Differential Diagnosis of Rapid Progressive Dementia Table 2: Supportive Tests for Pre-senile Dementia


Clinical History Course


Acute


Progressive Epileptic fits


Neurological Exam


Extrapyramidal signs


Cerebellar Pyramidal


Hallucinations


Imaging CCT


Tumour Global atrophy


Focal atrophy: frontotemporal temporal NPH


MRI


CJD (DWI, FLAIR, T2)


Vascular dementia, LBD, PDD, PSP (upgaze palsy), CBD (alien limb) MSA, paraneoplastic MSA, vascular LBD


Lymphoma, malignoma, metastasis Non-specific


FTD AD


Enlarged ventricles


Hyperintense basal ganglia, cortex, thalamus


Limbic encephalitis Temporal hyperintensities Encephalitis


Vascular dementia Subcortical gliosis, white-matter lesions Various signal intensity


Lymphoma Vasculitis


Angiography SPECT


DaTSCAN Neurolite


Laboratory Tests Vitamine B12, B1,


transketolase activity Antibodies


ANA, ANCA Thyroidal


decarboxylasis Anti-Hu/-Yo/-Ri


Nigrostriatal deficit LBD, PDD Hypoperfusion


PPA, FTD Malnutrition


Cerebral vasculitis SREAT


Paraneopastic disease


and parietal, whereas late-onset Alzheimer’s disease is remarkably atrophic in the hippocampus.16


The brains of patients with Alzheimer’s disease show marked atrophy of cortical structures and hippocampal formation. Histologically, two types of lesion are important diagnostic hallmarks: senile (neuritic) plaques and neurofibrillary tangles (NFTs). The amyloid core of senile or neuritic plaques contains an amyloid-like substance formed by peptides that originate through proteolytic cleavage of the membrane-associated precursor protein (amyloid precursor protein


[APP]). One of these, termed Aβ1–42, shows the highest propensity for aggregation of plaques, thus an important role in the pathogenesis of


Alzheimer’s disease was attributed to the plaque formation by Aβ1–42. Intracellular NFTs, which are neuronal inclusions consisting of abnormal cytoskeletal elements of hyperphosphorylated tau protein, are another characteristic pathological feature of AD. These tangles are found throughout the neocortex, in the nucleus basalis Meynert, in the thalamus and in the mammillary bodies. The formation of hyperphosphorylated tau protein in Alzheimer’s disease


EUROPEAN NEUROLOGICAL REVIEW Vasculitis


Multiple vascular lesions, vessel-wall thickening


Vessel-wall thickening, irregularities


Potassium channel Hyperintense signal – oedema


antibodies EEG


PSWC


CJD, non-convulsive status epilepticus


Epileptic discharges Encephalitis, SREAT Biopsy


Muscle Brain


Mitochondriopathy


Inflammatory disease, tumour, neurodegenerative disease


AD = Alzheimer’s dementia; ANA = antinuclear antibody; ANCA = antineutrophil cytoplasmic antibody; CBD = corticobasal degeneration; CCT = cerebral computed tomography; CJD = Creutzfeldt-Jakob disease; CSF = cerebrospinal fluid; DWI = diffusion-weighted imaging; EEC = electroencephalography; FLAIR = fluid attenuation inversion recovery; FTD = frontotemporal dementia; IgG = immunoglobulin G; LBD = Lewy body dementia; MRI = magnetic resonance imaging; MSA = multiple system atrophy; NPH = normal-pressure hydrocephalus; NSE = neuron-specific enolase; PCR = polyclonal chain reaction; PDD = Parkinson’s disease dementia; PERM = progressive encephalitis with rigidity and myoclonus; PPA = primary progressive aphasia; PRNP = prion protein; PSP = progressive nuclear palsy; PSWC = periodic sharp-wave complexes; SCA = spinocerebellar atrophy; SPECT = single-photon-emission computed tomography; SREAT = steroid-responsive encephalitis with autoimmune thyroiditis. Source: Heinemann30


and Heinemann.65


is hypothesised to result in disruption of binding to microtubules. Tau protein is phosphorylated at 21 sites, a process that leads to modification of its physiological properties. In pre-senile dementia, synaptic loss is more pronounced than in late-onset dementia, and there are more neuritic plaques and NFTs in the frontoparietal lobes.17


Both Aβ1–42 and tau (and its phosphorylated forms) became important biomarkers in the diagnosis of dementia. Various studies


demonstrated an increase in tau protein and a decrease in Aβ1–42 in Alzheimer’s disease patients compared with controls. The value of


these changes will be discussed later in the article. Three genes with pathogenic mutations have been identified so far (APP on chromosome 21, presenilin 1 on chromosome 14 and presenilin 2 on chromosome 1). APP is the precursor protein of Aβ. Presenilin 1 and 2 play a role in the function of β-secretase, which cleaves APP (to produce Aβ). A current concept regarding the cause of Alzheimer’s disease is that the mutations in all three genes lead in different ways to increased formation of pathological Aβ and senile plaques. In line with these findings, patients with Down’s syndrome,


23 CSF Routine Pleocytosis, oligoclonal IgG


Encephalitis, paraneoplastic disease Autoimmune encephalitis


Specific antibodies, Bacteria, virus PCR


Spinal tap Dementia marker 14-3-3


Aβ-amyloid Tau NSE


S100b p-Tau(181) Transthyretin Normal-pressure hydrocephalus


CJD, inflammation, tumour, ischaemia


neurodegenerative dementia CJD, AD


Hypoxia, CJD CJD, gliosis AD


AD, NPH paraneoplastic encephalitis Encephalitis


Neurodegenerative, paraneoplastic SREAT, vasculitis


Table 2: (continued)


Laboratory Tests (continued) Glutamat


Genetic analysis Polymorphism Mutation


PERM Codon 129 PRNP, ApoE-genotype


Chorea Huntington, AD, prion disease, SCA


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