common particularly evident in SCA2and SCA17.

81. Prion disease

82. Introduction and disease biology
• transmissible spongiform encephalopathies, affect both humans and animals.
• The human prion diseases have been traditionally classified into:
1- CJD
2- Gerstmann–Sträussler–Scheinker (GSS) disease
3- fatal familial insomnia
4- kuru.
• Animal prion diseases include :
- scrapie of sheep and goats
- transmissible mink encephalopathy
- chronic wasting disease of mule deer and elk
- bovine spongiform encephalopathy (BSE)
• Prion diseases are associated with the accumulation in the brain of an abnormal, partially
protease‐resistant, isoform of a normal cell surface glycoprotein found in healthy people
known as prion protein (PrP).

85. 1- Sporadic prion disease (Creutzfeldt–Jakob disease)
• a rapidly progressive multifocal dementia usually with myoclonus.
• The onset : 45–75 year
• progression : over weeks progressing to akinetic mutism and death often in 2–3
months; most die in under 6 months.
Prodromal features:
1- fatigue, insomnia, depression, weight loss, headaches, general malaise and
ill‐defined pain sensations.
1- neurological : include extrapyramidal signs, cerebellar ataxia (in 10%),
pyramidal signs and cortical blindness.
• Routine haematological and biochemical investigations are normal.
• Routine CSF examination is normal but 14‐3‐3 protein is usually elevated.
• New CSF tests such as the real‐time Quaking Induced Conversion (rtQUIC) assay
may be more specific.

88. • MRI :
- FLAIR or DW : high signal in the striatum and/or cerebral cortex
- Cerebral and cerebellar atrophy
• The EEG : pseudoperiodic sharp wave activity.
• Brain biopsy : to exclude treatable alternative diagnoses
• Neuropathological confirmation : spongiform change, neuronal loss and
astrocytosis together with positive PrP immunohistochemistry.
• Most cases of classic CJD are homozygous
• 10% of cases of CJD have a much more prolonged clinical course of over 2 years.
• Around 10% of patients with CJD present with cerebellar ataxia rather than
cognitive impairment, so‐called ataxic CJD, although this presentation should
lead to a consideration of acquired prion disease.
• Heidenhain’s variant of CJD refers to cases in which cortical blindness
predominates with severe involvement of the occipital lobes.

92. 2- Acquired prion diseases
A- Kuru:

93. B- Iatrogenic Creutzfeldt–Jakob disease
• The diagnosis is usually based on a progressive cerebellar syndrome and
behavioural disturbance or a classic CJD‐ like syndrome together with a history of
iatrogenic exposure to human prions, and may occur in any age group.
• EEG, CSF and MRI are generally less diagnostically helpful than in
sporadic CJD.
• PRNP analysis is important to exclude pathogenic mutations.
• Diagnosis is confirmed by PrP immunocytochemistry or Western blot of brain
tissue for PrPSc types 1–3.

95. C- Variant CJD
D- Secondary (iatrogenic) vCJD
Since 2004, four transfusion‐ associated cases of vCJD prion infection have been recognised
Clinical features and investigations are as for primary vCJD.

96. Inherited prion diseases
• These are adult onset , autosomal dominant , associated with PRNP coding
mutations
• They were first classified as familial CJD and GSS.
1- Classic GSS:
• chronic cerebellar ataxia with pyramidal features
• dementia occurring later
• prolonged clinical course than in CJD.
• The onset : the third or fourth decades
• Histologically: the presence of multi centric PrP‐amyloid plaques.
• PRNP should be analysed in all suspected cases of CJD, and certainly considered
in all early onset dementia and in ataxias.

98. • The identification of a pathogenic PRNP mutation allows subclassification according to
mutation, Over 30 pathogenic muta tions are reported
• The key clinical features in inherited prion disease are progres sive dementia, cerebellar ataxia,
pyramidal signs, chorea, myo clonus, extrapyramidal features, pseudobulbar signs, seizures and
amyotrophic features, which are seen in variable combinations.
2- Fatal familial insomnia:
- AD
- untreatable insomnia, dysautonomia and motor signs, and selective atrophy of the
anterior‐ventral and mediodorsal thalamic nuclei.

116. Dementia in young adults