The role of Neurology in Dementia Diagnostic Services

Nin Bajaj

Consultant Neurologist

NUH/SDAH

Background: Demographics

• Ageing population, especially among the “oldest old” (over 80s) means numbers set to rise more steeply in England than many developed and developing countries

• rising to over 750,000 by 2020

• And to over a million by 2050

Background: Dementia and Age

• Main risk factor is age• Prevalence rises to 12.2 per cent of people

at age 82• Cardiovascular factors are also important• Dementia over 65:“late-onset” dementia• At least a further 12,000 people in England

under 65 have “young-onset” dementia• This is thought to be under-diagnosed

Background: Young Onset Dementia

• particular problems for younger people• some GPs simply did not believe they could have

dementia because of their age• Diagnosis therefore often very delayed• “My wife is 56 and is now in a nursing home. By the time

the doctors diagnosed and referred her [to hospital] a lot of the damage was already done. Within months of being diagnosed she had to be sectioned.” (Focus group)

• “At one end you’ve got ‘You’re too young to have dementia’, and at the other you’ve got ‘you’re 75, what do you expect?’” (Focus group)

Background: Diagnosis

• DoH: early diagnosis and intervention in dementia is cost-effective

• But only a third to a half of people ever receive a formal diagnosis

• For patients on anti-dementia drugs, UK is in the bottom third in Europe, below almost all northern and western European nations

• Average reported time to diagnose the disease in the UK is also up to twice as long as in some countries

Background: Diagnosis

• The 2004 Facing Dementia Survey showed the reported time taken to diagnose Alzheimer’s disease

• longer in the UK (32 months)• than in France (24), Spain (18), Italy (14) or Germany

(10)• “It took 3½ years to get my diagnosis. I was referred

around in circles with a diagnosis of depression and eventually… through the Alzheimer’s Society, given an appointment with a psycho-geriatrician and, after tests,

• diagnosed.” (Focus group)

Background: Dementia and the GP

• GPs’ own attitudes could hamper early diagnosis• widely-held perception that little can be done• lack of urgency attached to diagnosing and management• < 2/3 of GPs felt it important to look actively for early

symptoms• GP’s knowledge survey on dementia: average score 47

per cent • Only 31 per cent felt they had enough training to

diagnose and manage the disease• seventy per cent felt they had too little time to spend on

people with dementia.

Background: Diagnosis

• Brain scanning (MRI or CT) recommended to establish a clear diagnosis

• Only used regularly by 66 per cent of CMHTs• significant gaps in CMHTs’ ability to access

specialist skills and services• A quarter had no access to a social worker• 29 per cent no clinical psychologist.

Why care about Diagnosis?

• Patient’s want to know- especially in the early stages when they may have insight

• Relatives want to know

• There may be familial consequences in apparent sporadic FTD, HD, some AD clusters

• There may be public health consquences e.g CJD, nvCJD

Why care about Diagnosis: New Therapies (1)

• Amyloid vaccines• The amyloid hypothesis• Amyloid plaques and NFTs are the

pathological hallmark of AD• NFTS made up of PHFs• PHFs consist of hyperphosphorylated tau• Plaques consist of degenerating neurones

surrounding extracellular core of B-amyloid

Amyloid vaccines

• AN-1792• immunotherapy with synthetic form of beta

amyloid peptide• stimulates an immune response against the

peptide that elicits clearance of beta amyloid peptide and plaques in AD (active immunization)

• 2001Elan/Wyeth Phase IIa study• study was halted after encephalitis reported in

four patients

Amyloid vaccines

• Plaque clearance observed in four autopsy cases from AN-1792

• Memory, attention and concentration improved at 12 months in anti beta amyloid antibody responders, according to a composite neuropsychological performance measure

• Levels of tau protein (a marker known to be elevated in AD) in cerebrospinal fluid (CSF) were lower in anti beta amyloid antibody responders

• Brain volume was lower in anti beta amyloid antibody responders as measured by magnetic resonance imaging (MRI)  

Amyloid vaccine• Holmes, C et al Lancet Neurology 2008. AN1792

• the degree of plaque removal varied significantly with mean antibody response attained during the treatment study period (Kruskal-Wallis p=0.02)

• Seven of the eight immunised patients who underwent post-mortem assessment, including those with virtually complete plaque removal, had severe end stage dementia before death

• In the whole cohort, there was no evidence of improved survival (hazard ratio 0.93, 95% CI 0.43-3.11; p=0.86) or of an improvement in the time to severe dementia (1.18, 0.45-3.11; p=0.73) in the AN1792 group versus the placebo group

• INTERPRETATION: Although immunisation with Abeta(42) resulted in clearance of amyloid plaques in patients with Alzheimer's disease, this clearance did not prevent progressive neurodegeneration.

Amyloid vaccines• AAB-001

Phase II study of a humanized monoclonal antibody, AAB-001• therapeutic antibody directly binds to and clears beta amyloid

peptide• this approach may eliminate the need for the patient to mount an

immune response to beta amyloid• such a “passive immunization” approach may reduce safety

concerns by avoiding stimulation of immune system in general• ACC-001• novel beta amyloid-related active immunization approach now in

Phase I clinical trials• intended to induce a highly specific antibody response to beta

amyloid• goal is to clear beta amyloid while minimizing side effects

Gamma Secretase Inhibition

• Tarenflurbil gamma-secretase modulater, binds to the APP molecule, changing the ratio of the less toxic Aβ-40 to the more toxic Aβ-42

• improves memory and behavioral performance in transgenic mice

• phase 2 study showed some efficacy in improving activities of daily living, global function, and cognition, in mild but not moderate AD (Wilcock GK et al. Lancet Neurol. 2008;7:483-493)

Gamma Secretase Inhibition• phase 3 trial• mild AD,MMSE 20-26 randomized to receive 800 mg of tarenflurbil

or placebo twice a day• 18 months, with a 30-day washout period at the end of the trial • Co-primary end points were the Alzheimer's Disease Assessment

Scale-Cognition (ADAS-cog), Alzheimer's Disease Cooperative Study Group activities of daily living scale (ADCS-ADL)

• Secondary outcomes included Clinical Dementia Rating sum of boxes (CDR-sb), the MMSE, the Neuropsychiatric Inventory (NPI), and QOL-AD, a measure of quality of life

• Results showed no effect of tarenflurbil on either the ADAS-cog (P = .860) or the ADCS-ADL score (P = .479); Kaplan-Meier curves were virtually identical over 18 months

The Amyloid Hypothesis

• Familial AD due to mutations in APP, PS-1 and PS-2 all predispose to longer, more amyloidogenic Abeta

• This is confirmed in various APP mice and double transgenic, PS-1/APP mice

The Amyloid Hypothesis

• Late 1990s• Elan/Wyeth amyloid vaccine tested in mice• Human trials closed in 2002 when 18/298

developed meningoencephalitis• Post trial analysis showed 20 of these patients

(including 2 with encephalitis) had developed antibodies against AB- these patients had a slow down in mental decline

• Lemere generated a shorter AB1-15 vaccine fragment that caused less T-cell activation

Who gets referred to neurology

• Young demented• Worried well• Unusual dementia: aggressive AD, fonto-

temporal presentation, familial cases• Dementia in the context of neurological

disorder e.g. 4 repeat tauopathy, spinocerebellar ataxia, adult Hallevorden Spatz, adult neuroacanthocytosis, Wilsons, HD

Who gets referred to Neurology

• CJD

• nvCJD

• Encephalopathy

• Dementia in the context of PD e.g. Lewy body, PDDC

What do Neurologists Do

• The major role is diagnosis

• Sometimes we look after people but only in the hospital setting

• Depending on trust, we may take the major role in PD related dementia

Current Service Models

• In many regions in the UK, neurology plays little role in dementia services

• In NUH, we have piloted a joint neurology-neuropsychiatry led clinic for 4 years

• This attracts referrals from secondary care colleagues in psychiatry and neurology

• 1/month therefore not open to GP referrals

Future Service Models

• Neurology diagnostics as part of the “over-arching” dementia strategy

• Nottingham Mental Health trust commissioning of weekly neurology diagnostic clinic

Diagnostic Techniques

• High field MRI 3T

• HMPOA SPECT

• Neuropsychometry

• EEG

• CSF analysis

• Blood screen

FTD

• 73 male• Father affected• Aggression• Obsessive cleaning• Sweet tooth• Semantic• Poor VM

Diagnostic Techniques: MRI

Diagnostic Techniques: Spectroscopy

4-repeat tauopathy

CBD

PSP

VGKC-LE

• 2 week confusion, seizures, memory loss

• Marked reduction Verbal and Visual M

• Mild CSF pleiocytosis (or normal), prot. up

• Unmatched bands

• Rx steroids, IVIG, PE

Hashimoto’s

• Can present as rapid dementia with myoclonus, seizures ddx CJD

• TFT normal

• CSF pleiocytosis, normal EEG, normal MRI, normal 14-3-3

• CSF thyroid peroxidase antibodies

• Responds steroids

Blood Analysis

• Usual B12/folate, autoimmune, syphilis, TFT

• For metabolic encephalopathy consider serum and urine amino and organic acids

• Note ammonia encaphalopathy secondary to liver failure, valproate or adult onset urea cycle disorder

Blood analysis

• Rare cases

• Adult onset leukodystropy presenting with cognitive decline (WCE; VLCFA)

• Dementia as part mitochondrial presentation (MIDD)(lactate)

Adult onset adrenomyeloleukodystrophy

MIDDFigure 1: A)MRI Brain i) Axial T2 weighted image; ii) Coronal T1 weighted image showing generalised atrophy and a frontal hyperintensity (arrow) B) Muscle biopsy stains i) Succinate dehydrogenase showing scattered darkly staining fibres (arrow); ii) Cytochrome oxidase showing negative staining fibres (arrowed)

CSF Analysis

• Cell count helps in inflammatory encephalopathy

• Several longitudinal studies show increased CSF total tau and raised Abeta40:Abeta42 predictive of AD (see Reimenschneider Arch Neurol 2002)

• 14-3-3 immunoblot useful in classic CJD