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Alzheimer Disease: Diagnostic Challenges
Perrine Depireux, MD | March 28, 2022
| Contributor Information
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Image from Flickr | National Institute on Aging, National Institutes of Health (NIH). [Public domain.]
Alzheimer Disease: Diagnostic Challenges
Perrine Depireux, MD | March 28, 2022 | Contributor Information
Alzheimer disease (AD) is the most common form of dementia and the seventh leading cause of death in the United States.[1] About 6.5 million Americans of all ages have AD. By 2050, a projected 12.7 million people aged 65 and older will be living with this condition.[1]
AD is characterized by a progressive deterioration of episodic memory. As the illness progresses, a symptom constellation develops that includes aphasia, apraxia, executive disorders, mood disturbances, and psychiatric symptoms. No specific therapy has been proved to delay the progression of AD.
Image from Flickr | National Institute on Aging, NIH. [Public domain.]
Alzheimer Disease: Diagnostic Challenges
Perrine Depireux, MD | March 28, 2022 | Contributor Information
At present, neuropathologic examination of the brain remains the gold standard for diagnosis of AD, with neuritic plaques and neurofibrillary tangles the diagnostic hallmarks. Postmortem studies, however, have indicated that there is only a modest correspondence between the clinical diagnosis of AD and the postmortem diagnosis.[2] In efforts to improve the accuracy with which AD can be diagnosed in living individuals, several neurodegenerative biomarkers (eg, from structural magnetic resonance imaging [MRI] and fluorodeoxyglucose [FDG]–positron emission tomography [PET]) and pathophysiologic biomarkers (eg, from amyloid PET and cerebrospinal fluid [CSF] analysis) are increasingly used in clinical settings.
Left image courtesy of Memory and Aging Center, University of California, San Francisco (UCSF). Right image from the National Institute on Aging, NIH [public domain].
Alzheimer Disease: Diagnostic Challenges
Perrine Depireux, MD | March 28, 2022 | Contributor Information
The MRI on the left shows diffuse cortical atrophy with bilateral hippocampal involvement, more advanced on the left side than on the right. The illustration on the right depicts how AD spreads through the brain.
End-stage AD can be easy to diagnose because of the severity and wide range of cognitive symptoms, which reflect the severe and diffuse underlying cortical atrophy. Typical late-onset AD, even if characterized by focal episodic memory dysfunction, can be harder to distinguish, especially when comorbidities (eg, depression, vascular risk factors, vitamin deficiencies) are involved.
Early-onset dementia, defined as starting before the age of 65 years, accounts for 2-10% of all AD cases.[3] In these younger patients, the first cognitive complaint often is unrelated to memory, and this could lead clinicians to misdiagnose the disorder. Training in atypical or early presentations of dementia is of particular importance because of the future emergence of new therapies coming from clinical trials that specifically target this young population.
Image courtesy of Memory and Aging Center, UCSF.
Alzheimer Disease: Diagnostic Challenges
Perrine Depireux, MD | March 28, 2022 | Contributor Information
An 81-year-old man comes to the clinic, accompanied by his daughter. The daughter reports that she has seen indications of progressive memory loss in her father over the past 5 years and has noticed that he becomes confused in paying bills and in using the remote control when watching TV at home. She notes that he recently became lost while walking his dog in the neighborhood. The patient has no history of stroke, depression, or vascular risk factors. He scores 14/30 on the Mini-Mental State Examination (MMSE) and exhibits significant difficulties in finding words, along with disturbed comprehension. Neurologic examination shows bilateral apraxia and an extrapyramidal increased tone in the right arm. MRI is performed, with the results shown above.
How would you describe the level of atrophy on MRI? On the basis of this brief clinical description, what is the chronologic order in which the following pathologic events took place in the patient's brain?
Atrophy on MRI
Accumulation of amyloid plaques
Cognitive symptoms
Accumulation of neurofibrillary tangles
Image from Wikimedia Commons | BruceBlaus. [Creative Commons Attribution-Share Alike 4.0 International License (CC by-SA 4.0).]
Alzheimer Disease: Diagnostic Challenges
Perrine Depireux, MD | March 28, 2022 | Contributor Information
Answers: The MRIs show severe diffuse cortical atrophy (decreases in gyral size and increases in sulcal size). The pathologic events occurred in the following order: B (accumulation of amyloid plaques), D (accumulation of neurofibrillary tangles), A (atrophy on MRI), C (cognitive symptoms).
The initiating event in AD is the formation of amyloid beta (Aβ) plaques in the brain, followed by synaptic dysfunction, which leads to reductions in CSF Aβ42 and increased amyloid PET tracer retention while individuals are still cognitively normal.[4] Subsequently, neurodegeneration becomes the dominant pathologic process. Neurodegeneration is connected to increased CSF tau and structural MRI measures of cerebral atrophy but also to decreased FDG uptake on PET. Only Aβ biomarkers can be used in early detection of the AD pathologic cascade; neurodegenerative biomarkers are correlated with clinical symptom severity.
Image courtesy of Memory and Aging Center, UCSF.
Alzheimer Disease: Diagnostic Challenges
Perrine Depireux, MD | March 28, 2022 | Contributor Information
A 64-year-old mathematics teacher notices a gradually progressive cognitive decline over the past 2 years. He has been experiencing difficulty in answering questions in class because he often does not remember what the question was and is becoming more and more easily distracted. He sometimes misplaces objects, and his colleagues say that he seems more irritable and forgetful. The patient has a medical history of hypertension controlled with medication, type 2 diabetes, and benign prostatic hypertrophy. He scores 27/30 on the MMSE, missing recall of all three words. On a self-reported scale, he denies depression.
On the basis of this clinical vignette and the MRIs shown above, which of the following is the most likely diagnosis or underlying pathology?
Undetermined mild cognitive impairment (MCI)
AD
Vascular MCI
MCI with underlying AD and white-matter disease
Image courtesy of Memory and Aging Center, UCSF.
Alzheimer Disease: Diagnostic Challenges
Perrine Depireux, MD | March 28, 2022 | Contributor Information
Answer: D. MCI with underlying AD and white-matter disease.
The MRIs show periventricular and pontine leukoaraiosis (white-matter hyperintensities [WMHs]). Silent hyperintensities on MRI, including silent incomplete infarcts and white-matter changes, are associated with subtle cognitive impairment.[5] No single neuropsychological profile is characteristic of vascular cognitive impairment, though dysexecutive function is common and verbal memory tends to be better preserved than in AD.
In this clinical vignette, the medical history confirms executive dysfunctions but also suggests a potential underlying memory impairment that is not severe enough to interfere with the patient's daily life or independent function. The MMSE results indeed confirm a predominant episodic verbal memory impairment. This patient has MCI that appears to be due to a combination of AD and white-matter disease.
Image from Wikimedia Commons | Jerome Walker. [CC by-SA 3.0.]
Alzheimer Disease: Diagnostic Challenges
Perrine Depireux, MD | March 28, 2022 | Contributor Information
Shown is the family tree of a 57-year-old man with suspected AD. His sister is 63 years old and lives in a nursing home because of severe dementia that is suspected of being AD but has not been confirmed as such by means of CSF analysis or genetic testing. The patient's mother and grandfather passed away years ago.
Confronted with this autosomal dominant transmission, which of the following tests should be ordered first to confirm AD in this family?
Amyloid precursor protein, presenilin 1, and presenilin 2 genetic testing to detect mutations
Apolipoprotein E (APOE) genetic testing to determine whether the patient is positive for APOE ε4
Both Aβ/phosphorylated tau (P-tau) ratio analysis in CSF and amyloid PET imaging
Either Aβ/P-tau ratio analysis in CSF or amyloid PET imaging
Biopsy
Image courtesy of Memory and Aging Center, UCSF.
Alzheimer Disease: Diagnostic Challenges
Perrine Depireux, MD | March 28, 2022 | Contributor Information
Answer: D. Either Aβ/P-tau ratio analysis in CSF or amyloid PET imaging.
Amyloid PET imaging is an in-vivo diagnostic technique using radioactive tracers that bind to fibrillar amyloid-β aggregates and correlate with neuritic plaque burden. The image shown above depicts a clearly positive amyloid PET scan, where tracer uptake is typically greater in cortical gray matter than in white matter.
Answer A (amyloid precursor protein, presenilin 1, and presenilin 2 genetic testing) is incorrect because these three mutations are responsible for only 30-50% of cases of autosomal dominant AD and for about 5% of all AD cases.[6] Answer B (genetic testing for APOE ε4) is incorrect because although APOE ε4 is a risk factor for AD, it is not an autosomal dominant genetic cause of AD. Answer C (both Aβ/P-tau ratio analysis in CSF and amyloid PET imaging) is incorrect because whereas these two procedures are different, they both enable clinicians to evaluate the presence of Aβ plaques, and it would be redundant to combine them in a clinical setting. Answer E (biopsy) is incorrect because this would be too invasive a diagnostic procedure, given lack of a robust treatment.
Image (inset) from Dreamstime | Lisa F Young.
Alzheimer Disease: Diagnostic Challenges
Perrine Depireux, MD | March 28, 2022 | Contributor Information
A 64-year-old police officer is seen in the clinic. Six years ago, he began to believe, without any conclusive evidence, that his wife was cheating on him. The couple went into marriage counseling, but without much success. One year ago, the patient started to think that one of his coworkers was stealing money from him. He confronted the coworker over and over, appearing increasingly delirious, aggressive, and agitated. Six months ago, the patient was fired from his job because of his disruptive behavior and lowered productivity. His wife confirmed suspicions of multitasking difficulties at home without disinhibition, loss of sympathy/empathy, dietary changes, or compulsive behavior.
On the basis of the preceding brief description, which of the following primary diagnoses is most likely?
Bipolar disorder
Behavioral variant of frontotemporal dementia (bvFTD)
Schizophrenia
AD
Severe depression
Image courtesy of Memory and Aging Center, UCSF.
Alzheimer Disease: Diagnostic Challenges
Perrine Depireux, MD | March 28, 2022 | Contributor Information
Answer: Either B (bvFTD) or D (AD).
As the next step in the evaluation, the Trail Making Test is administered to the patient. This test evaluates executive functions and requests that the patient draw lines to connect the numbers in ascending order as quickly as possible, without lifting the pen or pencil from the paper. As may be seen from the results shown above, the patient made two repetitive mistakes and was too slow and distracted to finish the test.
The patient also completed the Neuropsychiatric Inventory (NPI) questionnaire, which is a comprehensive assessment of psychopathology in patients with dementia. This questionnaire reviews the following 12 neuropsychiatric domains: (1) delusions, (2) hallucinations, (3) agitation/aggression, (4) depression/dysphoria, (5) anxiety, (6) elation/euphoria, (7) apathy/indifference, (8) disinhibition, (9) irritability/lability, (10) aberrant motor behavior, (11) sleep and nighttime behavior disorders, and (12) appetite/eating changes. In this case, the patient endorsed items 1, 3, 5, and 9. In conclusion, this patient is dysexecutive without significant other psychiatric symptoms, such as those described for bipolar disorder, schizophrenia, or severe depression.
Image courtesy of Memory and Aging Center, UCSF.
Alzheimer Disease: Diagnostic Challenges
Perrine Depireux, MD | March 28, 2022 | Contributor Information
The patient then undergoes computed tomography (CT) scanning of the brain, with the results shown above.
On the basis of the CT findings, as well as the clinical scenario up to this point, can you determine whether the patient has bvFTD or the frontal variant of AD (fvAD)?
Image courtesy of Memory and Aging Center, UCSF.
Alzheimer Disease: Diagnostic Challenges
Perrine Depireux, MD | March 28, 2022 | Contributor Information
Answer: This patient exhibits significant cortical atrophy, which is clearly predominant in the frontal (top arrows) and temporal (side arrows) regions of the brain. This pattern of atrophy is seen in bvFTD as well as in fvAD.
Although the diagnostic criteria for AD are well established, the clinical symptoms vary considerably.[7] Symptomatically, the presentation of fvAD is very similar to that of bvFTD. In general, fvAD patients present with greater executive impairment and milder behavioral symptoms than bvFTD patients do, but these cases still constitute major challenges for a differential diagnosis. Greater accuracy in diagnosis and patient management can be achieved only by means of neuropsychological tests, biomarker evaluation, and multimodal neuroimaging.
Image courtesy of Memory and Aging Center, UCSF.
Alzheimer Disease: Diagnostic Challenges
Perrine Depireux, MD | March 28, 2022 | Contributor Information
A 68-year-old right-handed retired architect is seen in the clinic. Three years ago, he started to complain about isolated hesitant speech and word-finding difficulties, without any other neurologic symptoms. His neurologic examination reveals only anomia, and he scored 29/30 on the MMSE because of poor repetition of the sentence. MRI reveals significant cortical atrophy (shown), which is clearly predominant in the left temporoparietal regions. The patient was diagnosed with the logopenic variant of primary progressive aphasia (lvPPA).
Which of the following is the most common pathology underlying a clinical diagnosis of lvPPA?
TDP-43 (transactive response DNA-binding protein 43 kd) deposition
Tau deposition
AD
Image from Illán-Gala et al. Alzheimers Res Ther. 2022;14(1):27. PMID: 35139897, PMCID: PMC8830043. [CC by 4.0.]
Alzheimer Disease: Diagnostic Challenges
Perrine Depireux, MD | March 28, 2022 | Contributor Information
Answer: C. AD.
Primary progressive aphasia (PPA) may be divided into three main variants, as follows[8]:
Nonfluent/agrammatic
Semantic
Logopenic (ie, lvPPA)
The above image shows group comparison of cortical thickness and cortical mean diffusivity between individuals with PPA and healthy controls. lvPPA = logopenic variant of PPA, nfvPPA = nonfluent/agrammatic variant of PPA, svPPA = semantic variant of PPA.
Nonfluent/agrammatic variants are mostly associated with tau protein deposition. Semantic variants are mostly associated with TDP-43 deposition. Logopenic variants are strongly linked to AD pathology.
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Contributor Information
Author
Perrine Depireux, MD
Head of Neurology
Clinique Saint-Luc Bouge
Bouge, Namur, Belgium
Disclosure: Perrine Depireux, MD, has disclosed no relevant financial relationships.
Reviewer
Shaheen E Lakhan, MD, PhD, MS, MEd
Adjunct Professor of Neuroscience
Virginia Tech
Blacksburg, VA
Disclosure: Shaheen E Lakhan, MD, PhD, MS, MEd, has disclosed no relevant financial relationships.
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