Dementia

Alzheimer's disease (~ 70%) is a primarily a disease of progressive short-term memory loss although, as we'll see it can cause many different clinical manifestations. Very roughly, it has an average lifespan of 10 - 15 years post symptom-onset (but the determination of this onset is often hard to establish in clinical practice). Vascular dementia (~15%) (combined multi-infarct dementia and cerebral amyloid angiopathy presents with a stepwise cognitive decline with an average lifespan of 5 years post diagnosis. Note that large-territory strokes with resultant cognitive dysfunction are also grouped within this heading. Lewy Body Dementia (~10%) is most easily thought of as a combination of dementia and parkinsonism. It has an average lifespan of 5 - 8 years post symptom-onset.

• Note that this is a generous estimate, other estimates are close to 3 - 5 years. We have quoted both estimates in this resource, as there is conflicting opinion on it.

Imaging

• It is recommended that all individuals suspected of dementia get brain imaging (CT or MRI) to rule-out any reversible causes.
• Importantly, we should look for subdural hematomas, which can present subacutely in the elderly population and cause prominent cognitive dysfunction.

Laboratory testing

• B12 testing and thyroid testing are warranted in all patients.
• We should check methylmalonic acid and homocysteine levels to look for evidence of B12 deficiency, if it is suspected.

Delirium is a common condition in elderly hospitalized patients (occurring in ~ 30% of patients). Delirium manifests with altered alertness, attention, and cognitive processing. Patients have fluctuations in consciousness, inattention, and abnormal thinking potentially with delusions and hallucinations. Mild cognitive impairment is a dementia prodrome – patients who have cognitive dysfunction beyond what is expected for normal aging but not yet to the threshold of dementia. The whiteboard tutorial Dementia provides an in-depth review of clinical and radiographic features of Alzheimer's disease, as well as some treatment strategies. Key Alzheimer's disease symptoms

• Short-term memory dysfunction occurs from hippocampal degeneration.
• Word-finding and naming issues arise from temporal lobe degradation (the temporal lobe is essential for language processing and production).
• Task-sequencing and visuospatial disturbances from parietal lobe degeneration that can produce significant apraxias.

Gross Pathology

• Temporal and parietal lobes (visuospatial dysfunction and memory loss).
• Severe degeneration of the hippocampal formation (short-term memory loss).

Histopathology

• Amyloid beta plaques are extracellular aggregates of fibrillar amyloid beta peptide that stain red with Congo red staining.
• Tau neurofibrillary tangles comprise intracellular conglomerations of hyperphosphorylated tau.
• Hirano bodies are intracellular eosinophilic rod (or almond) shaped structures.

Genetics

• See the dementia tutorial listed above or the Alzheimer's disease link for an in-depth review on Apolipoprotein E (APOE) gene; Amyloid Precursor Protein (APP) mutation, Presenilin 1 (PSEN1) mutation, Presenilin 2 (PSEN2) mutation; and trisomy 21 APP gene triplication (there are 3 copies of the APP gene).

Cholinesterase inhibitors increase cholinergic activity, which commonly causes GI hypermotility (loose stools or diarrhea), and potential bradycardia or cardiac conduction abnormalities, as well as the risk of COPD or asthma exacerbations. Cholinesterase Inhibitors

• Donepezil
• Rivastigmine
• Galantamine

Memantine is an NMDA antagonist: it reduces glutamate excitotoxicity. It is designated for moderate to advanced Alzheimer's disease, but, in practice it is used at all stages of the disease. Paradoxically, it can induce confusion and hallucinations. The whiteboard tutorial Dementia provides an in-depth review of clinical and radiographic features of vascular dementia and Lewy body dementia. If we ignore cognitive dysfunction from repeated large vessel infarcts, the following are the two key causes of vascular dementia:

• Multi-Infarct Dementia, specifically, subcortical vascular dementia causes an accumulation of microvascular disease, centrally. It is managed through vascular risk factor modification.
• Cerebral Amyloid Angiopathy causes cerebral cortical microhemorrhages and lobar hemorrhages. It is managed through blood pressure management and the avoidance/reduction of antithrombotic agents (when possible/appropriate). Amyloid stains with Congo red staining (it is "congophilic").

LBD is most easily thought of as a combination of dementia and parkinsonism. From a dementia standpoint, LBD produces:

• Visual hallucinations
• Delusions. Specifically indicate Capgras syndrome (aka imposter syndrome), in which patients are convinced their spouse (or caretaker) has been replaced by an imposter.
• Severe fluctuations in level of arousal with sudden sleep attacks.

From a parkinsonism standpoint, LBD produces:

• Symmetric rigidity, typically without tremor.
• Gait impairment.
• LDB patients have severe neuroleptic sensitivity, meaning typical antipsychotic medications (eg, haloperidol) will profoundly worsen the parkinsonism. Atypical antipsychotics are safer.
• REM sleep behavior disorder, in which patients act out their dreams, due to dysregulation of muscle atonia during REM sleep.

These symptoms will have a limited response to dopamine (unlike in PD wherein they respond dramatically and are sustained). For an in-depth review of Lewy body dementia pathology: cortical Lewy bodies and nigral Lewy bodies, see the tutorial listed above. The whiteboard tutorial Dementia: Advanced Topics provides an in-depth review of uncommon causes of dementia (frontotemporal dementia, Creutzfeldt-Jakob disease (CJD), CADASIL, normal pressure hydrocephalus (NPH). Frontotemporal dementia (FTD) typically affects individuals in their 50s to 60s. It manifests with behavioral or cognitive (including language) dysfunction out-of-proportion to memory loss. It is autosomal dominant in ~ 40% of cases with the remaining being sporadic. What unites the various frontotemporal dementia is, in fact, the finding of frontotemporal lobar degeneration. At present, three key molecular classes are:

• Tau (Pick bodies).
• TDP-43 (TAR DNA-binding protein of 43kDA)
• FUS (Fused in Sarcoma)

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an autosomal dominant genetic cause of strokes and dementia. CADASIL occurs secondary to a chromosome 19q13, notch 3 gene mutation. Anterior temporal lobe white matter disease is an early, helpful radiographic finding. Syphilitic dementia (aka dementia paralytica or "general paresis of the insane") is a late-stage manifestation of neurosyphilis. Patients develop a psychotic dementia with certain motor features, including limb hypotonia and intention tremors. CJD is a prion disease (a proteinaceous infectious particle). In short, PrPSc captures PrPC and then refolds it into the PrPSc conformation (the alpha-helices are converted to beta-sheets). The term spongiform encephalopathy is used to describe the sponge-like vacuolation of the cerebral gray matter that is consistently observed in prion disease. MRI sequence is the most sensitive and specific test in CJD (~ 90% sensitive, ~ 95% specific). An elevated CSF 14-3-3 protein finding is indicative of CJD but has poor sensitivity and specificity. The characteristic pathologic EEG finding in CJD is periodic sharp-triphasic waves at ~ 1Hz frequency (0.5 to 2 Hz), which also has poor sensitivity (~ 65%) and specificity (~ 75%). Transient global amnesia is a syndrome of transient anterograde amnesia (typically 24 hours in duration). Patients can access remote memories but have a temporary inability to generate new memories. Wernicke encephalopathy is secondary to thiamine (B1) deficiency. It presents with ataxia, delirium, and ophthalmoparesis. Classically, it occurs in patients with alcoholism, but it can occur in other patients with nutritional deficiencies. Wernicke's is a reversible condition but it can transition to Korsakoff syndrome when it becomes chronic and irreversible. Although numerous dementia etiologies exist, and you will see varying lists of potential causes, here we will present a working list of common etiologies and etiologies that are pre-mortem (and potentially reversible). The classic normal pressure hydrocephalus (NPH) triad is "wacky, wobbly, wet", which underscores the characteristic dementia, gait apraxia, and bladder incontinence that can occur. Ventriculomegaly with minimal cortical atrophy is the classic radiographic presentation. Treatment involves a CSF shunt. Ventriculoperitoneal shunt is placed in one of the lateral ventricles and drains into the abdominal peritoneum. As a diagnostic work-up for NPH, patients undergo large volume lumbar punctures to look for improvement in gait following CSF drainage. Note that there is considerable disagreement about the true prevalence of this disorder. Pseudodementia (aka the "dementia of depression") is the term for depression that masks itself as dementia. Notably, patients with depression are more likely to complain about memory loss than patients with dementia (who often classically deny having memory problems!). Look for psychomotor slowing and poor effort as potentially signs of depression. Note that patients with Parkinson's disease may exhibit similar behaviors. Parkinson's disease patients develop depression and ultimately dementia during their disease course. Hashimoto's encephalopathy (aka Steroid-Responsive Encephalopathy Associated with Autoimmune Thyroiditis (SREAT)) presents with subacute, progressive delirium (confusion and altered levels of consciousness) and may produce seizures or myoclonus (it is easy to confuse this potentially reversible condition with CJD). It is associated with high anti-TPO-Ab titers (thyroperoxidase) antibodies, and it characteristically responds well to steroid therapy.